key: cord-0009730-1mhyo1j6
authors: nan
title: 142nd Annual Meeting of the American Neurological Association
date: 2017-10-15
journal: Ann Neurol
DOI: 10.1002/ana.25024
sha: d9bf85e2d1a585efd3dd3a491ee2cb2b7c359ca8
doc_id: 9730
cord_uid: 1mhyo1j6

nan

Objective: Hypertrophic pachymeningitis (HP) is an intractable inflammatory disorder of the pachymeninges, with progressive thickening of the dura mater. The lack of an HP animal model makes it difficult to elucidate the mechanisms of dural hypertrophy. Previously, following a nationwide survey in Japan, we reported that IgG4-related disease is one of the major causes of HP. We aimed to establish a mouse model for HP to enable the assessment of novel treatments.

Methods: Using Linker for Activation of T cells (LAT) (Y136F) knock-in (KI), we produced mice over-expressing IgG1 (equivalent to human IgG4). Three-, six-, and 13week-old LAT(Y136F) homozygote KI mice and their littermates were used. We treated LAT(Y136F) KI mice by oral administration of irbesartan, one of the main angiotensin converting enzyme inhibitors, at a dose of 50 mg/kg/day from 3-6 weeks of age. Following magnetic resonance imaging, the mice were sacrificed and their brains immunohistochemically analyzed.

Results: Gadolinium enhancement of the dura began focally around the superior sagittal sinus at 3 weeks of age and successively extended over the brain in the following 10 weeks. Histologically, the dural lesions had massive infiltrations of plasma cells, B cells, T cells, macrophages, neutrophils, and IgG1-positive cells at 3 weeks, followed by marked fibrotic thickening by Masson-Trichrome and fibronectin staining. Immunoreactivity for tumor growth factor (TGF)-b1 was markedly upregulated, and Smad2/3 were highly phosphorylated in the lesions. Daily oral irbesartan (50 mg/kg), a TGF-b blocker, from 3 weeks of age almost completely abolished inflammatory cell infiltration and fibrotic thickening of the dura.

Interpretation: Our LAT(Y136F) KI mice are the first animal model of HP, in which the TGF-b1/Smad2/3 pathway plays a crucial role. The massive production of TGF-b1 by infiltrating macrophages and TGF-b1 receptorexpressing fibroblasts may become a novel therapeutic target. Irbesartan successfully ameliorated the progression of meningeal thickening, suggesting it may be a new therapeutic option for HP. Background: Giant cell arteritis (GCA) is a vasculitis of medium and large vessels. Neurological manifestations include headache, vision loss, and stroke. GiACTA is a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of tocilizumab (TCZ), an IL-6 receptor-a inhibitor, in GCA patients (Unizony SH et al. Int J Rheumatol. 2013; 2013:912562) .

Methods: Patients aged !50 years with active GCA were randomly assigned 1:1:2:1 to short-course (PBO126) or longcourse (PBO152) prednisone (26-week or 52-week prednisone taper1weekly subcutaneous [SC] placebo, respectively) or weekly (TCZ-QW) or every-other-week (TCZ-Q2W) SC TCZ 162 mg126-week prednisone taper. Primary and key secondary end points were the proportions of patients in sustained remission, comparing TCZ groups with PBO126 and PBO152, respectively (significance level, 0.005). Subgroup analysis was performed according to disease-onset status (newonset vs relapsing GCA) to evaluate time to flare.

Results: Randomization included 251 patients, 119 (47%) with new-onset and 132 (53%) with relapsing GCA. At baseline, new-onset localized headache and polymyalgia rheumatica (PMR) symptoms were each reported in approximately twothirds of patients, and jaw claudication, scalp tenderness, and temporal artery tenderness were each reported in approximately one-third of patients. In the TCZ-QW and TCZ-Q2W groups, 56.0% and 53.1% of patients, respectively, achieved sustained remission compared with 14.0% in the PBO126 group (both p<0.0001) and 17.6% in the PBO152 group (both p 0.0002). Patients with relapsing disease were in relapse-free remission longer and thus had lower risk for flare (hazard ratio) versus placebo when treated with TCZ-QW than with TCZ-Q2W. Hazard ratio (99% CI) for flare in relapsing patients was 0.23 (0.09-0.61) for TCZ-QW and 0.42 (0.14-1.28) for TCZ-Q2W versus PBO126 and 0.36 (0.13-1.00) for TCZ-QW and 0.67 (0.21-2.10) for TCZ-Q2W versus PBO152. Among 109 patients who experienced GCA flare, approximately two-thirds had cranial signs and symptoms at flare presentation whereas approximately half had PMR symptoms. Adverse events (AEs) were similar across the treatment groups. Serious AEs were reported in 15.0% of TCZ-QW, 14.3% of TCZ-Q2W, 22.0% of PBO126, and 25.5% of PBO152 patients. Serious AE rates were similar between patients with new-onset and relapsing GCA. No patients experienced vision loss.

Conclusions: TCZ126-week prednisone taper was superior to PBO126 and PBO152 tapers in achieving sustained remission at 52 weeks. The higher relapse-free survival rate of patients with relapsing GCA treated with TCZ-QW may influence treatment decisions in clinical practice.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Salaryemployee S103. Activating and Inhibitory Astrocytic Fcc Receptors Mediate IgG-Induced Internalization of the Aquaporin-4 Water Channel and Its Linked Glutamate Transporter EAAT2 Vanda A. Lennon, Ningling Luo, Thomas J. Kryzer, Ian C. Clift and Shannon R. Hinson. Rochester, MN Objective: To investigate early astrocytic membrane events preceding aquaporin-4 (AQP4) endocytosis following interaction with the neuromyelitis optica (NMO) autoantibody.

Background: AQP4-specific IgG causes characteristic immunopathology. Most experimental studies of NMO lesional events in vitro and in animal models have emphasized complement-mediated inflammation and astrocyte cytolysis. These are late events, associated with extensive blood-brain barrier (BBB) disruption. The BBB does not absolutely restrict CNS entry of IgG, but it does exclude macromolecular C1q, essential for activating the classical complement cascade. Patients' sublytic CNS lesions reflect events documented in vitro after IgG binds to AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement synthesis, release and activation, inflammatory cell recruitment and secondary demyelination (Lucchinetti et al, Brain Pathol 2014; Hinson et al, JExpMed 2008 , PNAS 2012 T. Vincent et al, JImmunol 2008) . Early events initiating these pathophysiological outcomes are poorly understood. Contributions of the AQP4-IgG-activated astrocyte are largely neglected: synthesis and secretion of complement, cytokines, chemokines and inflammatory mediators attracting NMOcharacteristic granulocytes (Howe et al, Glia 2014; Walker-Caulfield et al, JNeuroinflamm 2015) .

Design/Methods: Pooled AQP4-IgG1 NMO patient or healthy human serum, IgG or (Fab') 2 fragments, or mouse monoclonal IgGs specific for AQP4 extracellular domain (ECD) or C-terminal cytoplasmic domain (CCD), were applied to monolayer cultures of live rodent astrocytes (wild type and Fcc receptor [R] gamma subunit-null), without complement and with and without microglia. Membrane proteins were evaluated at intervals up to 16 hours by immunofluorescence microscopy, flow cytometry or western blot; interleukin-6 secretion by ELISA.

Results: AQP4 internalization required AQP4-ECDbound IgG to engage an astrocytic FccR. Microglia were not involved. IgG lacking Fc redistributed AQP4 within the plasma membrane and induced interleukin-6 release. However, AQP4 endocytosis required an activating (CD64) FccR gamma subunit and involved sequential FccR phosphorylation events and transient astrocytic membrane loss of the inhibitory (CD32B) FccR recruited into the multimolecular immune complex. Interaction of the membranebound IgG-AQP4 complex with FccRs triggers co-endocytosis and degradation of physically linked EAAT2.

Discussion: Requirement of FccR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early intervention in NMO. Definition of the signaling pathways through which FccRs mediate co-internalization of AQP4 and EAAT2 may reveal new candidate therapeutic targets for prevention or amelioration of NMO relapses.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Vanda Lennon and Thomas Kryzer are named inventors on a patent relating to AQP4 as NMO antigen, but receive no royalties from service tests performed by Mayo Medical Laboratories. Earnings from technology licensing have exceeded the federal threshold for significant interest.

Eliza Gordon-Lipkin, Laura Munoz-Arcos, Jessica Klein, Janet Dean, Izlem Izbudak and Carlos A. Pardo-Villamizar. Baltimore, MD and Charleston, SC Background: At presentation, the polio-like clinical syndrome associated with acute flaccid myelitis (AFM) may be difficult to distinguish from other spinal cord pathology including transverse myelitis or infarcts. More precisely defining the temporal profile and the neuroimaging features of this rare disorder offers opportunity to both provide beneficial interventions promptly and avoid treatments that may be detrimental. It may also provide insight into the pathophysiology of this newly described phenomenon.

Objective: To quantify the clinical profiles, neuroimaging features and functional outcomes in children with AFM.

Methods: Patients with diagnosis of AFM by CDC casedefinition were identified from the Johns Hopkins Transverse Myelitis Center. Transverse myelitis, spinal cord infarcts, and myelopathies of unknown etiology were excluded. Retrospective clinical data review and topographical MRI analysis were performed. T2 hyperintensities (T2HTN) on axial images were identified on first and last available MRI by two neurologists, one neuroradiologist.

Results: Fourteen patients were identified. Three had onset in 2014. Eleven had onset in 2016. Ten (71%) were male. Median age at onset was 5 [interquartile ratio (IQR) 3-7] years. All presented with upper respiratory infection symptoms several days prior to acute onset of limb weakness. Median onset of upper respiratory infection symptoms was 6 days. Median onset of neurological symptoms was <6 hours and eight (73%) awoke with paralysis. All patients had lower motor neuron neurological exam. On MRI, lesions were identified throughout the spinal cord (cervical > thoracic > lumbar), primarily, but not exclusively, in the gray matter. T2HTN in the dorsal brainstem surrounding the 4th ventricle was identified in 67% of patients. [4] [5] months median follow up, four (29%) had onelimb, three (21%) had two-limb, one (7%) had three-limb and six (43%) had four-limb weakness. Nine (64%) were wheelchair-dependent. Four (29%) were ventilator dependent. Temporal profiles of clinical symptoms and neuroimaging analysis will be illustrated in this presentation.

Conclusions: Key features of AFM include parainfectious, acute onset of weakness over hours, lower motor neuron exam and neuroimaging with T2HTN throughout the spinal cord gray matter. These features may help distinguish this condition from other forms of myelitis upon presentation, such as spinal cord infarct or transverse myelitis, to guide appropriate management. Several months later, all patients at our center had continued disability. Prospective studies of longitudinal outcomes will clarify the long-term morbidity of this condition. Background: Single-cell genomic technologies continue to advance. However, the cell recovery rate of current commercial platforms is only 5-60%, which has inhibited single-cell analyses of paucicellular biological specimens like cerebrospinal fluid.

Methods: An automated method and device for singlecell isolation and dispensing has been developed using a piezoacoustic dispenser mounted onto an x-y-z axis system and a camera with image recognition technology that can detect single cells when they are ready to dispense.

Results: Precise isolation of a wide range of cells with diameters up to 35mm has been achieved. In a series of dilution experiments, cell recovery is up to 90% of cells with a cell concentration of 25,000 cells/mL, consistent with typical cerebrospinal fluid cell counts of on average 30,500 cells collected from a given lumbar puncture in our multiple sclerosis cohort.

Conclusions: We describe an automated method for precise single cell isolation and high cell recovery rate, making this a promising technology for enabling single-cell genomic technologies including transcriptional and immune repertoire profiling of cells from paucicellular biological samples like cerebrospinal fluid.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Guilhem Tourniaire, Ophelie Berthuy and Eric Cheng are currently employees of Cellenion, the company creating the single cell software used to perform these experiments. Joshua Cantlon-Bruce and Cade Fox are employed by Scienion, the company which makes the robotic device used in these experiments.

Persistent Impairment in Neurocognitive and Adaptive Function Anusha K. Yeshokumar, Eliza M. Gordon-Lipkin, Ana Arenivas, Deanna Saylor and John C. Probasco. Baltimore, MD

Objective: This study examines neurocognitive and functional outcomes in patients with autoimmune encephalitis (AE) at least one year following initial diagnosis and treatment.

Background: AE is an increasingly recognized, potentially debilitating neurologic disease with a wide range of clinical presentations. Anti-NMDAR encephalitis is thought to be associated with good recovery, though with reported disability outcomes ranging from death to complete recovery. Long-term neurocognitive and functional outcomes studies, however, are limited.

Methods: Retrospective chart review of inpatient records at Johns Hopkins Hospital identified patients with AE diagnosed from 2005 to 2015. Patients and their families were asked to participate in a structured telephone interview. Neurologic disability was assessed using the modified Rankin Scale (mRS). Adaptive functional behavior was assessed using the Adaptive Behavior Assessment System-Third Edition (ABAS-3).

Results: 77 charts were reviewed. 39/77(51%) patients had AE-associated antibodies, including 12/77(16%) with anti-NMDAR antibodies, and 38/77(49%) had no detected antibody. Mean duration of follow-up since diagnosis was 4.0years (SD 3.0years). 9/77(12%) died, and 26/77(34%) had "poor" neurologic disability outcome (mRS3-5) at follow-up.

Anti-NMDAR encephalitis was associated with greater proportion of "good" outcomes (mRS 2) at last neurology follow-up (92%vs.48%, p<0.01) and of improved mRS from discharge to last neurology follow-up (83%vs.40%, p<0.05), despite no differences in mRS at admission or duration between symptom onset and treatment initiation. 44 subjects enrolled in the structured interview, of which 10/44(23%) had anti-NMDAR antibodies, and 34/44(77%) had other AE-associated antibodies or no detected antibody. 38/44(86%) subjects had ongoing difficulties with fatigue, emotional lability, short-term memory, and/or concentration. Fewer patients with anti-NMDAR encephalitis complained of emotional lability (30%vs.71%, p<0.05).

On the ABAS-3, 23/44(52%) scored "below average" for overall adaptive function [General Adaptive Composite Standard Score (GACSS): mean87.0, SD18.5]. 12/30(40%) of patients with "good" neurologic disability outcome (mRS0-2) scored "below average" in adaptive function (ABAS-III GAC<90). For patients with anti-NMDAR encephalitis, mean ABAS-3 score was within normal range (GACSS: mean97.2, SD14.1), while for patients with other forms of AE, mean ABAS-3 score was "below average" (GACSS: mean83.9, SD18.7; p<0.05).

Conclusions: Patients with AE frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive function. Many of these impairments are not adequately captured by mRS. Patients with anti-NMDAR encephalitis may have better long-term outcomes compared to those with other forms of AE. Clinicians should use caution in extrapolating findings from anti-NMDAR encephalitis to other forms of AE. S107. Multi-Modality Therapy in Acute Disseminated Encephalomyelitis in an Adult Male Sumanjit Kaur, Daniel Graf and Chilvana Patel. Galveston, TX Background: ADEM is a monophasic inflammatory demyelinating disease affecting the brain and spinal cord that presents within days to weeks of infection or immunization, and is characterized by multifocal sensory and motor symptoms. ADEM is common in children, however adults have a fulminant course. Pediatric prevalence, male predominance, encephalopathy, paraplegia, widely disseminated ill-defined perivenular lesions on MRI with frequent basal ganglia involvement distinguishes ADEM from Multiple sclerosis. ADEM is self-limiting, various treatment including steroids, Intravenous Immunoglobulin, plasmapheresis and immunomodulatory therapy may hasten recovery. Studies assessing treatment efficacy are lacking. Sudden onset, severe neurologic symptoms and unresponsiveness to glucocorticoids carries poor prognosis.

Design/Methods: Case report and literature review Results: 31year old male presented with sudden onset of lower extremity (LE) weakness and numbness, urinary retention and low grade fever for 2 23 days. No history of precipitating events. Exam revealed LE paralysis and areflexia, bladder incontinence and T6 sensory level. MRI brain revealed multiple subcortical mass-like lesions with faint ring enhancement. MRI Cervical, Thoracic and Lumbar spine showed abnormal signals in medulla, thoracic cord and conus medullaris with minimal enhancement in distal thoracic cord and leptomeninges. CSF studies revealed elevated protein, IGG index and lymphocytic pleocytosis. MR Spectroscopy suggested demyelinating disease. Aquaporin 4 antibodies, Infectious, Rheumatological and Malignancy work up were negative. Intravenous steroid treatment for presumptive diagnosis of ADEM resulted in no clinical improvement. Subsequent treatment with plasmapheresis and rituximab infusion resulted in clinical improvement over next 2 weeks. Patient received 2nd session intravenous steroids 2weeks after plasmapharesis. Patient was able to walk independently with some return of bladder and bowel function at one month follow up visit.

Conclusion: ADEM presents suddenly and often without preceding event. Early multi-modality treatment with various immunomodulatory agents may hasten recovery. S108. Ipilimumab Induced Auto-Immune Hypophysitis Nidaullah Mian, Lokesh Rukmangadachar and Ali Choucair. Springfield, IL Objective: We describe a case of Ipilimumab induced autoimmune hypophysitis. With the more common use of these drugs, early recognition and prompt treatment of this rare side-effect is important to prevent morbidity and mortality.

Background: A new era in the treatment of cancers is in the form of immunotherapy. One class of these drugs are Immune checkpoint inhibitors (anti-CTLA4, and anti-PD4), that are approved for the treatment of metastatic melanoma, non-small cell lung cancers, and renal cell carcinoma. Ipilumamab is an anti-CTLA4 monoclonal antibody that enhance anti-tumor immunity by targeting the T-cell inhibitory receptors. Adverse events might occur through immunologic activation and may involve every organ system. Neurological adverse events although rare, require prompt recognition and treatment to avoid substantial morbidity.

Description: A 72 year old male with melanoma of the left abdominal wall with metastasis to the left inguinal lymph node, was admitted to the hospital with a four-day history of fatigue, generalized weakness, and confusion. The patient had received three treatments of immunotherapy with Ipilimumab for metastatic melanoma. After his third dose 2 weeks back, the patient reported malaise, poor appetite, vomiting, headache and diffuse erythematous papules from head to toe. At admission, he was alert, followed simple commands, however scored 10/30 on MMSE for missing points on all domains of the test, and otherwise a non-focal exam. His labs revealed hypoglycemia (blood glucose 60), and hyponatremia (129). Further endocrine testing was performed after he required repetitive administration of glucose to keep his blood glucose normal, that revealed low cortisol, ACTH and TSH suggesting pan hypopituitarism. MRI brain revealed abnormally enhancing and swollen pituitary in addition to a swollen pituitary stalk. CSF specimen revealed 26 WBC with lymphocytic predominance, 61 protein, normal glucose, and negative for an infectious source. The patient was treated with methylprednisolone 1gm IV daily for 5 days, and maintained on tapering steroid and thyroxine supplements. His mentation improved with steroids and he was back to his baseline in a week.

Conclusion: Ipilumamab induced hypophysitis is a rare but significant neurological adverse event of immune checkpoint inhibitors, whose early recognition and treatment with steroids is important to prevent significant morbidity and mortality.

Matthew J. Ebright and Brian Callaghan. Ann Arbor, MI Background: Paraneoplastic neurological syndromes (PNS) are immune-mediated conditions caused by malignancy not accounted for by direct tumor infiltration or metastases. The Mayo Medical Laboratory paraneoplastic autoantibody panel tests 15 specific antibodies with additional reflex testing. Given the number of tests that are bundled together, false positive results are likely to occur frequently. We aimed to discover the clinical scenarios that prompt testing, the frequency of false positive tests, and the subsequent testing and treatment after positive results.

Methods: We performed a retrospective chart review of 100 patients who had the Mayo Laboratory serum or CSF paraneoplastic autoantibody evaluation ordered at the University of Michigan Hospital in the inpatient or outpatient settings in 2013. Medical chart abstraction was performed by a neurology resident. We determined the clinical scenarios prompting testing by categorizing into "classical" paraneoplastic neurologic syndromes and non-classical syndromes. We defined a false positive paraneoplastic panel result as a positive test with an alternate explanation for the clinical presentation found or a positive test for which the antibody found did not match a described clinical presentation, the patient did not improve with immunosuppressive therapies, and no new cancer was found. We compared diagnostic tests ordered and treatments provided between patients with true positive, false positive, and negative results.

Results: Of the 100 patients with paraneoplastic panels sent, 19 had a positive result. Of the positive results, 12 (63.2%) patients had a false positive result. Of the antibodies that were found, 7 out of 7 of the striated muscle antibodies and 3 out of 7 of the P/Q-type calcium channel antibodies were false positive results. There were two cases with multiple antibodies found that were false positives as well. An alternative explanation was found in 62% of patients. CT and PET scans were ordered more frequently in patients with positive results (42% and 21%, respectively) than in patients with negative results (32% and 5%). New cancer was discovered in 9 of the 100 patients (4 of the 9 with positive results).

Conclusion: The Mayo Laboratory paraneoplastic autoantibody panel has a frequent positive result rate. Importantly, the false positive rate is higher than the true positive rate. Continued research is warranted to define the clinical scenarios that should prompt testing, and to improve existing panels to minimize false positive results and the subsequent diagnostic and therapeutic cascade. Background: Microglia are innate CNS immune cells that mediate neuroinflammation. Kv1.3 potassium channels regulate microglial functions and are over-expressed in human and animal neuroinflammatory states andmay represent therapeutic targets in neurological disorders. However, Kv1.3-dependent molecular and cellular mechanisms in microglia remain undefined. Herein, we confirm Kv1.3 expression in microglia in acute neuroinflammation models, and identify and validate novel Kv1.3-regulated proteins, molecular mechanisms and cellular processes in pro-inflammatory microglial states using a systems pharmacology approach.

Methods: Immunoblotting and flow-cytometric assays of Kv1.3 channels were performed to confirm upregulation following LPS activation in Bv2 microglia and CNS mononuclear phagocytes (CNS MPs) freshly isolated from LPStreated adult mice. Quantitative proteomics was performed on Bv2 microglia lysates after 24h treatment with control, LPS (100ng/mL), ShK-223 (highly selective Kv1.3-blocking peptide,100nM) and LPS1ShK-223. Statistical comparisons identified LPS-regulated and Kv1.3-dependent proteins and Gene Ontology (GO) analyses identified enriched molecular functions and biological processes. These guided validation experiments including migration assays, focal adhesion formation, phagocytosis, MHCI trafficking and antigen presentation. In-vivo validation of findings was performed in a model of LPS-induced neuro-inflammation. Pathway analyses of LPS and Kv1.3-regulated proteins guided experiments to identify Kv1.3-dependent signaling and transcription events.

Results: LPS upregulated cell surface Kv1.3 channels in-vitro (Bv2 cells) and in-vivo in microglia and in CNSinfiltrating macrophages isolated from LPS-treated mice.

Quantitative proteomics identified 144 proteins differentially regulated by LPS (of 3141 proteins), of which 21 showed reversal of LPS-effect by ShK-223. Enriched GO terms included MHCI-specific antigen presentation (TAP1, EHD1), cell taxis and focal adhesion formation. In-vitro, ShK-223 decreased LPS-induced focal adhesion formation, reversed LPS-induced inhibition of migration and inhibited LPS-induced up-regulation of EHD1, a protein involved in MHCI trafficking without affecting phagocytosis of polystyrene microspheres. In-vivo, intra-peritoneal ShK-223 inhibited LPS-induced MHCI expression by CD11b1 CD45low microglia without affecting MHCI trafficking in CD11b1CD45high macrophages. ShK-223 inhibited LPS-induced MHCI-restricted antigen presentation to ovalbumin-specific CD81 T cells in-vitro and in-vivo. Kv1.3 co-localized with LPS receptor complex and was found to regulate LPS-induced early STAT1 phosphorylation (S727), IRF1 and IRF7 expression.

Conclusions: Kv1.3 channels are upregulated by CNS MPs in neuroinflammatory states. We identified novel Kv1.3-channel dependent mechanisms in pro-inflammatory microglial activation including MHCI trafficking and MHCI-dependent antigen presentation by microglia to CD81 T cells. We also provide exciting evidence for neuroimmunomodulation by systemically administered Kv1.3blocking peptides. CNS MP Kv1.3-channels may represent therapeutic targets in neuroinflammatory conditions. Faciobrachial dystonic seizures (FBDS) and limbic encephalitis closely associate with LGI1-antibodies. FBDS have a clinically-recognisable semiology and often predate the onset of the cognitive impairment (CI). We describe 103 consecutive patients with FBDS and LGI1-antibodies and characterise the clinical, therapeutic and serological differences between those with and without cognitive impairment (CI), and to determine whether cessation of FBDS can prevent CI. The 22/103 patients without CI typically had normal brain imaging, EEGs, sodium levels (p<0Á0001) and almost exclusive IgG4 LGI1-antibodies (p50.009), versus the frequent IgG1-antibodies in patients with CI (p50.03). Overall, cessation of FBDS with antiepileptic-drugs alone occurred in only 9/89 (10%) patients. In contrast, 30 days after immunotherapy initiation, 51% had cessation of FBDS (p<0Á0001); an effect which was more rapid in those without CI (p50.038). Every week of delayed immunotherapy conferred a 5% relative reduction in the probability of FBDS cessation, and shorter time to immunotherapy (p50Á031) and absence of CI (p50Á0014) predicted reduced disability at 24-month follow-up. Furthermore, of 80 patients with FBDS as their initial feature, 56% developed CI after 90 days of active FBDS. In contrast, only one patient developed CI after cessation of FBDS (p<0Á0001). FBDS show a striking time-dependent response to immunotherapy. Prompt immunotherapy appears to prevent development of CI, maybe via inhibiting IgG1-mediated complement deposition.

Martha Guadalupe Garc ıa-Toribio, Erik G omez and Laura Ch avez. Mexico City, Mexico

Background: The CNS inflammatory lesions in RA present as rheumatoid nodules, meningeal vasculitis and rheumatoid cerebral vasculitis, the latter being a rare and serious complication estimated in 1 to 8% where the blood vessel is the target of immune reaction. Most culminate in death, especially when cerebral vasculitis is associated with systemic rheumatoid vasculitis.

Methods: Case report. Case Report: A female 22 yo, secretary, diagnosis of RA one month prior to treatment with NSAID, who had fever, nausea and bifrontal headache, oppressive, which increased the Valsalva maneuver. 1 week after vomiting followed by inattention. The following day she presented disorientation and incomprehensible language, with improvement of these symptoms during the rest of the day. At her entrance she presented a conjugated deviation look to the left and right hemiparesis, she went to medical assessment.

Physical Examination: Awake, partially oriented, fluent language, incongruous, gnosis and praxis performed with difficulty, reasoning, abstraction and calculation altered. Cranial nerves and force are normal, generalized hyperreflexia, bilateral flexor plantar response. Palmomentonian reflex present. Cerebellum-vestibular gait unsteady, short steps, required help when performed with indistinct lateropulsion. Romber (1). Absent meningeal signs.

Laboratory and other diagnostic tests: normochromic, normocytic anemia (hemoglobin 11.6g/dl) leukocytosis 11000/mm3, lymphopenia 900/mm3, hypoalbuminemia 2.7mg/dl, increased LDH 343U/L. Renal failure (proteinuria 20) .

Inflammation (elevated C-reactive protein 97mg/L). Rheumatoid Factor (1) 203UI/ml. Immunological profile C3 81mg/dl, C4 13.2mg/dl, rest of antibodies in range not pathological. Non-reactive HIV1/ 2 ELISA. VDRL, anti-cysticercus antibodies, Mycological and culture for Tb mycobacterium in CSF was negative. CSF analysis: transparent, cells 11/mm3, hypoglycemia 29mEq/dl, proteins elevated 117mg/dl. EEG: Abnormal on waking, mild generalized dysfunction without epileptic activity.

Brain MRI on contrast-T1 weighted image, coronal section with meningeal enhancement compatible with pachymeningitis.

Macroscopic view of external surface of the encephalus, on the dorsal side there is slight congestion of the leptomeningeal vessels.

Histopathologic pattern of brain stem, central region blood vessel with wall necrosis, in addition to inflammatory infiltrate and the presence of nuclear dust. Histological section of kidney shows blood vessel with presence of wall necrosis and fibrin deposit.

Discussion: Rheumatoid cerebral vasculitis is an uncommon entity, with variable neurological manifestations, sometimes with signs of focalization or diffuse manifestations and characteristically with fluctuating evolution.

Conclusion: The literature reports the diagnosis is made retrospectively during a postmortem histopathological study in most cases, consistent with the case presented.

Optic Neuropathy Shilpa Chaku. Springfield, IL Objective: To describe a case of chronic relapsing inflammatory optic neuropathy Case: A 58 year old female presented to an ophthalmologist with two day history of acute worsening of vision both eyes. She had history of stable asymptomatic hydrocephalus. Ophthalmological examination revealed bilateral papilledema, left worse than right. Visual acuity (VA) was 20/200 in the right (R) eye and 20/800 in the left (L) eye with afferent pupillary defect (APD) on the left and pain with eye movements. The remainder of her neurologic examination was normal. MRI brain and orbits demonstrated moderate to severe stable ventriculomegaly and a small area of abnormal enhancement in the distal segment of the left optic nerve as evidence for optic neuritis. MRI spine was negative for demyelinating lesions. Lumbar puncture (LP) revealed normal pressure, WBC (40), protein (22) and myelin basic protein (6.06). Rest of serum and CSF inflammatory and infectious markers were negative. She received 5 days of solumedrol and was discharged home with a steroid taper. On day of discharge, her VA was much improved with her R eye (20/25) and L eye (20/70). At clinic follow up a few weeks later, patient's VA was stable and she was found to have slight disc edema on the L. However a few weeks later, patient again developed subacute left visual disturbance. VA in L eye was 20/400, with color desaturation and APD. Repeat CSF studies were unremarkable. She underwent another course of solumedrol with repeat improvement in her vision. At clinic follow up, VA in R eye (20/30), (20/25) in the L eye, APD on the L, no color desaturation on the L and pallor in the L optic disc. The rest of her neurologic exam remained normal.

Conclusion: Chronic relapsing inflammatory optic neuropathy is a unique entity which must be considered in cases of steroid responsive recurrent optic neuropathy not associated with CNS demyelinating diseases, autoimmune disorders or other common causes of optic neuritis. Patients may require chronic steroid or immunosuppressive therapy. S114. Autoimmune Encephalitis Secondary to Neuronal Ganglionic Acetylcholine Receptor Antibodies Alicia S. Parker, Sarah Rehl, Leila Saadatpour, Usama Tariq, Rocio Polanco Fernandez, Mohammadhossein Alimardani, Leilani Doty and Kenneth Heilman. Gainesville, FL Background: Autoimmune encephalopathy can be used to describe a range of neuropsychiatric disorders in which autoantibodies are directed against central nervous system targets. While nicotinic ganglionic acetylcholine receptor autoimmunity has been commonly reported in dysautonomia and peripheral neuropathy, this type of autoimmunity has rarely been shown to cause encephalopathy. Currently, there is limited data regarding the cognitive and behavioral changes which occur in this syndrome, and the efficacy of immunomodulatory therapy.

Significance: We seek to characterize the clinical symptoms and describe the treatment paradigm of a rare case of autoimmune encephalitis secondary to neuronal ganglionic acetylcholine receptor autoimmunity.

Methods: A case report. Case Report: A 54 year-old previously healthy, righthanded male presented to clinic for evaluation of one year of cognitive impairment which was simultaneous with the onset of severe eczema. He reported weekly cognitive fluctuations and brief involuntary jerks. Symptoms involved difficulty with executive function, working memory, word finding, and calculations; there were no symptoms suggestive of dysautonomia. Cognitive exam revealed poor orientation, impaired comprehension and repetition, dysfunction of working memory and response inhibition, phonemic errors, paucity of functional words, ideomotor apraxia, acalculia, apraxic agraphia, and right-left confusion. Serologies indicated a high antibody titer to alpha-3 neuronal ganglionic acetylcholine receptor antibodies. MRI showed nonspecific T2 lesions. During IVIG treatment, jerking movements ceased and symptoms rapidly improved, particularly in language and short-term memory. His EEG, which was consistent with metabolic encephalopathy pretreatment, normalized after his IVIG course.

Discussion: Encephalopathy associated neuronal ganglionic acetylcholine receptor antibodies has been rarely reported, and tends to occur with dysautonomia and peripheral neuropathy. In this case, we describe the spectrum of cognitive findings our patient presented with along with his clinical and electrographic improvement following treatment with IVIG.

Cynthia Wang and Benjamin M. Greenberg. Dallas, TX Background: Anti-myelin oligodendrocyte glycoprotein (MOG) has been found in cohorts of patients with ADEM, optic neuritis (ON), transverse myelitis (TM), and neuromyelitis optica spectrum disorder (NMOSD). Features of these patients include young age, presence of encephalopathy, and polyfocal symptoms. MOG-related syndrome is commonly on the differential with relapsing demyelinating disorders such as MS, NMOSD, and chronic relapsing inflammatory optic neuropathy (CRION). Whether anti-MOG syndromes are associated with favorable outcomes and whether they are relapsing diseases has been debated and the data thus far shows mixed results. We add our institution's experience to the current literature.

Methods: In the retrospective chart review study, 33 pediatric patients with diagnoses including acute disseminated encephalomyelitis, optic neuritis, encephalitis, NMOSD, and unknown relapsing demyelinating disease were tested for anti-MOG antibodies with a cell-based assay.

Preliminary results: In the cohort of patients, 15 out of 33 patients (45%) tested positive for MOG. The MOG positive group had a significantly higher female to male ratio, 4:1 versus 1.1:1. The indication for sending MOG testing was more homogeneous in the MOG positive group, namely having a history of ADEM and/or optic neuritis (bilateral ON in all cases except one). The MOG negative group was primarily comprised of patients with suspected NMOSD and unknown relapsing demyelinating disease. In the MOG positive subset, the predominant race/ethnicity was non-hispanic White (47% vs 20% Hispanic white 20%), while it was Hispanic White (50% vs 28% non-hispanic white) in the MOG negative subset. 3 of 15 (20%) of MOG positive patient had evidence of a clinical and radiological relapse during follow-up period ranging from 1-14 years whereas 6 of 18 (33%) MOG negative patients had a relapse during follow-up period 1-5 years.

Preliminary conclusions: In MOG positive patients were more likely female and non-hispanic White compared to the MOG negative group. The MOG positive group consisted of more homogeneous syndromes, namely ADEM and bilateral optic neuritis. The MOG positive group also required less aggressive acute treatment, and were less likely to have relapsing disease that would prompt chronic immunomodulatory therapy. This study is limited by small sample size, retrospective methodology, and limited duration of follow-up. More studies on the role of MOG antibodies in pediatric demyelinating diseases are needed to characterize the natural history of this condition and guide management. S116. The c-Abl Inhibitor, Nilotinib, as a Potential Therapeutic Agent for Chronic Cerebellar Ataxia Chan-Young Park, Hye-Rim Shin, Seon-Jae Ahn, Yoonhyuk Jang, Woo-Jin Lee, Han Sang Lee, Jin-Sun Jun, Yong-Won Shin, Tae-Joon Kim, Jangsup Moon, Soon-Tae Lee, Keun-Hwa Jung, Kyung-Il Park, Ki-Young Jung, Manho Kim, Sang Kun Lee and Kon Chu. Seoul, Republic of Korea Chronic cerebellar ataxia (CA) is a neurologic disorder that progressively deteriorates patients' quality of life. However, currently established treatments for chronic CA remain in the level of symptom alleviation. Nilotinib (Tasigna V R ) is a potent inhibitor of non-receptor tyrosine kinase BCR-ABL that penetrates blood-brain barrier. As recent evidences suggest that nilotinib might be effective in treating chronic CA, we present twelve cases of chronic CA who were nonresponsive to other treatment options (modified Rankin scale [mRS] scores of >2) and received daily nilotinib therapy. Twelve patients (four males and eight females) were followed-up for 10.1 6 3.1 (range 5-16) weeks with nilotinib treatment (daily doses of 150-300mg). According to underlying etiologies, four patients were classified as autoimmune, three as degenerative, three with genetic, and two with idiopathic. At nilotinib initiation, the median mRS score was 3.5 (range 3-4). At follow-up, improvement in mRS scores was observed in 7/12 (58.3%) patients (P50.016) and a favorable outcome (mRS scores of 2) was reported in 6/ 12 (50.0%) patients. For the responders, clinical improvement was noticed in 0.5-3 weeks after drug initiation, and maintained throughout the treatment without severe adverse events. In the analysis of pre-treatment MRI findings, atrophic changes in cerebellar vermis was negatively associated with favorable outcomes (P50.005). Pontine atrophy (P50.061) and cerebellar hemispheric atrophy (P50.080) also showed a tendency of being negatively associated with favorable outcomes. Etiologic categories of CA was not significantly associated with functional outcomes (P50.182). These findings indicate that nilotinib might improve functional outcomes of the patients with chronic cerebellar ataxia with a favorable safety. The clinical response to nilotinib might be detected in early treatment phases. Not underlying etiologies, but atrophic changes in cerebellar and brainstem structures might predict a negative responsiveness to nilotinib. S117. Cyclic Symptoms of Narcolepsy with Cataplexy: An Unusual Presentation of Immune-Mediated Encephalitis Rafer Willenberg and Jonathan D. Bui. San Diego, CA Introduction: We report a case of encephalitis having a presentation most consistent with narcolepsy with cataplexy and cyclical exacerbation, but with non-confirmatory laboratory findings. The patient's symptoms resolved with immunotherapy, reflecting that cyclic symptoms of narcolepsy with cataplexy are one presentation of immune-mediated encephalitis.

Case: A 15-year-old boy presented with hypersomnolence following a febrile illness with headache. He had monthly exacerbations when he would sleep 16-20 hours a day, had difficulty concentrating, and between exacerbations did not return to baseline. He exhibited no hypersexuality, hyperphagia, or apathy, though had diminished appetite.

Workup revealed a normal brain on MR imaging, blood was negative for Lyme antibodies, and polysomnography with mean sleep latency testing (MSLT) did not reveal shortened mean sleep latency to confirm a sleep disorder. Within 5 months he developed paralysis with waking and weakness with emotional events consistent with narcolepsy with cataplexy, but still did not fall asleep during the day, did not have hypnogogic hallucinations, and did not have sleep fragmentation. He was evaluated by the Stanford Narcolepsy Group who performed repeat polysomnography with MSLT showing one sleep-onset REM period but no shortened sleep onset, and found he was negative for the narcolepsy allele HLA-DQB1*0602, and thus regarded him to not have narcolepsy.

Ten months following his initial presentation he continued to have cyclically-worsening hypersomnolence. He was regarded to likely have an autoimmune encephalopathy given his negative workup, and immunotherapy was scheduled.

Repeated lumbar puncture revealed no oligoclonal bands and he was seronegative for all antibodies on the Mayo Autoimmune Encephalitis Panel. Intravenous immunoglobulin (IVIG) therapy resulted in remarkable resolution of the patient's hypersomnolence, weakness, and cognitive problems. He had a recurrence 7 months later, with brain MRI again normal, and was again treated with IVIG therapy with symptom resolution.

Discussion: This patient had symptoms of narcolepsy and cataplexy with cyclic exacerbation and relief by IVIG therapy, reflecting an immune-mediated encephalitis despite being seronegative. Symptoms of narcolepsy and cataplexy are rarely reported in cases of encephalitis, but have been documented in a few cases of autoimmune encephalitis associated with Ma2 antibodies (Dalmau et al., Brain 127:1831 -1844 , 2004 . Cyclic symptoms of narcolepsy with cataplexy are a presentation of immune-mediated encephalitis, and immune therapy should be considered for treatment, even if the patient is seronegative and brain MRI is normal. Prevention and early recognition of critical illness in patients with autoimmune encephalitis (AE) is essential to achieve better outcome. Here, we studied risk factors for intensive care unit (ICU) admission and its prognostic impact in patients with AE encephalitis.

A retrospective chart review and reclassification of patients evaluated for AE between 2011 and 2016 at our tertiary care center revealed 17 "definite" and 15 "probable" AE cases. Thirteen patients (41%) required ICU care and the underlying conditions were intractable seizures or status epilepticus (54%), altered mental state (39%) and respiratory failure (8%). Development of critical illness was associated with longer time from first symptoms to hospitalization (P50.046). Regression analysis revealed that anaemia on admission and detection of neuronal antibodies was associated with a higher risk for ICU admission. At last follow-up after a median of 31 months (range 2.5-52.4), seven patients had died (23%) and 63% had a good outcome (modified Rankin Scale 0-3). Anaemia was associated with poor prognosis (p50.021), whereas development of critical illness did not impact mortality and functional outcome.

Our study confirmed the need for ICU care in a subgroup of patients with AE and disclosed that the prevailing objective is improved seizure control. While the presence of neuronal antibodies and anaemia were identified as risk factors for development of critical illness, we corroborate a paradigm shift with regard to prognosis which did not differ from non-ICU treated patients. S119. Anti-GM1 IgG Antibody in Central Nervous System (CNS) Inflammatory Diseases Hye-Rim Shin, Seon Jae Ahn, Han Sang Lee, Tae-Joon Kim, Jin Sun Jun, Jangsup Moon, Soon-Tae Lee, Keun-Hwa Jung, Kyung-Il Park, Ki-Young Jung, Manho Kim, Sang Kun Lee and Kon Chu. Seoul, Republic of Korea Though GM1 is a major ganglioside in the CNS of higher vertebrates, CNS disease associated with anti-GM1 antibodies are rarely reported. Nevertheless, there are several reports describing acute disseminated encephalomyelitis with high titer anti-GM1 IgG antibodies. The purpose of this study is to evaluate whether the presence of anti-GM1 IgG antibodies have influence on symptoms and treatment effects in CNS inflammatory diseases. Between January 2010 and December 2016, a total of 1604 patients underwent serum anti-GM1 IgG ELISA tests (B€ uhlmann Laboratories AG, Switzerland) at Seoul National University Hospital, South Korea. One hundred and twenty-seven patients were tested positive. Using to International Classification of Diseases-10 code, 621 and 799 patients were classified as central and peripheral nervous system disorders, respectively. Further classification of CNS diseases needs to be performed using medical records, lab results, and brain images. The kit used in this study is known to have positive results in 1-2% of the normal population. We believe the results of our study will guide the clinicians' decision on diagnosis and treatment in CNS inflammatory diseases with positive serum GM1 IgG results. S120WIP. SHP2: A Potential Therapeutic Agent for MuSK-Myasthenia Michelangelo Cao, Saif Huda, Pedro Rodriguez-Cruz, Judith Cossins, Wei Wei Liu, David Beeson and Angela Vincent.

We previously showed that a SHP2 (phosphatase) inhibitor, NSC87877, reverses in vitro the effects of MuSK-MG patient sera on AChR clustering (Huda et al. in preparation) .

The effect of NSC87877 on MuSK phosphorylation was studied in parallel with agrin-induced AChR clustering in (a) C2C12 myotubes exposed to agrin and purified MuSK-MG IgG subclasses; and (b) MuSK KO C2C12 cells (created using the CRISPR/Cas9 system) in order to determine if NSC87877 might also act downstream in the AChR-clustering pathway.

IgG, IgG4 or IgG1-3 subclasses derived from MuSK-MG patients reduced AChR clustering. Total IgG and IgG4 markedly reduced MuSK phosphorylation while, surprisingly, IgG1-3 antibodies had no effect on MuSK phosphorylation.

Nevertheless, NSC87877 increased MuSK phosphorylation and AChR clustering in wild type myotubes treated with all three MuSK-IgG preparations. In MuSK KO myotubes, neither agrin nor NSC87877 induced AChR clustering.

We show that MuSK IgG1-3 inhibits AChR clustering without altering MuSK phosphorylation while IgG4 decreases MuSK phosphorylation. The effect of NSC87877 depends on functional MuSK and reverses the pathogenic effects of all IgG subclasses, SHP2 inhibition could play a role in treatment of MuSK-MG and other disorders associated with defects in the agrin-MUSK AChR-clustering pathway.

Behavioral Neurology S121. Crucifixion Cenesthesia: Peripheral Neuropathy of Marfan's Syndrome Sulekho Egal, Henao Jose and Hirsch Alan. Willemstad, Curacao, Netherlands Antilles; Willemstad, Netherlands Antilles and Chicago, IL Introduction: Cenesthesias or body image aberration describes abnormal bodily sensations (Gesnerus, 1977) . As part of schizophrenic delusions, cenesthesias present with perceptions of movement, enlargement (Rohricht, 2002) , expansion of body or pulling of the body viscera or surface (Parnas, 2003) . Cenesthesis as a manifestation of peripheral neuropathy has not been described.

Method: Case Study: A 23 year right handed single female presented with a past diagnosis of Marfan's Syndrome with aortic root dilation, and ectopic lentis, presented with four months of gripping pain, a feeling she was being stretched, as if being tortured on a rack, or nailed to a crucifix, -as if her extremities were being disarticulated from her body. She sensed as though her hands were falling off her arms and her ribs were being ratcheted downwards to the floor. At other times she felt as if her knees were being struck by a hammer. She also experienced extremity coldness, diffuse creeping pain with formication, migratory numbness, where body parts randomly fall asleep. These somatic symptoms were alleviated with showering and selfpunching of her extremities.

Results: Abnormalities on Neurologic Examination: Height 72 inches/Arm span 74.5 inches, Arachnodactyly, Pes Planus. Mental status Examination: unable to interpret similarities. Mood sad and anxious with congruent affect, poor eye contact. Reflexes: Absent except 11 bilateral triceps. Neuropsychiatric Testing: Beck Depression Inventory -II: 27 (definite depression). General Anxiety Disorder Screener-7: 10 (moderate anxiety). MRI of Thoracic and Lumbar Spine: Dural sacs with septation at S1-S2 with remodeling of adjacent vertebral bodies. Revised Ghent criteria for the diagnosis of Marfan's Syndrome and related conditions: 7 (Probable Marfan's Syndrome) (Loeys, 2010) .

Discussion: Contents of her vivid description of somatic sensory phenomena may be viewed within the realm of an underlying peripheral neuropathy. This diagnosis is validated by the presence of areflexia. The alleviation of sensory complaints with stimulation of large nerves fibers as occurring with self mutilations of self punching and exposure to pounding water pressure from the shower suggests underlying peripheral neuropathy, rather than this representing a delusion. Her descriptions may reflect intellectualization based on her comprehension of Marfan's Syndrome, superimposed upon her sensation of peripheral neuropathy. In patients who present with kinesthesia, it may be worthwhile to assess for presence of peripheral neuropathy. Treatment response may be oriented towards alleviation of neuropathic pain as supposed to primary treatment of any delusional disorder.

Leila Montaser-Kouhsari and Christof Koch. New York, NY and Seattle, WA Can the brain assign values to objects without us becoming aware of their identity, or is conscious perception a pre-requisite for stimulus valuation? We investigated this question using fMRI while subjects made economic choices about which snack foods to eat under otherwise similar subliminal and supraliminal presentations. Words denoting the foods were masked to manipulate visibility. Independently obtained measures of the food's value had two order of magnitude greater influence on choices in the supraliminal than the subliminal condition, although subliminal stimuli still primed reaction times in a separate experiment. The hemodynamic BOLD activity in ventromedial prefrontal cortex tracked value only during conscious perception of the stimuli, whereas ventral striatum reflected value under both conditions. The findings suggest a striking dissociation between the two main components of the brain's system for evaluating the subjective value that drives economic choices.

Saad M. Alrajeh, Nada AlTassan, Najeeb Qadi, Sara Abdulaziz, Nada Majrashi, Maznah Alinizi and Fadia Elbitar. Riyadh, Saudi Arabia Alzheimer's disease (AD) is the most common form of dementia and neurodegeneration. AD is mainly sporadic that occurs in the elderly. A small percentage of cases before age of 65 displays mutations related to familial forms of Alzheimer's disease (AD) and is defined as early onset familial Alzheimer's disease (EO-FAD) . This disorder is known to be associated with cerebral atrophy, beta amyloid aggregation and intra-neuronal neurofibrillary tangles. No molecular background has been yet demonstrated on Alzheimer's disease in Saudi population.

In this study, we examined the genetic cause of Alzheimer's disease in Saudi patients. We recruited 100 AD familial and sporadic cases and screened them by direct sequencing for possible pathogenic mutations in AD related genes: PSEN1, PSEN2, APP, SORL1 and APOEe4. We found out of 77 variants, 2 non synonymous and one synonymous substitutions HGMD-listed variants in SORL1 that were defined respectively as disease-causing mutation in p.E270K of exon6, disease-associated polymorphism with additional supporting functional evidence in p.A528T of exon11 and disease-associated-polymorphism in p.S1187S of exon25. The allelic variants in both missense mutations of SORL1 occurred in heterozygous state. SORL1 alterations on exons 6 and 11 were present in 2 cases of EO-FAD and in one case belonging to late-sporadic AD. This work will permit to establish clinical and molecular database for AD mutations in Saudi population and will provide knowledge to understand the genetic complexity related to this devastating disorder.

Adila Abulhamail and Doris A. Trauner. La Jolla, CA Objectives: Nephropathic cystinosis is a rare autosomal recessive disorder of cystine metabolism in which there is lysosomal accumulation of the amino acid cystine. Previous studies have shown visual spatial and visual memory deficits in patients with cystinosis, with corresponding structural changes in the parietal white matter. The current study was conducted to examine parietal lobe function in children with cystinosis using tasks specifically mediated by the parietal lobe.

Methods: 38 children with cystinosis and 67 typical controls were tested using 2 tasks thought to be specific for parietal lobe function, Non-Canonical Views (NCV) and Judgment of Line Orientation (JLO), as well the Test of Facial Recognition (FR), thought to be mediated by the fusiform gyrus.

Results: Children with cystinosis performed significantly more poorly than did controls on NCV and JLO, but performed at similar levels to controls on FR.

Conclusions: Visual processing in the brain is thought to consist of 2 systems, the "where" system mediating visual spatial function and involving the dorsal stream (primarily the parietal lobe) and the ventral "what" system mediating visual perception and primarily involving the temporal lobe. Cystinosis appears to preferentially affect the "where" system, with impairment in visual spatial function but not in visual perception. These results suggest that the gene for cystinosis plays a role in brain development, with alterations in dorsal stream development in particular. Herein, we present a demonstrative case of a large located arachnoid cyst in an elderly patient with significant behavioral changes and cognitive decline and briefly review the literature of behavioral changes and arachnoid cysts. An 89year-old male with history of vascular dementia presented to the emergency room after a fall. Family reported a rapid decline in cognitive function in the past 6 months. According to family the patient had displayed periods of behavioral changes, with aggressive behavior, word finding difficulty in the past few months. Patient had periods in which he "wasn't there," during which he did not answer any questions or initiate any conversation. MRI revealed a large cyst with midline shift, characterized as a large loculated extraaxial CSF-like fluid collection centered in the right sylvian fissure and extending along the entire right convexity. Septations along the anterior and posterior margins with thinning of the adjacent bone were seen. Mass effect with effacement of the sulci and compression of the right lateral ventricle was noted by 10 mm midline shift to the left and a subfalcine herniation. This most likely consistent with an arachnoid cyst.

Arachnoid cysts are a common neurodevelopmental disorder with an estimated prevalence of 0.2% to 1.7% Arachnoid cysts have a predilection for the middle cranial fossa. They account for 1% of intracranial space occupying lesions. Of patients undergoing a brain MRI, only 1.4% are identified to have an arachnoid cyst. Only 5% of arachnoid cysts are symptomatic. The clinical manifestation of these cysts varies depending on their location and the patient's age. Hydrocephaly or cranial deformation are the most common manifestation in the pediatric population while in adults, headaches and convulsive episodes are the most common.

Other signs and symptoms include ataxia, ocular alterations, focal signs, dizziness, and altered memory. Intracranial arachnoid cysts have been reported in literature to cause deficits in higher level executive functions, such as inhibition, cognitive flexibility, rule learning, planning, problem solving, and initiating tasks which improve significantly after neurosurgical intervention. Even though these cysts are congenital and have affected the brain tissue for a long duration, the effect appears to be of a reversible suppression.

Working Memory Summer L. Sheremata. Boca Raton, FL Hemispheric asymmetries have a long and controversial history in the study of human behavior and cognition. Behavioral deficits in neuropsychological populations have, for a long time, provided the only evidence for functional lateralization. Theories of right hemisphere dominance for attention stemmed from hemispatial neglect, a disorder in which predominantly right hemisphere lesions result in the inability to direct attention to the opposite visual field (Mesulam, 1981) . However, within healthy populations, neuroimaging studies have not consistently supported these asymmetries. Both hemispheres demonstrate retinotopic organization, with areas in each hemisphere responding to and directing attention to information from the opposite visual hemifield.

Within areas that show retinotopic organization, task demands elicit asymmetric processing during visual attention (Sheremata & Silver, 2015) and visual short-term memory (Sheremata, Betttencourt and Somers, 2010) , two distinct yet inter-related processes. Both tasks have been shown to recruit the dorsal attention network bilaterally. Here, a series of fMRI and behavioral experiments investigated how each hemisphere represents stimuli during each task and how asymmetries affect behavioral performance across the visual field.

While attention and VSTM activated similar cortical areas, BOLD amplitude and functional connectivity in the parietal cortex differentiated the two tasks. Within the dorsal attention network, VSTM increased BOLD amplitude in the intraparietal sulcus (IPS) relative to attention. Compared to the attention task, IPS was more strongly connected with other fronto-parietal areas and more weakly connected with occipital cortex. In contrast, both tasks converged on a pattern of hemispheric asymmetry for spatial processing. A contralateral bias, defined by greater activity for items presented in the opposite visual hemifield, was stronger in the left than right hemisphere across tasks. Comparable spatial biases across tasks suggest asymmetries in IPS are characteristic of processes common to attention and VSTM.

Furthermore, behavioral studies demonstrated that hemispheric asymmetries in VSTM processing give rise to differences in memory capacity, or the number of items held in memory, across the visual field. Consistent with theories of right-hemisphere dominance in visual attention, participants had highest capacities for items in the left visual field, opposite the right hemisphere. Furthermore, an investigation of participants' patterns of errors showed each remembered item was maintained more precisely. These findings demonstrate that the higher capacity for objects presented in the left visual hemifield occurs without sacrificing the precision of the object representation. Together, these results delineate asymmetries in the brain and how they impact behavior.

Kalen Petersen, Nelleke Van Wouwe, Adam Stark, Hakmook Kang, Manus Donahue and Daniel Claassen. Nashville, TN Background. Dopamine agonists induce Impulse-Control Disorders, such as binge eating and hypersexuality, in a subset of PD patients, though prevalence estimates vary. We sought to identify acute metabolic changes in the brain associated with ICDs, and determine whether functional connectivity is altered in striato-cortical networks. Since individuals with ICDs are highly sensitive to rewarding behavioral outcomes, we proposed that altered incentive learning is a cognitive mechanism contributing to ICDs.

Methods. PD patients (n537) were recruited from the clinic and classified as ICD-positive or -negative based on a structured interview. We applied a multimodal imaging protocol, including arterial spin labeling (TR/TE54000/11ms; post-labeling delay51500ms), and baseline blood oxygenation level-dependent (TR/TE52000/35ms) fMRI. We administered an incentive-based learning task required subjects (n520) to respond to visual stimuli by either acting or withholding action. Choices were either rewarded or punished by gain or loss of money. Reward and punishment learning were defined by cumulative accuracy on this task. Scans and incentive-learning tasks were performed both on-DAA and off-dopamine.

We hypothesized that (1) the ventral striatum exhibits increased blood flow in response to agonists in PD patients with ICDs compared to those without; (2) ICD-positive patients on-DAA have elevated functional connectivity in the limbic loop involving the ventral striatum, anterior cingulate gyrus, and orbitofrontal cortex, and; (3) limbic network connectivity correlates with reward learning.

Results. We found that ventral striatal hemodynamic response to DAAs was significantly higher (p50.03) in ICD-positive patients. Functional connectivity between the ventral striatum and the globus pallidus (p50.024), thalamus (p50.016), putamen (p50.013), dorsal anterior cingulate gyrus (p50.033), and subgenual anterior cingulate gyrus (p<0.01) was significantly greater in the ICD-positive group. ICD-positive were significantly better at reward learning than ICD-negative patients (p<0.01). Connectivity between the ventral striatum and subgenual anterior cingulate correlated positively with both reward learning (q50.54, p<0.01) and punishment learning (q50.53, p<0.05), while on-DAA, but not off-dopamine (p>0.05).

Conclusion. Our results demonstrate that maladaptive behavioral responses to dopaminergic therapy reflect differences in ventral striatal activity and connectivity, and that mesocorticolimbic network synchrony is related to incentive-based learning proficiency. We propose a model in which DAAs produce ICDs by increasing activity at the ventral striatum and connectivity with the limbic loop, thus enhancing reward-reinforced learning and hedonic behavior. Functional near-infrared spectroscopy (fNIRS) measures near-infrared light attenuation to quantify hemodynamic response. This technology can be used to measure bloodoxygenation-level dependent response (BOLD) in the same manner as functional magnetic resonance imaging (fMRI) in brain tissues. fNIRS has been used to delineate differences in functional brain responses, particularly in cortical areas such as dorsolateral prefrontal cortex. Current implementations of fNIRS are capable of penetrating up to 4 cm deep. At this depth, studies have demonstrated that fMRI and fNIRS measurements are highly correlated. While fNIRS is a newer technology for measuring brain activity, it has advantages both scientifically and economically as compared to fMRI. fNIRS is relatively inexpensive, portable, and offers flexibility in research design similar to that of electroencephalography (EEG) measures. Additionally, fNIRS is quiet with less mobility restrictions which can be appealing to individuals with anxiety conditions such as claustrophobia. Movement artifact is far less problematic. In fact, fNIRS can employed when participants are asked to move such as in gait studies. For these reasons, fNIRS would be an excellent method to study brain function, such as prefrontal activity during aging. To date, fNIRS has been used in only a limited extent to study prefrontal activity in the oldest old or in the context of successful cognitive and brain aging. In this review, we will discuss the basic theories and methods of fNIRS, including its application in the study of functional brain activity changes in neurological disorders. This will be followed by a review of functional changes documented by similar techniques such as fMRI occurring in the context of normal cognitive aging. Finally, we will discuss strengths and limitations of these methods, and directions of future research needed to address the brain changes occurring with aging.

Muktiben M. Patel, Brittany L. Avonts, Nigam D. Patel and Alan R. Hirsch. Oranjestad, Aruba; Lake Forest, IL; Nanjing, China and Chicago, IL Introduction: Wine tasters judge the chemosensory components of wine based on color (Parr, 2010) and the color of soda influences perception of flavor (Hyman, 1983) . Context effect in those which chemosensory dysfunction has not been described. An anosmic patient with context dependent olfaction is presented.

Method: Case: A 42-year-old right-handed male, one year prior to presentation underwent cardiac ablation followed by complete loss of taste and smell. Since then he experiences one olfactory window every morning and one every other week lasting 20 seconds, precipitated by nonolfactory and non-gustatory sensory cues. For instance, hearing the coffee pot percolate each morning would cause an immediate olfactory perception of espresso, however on drinking the coffee, it had no smell or taste. Similarly, the act of cutting herbs and garlic would induce him to smell garlic, but eating it had no taste. Being told that there was an aroma of nachos infused in the room, would induce him to transiently experience the smell of jalapeno.

Results: Olfactory anosmia to: Phenylethyl Alcohol Threshold, Quick Smell Identification, Brief Smell Identification, Olfactometer N-butanol Threshold, Alcohol Sniff, University of Pennsylvania Smell Identification, Pocket Smell Identification, Sniff Magnitude, Sniff-n-Sticks Threshold, Odor Memory, Suprathreshold Amylacetate Odor Intensity, and Retronasal Olfaction. MRI of brain with and without infusion: normal.

Discussion: The mechanism whereby context induced olfactory windows is unclear. Expectation effect acting upon olfactory perception has been described in both laboratory and group setting (Slosson, 1899; O'Mahoney, 1978) . Alternately this may represent change in focus of attention to olfactory stimulus. The non-olfactory sensory cues cause him to seek olfactory stimulation. Attention to olfactory stimulation may thus enhance olfactory ability, which allowed him perceive an aroma (Spence, 2001) . Verbal or non-chemosensory sensory cues may have induced the patient to form a mental image of the source of the aroma, which would then act to enhance his olfactory ability in detecting this odor (Kollndorfer, 2015) . Alternatively, this may be a chemosensory equivalent to confabulation of Korsakoff syndrome, where there is a tendency for the mind to fill in the gap in sensory experience, a proclivity towards continuity (similar to what appears in the visual sphere with incomplete illusions with the Law of Closure) (Vernon, 1962) . Such contextual induction of olfactory experience may be utilized in helping to train or refine olfactory ability in those with olfactory loss. S130. Network Localization of Free Will Perception Ryan Darby and Michael D. Fox. Boston, MA While the existence of free will remains controversial, our perception that our actions are freely willed is not. This perception of free will is thought to involve two processes: the motivation to move, referred to as a sense of volition; and the feeling that movement is voluntary, referred to as a sense of agency. Focal brain lesions can impair the perception of free will; lesions impairing volition result in akinetic mutism, while lesions impairing agency result in alien limb. However, lesions in several different locations can cause each of these clinical syndromes, making it difficult to localize disorders of free will perception to specific neuroanatomical locations. Here, we test an alternative hypothesis: that lesions impairing free will perception localize to a unique network of brain regions, rather than a single location. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. To test this hypothesis, we first identified 28 lesions causing akinetic mutism, and 53 lesions causing alien limb. Lesions were spatially heterogeneous, and no single location was involved in the majority of cases for either syndrome. Next, we used a new technique called lesion network mapping to determine brain regions functionally connected to each lesion location. 100% of lesions causing akinetic mutism were functionally connected to the same location in the anterior cingluate cortex (ACC). Connectivity to this region was specific to lesions causing akinetic mutism but not lesions causing loss of movement with intact volition (hemiparesis). Lesions causing akinetic mutism were significantly connected to the peak region identified in a meta-analysis of fMRI studies evaluating volition. Similarly, 93% of lesions causing alien limb were connected to the same location in the precuneus cortex. Again, connectivity to this region was specific when compared to a group of patients with involuntary movements but intact sense of agency (hemichorea). Lesions causing alien limb were also significantly connected to the peak region identified in a meta-analysis of fMRI studies evaluating sense of agency. Finally, we found that the precuneus and ACC regions identified in our analyses were part of a common functional brain network. Taken together, our results suggest a network localization for free will perception, lending insight into the neurobiology of this unique phenomenon.

Insulin-Dependent Diabetes Jennifer I. Merickel, Robin High, Lynette Smith, Emily Frankel, Kaitlin Smits, Andjela Drincic, Cyrus Desouza, Kazutoshi Ebe and Matthew Rizzo. Omaha, NE and Ann Arbor, MI Background: Our overarching goal is to measure real-time effects of neurocognitive dysfunction in safety-critical realworld tasks such as automobile driving. This study addresses effects of encephalopathy due to blood glucose (BG) changes in type 1 (T1) insulin-dependent diabetes (DM). DM drivers have elevated crash risk in association with repeated brain exposure to abnormal fluctuations in BG levels, low and high. Method: To tackle this safety critical neurocognitive problem, we recorded continuous data (4 weeks; 3,687 drives) from sensors installed in 35 drivers' own vehicles (19 DM; 16 without DM) and measured real-time BG levels in the DM drivers using continuous glucose monitoring (CGM). We tested the hypothesis that real-world DM driver risk is linked to at-risk BG levels (<70; >300 mg/dL). Results: DM drivers (1,940 drives) had atrisk BG 17.96% of total study time, elevating the risk of driving while impaired. DM drivers had at-risk BG 13% of time during driving (<70 mg/dL, 3.4%; >300 mg/dL, 9.6%), showing insufficient self-restriction. Driver risk in DM (based on vehicle accelerometer profiles) exceeded controls' even during euglycemia to moderate hyperglycemia (b 5 0.14, SE 5 0.04, p 5 <0.001). DM driver risk in impaired BG states (particularly hypoglycemia) exceeded control risk, particularly on high-speed roadways (b 5 0.01, SE 5 <0.01, p 5 <0.001). Individual DM driver behavior modeled as a function of BG mirrored across-group comparisons. DM drivers performed worse that controls in visual search and multi-tasking while driving (b 5 0.57, SE 5 0.3, p 5 0.05). State DMV records showed DM drivers accounted for all crashes (N 5 3) and 85% of citations (N 5 13) in the two years preceding the study. Results show that vehicle sensor and physiologic data can be successfully linked to quantify individual driver performance and behavior in drivers with metabolic disorders that affect brain function (encephalopathies). Discussion: Real-time BG is linked to momentary real-world changes in DM driver behavior. Behavior fluctuations and risk are driven by exposure to at-risk BG levels, particularly hypoglycemia, and neurocognitive dysfunction. Real-world sensor data coupled with phenotypes of driver behavior can inform patients, caregivers, interventions (education, training, medical), policy, and design of supportive in-vehicle technology responsive to driver's momentary neurocognitive state.

Mohammadhossein Alimardani, Alicia Parker, Leila Saadatpour, Usama Tariq, Laylo Mukshinova, Erham Somji and Kenneth M. Heilman. Gainesville, FL Background: The primary progressive aphasias (PPA) are clinical syndromes in which language capabilities become progressively impaired. The underlying, pathology are neurodegenerative diseases such as Alzheimer's disease or frontotemporal lobar degeneration. The three best-known variants of PPA include nonfluent/agrammatic, semantic, and logopenic PPA.

Significance: To describe a novel variant of PPA. Methods: A Case Report. Report: A 55-year-old right-handed woman with a history of migraines and hyperlipidemia presented to the Memory Disorders Clinic for evaluation of a 7-year gradual decline in her cognition. On history, she reported deficits related to her short-term memory. Neurological evaluation was remarkable for impairments of working memory and of repetition. Her speech was otherwise fluent, with intact comprehension and normal naming. Her score on the Boston Naming Test was 56 correct out of 60, which is within normal limits. Her lab work evaluation, including MRI, were normal except a mild B12 deficiency for which she is being treated.

Discussion: Unlike logopenic PPA this patient with impaired repetition, had no impairment in naming and to our knowledge this form or PPA has not been previously reported. Baddeley (1986) suggested that working memory has several components including an "articulatory loop" and a "central executive." Therefore, her repetition and working memory impairment may be related to posterior temporalinferior parietal dysfunction (articulatory loop) (Warrington and Shallice, 1969) or frontal dysfunction (central executive). Hopefully, the description of this variant of PPA may assist with clinical recognition and prompt further research in this new form of primary progressive aphasia.

Khurram A. Janjua, Kamran Kaveh, Mohamed Salah, Feras Shalabi, Mohammad Tasnim, Mohammad Dima and Alan R. Hirsch. Rodney Bay, Saint Lucia; Curacao, Netherlands Antilles; Kralendijk-Bonaire, Netherlands Antilles and Chicago, IL Introduction: Olfactory dysfunction and sniffing induced phantogeusia has not heretofore been described. Three patients noted, upon nasal insufflation, that they would detect an aroma, which was not actually present, followed immediately by the detection of a taste of the aroma. In all three, digital obstruction of the nares eliminated both the phantosmia and phantogeusia.

Methods: Case 1: A 28-year-old female presented after a traumatic brain injury followed by anosmia, phantosmia, dysgeusia, phantogeusia, and subjective hypogeusia. Inhalation would induce both a floral phantosmia and phantogeusia.

Results Case 2: A 54-year-old male after 6 weeks of treatment for septic arthritis with daptomycin and fluconazole, developed dysosmia, hyposmia, phantosmia, palinosmia, cacosmia, palinageusia, phantogeusia, cacogeusia, dysgeusia, and subjective hypogeusia. Nasal inhalation induced both a metallic phantosmia and phantogeusia.

Results: BSIT: 6 (A). Pocket Smell Identification Test (PSIT): 1/3 (A). OID: L57; R58 (A). OBT: L 0; R 4 (A). RSI: 0/9 (A). PTD: 10/10 (N) . Saline Infusion (no effect).

Case 3: A 59-year-old male metal worker with chronic exposure to paints and solvents presented with hyposmia, dysosmia, cacosmia, phantosmia, palinosmia, subjective hyperosmia, cacogeusia, palinageusia, phantogeusia, hypogeusia, and dysgeusia. Nasal inhalation induced both a chemical phantosmia and phantogeusia.

Results: Quick Smell Identification Test (QSIT): 3. PSIT: 3 (N) . AST: 23 (N) . OBT: L58; R53.5 (A).

OID: R520 (A); L518 (A). Sniff Magnitude Ratio 1.87 (A). Sniff N Sticks bilaterally: Discrimination 8 (A), Identification 6 (A), Threshold <1 (A). Odor Memory: 1 at 10 seconds, 0 at 30, 1 at 60, total 2 (A). Suprathreshold Amyl Acetate. Hedonic and Intensity: crossed pattern (A). Fungiform Papillae R522, L524 (N). RSI: 4 (A). Taste Quadrant Testing: decreased anterior tongue to all modalities bilaterally (A) and whole mouth weakness to NaCl (A). Taste Threshold Testing: Normogeusia to Phenylthiocarbamide, Urea, and Sucrose; Mild hypogeusia to NaCl and HCl. Saxon 4 gm (N) Astrocytes provide support to neurons during injury. We have previously shown that neurons contain the prothrombin (FII) gene and under stress will secrete the protein. We created neuronally targeted FII knockout mice under tamoxifen induction. We prepared conditioned media from neurons with or without FII KO during OGD, and applied the media to WT or PAR-1 KO astrocytes. Conditional knockout and wild type mice were subjected to MCAo to study the effect on astrocyte activation and infarct volume. Media from OGD neurons contains thrombin; the media stimulates astrocyte activation; such astrocyte activation can be reproduced with low doses of thrombin; and media-induced astrocyte activation is blocked by either thrombin inhibitor or by knocking down or knocking out PAR-1 from the astrocytes. In vivo, after neuronal FII knockout, MCAo induced infarction was significantly enlarged and correlated with reduction of astrocyte activation. Both activation and infarct reduction were partially restored by Lentivirus mediated prothrombin gene restoration into the KO mice. Our recent data powerfully confirm that thrombin constitutes a necessary and sufficient signal from neurons to activate adjacent astrocytes in a PAR-1 dependent manner, which appears to influence infarct volume. S135. Response to Modified Constrain-Induced Aphasia Therapy Protocol After Priming with iTBS Jerzy P. Szaflarski, Joseph Griffis, Jennifer Vannest, Jane B. Allendorfer, Rodolphe Nenert, Amber N. Martin, Victor Mark and Xiaohua Zhou. Birmingham, AL and Cincinnati, OH Constraint-induced aphasia therapy (CIAT) and neurostimulation studies (e.g., repetitive transcranial magnetic stimulation (rTMS) or intermittent theta burst stimulation (iTBS)) may be useful in treating chronic post-stroke aphasia. In this study, patients with chronic post-stroke aphasia received a course of CIAT after priming with iTBS applied to the affected hemisphere.

Twelve subjects with chronic post-stroke aphasia were enrolled (3 female) in CIAT group therapy (3-4 subjects/ session). All received 3T fMRI with block-design semanticdecision/tone-decision task 1-2 weeks before (T1) and 1-2 weeks after (T2) the interventions, and then 12-20 weeks after the interventions (T3). Subjects underwent 10 daily priming sessions of iTBS applied to the fMRI "hot spot" in the left fronto-temporal regions (ipsilateral to aphasia-producing stroke; 600 stimuli over 200 seconds using the previously established protocol. Neuropsychological assessments of language were obtained at the same time points as fMRI and included Western Aphasia Battery (WAB), Boston Naming Test (BNT), Semantic Fluency Test (SFT), and Controlled Oral Word Association Test (COWAT). Modified, ten 1-hour long sessions of CIAT were administered daily by skilled speech-language pathologists within one hour of the iTBS with patients receiving iTBS on a rotating schedule.

Neuropsychological assessments of language showed a significant effect of session on WAB aphasia quotient (p50.04). There was a significant effect of session for spontaneously corrected responses on BNT (p50.002) with improvement noted from T1 to T2 (p50.002) and from T1 to T3 (p50.05). Non-significant improvements were noted on SFT and COWAT. Comparison of fMRI data between timepoints showed significant changes between all timepoints indicating continued changes in language activation patterns after cessation of the interventions. Post-hoc correlations revealed that improvements in WAB from T2 to T3 were associated with less BOLD signal in the left inferior parietal lobe while improvements in BNT between T1 and T3 were associated with decreased signal in right inferior frontal gyrus.

This study indicates potential for combining behavioral and neurostimulation interventions into one protocol. Observed changes were small but significant clinically as documented with the neuropsychological testing. Further, neuroimaging changes corresponded to the observed improvements in linguistic abilities. These data support further development and testing of the combined CIAT and iTBS protocol and comparisons to either CIAT or iTBS applied alone for the treatment of post-stroke aphasia. Background: With increased utilization of imaging in clinical and research settings and improved imaging quality, incidental findings on brain MRI are commonly detected. However, the reported frequency of such findings is variable. This is especially true for incidentally-detected acute cerebral infarction (CI) . The objective of this study was to determine the frequency of incidental acute or subacute CI in a population-based study.

Methods: MRI scans with Diffusion Weighted Imaging (DWI) sequences (n53,230) were obtained from 2,095 participants in the population-based Mayo Clinic Study of Aging. Neuroradiologists reviewed the images for any abnormalities. The radiology reports were then queried for key words "acute" or "subacute""infarct", "stroke" or "ischemia" or "restricted diffusion." Data including participant demographics, vascular risk factors, medications, clinical symptoms, and neurological examination of each participant at the time of the CI were abstracted from the comprehensive medical record. The etiologic mechanism for the CI was determined.

Results: Nine acute or subacute CIs were identified with a frequency of 0.28% among individual MRI scans and 0.43% among unique individuals. Of these nine CIs, six were acute and three were subacute. The majority of the participants were male (78%) with a mean age of 76.9 (SD: 66.74). All were asymptomatic at the time of CI. Hypertension and hyperlipidemia were each present in seven participants. Two had type 2 diabetes mellitus, and two had atrial fibrillation. Two had a history of smoking. Six participants were on an antithrombotic medication at the time of the scan. Mechanism of CI was small vessel disease in 6 patients, cardioembolic in 2 patients, and cryptogenic in 1 patient.

Conclusion: Acute and subacute cerebral infarcts occur as incidental findings in approximately 1 in 200 people, particularly in elderly males with vascular risk factors. As brain MRI becomes more widely used in clinical practice and research, incidentally found acute or subacute infarcts will provide an opportunity to address and improve secondary stroke prevention. S138. Transient Aphemia in a Patient with Progression of Symptoms from an Evolving Infarct Derrick A. Fox, YongXing Zhou, Roger L. Weir and Annapurni J. Trouth. Washington, DC Aphemia is a speech disorder characterized by difficulty with speech articulation with retained ability to write language. Also termed apraxia of speech (AOS), aphemia is easily confused with Broca's aphasia until language assessment renders the ability to communicate through writing. Patients with aphemia are rare in part because the blood supply of the affected area is the middle cerebral artery (MCA), which also supplies the left inferior frontal gyrus, significant for Broca's region of the brain. AOS has been shown to have anatomical correlation to the left precentral gyrus (Ogar, Brain and Language, 2006) . It is rare to see an isolated aphemia case previously only shown in several case reports. A review of the literature revealed three cases with transient episodes that improved significantly (Feng, Clinical Neurology and Neurosurgery, 2015; Ottomeyer, Journal of Neurology, 2008; Fox, Clinical Neurology and Neurosurgery, 2001; Ojha, Neurology India, 2011 ). An extensive literature review of case reports documented only one notable presentation of persistent AOS (Ojha, Neurology India, 2011) . A 72-year-old male with transient and fluctuating onset of aphemia for seven days before he presented to our hospital. Nine days after his hospital presentation his symptoms progressed to Broca's aphasia, accompanied by right hemiparesis and dysphagia. He was initially found to have infarctions of the left precentral and postcentral gyrus on MRI. Interestingly, serial imaging revealed an evolving large infarction, now expanding to the left inferior frontal gyrus. Work-up during hospitalization revealed occlusion of left M1 to M2 segments of the MCA on head and neck MRA. Cardiac tests including telemetry monitoring, electrocardiogram and echocardiogram were negative for embolic source to date. Prior to the infarct, the patient was not taking aspirin. Dehydration and hypernatremia could have played a role in the evolution of the infarction as the patient was eating and drinking less during the subacute period of his stroke yielding a lower mean arterial pressure. The patient's relatively decreased perfusion even beyond the permissive hypertension window may have caused enhancement of the anatomical territory affected by the stroke. The patient's symptoms plateaued and he was started on cardiac event monitor. He was started on aspirin, high dose statin, oral hypoglycemic agent and his anti-hypertension medication regimen was reoptimized allowing for more liberal control of systolic blood pressure below 140.

Peter Jin, Ivan Matos, Laura Stein, Alison Thaler, Stanley Tuhrim and Mandip S. Dhamoon. New York, NY Background: In older adults with stroke, there is an increased risk of cardiovascular events in the intermediate period, up to 1 year after stroke. Risk of cardiovascular events in this period in young adults has not yet been studied. We hypothesized that in the intermediate risk period, young adults with ischemic stroke have an increased risk of recurrent stroke and a smaller increase of cardiac events. We also examined common vascular risk factors and their effect on risk of recurrent stroke and cardiac events in young adults.

Methods: The Nationwide Readmissions Database is a national database of readmissions for all payers and the uninsured with data on >14 million U.S. admissions during the year 2013. We identified ischemic stroke admissions among those aged 18-45 years using International Classification of Disease, Ninth Revision, Clinical Modification codes to identify index vascular events and risk factors. Primary outcomes were readmission for cardiac events and recurrent ischemic or hemorrhagic stroke. Multivariable Cox proportional hazard models and Kaplan-Meier analysis estimated risk of primary outcomes stratified by vascular risk factors.

Results: We identified 12812 young adults with index stroke. The readmission rate due to recurrent stroke was higher than for cardiac events (3039.1 vs 1116 per 100,000 index hospitalizations at 90 days). Kaplan-Meier analysis of all available follow-up data found that the cumulative risk of hospitalization for recurrent stroke was persistently higher compared to risk of cardiac events: 0.034 vs 0.025, respectively, at 100 days, 0.045 vs 0.032 at 200 days, and 0.057 vs 0.039 at 300 days. There was a higher cumulative risk of cardiac events in the presence of baseline diabetes, hypercholesterolemia, and atrial fibrillation. There was a higher cumulative risk of recurrent stroke in the presence of diabetes and hypercholesterolemia.

Conclusion: In a large, nationally representative database, the intermediate risk of recurrent stroke after index stroke in young adults was higher than the risk of cardiac events. The presence of vascular risk factors augmented this risk but did not entirely account for it. The aggressive control of hypercholesterolemia and diabetes may play an important role in secondary prevention in young adults with stroke.

Atherosclerotic Stroke Natasha Shroff, Bradley P. Ander, Boryana Stamova, Glen C. Jickling and Frank R. Sharp. Sacramento, CA Background: HDAC9 polymorphisms rs2107595 and rs11984041 are associated with large vessel atherosclerotic stroke. HDAC9 regulates gene expression and is expressed in circulating leukocytes that are involved in atherosclerosis. In this study, we sought to determine whether HDAC9 single nucleotide polymorphisms (SNPs) rs2107595 or rs11984041 influence gene expression in circulating leukocytes of patients with large vessel atherosclerotic stroke (LVAS).

Methods: In 155 patients (43 LVAS and 112 vascular risk factor control) HDAC9 was genotyped for SNPs rs2107595 and rs11984041. RNA was isolated from whole blood and gene expression differences between SNP positive and SNP negative LVAS patients identified using human transcriptome microarrays. Pathway analysis was performed for each SNP to identify canonical pathways and molecular functions associated with HDAC9 SNPs in LVAS.

Results: In rs2107595 SNP positive LVAS patients there were 155 genes differentially expressed compared to SNP negative patients (Fold Change >|1.2|, p<0.05). Over represented pathways corresponded to IL6 signaling, cholesterol efflux and platelet aggregation. In rs11984041 SNP positive LVAS patients there were 419 genes differentially expressed genes compared to SNP negative patients (FC > |1.2|, p<0.05). Over represented pathways included NF-jB signaling, T cell response and macrophage activation.

Conclusions: This study indicates polymorphisms in HDAC9 are associated with differences in circulating leukocyte gene expression in patients with LVAS. The risk alleles at these HDAC9 SNPs may affect biological functions in peripheral immune cells involved in atherosclerosis, plaque stability and inflammation. S142. Partial Loss of Autophosphorylation of CSF1R in a Patient with Familial Ischemic Cerebrovascular Syndrome Takuya Konno, Andrea M. Harriott, Takeshi Miura, Naomi Mezaki, Emily S. Edwards, Owen A. Ross, James F. Meschia, Takeshi Ikeuchi and Zbigniew K. Wszolek. Jacksonville, FL and Niigata, Japan

Background: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutation in CSF1R. It is a common but frequently misdiagnosed form of adult-onset leukoencephalopathy. In vitro, complete loss of autophosphorylation has been observed in mutant CSF1R. Brain MRI studies demonstrate white matter lesions with restricted diffusion. Although rare, stroke-like episodes have been observed in patients with ALSP.

Methods: We sequenced CSF1R exons 12-22 encoding tyrosine kinase domain and flanking intronic sequences in 123 patients with definite acute ischemic cerebrovascular syndrome and positive family history of stroke. To assess the pathogenicity of newly identified variants, we conducted in silico analysis and function assay. Mutant CSF1R constructs were generated. We transfected wild-type and the mutant CSF1Rs into HEK293 cells and analyzed the levels of autophosphorylation of CSF1Rs in two different culture conditions: 1) standard media with 10% fetal bovine serum (FBS), 2) standard media with treatment with ligands (CSF1 or IL-34) in the absence of FBS. Cell lysates were subject to immunoblot analysis using antibodies including C-20 to detect total CSF1R and phospho-specific antibodies (Tyr546, Tyr708, Tyr723, and Tyr923). The levels of autophosphorylation were compared between wild-type and mutant CSF1Rs.

Results: We identified 8 CSF1R variants in our cohort of 123 patients. Six of them were known non-pathogenic polymorphisms. Other two were newly identified missense variants (p.Glu573Lys and p.Gly747Arg). Each of them was identified in a single patient. p.Glu573Lys was predicted by in silico analysis to be probably damaging and p.Gly747Arg was benign. Functional assay revealed that levels of autophosphorylation of p.Gly747Arg were comparable to those of wild-type in both media conditions, while those of p.Glu573Lys were significantly decreased compared with those of wild-type but phosphorylation was still detected. The clinical presentation of the patient with CSF1R p.Glu573Lys was consistent with cerebral embolism. However, periventricular white matter abnormalities unrelated to the recent infarct were evident on brain MRI. The patient had the vascular risk factors but did not have any other findings suggestive of ALSP.

Conclusions: In contrast to ALSP-associated mutations, CSF1R p.Glu573Lys variant showed partial loss of autophosphorylation of CSF1R suggesting that p.Glu573Lys may affect the clinical phenotype of variant carriers. Further investigation would be warranted to elucidate the significance of partial loss of autophosphorylation of CSF1R. At this juncture, we are also collecting clinical data on proband's family with p.Glu573Lys variant. Over 100,000 carotid revascularization procedures are done annually in the US for asymptomatic carotid arterial stenosis. The safety of carotid endarterectomy (CEA) and carotid stenting (CAS), and the efficacy of medical therapy in altering the progression of atherosclerosis have improved. Therefore, the applicability of prior randomized trials in asymptomatic carotid stenosis to current treatment decisions has been called into question. The aim of the NINDSfunded CREST-2 is to compare CEA and intensive medical therapy (IMT) versus IMT alone (n51240), and CAS and IMT versus IMT alone (n51240), through two parallel randomized clinical trials. CREST-2 is leveraging the NINDS clinical trials network known as StrokeNet (University of Cincinnati, Coordinating Center). The composite primary outcome is any stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter up to 4 years. Secondary outcomes include cognitive function, which is assessed on a regular schedule through computer-assisted telephone interview. IMT is directed centrally and includes tight control of blood pressure (systolic target < 140 mm Hg) and cholesterol (LDL target < 70 mg/dl) as well as lifestyle coaching. As of March 27, 2017, the Site Selection Committee has approved 131 sites, of which 100 (76%) have enrolled at least one patient. The Surgical and Interventional Management Committees have credentialed 342 surgeons and 143 interventionists. An additional 117 interventionists have been approved to submit additional cases via the CREST-2 Companion Registry, providing a CMSreimbursed pathway for full credentialing in CREST-2. Social media tools are being used to inform potential participants about the trial. 543 patients have been randomized, 250 (46%) patients in the endarterectomy trial, and 293 (54%) patients in the stent trial. In addition to continued recruitment and ongoing follow-up, a major goal this year is roll-out of an MRI-based substudy known as CREST-H (Randy Marshall, MD, Columbia University, Study PI), with a primary aim being the study of the cognitive effects of revascularization in patients with hemispheric hypoperfusion.

Lewis Morgenstern, Chengwei Li, Darin Zahuranec, Erin Case, Brisa Sanchez, Devin Brown and Lynda Lisabeth. Ann Arbor, MI Background and objective: Mexican Americans (MAs) have higher stroke incidence and recurrence and worse functional and neurologic outcome compared with non Hispanic whites (NHWs). In a population-based study we examined 3, 6 and 12 month cognitive outcome following stroke in MAs and NHWs.

Methods: All stroke patients from October, 2014 -January, 2016 were ascertained as part of the Brain Attack Surveillance in Corpus Christi (BASIC) project. Cases were validated using source documentation. Descriptive statistics were calculated for demographics and risk factors overall and by ethnicity, and differences were assessed using Chisquared and Kruskal-Wallis tests for categorical and continuous variables, respectively. Ethnic differences in cognitive outcome (Modified Mini-Mental State Examination (3MSE): range 0-100 with lower score worse) at 3, 6 and 12 month were assessed with linear mixed effects regression models adjusting for: (1) age and sex; (2) Model 1 1 prestroke cognition (IQCODE); (3) Model 2 1 insurance status; (4) Model 3 1 diabetes and comorbidity index; (5) Model 4 1 initial NIHSS.

Results: Among the 576 subjects followed, 315, 244 and 227 subjects fully completed 3, 6 and 12 month assessments, respectively. There were no significant ethnic differences at baseline in sex, tobacco use, hypertension, alcohol use, cholesterol, heart disease, previous stroke, NIHSS, insurance status, IQCODE or comorbidity index. MAs were younger (median age 66 vs. 70, p50.018), had more diabetes (54% vs. 36%), p<0.001, and less atrial fibrillation 13% vs. 20%, p50.025) than NHWs. At 12 months, MAs median 3MSE was 86 (IQR 73-93) and 92 for NHWs . In unadjusted analyses MAs scored 5.56 (95% CI 2.67, 8.44) points worse on the 3MSE than NHWs, P<0.001. The disparity increased with adjustment: Model (1) 6.88 (95% CI 4.15, 9.60) ; Model (2) 7.04 (95% CI 4.09, 9.99); Model (3) 7.04 (95% CI 4.06, 10.02); Model (4) 7.11 (95% CI 4.10, 10.11); Model (5) 6.73 (95% CI 3.88, 9.57); all p<0.001. The disparity did not change over the three time points, P>0.2.

Conclusions: This population-based study found a highly significant, worse cognitive outcome following stroke in MAs compared with NHWs even after adjusting for age, sex, pre-stroke cognition, insurance status, comorbidities and initial stroke severity. Further study is needed to reduce the stroke impact in MAs, the largest minority population in the U.S. S145. Midbrain-Pontine Junction Cavernous Angioma with Interval Hemorrhage and Development of Unilateral Hypertrophic Olivary Degeneration Jared S. Rosenblum, Matthew A. Nazari, Yasir Al-Khalili and Erol Veznedaroglu. Philadelphia, PA Several cases of Hypertrophic olivary degeneration (HOD) have been reported, none directly following interval bleed of a stable midbrain-pontine cavernous angioma (CA). HOD is a rare phenomenon in the dento-rubro-olivary pathway first described by Oppenheim in 1887. It is a an uncommon condition and creates unique diagnostic, observational, and therapeutic challenges. We report a case of development of unilateral HOD with interval hemorrhage of a midbrainpontine junction cavernous angioma, summarize the literature on HOD, suggest a possible mechanism and comment on the management of the CAs in light of HOD. A 57year-old female with multiple known CA in the frontal-, parietal-lobe, and midbrain and occipital approach VP shunt for hydrocephalus and history of ruptured and clipped aneurysm, presents 10 months from last follow up with gait instability, ataxia, headache, blurred vision and dysarthria. CT scan of the head showed the known CA without significant change as compared to prior studies. MRI of the brain showed a well-defined lobulated lesion in the left parasagittal midbrain and superior pons with characteristic mulberry appearance. The lesion demonstrated heterogeneous appearance with T1-and T2-hyperintensity centrally with thin margin of T2/GRE hypointensity peripherally, similar to studies 10 months prior. The CA decreased in size from 17 x 15 x 22 mm 10 months prior, to 11 x 10 x 13 mm at present. There was interval development of a 7mm round T2 hyperintense focus within an enlarged left lateral superior medulla. The two additional CAs-in the frontal and parietal lobes-were noted to be stable since prior studies which indicates a familial pattern. Despite the presence of the midbrain-pontine junction CA in our patient on previous imaging, HOD was not present and the patient was asymptomatic. Progressive neurological deterioration followed apparent interval bleed of the CA evinced by reduced size of the CA, surrounding GRE sensitive blood product, and 7mm round T2 hyperintense focus within a slightly enlarged left lateral superior medulla consistent with HOD. While the appearance of HOD has been reported in the literature following resection of midbrain and pontine cavernous angiomas, this is the first report to our knowledge of interval bleed directly leading to the development of HOD. The development of HOD may represent a compelling benchmark for resection of midbrainpontine CAs considering that it is a reported complication of resection.

After Non-Disabling Stroke Daniel Vaclavik, David Skoloudik and Tana Fadrna. Ostrava, Czech Republic and Olomouc, Czech Republic Background: Quality of life (QoL) is one of the main endpoints of stroke treatment studies. Objective: The study aimed to assess QoL of self-sufficient post-stroke patients with carotid stenosis compared to control group.

Material and methods: Self-sufficient patients with carotid stenosis, aged 50-80 years, without severe disease during last 12 months, without dementia or psychiatric disease including depression were included to the study after signing the Informed consent. Patients with a history of stroke were allocated to the Group A, stroke-free patients were allocated to the control Group B. All patients filled in 2 standardized QoL questionnaires (WHOQOL-BREF, EQ-5D-3L), visual pain scale, provided anamnestic data (medication, education, social situation), and blood pressure and body mass index (BMI) were recorded. Categorical variables were compared by Fisher's exact test, continuous variables by Mann-Whitney test. Logistic regression was used to identify factors affecting the individual domains of QoL questionnaires.

Results: Totally 502 out of 584 consecutive patients met all inclusion criteria. Out of them, 344 patients filled in both QoL questionnaires completely -145 post-stroke patients in Group A (78 males, aged 70.4 6 7.0 years), 199 control group patients in Group B (86 males, aged 68.9 6 8.3 years). Post-stroke patients did not differ from patients in control group in any domain of WHOQOL-BREF questionnaire -physical health (p50.09), psychological status (p50.45), social relationships (p50.34), environment (p50.45); in QoL evaluation (p50.16), present health status (p50,57), health status satisfaction (p50.44), mobility (p50.22), self-service (p50.07), activities of daily living (p50.23), pain (p50.53) nor anxiety (p50.63). An independent predictor of worse QoL in all domains was pain. Independent factors decreasing the QoL were blood pressure in the physical health domain, female gender in the psychological domain, and male gender in the social relationships domain. Independent factors decreasing satisfaction with health status were female gender, lower education level, and higher blood pressure. Factors negatively influencing the satisfaction with the QoL were living alone, lower education level, and higher blood pressure. Factors negatively influencing mobility were age, male gender, living alone, lower education level, and higher BMI (p<0.05 in all cases).

Conclusions: Non-disabling stroke has no negative effect on QoL. Pain, blood pressure, BMI, education, living with a partner, gender, and age were identified as the independent factors influencing the QoL in patients with carotid stenosis.

Supported by the Ministry of Health of the Czech Republic grant No. 17-31016A. S147. Machine Learning Approach to Automating Detection of Cerebral Vasospasm Using Transcranial Doppler Monitoring Gyanendra Kumar and Arie Nakhmani. Phoenix, AZ and Birmingham, AL Objective: To develop an algorithm for detection of cerebral vasospasm (CV) based on transcranial Doppler (TCD) audio signal.

Background: Patients with aneurysmal hemorrhage (SAH) often develop CV which leads to cerebral ischemia and poor outcomes. TCD can not only effectively detect CV but TCD-CV is also a predictor of delayed cerebral ischemia. TCD is unable to be utilized as a continuous "vasospasm monitor" due to lack of automation. To circumvent this barrier, we developed an algorithm for automatic CV detection using signal analysis and machine learning techniques that will allow continuous TCD monitoring with automatic detection of and alarming for CV.

Methods: We used TCD audio signals from 267 arterial segments of SAH patients from an IRB approved prospective SAH registry. The Doppler audio files, obtained as short sequences of 3-15 seconds, were evaluated by the developed classification algorithm for automatic detection of CV and compared to the Neurologist's pre-existing diagnosis. This supervised learning algorithm for classification was implemented in Matlab and used signal features such as zero crossing density, spectral centroid, and median of Welch spectrum estimator. The cross-validation was used for training a classifier. The data were partitioned into 5 subsets. One subset was used for validation and others for training. Then this procedure was repeated with other subsets a few times to prevent overfitting. The data were classified into two different categories: Normal and CV.

Results: A total of 267 files were evaluated using the proposed classifier. The data classification into two categories yielded 92% accuracy. The sensitivity for vasospasm was 96% and the specificity was 63%. PPV was 90% and NPV was 82%.

Conclusions: Novel algorithm for CV detection, based on audio signal analysis of TCD spectra, was developed using supervised machine learning. Our autonomous CV detector demonstrated a high success rate. S148. Cerebral Microvasculopathy Associated with a De Novo FOXP3 Mutation Alfonso S. Lopez Chiriboga, Jennifer Gass, Paldeep Atwal, Dennis W. Dickson and James Meschia. Jacksonville, FL Introduction: Immunodysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome2 is an X-linked immunologic disorder of the childhood caused by mutations in the FOXP3 gene. We describe the clinical, radiographic, and pathologic features of an adult patient with a small vessel ischemic stroke who has a de novo mutation in the FOXP3 gene that may be related to pathogenesis.

Case: A 37-year-old man with a history of attention deficit hyperactivity disorder sustained a motor vehicle accident. Because of reported blurry vision and dizziness following the accident, he underwent a head CT revealing no contusion or hemorrhage but showed a frontal hypodensity (Figure 1 A). Brain MRI revealed T2 FLAIR hyperinitensities in the right frontotemporal lobes,associated with multifocal hemorrhage in the same distribution (Figure 1 B) and punctate enhancement. His neurological examination was normal. A biopsy of the lesion showed perivascular lymphohistiocytic inflammation with normal cerebral gray and white matter and an unremarkable dura. Parenchymal and meningeal vessels had microvascular pathology with increased CD68-positive histiocytes, sparse B-lymphocytes and small lymphocytes with no evidence of necrotizing or granulomatous vasculitis. (Figure 2 ) Digital subtraction angiography showed no evidence of large-vessel vasculitis. CSF analysis was unremarkable.

A comprehensive stroke evaluation including catheter angiography was negative. PETCT revealed a hypermetabolic right cervical lymph node (Figure 1 H) that was excised, and pathologic analysis was consistent with normal lymphoid tissue with no evidence of malignancy. Biopsied brain showed no evidence of amyloid angiopathy, however diffuse pre-amyloid A-beta deposits were noted in cortex. Whole exome sequencing analysis did not show abnormalities in APOE, but did show a de novo frameshift (p.C199X) mutation in FOXP3. He was noted to be a mosaic in blood. At 6 month follow-up, he has experienced intermittent episodes of headache but his neurologic clinical status continues to be stable.

Discussion: IPEX syndrome is a primary immunodeficiency caused by mutations in the FOXP3 gene, which codes a transcription factor crucial for maintenance of thymus-derived regulatory T cells, T-cell dysfunction leads to multi-organ autoimmunity. In our case, besides the lymphadenopathy and inflammatory arteriopathy, the patient has no clinical features consistent with autoimmunity. We speculate that his mosaic genotype resulted in a milder phenotype.

Conclusion: This case adds vasculitis to the IPEX phenotype and illustrates the importance of genetic evaluation for atypical young stroke. S149. Incidence of Ischemic and Hemorrhagic Stroke Amongst Asians in the United States Antonio Moya, Babak Navi, Hooman Kamel and Santosh Murthy. New York, NY Background: Studies on stroke epidemiology from Asia suggest that the overall proportion of hemorrhagic stroke is much higher compared to other parts of the world, presumably due to underlying genetic factors. We sought to evaluate the incidence of ischemic and hemorrhagic strokes in Asians versus other ethnicities in a large nationally representative sample.

Methods: We identified all adult patients with acute ischemic and hemorrhagic strokes in the Nationwide Inpatient Sample from 2002-2011, using well-validated International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Our predictor variable was Asian patients with stroke. Our primary outcome was incidence of ischemic and hemorrhagic strokes. Survey weights were used to account for the sampling methodology. Trend analysis was then performed using the Chi square test for linear association.

Results: We included 4,449,516 patients in the U.S. with stroke, of whom 3,794,438 (85.3%) had ischemic stroke, and 655,078 (14.7%) had hemorrhagic stroke. Of these patients, 98,964 (2.2%) were Asians. Amongst stroke patients, Asians had a higher proportion of hemorrhagic strokes compared to the general population (24.0% vs. 14.5%, p<0.001). Asian patients were more likely to have stroke risk factors such as diabetes mellitus (28.8% vs. 23.7%, p<0.001) and hypertension (82.4% vs. 75.1%, p<0.001) compared to other ethnicities. Conversely, atrial fibrillation was less common in Asians (14.8% vs. 19%, p<0.001). There were no significant trends in the incidence of stroke subtypes amongst different ethnicities over the past decade.

Conclusions: The incidence of hemorrhagic strokes appears to be higher amongst Asians compared to other ethnicities in the U.S. Further study is warranted to delineate the role of genetic versus stroke risk factors that influence stroke incidence amongst Asians living in the US. Daniel Vaclavik, Tomas Hrbac, David Skoloudik, David Otahal and Tana Fadrna. Ostrava, Czech Republic and Olomouc, Czech Republic Background: Nerve injuries, wound complications and poor cosmetic results still have an important impact on patient's outcome after carotid endarterectomy (CEA).

Objective: The study aimed to compare 30-day morbidity and cosmetic outcome between patients undergoing CEA using short longitudinal incision (SLI) and transverse skin incision (TSI).

Methods: All consecutive patients with ICA stenosis >70% indicated for CEA were screened in this monocenter prospective study and randomly allocated to SLI or TSI group. Physical and neurological examinations were performed 30 and 90 days after surgery. Cosmetic results were evaluated using the Patient and Observer Scar Assessment Scale (POSAS) 90 days after surgery. Categorical variables were compared by Fisher's exact test, continuous variables by Mann-Whitney test.

Results: Out of 189 enrolled patients, SLI was used in 102 patients (71 males; mean age 64.0 6 7.1 years) and TSI in 87 patients (58 males; mean age 66.4 6 7.2 years). Stroke or transient ischemic attack occurred during 30 days in 4 (3.9%) patients in SLI group and in 2 (2.3%) patients in TSI group (P 5 0.689). The scar quality assessed using POSAS was higher in TSI than in SLI patients (12.4 vs. 16.6 points; P < 0.01). Patients in TSI group evaluated better than SLI patients the pigmentation (1.6 vs. 2.2 points; P < 0.01), thickness (2.2 vs. 3.3 points; P < 0.01), relief (2.2 vs. 3.1 points; P < 0.01), pliability (2.3 vs. 3.1 points; P < 0.01) and surface area (2.1 vs. 2.5 points; P < 0.01) of the scar, resp. No significant differences were found in the occurrence of local complications (8.0% in TSI and 8.8% in SLI group; P 5 1.00).

Conclusion: Better cosmetic results were observed in patients after CEA using TSI than SLI. No differences in morbidity and in the occurrence of local complications were observed.

Supported by the Ministry of Health of the Czech Republic grant No. 17-31016A. S152. Resolution of Occlusive Carotid Artery Thrombus Treated with Anticoagulation, as Demonstrated on Duplex Ultrasonography Laura K. Stein, John W. Liang, Deborah Horowitz and Jesse Weinberger. New York, NY and Philadelphia, PA Background: While the majority of cerebral ischemic events due to carotid occlusive disease result from atherosclerotic plaque rupture, intraluminal carotid artery thrombus occasionally occurs in patients without preexisting carotid atherosclerosis. Identification of nonatherosclerotic thrombus as the cause of the carotid occlusive disease can obviate the need for an interventional procedure, and resolution of thrombus can be monitored with B-mode duplex ultrasonography.

Methods: We reviewed three patients treated on The Mount Sinai Hospital Stroke Unit with anticoagulation for nonatherosclerotic carotid thrombi and followed with serial doppler ultrasonogrpahy.

Results: Two patients presented after resolution of transient symptoms and one presented with established infarct on computed tomography (CT). In each case, duplex ultrasound identified the acute thrombus as a low-density structure reflecting the ultrasound beam with an attachment site but no underlying plaque. The low density subacute thrombus became progressively narrower with systemic anticoagulation. This transition from the acute to the subacute thrombus, and then the gradual resolution of the thrombus, was consistent in each case presented.

Conclusion: Differentiation between a stenotic plaque and occlusive thrombus can be achieved by ultrasonographic analysis of thrombus morphology, attachment site potential, and characteristics of a resolving thrombus. Systemic anticoagulation may safely and effectively eliminate the risk for future embolization and complete occlusion of the carotid artery in patients who present with transient ischemic events or completed infarcts of small size. Our ability to demonstrate resolution of occlusive carotid thrombus on duplex ultrasonography supports a non-interventional approach utilizing systemic anticoagulation to managing more patients with carotid thrombi without underlying arteriopathy. Duplex ultrasound is a safe, effective, and rapid method to identify, follow, and guide therapy for intraluminal carotid clot. S153. Analysis of Baseline Characteristics and Readmissions After Cerebral Venous Sinus Thrombosis in a Nationally Representative Database Yaowaree L. Leavell, Mian Khalid, Tuhrim Stanley and Dhamoon Mandip. New York, NY Background: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke with serious complications including seizure, hemorrhage, and death. Epidemiologic data is scarce, with the largest multi-center international studies yielding <1,000 cases for analysis. We take a novel approach to characterizing CVST by using the National Readmissions Database to capture index admissions data and readmission rates for conditions associated with CVST.

Methods: A thorough literature search revealed 2/58 articles describing International Classification of Diseases Clinical Modification-9 (ICD-9) code usage, which we expanded upon to build an ICD-9 library for relevant conditions. We used ICD-9 codes 671.5X, 437.6, 325.00 to identify all patients admitted with CVST during the year 2013. Baseline characteristics, including comorbid conditions, demographics, household income, and All Patient Refined Diagnosis Related Group (APRDRG) risk of mortality and illness severity were obtained. We calculated 30-, 60-, and 90-day readmission rates (per 100,000 index hospitalizations) for various neurological complications. Multivariable Poisson regression was used to calculate rate ratios (RR) of associations between index admission variables and all-cause readmission rates up to 1 year.

Results: Among 1817 patients with index admission for CVST, mean age was 49.6 (SD 18.2) years; 60% were female, and <1% were pregnant, substantially lower than previous study populations. Concurrent hemorrhagic stroke (17.5%) was more common than ischemic stroke (12%), concurrent seizure occurred in 18%, and 4.3% of patients died during index hospitalization. 90-day readmission rate (per 100,000 index CVST hospitalizations) was highest for CVST (1311) and ischemic stroke (874). Using Poisson regression, diabetes (RR 1.11, 95%CI 1.003-1.23), APRDRG risk of mortality (RR 1.17, 95%CI 1.05-1.31 for level 4 vs. 1), APRDRG severity (RR 0.85, 95%CI 0.77-0.94 for level 2 vs. 4), and discharge disposition (RR 0.87, 95%CI 0.80-0.94 for discharge home from index hospitalization vs. other destination) were associated with readmission rate.

Conclusions: We provide nationally representative data of baseline characteristics and readmission rates after CVST over a 1-year period. Mortality rate and association with pregnancy were lower than previously observed. Ischemic and hemorrhagic stroke and seizure commonly co-occurred with CVST. Several factors were independently associated with increased readmission rate. Our results suggest interesting differences in previously understood CVST risk factors and complications, perhaps related to different methods of data acquisition.

Nilesh H. Pawar, Preeti Malik and Farhad F. Vasanwala. Singapore, Singapore and New York, NY Objective: Case presentation of a patient with worsening Chronic Kidney Disease (CKD) after starting on warfarin regimen for stroke prevention with labile International Normalised Ratio (INR).

Background: Atrial fibrillation (AF) is the most commonly sustained arrhythmia. Warfarin is used in the patients with AF to prevent stroke. Patients with non-valvular AF and a history of stroke, transient ischemic attack or CHA2DS2-VASc score of 2 or greater should be treated with warfarin or novel oral anticoagulant (NOAC). Warfarin is an oral anticoagulant of choice in non-valvular AF with normal renal function, but may not necessarily be the case for a patient with significant renal impairment. Warfarinrelated nephropathy (WRN), reported recently, is associated with increased all-cause mortality and worsening of renal function leading to progression of CKD and can occur in patients with or without CKD.

Case Presentation: A 77-year-old Chinese female with CKD stage 4-5, on a background of diabetes, hypertension and cardioembolic stroke, who was initiated on warfarin for AF a month ago, was admitted for warfarin Coagulopathy, with an INR of 6.02. Patient complained of generalized itchiness and tiredness. She had bi-basal crepitations and pedal oedema, laboratory investigations showed worsening of renal function. Due to fluctuating INR and drug to drug interaction her warfarin dose was not titrated well. It was noted that her renal function worsened after starting on warfarin. Options of NOAC were explored but was not initiated due to significant renal impairment. Finally, a decision was made to switch to aspirin.

Discussion: Aspirin can be considered over warfarin in the treatment of non-valvular AF in elderly patients with significant renal impairment and at risk of dialysis. Physicians should be familiar with WRN and should monitor renal function and INR in patients on warfarin treatment. Physicians can also consider using aspirin over warfarin for patients with similar clinical circumstances as a safe option. We also would like to highlight that more studies need to be done on the antithrombotic of choice for preventing stroke in patients with AF and CKD stages 4 to 5. S155. Aortic Stenosis: From a Neurological Perspective Tasneem F. Hasan, Hunaid Hasan, Peter N. Starr and Adham S. Kamel. Galveston, TX Objective: To explore the neurological manifestations of aortic stenosis.

Background: As modern medicine evolves into a highly system based approach, we as neurologists, when consulted, are likely to make the central nervous system (CNS) our primary focus. Consequently, other system issues can be overlooked. Our case demonstrates the importance in approaching any neurological consult holistically. Understanding the primary process is crucial in the management of any patient. In our patient, identifying aortic stenosis (AS) as the primary cause for CNS dysfunction is pivotal in the approach to long-term management.

Methods: Case report.

Results: Eighty-one year old female with known past medical history of coronary artery disease (CAD), atrial fibrillation (Afib), and critical AS (echocardiogram: valve area 0.5cm 2 , mean valve gradient 15.2mmHg, left atrium moderately dilated, index volume 42ml/m 2 ), presented for syncope. Patient had multiple previous admissions for syncope. Varying diagnoses including epilepsy (without correlating EEG) were given. Anti-epileptics were started. Workup for atypical chest pain was negative. During current admission, CT and MRI brain demonstrated worsening bilateral hypodensities in the occipito-parietal watershed region and acute on chronic bilateral parieto-occipital infarcts and cortical laminar necrosis, respectively. After careful history-taking, history of rheumatic fever (RF) at age eight, overlooked during prior admissions, was revealed. Consequently, patient demonstrated cardinal symptoms of rheumatic heart disease, including AS. Consultation for aortic valve replacement (AVR) and blood pressure optimization was recommended. However, cardiothoracic surgery deemed patient to be poor surgical candidate for AVR. Patient was medically managed for CAD and discharged home.

Conclusion: Although AS has widespread CNS effects, they have been scarcely reported in literature. In our patient, AS may be the underlying cause for Afib, CAD, atypical chest pain, cerebral hypoperfusion, and watershed infarcts.

Moreover, AS can have direct and indirect CNS effects. Direct effects cause cerebral hypoperfusion, leading to CNS ischemia, thereby evolving into watershed infarcts. Coronary hypoperfusion causing coronary ischemia, reduces cardiac output, further exacerbating cerebral ischemia. Worsening AS leads to left atrium dilatation, resulting in Afib and subsequent embolization to the CNS. Moreover, literature has reported an acquired form of von Willebrand Syndrome in AS patients which indirectly has cerebrovascular effects. Gastrointestinal arteriovenous malformations (AVMs) have been reported in AS patients, but no cerebral AVMs. Thus, considering the utility of cerebral angiograms to assess cerebral AVMs in AS patients is crucial. Finally, this case highlights the utmost importance in holistic evaluation of primary process and its associated manifestations. S158. "Reversible Cerebral Vasoconstriction Syndrome (RCVS) Triggered by Aseptic Meningitis" Neel Fotedar, Yogesh Gujrati and Michael DeGeorgia.

Objective: To report a rare case of Reversible Cerebral Vasoconstriction Syndrome (RCVS) triggered by aseptic meningitis.

Background: RCVS is characterized by severe headaches, with or without acute neurological symptoms, and diffuse segmental constriction of cerebral arteries that resolve spontaneously within 3 months. CSF pleocytosis is generally not seen in RCVS.

Methods: Case report and literature pertinent to RCVS and aseptic meningitis was reviewed.

Case: A 47-year old woman developed acute headache. Head CT and CTA were normal. LP revealed CSF pleocytosis (30 WBCs, 85% lymphocytes) and mildly elevated protein. She was diagnosed with aseptic meningitis and treated initially with intravenous acyclovir. CSF cultures and HSV PCR were negative. She was discharged home but continued to have headache, nausea and vomiting. Ten days later, she developed right hemiparesis and confusion. Brain MRI showed acute, bilateral watershed territory hemispheric infarcts. Intracranial MRA showed diffuse and multifocal vascular narrowing. Intravenous methylprednisolone was started initially for possible CNS vasculitis. She developed worsening right hemiparesis associated with low blood pressure. Repeat brain MRI showed enlargement of the previous watershed territory infarcts and a new left cerebellar infarct. Following blood pressure augmentation, her exam stabilized. Repeat LP showed persistent but improving CSF pleocytosis (7 WBCs). Cytology showed no evidence of malignancy and VZV PCR was negative. Rheumatologic work up revealed no evidence of autoimmune disease. Catheter angiography revealed widespread and diffuse vasoconstriction that responded dramatically to intra-arterial injection of verapamil. She was started on oral Verapamil, improved clinically, and was discharged to acute rehabilitation.

Conclusion: RCVS is a clinical diagnosis. CSF pleocytosis is very uncommon occurring in only 3-8% of patients. Our patient presented with aseptic meningitis and had normal vasculature initially only to develop severe vasoconstriction 10 days later. This suggests that RCVS may, in some cases, be triggered by aseptic meningitis. S159. "Eight-and-a-Half" Syndrome in a Post Renal Transplant Patient Nidaullah Mian and Tamer Abdelhak. Springfield, IL and Grand Rapids, MI Objective: Describe an interesting case of the rare "eightand-a-half" syndrome in a post-renal transplant patient caused by lacunar pontine infarcts. The infrequency with which it is encountered makes its identification a diagnostic challenge.

Background: "Eight-and-a-half" syndrome is a rare condition with a handful of cases reported in literature. It is a combination of ipsilateral one-and-a-half syndrome (internuclear ophthalmoplegia plus horizontal gaze palsy), and ipsilateral lower motor neuron type seventh cranial nerve palsy. The lesion is localized to dorsal tegmentum of the caudal pons involving (i) the parapontine reticular formation (PPRF) or abducens nucleus, (ii) the medial longitudinal fasciculus (MLF), and (iii) facial nerve nucleus or fasciculus. Common etiologies include lacunar stroke and demyelinating lesions.

Design: Case report Description: A 45-year-old male with history of hypertension, coronary artery disease, lupus nephritis resulting in end-stage renal disease reported complaints of double vision and left eye irritation the night after undergoing a live-donor renal transplant. His examination was significant for binocular diplopia, that would disappear with closing either eye. The patient had a left horizontal gaze palsy with impaired Abduction of the right eye. He had exotropia of the right eye with intact convergence. In addition, he had a left upper and lower face weakness with Bell's phenomenon. MRI of the brain with 4mm cuts through the brain stem revealed a punctate infarct involving the dorsal tegmentum of the caudal pons on the left, and an additional punctate infarct of the ventral pons on the left. The patient was started on a full dose of Aspirin, and a moderate intensity statin. He reported improvement of his diplopia over the next 2-3 days, and his horizontal gaze palsy and internuclear ophthlamoplegia resolved within a week.

Conclusions: Lesion of the dorsal tegmentum of the caudal pons leads to the rare "eight-and-half" syndrome. The patient responded well to the anti-platelet and statin regimen with resolution of the syndrome. S160. Acute Onset Isolated Unilateral Trochlear Nerve Palsy Due to Bilateral Carotid Cavernous Fistula: A Case Report and Literature Review Prashant K. Rai, Daniel Graf, Sarah Dehbashi and Adham S. Kamel. Galveston, TX

Objective: To report a case of isolated trochlear nerve palsy due to bilateral carotid cavernous fistula.

Background: Isolated trochlear nerve palsy has been attributed to a number of causes, the most common being trauma followed by idiopathic. However, rare causes such as carotid cavernous (CC) fistula and aneurysm can also result in acute isolated trochlear nerve palsy. CC fistula can cause ocular motor nerve palsies of CN III (72%), IV and VI, of which trochlear nerve is the rarest. There is a paucity of cases reported in the literature, to our knowledge only 5 cases of trochlear nerve palsy due to CC fistula have been described. We report this rare entity to broaden the differential diagnosis of isolated trochlear nerve palsy, in the hope of facilitating early management and avoiding complications due to delayed diagnosis.

Case Description: A 51 year-old male with no past medical history presented with sudden onset vertical diplopia which worsened on downward gaze and improved with upward gaze and head tilt to the left. He also complained of right sided headache. There was no history of trauma. Thyroid dysfunction and other medical causes were ruled out. CT Angiography performed within 24 hours was normal therefore conventional four vessel angiogram was prompted for diagnosis. Angiogram demonstrated carotid cavernous fistula with bilateral ascending pharyngeal arteries feeders and bilateral cavernous ICA feeders. Embolization of bilateral internal and external carotid feeders via left IPSS using ethylene vinyl alcohol (Onyx V R LES) was performed after 10 days.

Conclusions: Isolated trochlear nerve palsy is rare and most often due to traumatic etiology. Carotid cavernous fistula can be a rare cause of isolated trochlear nerve palsy. Therefore, conventional angiogram is recommended in cases without antecedent trauma and normal imaging studies. Early embolization of the fistula may be beneficial to prevent late complications.

Kyan Younes and Amanda Jagolino. Houston, TX

We report a case of suspected acute dominant middle cerebral artery stroke that turned out to be a stroke mimic in an acute liver failure patient with hyperammonemia whose focal symptoms were reversed with medical management. Our patient presented 12-hours following an elective TACE procedure for a known hepatocellular carcinoma with sudden onset aphasia and right sided weakness in the window for both tPA and IAT. Her MRI brain revealed restricted diffusion in the subcortical basal ganglia more prominent on the left side. Nonetheless, her presentation included striking cortical symptoms of aphasia and homonymous hemianopia. Given the disconnect between imaging studies and clinical presentation, she underwent digital subtraction angiogram that revealed completely patent intracranial vessels. Her labs were significant for elevated ammonia of 81 uMol/L. Her AST increased from 61 unit/L before TACE to 250 unit/L after TACE and ALT increased from 51 to 61. Her Platelets count was 84 K/CMM and her INR was 1.29. With medical management, she showed steady improvement and recovery to her neurological baseline. We postulate that this presentation can be explained by dysfunctional flow and energy metabolism due to hyperammonemia rather than tissue ischemia secondary to acute vascular occlusion. Reduced MCA blood velocity in cirrhotic patients has been reported. Impaired autoregulation of cerebral blood flow has been shown in a small cohort of patients with Hepatic Encephalopathy (HE). Studies using positron emission tomography and transcranial Doppler ultrasonography have shown significantly reduced brain oxygen metabolism and cerebral blood flow in HE. Characteristic MRI changes of acute brain injury including T2 hyperintensity can be seen with acute hyperammonemia and patients with ornithine transcarbamylase deficiency. This case demonstrates the importance of distinguishing noncerebrovascular stroke mimics from acute ischemic stroke, and highlights the need to carefully assess background pathophysiology when evaluating patients exhibiting stroke-like symptoms. In this patient population, we suggest assessing Ammonia level and coagulopathy as part of the acute stroke evaluation.

-Imaging and references will be provided in our poster. Background: Stroke complicates many cardiac procedures, but literature on stroke risk following cardiac procedures addresses only perioperative and long-term risk following limited higher-risk procedures, is poorly generalizable, and often fails to stratify by stroke subtype. The objective of this study was to directly compare the stroke risk in the intermediate risk period following transcatheter aortic valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR) and coronary artery bypass graft (CABG) vs. percutaneous coronary intervention (PCI). Methods: The 2013 Nationwide Readmissions Database (NRD) is a national database of readmissions for all payers and the uninsured with data on >14 million U.S. admissions. We used International Classification of Disease, Ninth Revision, Clinical Modification codes to identify index cardiac procedures. We used Cox regression to calculate hazard ratios (HR) of stroke risk up to 1 year, comparing TAVR vs. SAVR, and CABG vs. PCI, adjusting for baseline vascular risk factors, hospital bed size, teaching hospital status, income quartile of patient's zip code, risk of mortality and illness severity, and National Center for Health Statistics urban-rural location classification.

Results: There was a consistently elevated cumulative risk of ischemic and hemorrhagic stroke after TAVR compared to SAVR that was also seen in unadjusted and adjusted Cox models. The hazard ratio for ischemic stroke after TAVR, compared to SAVR, in fully adjusted Cox models, was 1.38 (95% CI 1.07-1.79) and 2.63 (95% CI 1.57-4.42) for hemorrhagic stroke. Kaplan-Meier cumulative risk curves demonstrated an increased risk of ischemic stroke initially following CABG compared to PCI that became comparable around 300 days. Adjustment for risk of mortality and illness severity reversed this association, showing lower ischemic stroke hazards after CABG compared to PCI. After adjusting for vascular risk factors and hospitalization characteristics, there was no difference in ischemic stroke hazards comparing CABG and PCI. The cumulative risk of hemorrhagic stroke was similar for CABG and PCI throughout follow-up, and unadjusted and adjusted Cox models also showed no difference.

Conclusions: We directly compared TAVR and SAVR and found almost 40% increased risk of ischemic stroke with TAVR compared to SAVR, and more than 2.5-fold increased risk of hemorrhagic stroke. There was no difference between CABG and PCI. Non-fluent/agrammatic PPA (nfvPPA) is a neurodegenerative disorder characterized by isolated and progressive speech and language impairments caused by anatomical damage in the inferior frontal gyrus (IFG), dorsal insula, supplementary motor area (SMA), striatum, inferior parietal and temporal regions. These regions are linked to form a specific network for speech production, and are compromised in nfvPPA. However, it is not known whether and how this network is topologically distinctively organized in nfvPPA to address this damage. Recently, advanced mathematical models have been introduced to investigate the complex relationships between connected brain regions. We applied graph theory to compare the topological configuration of the speech production network in nfvPPA and the healthy brain. First, we defined the speech production and default mode networks in healthy subjects with a ROI-based approach using resting state functional MR data. Graphs were built by defining nodes with a parcellation of the entire network's maps in the healthy subjects. Edges were defined as functional connectivity between each pair-wise node extracted for each subject. For both groups, we extracted graph-theory measures to identify the hubs of the network (nodal degree and betweeness centrality), quantify information flow efficiency (global efficiency) and cluster organization (modularity and cluster coefficient). We found that the speech production network in nfvPPA did not show the same topological configuration as controls. In the left hemisphere, hubs were not present in the left frontoparietal regions, and they were located more anteriorly within the frontal regions. Additional hubs were also identified in the right hemisphere. Global metrics showed a network of speech production less efficiently wired and less optimally clustered in nfvPPA. No differences were found in the topological organization of the default mode network. Additionally, after simulating the damage of disease in healthy controls after excluding the nodes that lost their designation as hubs in nfvPPA, we observed that the new configuration of hubs was similar to that obtained in nfvPPA. These results suggest that nfvPPA presents a hierarchical reorganization within the speech production network, essentially downshifting operations to hubs less centrally important to the healthy network and that the reorganization is widespread and specific to this network with loss and gain of crucial hubs and decreased global efficiency. Graph theory is a promising technique to understand the pathophysiology of network-level dynamics in neurodegenerative diseases. S166. Biologically Produced Abeta Species Induce AD-Related Pathological Phenotypes In Vitro Mariko Sawa, Xu Chen, Orlangie Natera, Matthew Pearn and William Mobley. La Jolla, CA Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is growing in prevalence. The molecular pathogenesis of AD starts decades prior to clinical diagnosis; so early detection and intervention is critical to halting it's progression; perhaps even abating symptoms altogether. An early and critical neuronal phenotype of AD is accumulation and enlargement of early endosomes (EE) and increased activation of Rab5. EE enlargement contributes to neurodegeneration by impairing axonal transport of trophic factors necessary for neuronal survival. To better understand the molecular mechanisms underlying the abnormalities, we employed the conditioned medium (CM) of a CHO cell line (7PA2) which expresses the human Indiana mutation of APP (APP V717F); CM7 is used to designate this CM. Wild type CHO cells are used as a control; CMC is used to refer to this CM. CM7 contains biologically relevant amyloid beta (Abeta) species including soluble oligomers. We assessed the effects of CM7 in PC12 cells and rat primary neurons. We observed that 2hr-treatement of CM7 induced abnormalities in; endosomal pathways, neurotrophin signaling, axonal trafficking and synaptic structures. Immunodepletion analysis showed that Abeta42 is responsible for these phenotypes. In addition, CM of 7PA2 cells pretreated with c-secretase modulator, GSM15606, diminished the abnormalities led by CM7. We conclude that CM7 recapitulates AD related cellular abnormalities in vitro, and Abeta 42 was the responsible to those phenotypes. We will discuss the molecular linkages between Abeta species and the AD-related pathologies. Heterozygous loss of function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), and most likely cause disease through progranulin haploinsufficiency. Homozygous GRN mutations that produce complete progranulin deficiency cause the lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL), revealing that progranulin is critical for proper lysosomal function. Impaired lysosomal function may also play a role in FTD due to GRN mutations (FTD-GRN), as brains from FTD-GRN patients exhibit elevated levels of lysosomal proteins. As in humans, progranulin-deficient mice (Grn -/-) exhibit lysosomal abnormalities, with elevated levels of lysosomal proteins, complex changes in lysosomal enzyme activity, and accumulation of lipofuscin granules throughout the brain. In this study, we investigated whether brains from Grn -/mice and FTD patients with GRN mutations exhibit similar lysosomal abnormalities, and tested whether restoration of progranulin to Grn -/mice would reverse these abnormalities. Brains from FTD-GRN patients and Grn -/mice exhibited similar changes in the activity of several lysosomal enzymes, including reduced activity of b-glucocerebrosidase (GBA), an enzyme with previously reported abnormal trafficking in progranulin-deficient cells. Grn -/mice also exhibited additional enzymatic changes not present in FTD-GRN samples. Restoration of progranulin to Grn -/mice by intracranial injection of an adeno-associated viral (AAV)-progranulin vector normalized activity of GBA and other lysosomal enzymes and reduced lipofuscin levels throughout the brain. These data indicate that lysosomal dysfunction due to progranulin deficiency is reversible, which supports the use of progranulin-boosting therapies for FTD-GRN patients and NCL patients with GRN mutations, particularly in the early stages of disease. S168. Targeting Microglial and Macrophage Kv1.3 Potassium Channels as a Therapeutic Strategy in Alzheimer's Disease Srikant Rangaraju, Syed Ali Raza, James J. Lah, Malu Tansey and Allan I. Levey. Atlanta

Background: Microglia and CNS-infiltrating macrophages (CNS mononuclear phagocytes/CNS-MPs) mediate complex neuroinflammatory responses in Alzheimer's Disease (AD) but specific inhibitors of pro-inflammatory CNS-MP responses have not been developed. We have recently shown that voltage-gated potassium channel Kv1.3 may be a key regulator of pro-inflammatory CNS-MP functions, and is highly expressed around Ab plaques in human AD. We hypothesize that Kv1.3 channels are specific regulators of pro-inflammatory CNS-MPs in AD which can be selectively blocked by ShK peptides resulting in neuro-immunomodulation and lower Ab plaque burden. The objectives of this study were: (1) to determine expression patterns of Kv1.3 channels in pro-inflammatory and anti-inflammatory CNS-MPs, and explore differential expression in microglia and CNS-infiltrating macrophages;

(2) to test the ability of systemically administered ShK peptides to engage target Kv1.3 channels in CNS-MPs; and (3) test the effects of long-term Kv1.3 blockade on Ab plaque load in the 5xFAD mouse model.

Methods: Using purified CNS-MPs from adult wild-type and 5xFAD mice, whole-cell patch clamp recordings of K currents, flow cytometric immuno-phenotyping, flow-cytometric detection of functional Kv1.3 channels and phagocytosis assays were performed. The ability of intravenous fluorescein-conjugated ShK peptide (ShK-F6CA) to bind to CNS-MPs was determined by flow-cytometry. In a three month trial of adult 5xFAD mice (N510/group, age 3 months), the effects of Kv1.3-blocking peptide ShK-223 (IP twice-weekly) on Ab load, CNS-MP immunological phenotypes and phagocytosis were tested.

Results: Higher Kv1.3 currents were observed in 5xFAD CNS-MPs compared to wild-type mice. In flow cytometric studies, we found that Kv1.3 channels were upregulated by CNS-infiltrating macrophages but not microglia in 6 month old 5xFAD mice. Cells that upregulated Kv1.3 channels also upregulated pro-inflammatory marker ICAM-1, down-regulated anti-inflammatory marker MGL and upregulated TREM-2. Following a single IV ShK-F6CA dose, we detected increased ShK-F6CA fluorescence in both microglia and CNS-infiltrating macrophages indicating CNS bioavailability. Chronic ShK-223 treatment resulted in lower CD81 T cell activation in the brain, and lower Ab plaque load and size especially in the hippocampal formation, without affecting recruitment of CNS-infiltrating macrophages or phagocytic properties of CNS-MPs.

Conclusions: Our data suggest that Kv1.3 channels are up-regulated by pro-inflammatory CNS-infiltrating macrophages in AD. We provide the first evidence for CNS bioavailability of ShK peptides and demonstrate Ab lowering and anti-inflammatory effects of ShK-223 in 5xFAD mice. CNS-MP Kv1.3 channels may represent therapeutic targets for selective neuro-immunomodulation in neurodegenerative disorders such as AD. Background: Previous studies have linked a Mediterraneanstyle diet to reduced risk of dementia in New York and Chicago populations with reductions ranging from 35-50%. While these studies have provided solid information regarding dietary modification of risk reduction for dementia in urban populations, it is unclear if the benefits of a Mediterranean-style diet extend to early cognitive decline such as mild cognitive impairment (MCI) or to populations with high cerebrovascular risks such as those found in the strokebelt. The present study was undertaken to explore these issues.

Methods: The National Health and Nutrition Examination Survey (NHANES) Food Frequency Questionnaire (FFQ) was administered to participants in the University of Kentucky Alzheimer Disease Center longitudinal cohort comprised primarily of cognitively normal elderly (older than 65 years) participants (n5506). Standard portion sizes were used for the estimation of consumed quantities, and nutrient intakes were calculated from the United States Department of Agriculture (USDA). Total nutrient intake was calculated by summing up nutrients from all food items. The MEDI score was adapted from the Mediterranean diet scale, and after excluding subjects with partially incomplete dietary surveys the final sample size was 243. Cognitive diagnosis over 3 years of follow-up was coded into transition status if subjects progressed from cognitively intact to MCI, or from MCI to dementia. Age, gender, race, and years of education were used as covariates.

Results: After adjusting for age, gender, and education, a higher MEDI score was found to be associated with a lower risk of cognitive transition in our study population (OR50.65, 95%CI: 0.49-0.87). Advanced age (OR51.31, 95%CI: 1.17-1.47) and lower educational attainment (OR50.52, 95%CI: 0.39-0.68) were also associated with an increased risk of transition.

Discussion: These data demonstrate that the previously reported associations of a Mediterranean-style diet with lower risk of cognitive decline extend to our population in the Kentucky stroke-belt and that the association holds for a mild cognitive decline from normal to MCI. Further work examining which aspects of a Mediterranean-style diet may be most beneficial in reducing the risk for cognitive transitions and may guide the implementation of practical dietary modifications in the general population in order to lower risk for future cognitive transitions.

References Background: Alzheimer's disease (AD) and vascular dementia (VaD) often co-exist and may share common risk factors. Debate is ongoing as to whether these disease states are additive or whether they act synergistically in the development of cognitive decline and dementia. Recent reports suggest that AD may be responsible for subcortical white matter hyper intensities (WMH), previously thought due solely to cerebrovascular risks, further confounding this issue. The present study was undertaken to explore potential synergistic action of AD and VaD on the development of subcortical WMH Methods: A Cross-sectional analysis of spinal fluid amyloid levels (CSF Ab 1-42), cardiovascular (CVD) risk factors, and quantitative MRI WMH volumes on 72 subjects with normal cognitive function (n532) and mild cognitive impairment (MCI; n540) was performed. Partial correlation of WMH volumes, CSF Ab 1-42 levels and CVD risk factors were performed to examine the association between these variables and WMH volumes. Mediation analysis models, adjusted for age, gender, and education, were constructed to examine the interdependence of WMH volumes on CVD risks vs. CSF Ab 1-42 levels.

Results: Results from the partial correlation model for CVD risks showed that only hypertension (HTN) was correlated with WMH volume (p5 0.008) in this sample, but not with CSF Ab 1-42 level as a marker for AD pathology (p5 0.8). Mediation analysis showed that CSF Ab 1-42 did not alter the relationship between HTN and WMH volume (Indirect effect 5 0.05 [0.00 -0.15], direct effect 5 0.23 [p5 0.026]). Furthermore, HTN did not mediate the relation between CSF Ab 1-42 and WMH volume, suggesting independent contributions to the development of WMH in aging and MCI.

Conclusion: Results from this study suggest that the relationship between VaD and AD may be additive rather than synergistic. These results suggest that therapeutic interventions designed to prevent or treat these common brain pathologies may require combination therapy targeting VaD as well as AD to show beneficial effect in the vast majority of MCI and dementia patients that have evidence for comorbid disease. S171. Severity of Heart Failure Signs and Symptoms and Cognitive Performance in Congestive Heart Failure Patients Nicole L. Williams, Andrew Gaddis, Yessenia Gomez, Tanya Simmons, Nisha Chandra-Strobos, Rosanne Rouf, Serban Negoita and Rebecca F. Gottesman. Baltimore, MD and Roanoke, VA Background: Studies have shown that there is an association between congestive heart failure (CHF) and impaired cognitive performance; however, little is known about how CHF clinical signs and symptoms relate to extent of cognitive impairment.

Methods: Neuropsychological tests were administered to 154 CHF patients with acute heart failure symptoms in an outpatient diuresis clinic. Pulmonary or peripheral edema and/or ascites was categorized as none (0), mild (1), moderate (2), or severe (3) resulting in a status scale of 0-9, with higher numbers indicating more edema. In addition, number of areas (peripheral edema, pulmonary edema, ascites) with at least moderate to severe edema was tallied. Ejection fraction data, available from echocardiography or cardiac catheterization, were classified as <40% (heart failure with reduced ejection fraction (HFrEF)) and !40% (heart failure with preserved ejection fraction (HFrEF)). Z-scores were also calculated for those cognitive tests with normative data available.

Results: Cognitive Z-scores for this cohort, based on ageand sex-based normative data, were below the average for all evaluated tests; the mean value for a global Z-score, reflecting an average of 6 tests with normative data available, was 20.93; three-quarters of the cohort performed below the standardized mean. As the edema status score increased, CHF patients generally had poorer performances on a range of cognitive tests, but none reached statistical significance. When the number of areas with moderate to severe edema was considered, individuals with moderate to severe edema in at least two areas also tended to have worse cognitive scores than those with fewer areas involved in their CHF symptoms. In models adjusted for other vascular risk factors, individuals with moderate/severe pulmonary edema on presentation to the diuresis clinic had statistically significantly slower times on the Grooved Pegboard (dominant) task (adjusted Beta530.3, 95% CI55.9, 54.6) than did people with no or mild pulmonary edema. Generally, HFpEF and HFrEF patients did not have statistically different cognitive scores across a range of tests.

Discussion: These preliminary results in CHF patients suggest a pattern towards worse cognitive scores in patients with more edema on presentation to a diuresis clinic with acute CHF, although few statistically significant associations were observed. These results support further evaluation of cognition in CHF patients. Background: Previous studies assessed higher frequency of late-onset Alzheimer Disease (LOAD) in admixed populations such as African American and Hispanics compared with non-Hispanic Whites; admixture mapping is an innovative method to estimate the ancestry both globally and locally along the genome, in order to identify disease-associated loci by computing excess ancestry with respect to LOAD.

Methods: Data were derived from two studies of 5,437 Caribbean Hispanics: I) the Washington Heights and Inwood Columbia Aging Project (WHICAP); II) Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA). A subset also have MRI data available (n5398). Global and local admixture analyses were performed using the ELAI software, using African Yorubian and Whites with European Ancestry from the HapMap project, and individuals from the Human Genome Diversity Project as surrogates for European, African and Native American ancestral populations respectively. We studied the association of LOAD risk with global and local ancestry employing a mixed model adjusting for fixed effect of age, sex, APOE4 and the kinship matrix as a random effect. The boundaries of the regions indicated by admixture mapping were defined as the region bound by sites within a 2 unit drop of -log10(p-value) of the association analyses.

Results: Global admixture analyses revealed that European lineage accounted for 57%, followed by the African (33%) and the Native American one (8%). No significant association was found between global ancestries and LOAD, although a significant interaction between the degree of African component and APOE4 was observed (OR51.2, p50.007). This interaction was also associated with faster rate of atrophy in hippocampus volume (beta50.53, p50.03). Local admixture mapping revealed two admixture sites of excessive African and Native American ancestry between LOAD cases and controls located on chr 11 and 10 respectively.

Discussion: to our knowledge, this is the largest attempt of admixture mapping analyses in a Caribbean Hispanic cohort phenotyped for LOAD. We found that global African ancestry is associated with higher risk of LOAD and faster atrophy in LOAD-key brain regions in APOE-e4 alelle carriers. Furthermore, we identified genomic regions with higher african and native ancestral component associated with higher susceptibility for the disease. S173. Polygenic Hazard Score Is Associated with In Vivo Imaging Biomarkers of Alzheimer's Disease Leonardino A. Digma, Barbara E. Spencer, Chun C. Fan and James B. Brewer. La Jolla, CA Considerable evidence suggests that the pathological processes that lead to cognitive decline in Alzheimer's disease (AD) initiate decades before the manifestation of clinical symptoms. The long, clinically silent period of AD proposes the need for markers that predict disease risk. A recently developed polygenic hazard score (PHS) (Desikan, PLOS Medicine, 2017) was shown to predict AD age-of-onset. In the present study, we assess the relationship between PHS and in vivo imaging biomarkers among a cohort of non-demented elderly subjects.

Florbetapir PET and structural MRI were used to measure amyloid deposition and hippocampal atrophy, respectively, in non-demented subjects from ADNIGO/2 (N5654). Additionally, polygenic hazard scores (PHS) were calculated for each subject using 31 common genetic variants. Linear regression was performed to assess the relationship between PHS and florbetapir SUVR, and between PHS and hippocampal occupancy (a proxy for hippocampal atrophy). Age and sex were included as covariates in all analyses.

We found that PHS is significantly associated with both imaging biomarkers, such that higher PHS was associated with increased amyloid deposition (p<1e-5) and more severe hippocampal atrophy (p50.009).

In the present study, we found that PHS was related to in vivo imaging biomarkers in non-demented older individuals. Our findings indicate that examining common genetic variants may be useful in identifying individuals with elevated risk for developing Alzheimer's disease. Longitudinal studies are further needed to examine the utility of the PHS in predicting neurodegeneration and cognitive decline.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Dr. Brewer has served on advisory boards for Elan, Bristol-Myers Squibb, Avanir, Novartis, Genentech, and Eli Lilly and holds stock option in CorTechs Labs, Inc. and Human Longevity, Inc. S174. Early-Onset Alzheimer's Disease Is Associated with APOB and Higher Plasma Cholesterol Independent of APOE Thomas S. Wingo, David J. Cutler, Aliza P. Wingo, Ngoc-Anh Le, Gil D. Rabinovici, Bruce L. Miller, James J. Lah and Allan I. Levey. Decatur, GA; Atlanta, GA and San Francisco, CA Background: Elevated mid-life cholesterol is an important risk factor for late-onset Alzheimer's disease (LOAD; i.e., AD onset on or after 65 years). The apolipoprotein E (APOE) E4 variant is strongly associated with an increased risk of LOAD and higher cholesterol. Cholesterol and APOE E4 are statistically separable risks for LOAD, but their genetic independence has not been shown. Their relationship with early-onset AD (EOAD; i.e., AD onset before 65 years) is also unknown. Here, we sought to determine the association between low-density lipoprotein cholesterol (LDLc) and EOAD and to identify rare coding genetic variants underlying this association.

Methods: The relationship between LDLc and EOAD was examined using linear regression in 291 EOAD cases and controls from the Emory and University of California San Francisco Alzheimer's Disease Centers (ADRCs). To identify genetic variants underlying this association, we performed targeted sequencing of APOB because it is known to contain variants that can raise or lower LDLc independent of APOE. We sequenced 483 EOAD cases and 844 controls from 28 ADRCs and used Sequence Kernel Association Testing (SKAT) to test for significance.

Results: We found that EOAD had higher LDLc levels compared to aged controls after adjusting for APOE and other risk factors (N5291, p52.6x10 26 ). There was a significant enrichment of rare APOB coding variants in EOAD after adjusting for APOE and other relevant factors (N51327, p59.0x10 25 ).

Conclusion: High LDLc and rare genetic variants in APOB associate with EOAD independent of APOE. These data suggest that genes that regulate LDLc influence AD risk. Background: Synaptic damage is well-recognized as part of Alzheimer's disease (AD) neuropathology and correlates with cognitive measures. Neuronal pentraxin 2 (NPTX2) is a presynaptic protein secreted by pyramidal neurons that binds GluA4, an AMPA receptor subunit, and is essential for parvalbumin neuron function in regulating homeostatic scaling, a critical process in memory and learning. We examined NPTX2 in human brain tissue, rodent models relevant to AD, and cerebrospinal fluid (CSF).

Methods: NPTX2 protein and mRNA were measured in postmortem brain tissue from AD, Down syndrome (DS), and controls with variable AD pathology. We assessed the time course of amyloid deposition and electrophysiology in a hAPPxNPTX2-/-transgenic mouse model. NPTX2 was characterized in CSF by Western immunoblotting, and analyzed with a specific in-house ELISA in subjects with AD, Mild Cognitive Impairment (MCI) and controls. Progression in subjects with MCI and AD was assessed by longitudinal measures of cognition and global function.

Results: In postmortem temporal and frontal cortex, levels of NPTX2 protein and mRNA were markedly decreased in AD and DS, but not in controls with high AD pathology, relative to cognitively normal low pathology controls. Levels of two miRNA's that can regulate NPTX2 mRNA (miR-182 and miR-1271) were increased in AD brain. In a cell culture model, these miRNAs were able to decrease mRNA levels of NPTX2. In transgenic mice, NPTX2 knockout and A-beta amyloidosis synergistically disrupted hippocampal rhythmicity and GluA4 expression. Levels of NPTX2 were decreased in CSF in AD and MCI compared to age-matched controls, replicated across two cohorts. In subjects with MCI and AD, CSF levels of NPTX2 correlated with the Mattis DRS, an overall test of cognition, and with measures of hippocampal volume to a greater extent than did other CSF biomarkers such as tau or P-tau181. CSF A-beta42 did not correlate with these cognitive or MRI measures. CSF levels of NPTX2 at baseline correlated with longitudinal progression of DRS scores over 24 months in MCI and AD subjects.

Conclusions: Our findings suggest that NPTX2 downregulation is an important part of AD pathogenesis, linked to cognitive decline in AD and present in DS. This downregulation may alter homeostatic regulation of synaptic activity. CSF levels of NPTX2 may have diagnostic utility and may provide a prognostic biomarker in patients with symptomatic AD.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Consulting Fees from: vTv Pharmaceuticals, Inc; Fujirebio, Inc.

Honoraria fromL BioMed Central, Inc. Objectives: Sleep disturbances, such as poor sleep efficiency or inadequate sleep time, are associated with increased risk of Alzheimer's disease. Amyloid-b (Ab) concentration fluctuates with the sleep-wake cycle suggesting that decreased sleep time may increase Ab concentration and therefore deposition in the brain. However, the mechanism driving this change in concentration is unclear. The purpose of this study is to determine if sleep alters Ab concentrations in the human central nervous system via a production or clearance mechanism. Methods: We collected serial cerebrospinal fluid (CSF) samples via intrathecal lumbar catheter every 2 hours for 36 hours in 23 adults 18-60 years old during behavioral sleep deprivation, increased slow wave sleep via administration of sodium oxybate, and control. Four participants completed the study a second time in a different intervention group; four participants completed all three intervention groups. All participants were infused with 13C6-leucine to isotopically label Ab. Labeled and unlabeled Ab was quantitated by mass spectrometry. Sleep-wake activity was monitored with polysomnography.

Results: We found that the mole fraction of isotopically labeled Ab was the same across all intervention groups, despite the absolute Ab concentration of sleep-deprived participants increasing over waking baseline by 25-40% compared to the drug and control groups (p<0.05). Further, the mole fraction of labeled Ab was not different between the drug and control groups. Sleep-mediated clearance mechanisms are predicted to decrease the percent of labeled Ab. Labeled Ab as a percentage of the waking baseline is higher in the sleep-deprived group compared to the drug or controls groups, supporting that sleep loss drives increased Ab production.

Discussion: Our study supports a mechanism of increased Ab production in the setting of sleep loss. Ab deposition in the brain is concentration-dependent and a key first step in Alzheimer's disease pathogenesis. Since increases or decreases in Ab concentration of 25-40% have been associated with causing or preventing Alzheimer's disease, these results support that sleep loss increases Alzheimer's disease risk via an Ab mechanism. Future investigations will be needed to determine if decreasing Ab production by increasing sleep time can prevent Alzheimer pathology.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? The 13C-leucine used in this study was partially supported by a donation from Cambridge Isotope Laboratories.

Randall J. Bateman is a co-inventor of the amyloid-beta stable isotope labeling kinetics method that is licensed to C2N Diagnostics. Both he and Washington University receive part of the profits from any sales of these tests by C2N and have a financial stake in the company. S177. Progressive Multifocal Leukoencephalopathy in a Patient with Untreated Myelodysplastic Syndrome Caroline T. Goldin, Samuel F. DeStefano, Douglas Ney, Daniel H. Vela Duarte and Kenneth Tyler. Aurora, CO Objective: To present the first case of progressive multifocal leukoencephalopathy (PML) in a patient with untreated myelodysplastic syndrome (MDS).

Background: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder caused by reactivation of the JC virus. It is progressive and rapidly fatal. It most often occurs in patients with immunosuppression from HIV or autoimmune disease modifying medications; however, recent literature suggests that transient immune dysfunction can contribute to PML. We also explore the effect of experimental low-dose IL-2 treatment in PML.

Methods: Case report Results: A 77-year-old woman with a history of untreated MDS developed dysarthria and ataxia over the course of a month. Brain MRI showed nonenhancing hyperintense T2 signal in the right brachium pontis. Cerebellar ischemic stroke was presumed. Over the next four months, however, her symptoms progressed. Repeat MRI revealed increased lesion size. Significant neurologic findings included dysarthria, nystagmus on right lateral gaze, right hemibody ataxia, and dysdiadochokinesia. Biopsy was immunopositive for polyoma virus without associated cerebellar granule cell neuronopathy. Although conventional CSF JC virus PCR was negative, ultra-sensitive testing sent to NIH showed 52 copies/ mL. Laboratory workup showed HIV: negative; WBC: 1.6x103/mL (lymphocytes: 0.4x103/mL; CD3: 240cells/mL, CD4: 148cells/mL, CD8: 96cells/mL, NK: 104cells/mL; neutrophils: 1.0x103/mL); and platelets: 97x103/mL. She started mirtazapine and was titrated up to 30mg qday; however, due to intolerable side effects, this treatment was discontinued. She recently received a course of low-dose IL-2 treatment and will soon recieve a repeat MRI to assess for extent of disease. She remains clinically stable 8 months after diagnosis (1.5 years after initial symptoms).

Conclusions: Although no reports exist in the literature implicating untreated MDS in PML, recognition of PML in the absence of overt immunosuppression is increasing. Treatment with mirtazapine has been suggested because of the theoretical blocking of JC virus spread through 5HT-2 receptors; however, continued review of these cases may help determine potential therapies for these patients. Treatment with low-dose IL-2 has shown promise in case reports,; this treatment has recently been implemented in our patient, and disease progression will be followed. Our patient's slow progression prior to IL-2 treatment suggests that occult opposed to overt immunosuppression may have implications on prognosis. Apathy is a common symptom in amnestic mild cognitive impairment (aMCI) patients. The neural substrates of apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated proton magnetic resonance spectroscopy (1H-MRS) in brain regions that may underlie apathy in aMCI patients. Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls completed neuropsychological assessments and 1H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additional analyses of covariance were performed to compare high and low apathy patients. Degree of apathy was negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetyl aspartate (NAA)/mI was reduced in aMCI without apathy group but not in the aMCI with apathy group. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group and reduced in association with depression scores. Apathy in aMCI patients is associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. The apparently contrasting associations of Glx in the DACC with apathy versus depression deserve further investigation. We conclude that, in a clinically diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy. Targeted The objective was to investigate the effect of alpha synuclein antisense oligonucleotides on the spread and toxicity of a pathological form of alpha synuclein. Parkinson's disease is a prevalent neurodegenerative disease for which there are no approved disease-modifying therapies. Alpha synuclein accumulation is a pathological hallmark of PD. Multiplication of the alpha synuclein gene, SNCA, alone can result in PD. Antisense oligonucleotides designed to target Snca RNA result in reduced production of alpha synuclein and thus have the potential to slow spread of pathology and modulate disease progression. Endogenous mouse and rat alpha synuclein transmission pre-formed fibril (PFF) inoculation models were evaluated. These models are based on intrastriatal injection of alpha synuclein fibrillar fibrils (PFFs) that lead to the deposition and aggregation of alpha synuclein, which accumulates and spreads through neural networks over time. Following characterization of timing of fibril deposition in the models both pre (preventive) and post (therapeutic) fibril deposition paradigms were evaluated with central delivery (intracerebroventricular) of Snca targeting antisense oligonucleotides. Following study completion Snca RNA was evaluated by RT-PCR and phosphorylated alpha synuclein pathology was evaluated histologically. Snca targeting antisense oligonucleotides in both species led to Snca RNA target reduction and slowed deposition and spread of a phospho-specific form alpha synuclein. Antisense oligonucleotides designed against SNCA have the potential to be a disease modifying therapeutic for Parkinson's disease patients.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? I am an employee of Ionis pharmaceuticals and receive a salary from my employment. Antemortem behavioral and anatomic abnormalities have been associated with right hemisphere disease in behavioral-variant frontotemporal dementia (bvFTD), but postmortem neuropathological examination of hemispheric lateralization of pathology remains to be defined. Here we measured the severity of postmortem grey and white matter pathology using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 24 bvFTD patients, including those with tau (n59), or FUS (n51) proteinopathy. We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of lateralization independent of direction) revealed highly lateralized pathology for both grey and white matter in all four regions sampled (p<0.01), with relatively greater proportion of pathology in white matter in tauopathies than TDP-43 proteinopathies. Direct inter-hemispheric comparisons of regional pathology measurements found higher frequency of patients with increased grey matter pathology in the right orbitofrontal region compared to the left in the tauopathy group, and for white matter pathology in the right orbital frontal region in the TDP-43 proteinopathy group (p<0.02). We also found increased pathology in the left hemisphere compared to the right hemisphere in the ventrolateral temporal lobe grey matter in the total cohort (p<0.02). There was a direct association of increasing pathologic burden of pathology with decreasing cortical thickness on antemortem MRI in exploratory analyses of the subset of patients (n515) with imaging data in FTLD-Tau (n57, b5-3.1, t5-3.7, p50.001) and a trend for FTLD-TDP (n58, b5-0.1, t5-1.9, p50.06). Exploratory clinical-pathological correlations demonstrated a higher frequency of patients with a high level of socially inappropriate behaviors in patients with lateralization of pathology in the right orbitofrontal region and reduced semantically-guided category naming fluency was associated with higher burden of white matter pathology in the left ventral-temporal region. We conclude that pathologic disease burden is not distributed symmetrically in behavioral-variant frontotemporal dementia, and this asymmetry of disease burden contributes to the clinical heterogeneity of the disorder. While pathologic burden is lateralized in bvFTD, this is not always to the right hemisphere, and may diverge between tauopathies and TDP-43 proteinopathies. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem observations of lateralized clinical disease, and these observations may contribute to antemortem identification of molecular pathology in bvFTD. Roughly 40% of patients with Lewy body disorders (LBD) (i.e., Parkinson's disease, PD; PD with dementia, PDD; dementia with Lewy bodies, DLB) have sufficient amyloid plaque and tau tangle pathology for a secondary diagnosis of Alzheimer's disease (AD) at autopsy. Furthermore, increasing levels of cerebral tau and amyloid pathology in postmortem brains of LBD patients are associated with shorter survival. Thus, antemortem identification of AD copathology has prognostic value in LBD. Cerebrospinal fluid (CSF) levels of the protein constituents of AD neuropathology i.e., total-tau (t-tau), phosphorylated-tau (p-tau) and amyloid-beta (Ab1-42) have been extensively studied in the context of AD, but recent work in LBD is largely restricted to living cohorts without postmortem validation.

Here we examine the relationship between antemortem CSF AD biomarkers with postmortem AD pathology in LBD. 23 autopsy-confirmed LBD (15PD, 115PDD, 115DLB) and antemortem CSF samples were studied. Standard neuropathological criteria were applied, and 9 patients had significant AD co-pathology (SYN1AD) and 14 patients did not (SYN-AD). CSF analyte measurements were performed using a Luminex platform. Ordinal ratings (i.e.0-3) of pathology severity for tau tangles and Ab neuritic plaques were averaged across five regions to obtain a global cerebral score. CSF analyte levels were compared between groups using an independent samples t-test and correlated with global cerebral pathology scores using a partial correlation with time interval from CSF collection to death as a co-variate. Exploratory diagnostic accuracy for postmortem SYN1AD was tested using receiver-operating curve analysis.

SYN1AD patients had higher levels of CSF t-tau (t53.8,p<0.001) and p-tau (t52.1,p50.05), and lower p50 .003), compared to SYN-AD. SYN1AD had higher CSF t-tau/Ab1-42 ratio (t56.4,p<0.001) and p-tau/ Ab1-42ratio (t53.8,p<0.001) compared to SYN-AD. CSF ttau (r50.48,p50.02), but not CSF p-tau (r50.30,p>0.1), correlated with postmortem global cerebral tau scores. CSF Ab1-42 had a strong inverse correlation with global cerebral Ab neuritic plaque scores (r5-0.71,p<0.001). Diagnostic accuracy for SYN-AD was highest for t-tau/AB ratio (AUC51.0, p<0.001), followed by t-tau (AUC50.89,p50.002), p-tau/AB ratio (AUC50.87,p<0.01), Ab1-42 (AUC50.84,p<0.01) and ptau (AUC50.76,p50.04).

Antemortem CSF t-tau and Ab1-42 levels directly correlate with their respective postmortem AD pathologies in autopsy-confirmed Lewy body disease. The stronger association with t-tau vs. p-tau suggests that interactions between alpha-synuclein and tau pathology may affect CSF p-tau in LBD. Antemortem CSF analysis may predict presence of AD co-pathology in LBD, which has important prognostic and treatment implications. Objective: LRRK2 mutations are the major cause of familial late-onset Parkinson's disease (PD). However, the interplay between LRRK2 and alpha-synuclein (aSyn) PD pathophysiology is still of debate and undergoing extensive research. To determine whether LRRK2 expression modifies aSyn pathology spreading, we lowered endogenous LRRK2 by antisense oligonucleotide (ASO) in mice injected with pre-formed aSyn fibrils (PFF), a model of PD.

Methods: In short term study, wildtype mice were injected intracerebroventrically (ICV) with LRRK2 ASOs 14 days before intra-striatal inoculation of aSyn PFF, and were sacrificed at 56 days post ICV. In long term study, mice were also pretreated with ASO before PFF inoculation as short term study. However, mice received a 2nd ICV dose at 90 days, and were sacrificed at 180 days post 1st ICV treatment. LRRK2 mRNA, protein, and phosphorylated aSyn pathology were assessed by RT-QPCR, western blots, and immunohistochemical methods, respectively.

Results: Preventive ASO-mediated suppression of endogenous LRRK2 reduced pathological spread of aSyn pathology in both short and long term studies. Furthermore, mice were protected against aSyn pathology-induced wirehang deficit in a-syn PFF inoculation mouse model.

Conclusions: LRRK2 may play an important role in aSyn pathology formation and progression. Thus, ASO targeting LRRK2 is of potential therapeutic use for PD and other synucleinopathies.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? I'm a full time employee of Ionis Pharmaceuticals, Inc. Methods: In HIV1 individuals without major neurocognitive (NC) comorbidities, impairment (NCI) was classified as asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) or HIV-associated dementia (HAD). We measured volumes of cortical, subcortical and cerebellar gray matter (CGM; SGM; CeGM), abnormal white matter (aWM), and cerebrospinal fluid (CSF). MRS measured N-acetyl aspartate (NAA), choline (Cho), myoinositol (MI) and creatine (Cr) in frontal (FGM) and basal ganglia (BG) gray and WM (FWM). Adjusted odds ratios compared HAND to unimpaired (NCU).

Results: Among 253 participants, HAND diagnoses were 54 ANI, 37 MND and 10 HAD. Higher NCI odds was associated with more AbWM. HAD showed less CGM, SGM and more CSF. MND had less CGM. ANI and MND did not differ. MND showed less FWM-CR and more FGM-CHO. HAD and ANI had less BG-NAA.

Conclusions: HAND showed specific alterations (increased aWM and inflammation, reduced GM and neuronal integrity), in some cases differentiating milder HAND. Alterations may represent legacy effects (prior injury) or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy or chronic HIV. Objective: We examined the association between the 21year pattern of high-sensitivity C-reactive protein (CRP) levels and late-life markers of white matter integrity in the Atherosclerosis Risk in Communities Study.

Methods: 1,532 participants (mean age576, 2011-2013) underwent 3T brain MRI which quantified white matter hyperintensity (WMH) volume and whole-brain WM microstructural integrity (fractional anisotropy [FA] ). CRP was measured concurrently with MRI and at two visits during midlife (1990-92; 1996-98) . Participants were categorized into one of six groups based on their 21-year pattern of low (<3mg/L) versus high (!3mg/L) CRP. Multivariate linear regression quantified associations of CRP trajectory classes with WMH and FA.

Results: Compared to the group with low CRP at all visits, the group which transitioned from low to high CRP at both follow-up visits demonstrated greater WMH volume (ß50.461, p5.014) and poorer FA (ß5-0.011, p5.002) after adjusting for demographic variables and cardiovascular risk factors. The group with high CRP at all visits also demonstrated greater WMH volume (ß50.230, p5.014) and poorer FA (ß5-.006, p5.004), but only after accounting for differential attrition. Background: Blood biomarkers of Alzheimer's disease (AD) are essential for rapid and inexpensive screening of the hundreds of millions of people at risk for AD. Due to the challenges of CSF collection and PET scans, there is an urgent need for a simpler, more practical Ab biomarker for CNS amyloid deposition.

Methods: In a prospective longitudinal biomarker trial design (NCT02021682), 41 SILK studies (>500 blood samples) were completed in participants with or without CNS amyloidosis by Ab amyloid imaging and/or CSF Ab measures to detect CNS amyloidosis. Participants were given a bolus of 13C6-leucine label followed by blood sampling over 24 hours.

Results: We found Ab42/40 fractional turnover rate ratios were significantly faster in amyloid positive participants compared to amyloid negative participants. We found that the individual plasma Ab42/40 concentrations across all hours demonstrates highly consistent differences in those with CNS amyloidosis.

Conclusion: These results suggest that blood-derived Ab may be useful as a screening test for CNS Ab amyloidosis. This simple and inexpensive blood test for screening is likely to accelerate clinical trials and future screening for treatment and prevention. Objective: The purpose of this study was to develop a structure for peer observation and feedback of resident rounds on a neurology service and to evaluate resident perceptions of peer feedback.

Background: Peer observation and feedback of teaching have been shown to be feasible and rewarding for both residents and faculty in internal medicine. This structure has not yet been implemented or evaluated on a neurology service, which has unique challenges given the necessary focus on and time dedicated to the bedside neurologic examination.

Design/Methods: Senior neurology residents (n 5 16) participated in this peer observation study. While leading morning rounds, residents were observed by a peer. Peer observers were specifically asked to put aside the clinical content of the discussion and instead focus on the resident's teaching style, bedside teaching techniques, and management of rounds. On the same day as the observation, peer observers provided in-person feedback to the senior resident and also received a survey to capture what they learned from observing. At the end of the study, residents received a survey to characterize their attitudes toward the peer observation and feedback initiative.

Results: Common teaching techniques that worked well during rounds pointed out by the peer observer included highlighting patient examination findings at the bedside, verbally or visually summarizing each case with bulleted teaching points, and allowing for junior resident autonomy in decision-making. Preliminary results from our end-ofstudy survey showed that peer observation and feedback were very well received. After taking place in the initiative, 63% of residents felt that all residents should be observed and observe others during neurology rounds. 75% of residents felt that the initiative improved their comfort with giving and receiving peer feedback as well as positively impacted their teaching behavior on rounds. Strengths noted were the relatively low time commitment and the structured venue for learning from peers. Weaknesses noted were logistical related to the initiative occur during changes in rotations for residents.

Conclusions: Resident peer observation and feedback on teaching was feasible and rewarding on a neurology service. It improves comfort with residents giving and receiving peer-level feedback and positively impacts teaching behavior. Objective: Demonstrate the necessity for neurology education in underserved countries to better serve their patient populations and explore a model to address this need.

Background: Many underserved nations, including Cambodia, face great obstacles when it comes to treating their patients with neurological disorders. One of the biggest barriers, is the lack of appropriate training in the field of Neurology. Currently, there are zero neurology training programs in Cambodia. As of 2004, only 10 out of the 3,000 physicians were trained in Neurology for a population of approximately 15 million. There were zero neuro-pathologist or sub-specialty trained neurologist in the country. In order to receive training in neurology, physicians are forced to travel to France in their final year of residency training. In 2015, the World Federation of Neurology (WFN) funded a program to allow a team of 5 neurologist from the University of Southern California (USC), Los Angeles to travel to Cambodia on two separate occasions to provide fundamental training for diagnosing and treating neurological disorders.

Design/Method: Information was gathered from Dr. Shri Mishra and USC library.

Results: Drs. Soma Sahai, Giselle Petzinger, Shri Mishra, Holly MacCallum, Sandhya Ravikumar and Heng Nhoung visited multiple medical education centers in 2015 and 2016 across Cambodia to educate undergraduates, medical students and physicians in neurological diseases. They provided hands-on training, Neurology books, and examination kits. In addition, they started building an online database of training materials that can be accessed by Cambodians at all times.

Conclusion: These trips and educational workshops are a small step in the right direction. The USC group hopes to help Cambodia establish its first neurology residency in late 2017 or early 2018. If this effort is successful, the hope is to replicate the process in other underserved nations and lower the global burden of neurological disorders. Methods: Between July 2010 and June 2013, all patients assessed and presented by on-call junior residents during daily morning report were captured in a caselog. We recorded residents' initial diagnostic impressions and "closed the loop" by later revisiting each case after reviewing the final diagnosis. Cases were categorized as having a final diagnosis of a primary neurological or non-neurological condition. If the case was a neurological disorder that was initially thought to be medical or a medical disorder that was initially thought to be neurological, we analyzed the specific etiologies of these errors.

Results: 834 cases were presented with a total of 198 diagnostic errors. 77 (38.9%) were erroneously deemed neurological when the final diagnosis proved to be non-neurological, including 41 medical, 15 psychiatric, 1 ophthalmological, and 20 "other" cases. The 41 cases of medical illness were mistakenly thought to be seizure (13), ischemic stroke (12), demyelinating disease (5), headache (2), neuropathy (2), movement disorder (1), CNS infection (1), and dementia (1). These cases eventually were revealed to be syncope (8), systemic infectious/inflammatory disease (8), drug/alcohol related (7), metabolic derangement (5), heart disease (3), electrolyte imbalance (2), orthopedic (2), endocrine (1), and hematological (1). Four cases were excluded due to missing data points. Conversely, 25 cases (12.6%) that proved to be neurological were initially diagnosed as medical (20), psychiatric (4), and ophthalmological (1) conditions. The 20 cases of neurological illness were mistakenly thought to be systemic infectious/inflammatory disease (8), metabolic derangement (3), orthopedic (2), liver disease (2), electrolyte imbalance (1), and heart disease (1). These cases were later revealed to be seizure (4), ischemic stroke (4), hemorrhagic stroke (3), spinal cord disease (2), demyelinating disease (1), CNS neoplasm (1), CNS infection (1), and serotonin syndrome (1). Three cases were excluded due to missing data. The remaining 48.5% of total errors were correctly judged to be neurological presentations, but were etiologically inaccurate.

Conclusion: This educational initiative further examines diagnostic errors made by neurology residents. When inaccurate, residents tended to over-interpret cases as neurological. Differentiating neurological disease from medical disease presented a particularly difficult diagnostic challenge for residents, especially with regards to distinguishing seizure and stroke from medical mimics. S190. Redesigning the Student Interest Group in Neurology (SIGN) Chapter Ross Smith and Raghav Govindarajan. Columbia, MO Objective: To describe innovative changes in student interest group in neurology (SIGN) and its impact on student enrollment in the chapter and faculty participation.

Background: SIGN chapters across the country provide opportunities for medical students to participate in clinical, research, and service activities in neurology. Despite these, enrollment in SIGN chapters has been traditionally low (including the author's institute).

Design/Methods: Student enrollment, class distribution, faculty involvement, number of activities planned, number of activities conducted, number of students interested in neurology residency, number of research projects involving students were collected prior to changes and compared to values after changes were introduced.

Results: The student enrollment in the SIGN chapter prior to changes were 15, faculty involvement was limited to 2, number of activities planned was 14 and number executed was 3, number of students interested in neurology residency was 2, number of research projects done was 1. Following changes were introduced: an open board style SIGN chapter executive committee with greater active engagement of first and second year students, three types SIGN chapter activities including journal club articles, hands on workshop (example EMG), celebration/cause events (example ALS walk). In addition a SIGN chapter run free clinic was introduced. Activities were planned in consultation with office of medical education, and were organized during down times. After these changes were introduced student enrollment is up to 60 (50% first and second year students, p<0.01), there are 6 new research projects ongoing, student activities planned are 8 and executed are 8, number of students interested in neurology is 12 (6 third year students) and faculty involvement is at 8 (out of 24).

Conclusion: An open chapter with early engagement and involvement of first and second year medical students, creating a variety of chapter activities with greater hands on involvement, planned in conjunction with office of medical education has reinvigorated our SIGN chapter.

Puncture as a Learning Module in Neurology Residency Education Yi Li, Swetha Ade and Kate Daniello. Worcester, MA Objective: To implement ultrasound guided lumbar puncture as a learning module for neurology residency training, with the aim to improve the technique for neurology residents and the quality of the procedure for patients.

Background: Lumbar puncture (LP) is a widely used procedure among neurologists for both diagnosis and treatment of various neurologic diseases. We frequently encounter patients where it is difficult to palpate anatomical landmarks for many reasons: obesity, scoliosis, or osteoarthritis. Ultrasound machines are readily available in most residency programs, especially for the purposes of assisting in localization for other invasive procedures. Ultrasound guided LP has been described in the ED setting with case cohort studies, but has not been used to train as an alternative method for LP in neurology residency, nor has it been studied in patients with potentially difficult anatomy in neurological spectrum diseases.

Design/Methods: A resident-driven quality improvement project designed and developed a standardized teaching module for the technique of ultrasound guided LP. This teaching module contains a one-hour lecture, providing the basic orientation of ultrasound mechanisms, identification of ultrasound markers, standardized protocol of the procedure, a 10-minute video of ultrasound guided LP, and a 30minute practice session on the real-time identification of intervertebral space with the ultrasound machine. A survey was administered to residents after this educational experience for feedback. After the training, the residents are currently participating in a prospective, randomized control study of ultrasound guided LP in patients coming for elective lumbar puncture to investigate whether assistance with ultrasound helps to increase the success rate and decrease side effects of LP.

Results: 81.05%% of residents responded that it is very helpful to implement the training of ultrasound guided LP as a part of neurology residency learning and 82.94% of residents also feel it will improve patients' satisfaction. 90.53% of residents reported that it is specifically helpful for potentially difficult patients (such as BMI>25 or previous back surgery). 87.89% of residents prefer to try ultrasound guided LP as their first method for potentially difficult patients after the training module.

Conclusions: This study demonstrated that residents are open to learning ultrasound guided LP techniques and they prefer to use it when anatomical landmarks are challenging. It serves as supporting evidence that it is beneficial to utilize the ultrasound guided lumbar puncture as a learning module in neurology residency education. Objective: To recognize the gap in knowledge when looking for neurology residency programs for match. To the best of our knowledge, there is no data available that has looked into the usefulness and usability of program websites for neurology residency applicants. It is the most important information used by the applicants for decision-making while applying for programs.

Methods: We used the ERAS website to obtain the list of all the programs that offered Neurology residency in the United States for 2017. The homepage(s) of Neurology residency programs were assessed for amount and ease of accessing information available that influences the decision for selection of a residency program. We looked at four questions that influence decisions while choosing a program. These included: number of residency spots offered, if categorical programs provided curriculum for PGY1 (internal medicine/transitional) year, electives offered through PGY2-4, and career paths after graduation (fellowship VS private practice).

Results: There were a total of 139 programs that included: categorical, advanced, mixed categorical & advanced and advanced-linked programs that offer neurology residency in United States. Out of these, 73 were categorical alone, 45 were advanced alone, 10 offered both categorical and advanced positions, 5 were advanced-linked and no information was available for 6 programs. 79% programs gave information about number of residency spots. While 83% gave information regarding which year they offer elective rotations, only 53.5% gave information regarding their former graduate residents. Out of 83 categorical, mixed categorical, and advanced programs only 67% provided the information regarding the PGY1 (internal medicine) curriculum.

Conclusion: Our findings provide valuable insight about the information available on the homepage of neurology residency programs. Surprisingly, not all the websites provided all the information. Further studies need to be done to measure what other resources are used by medical students and to compare how reliable the information provided is as compared to the official website.

Yu Wang, Shuntong Hu, Kasia Glanowska, Tuo Ji, Wei Niu, Geoffrey Murphy and Jack Parent. Ann Arbor Focal cortical dysplasia (FCD) is a major cause of intractable focal epilepsies and has been clearly linked to abnormal MTOR signaling pathway. Recently, genetic mutations in this pathway have been increasingly identified in familial and sporadic focal epilepsies. However, there is no animal model that concordantly recapitulates pathological and electrophysiological changes observed in resected human tissues. Therefore, it has been challenging to develop new effective medical or surgical therapies. Here, we use CRISPR genomic editing tools to establish a novel FCD animal model that shows cortical dyslamination, ctyomegaly and increased intrinsic excitability. Everolimus is able to reverse the increased soma size and ameliorate the seizure burden. We also use genetically engineered human stem cells for in vitro study with hopes to develop a cell-based transplant therapy and a medium-throughput drug-screen platform. Background: The DEPDC5 (DEP domain-containing protein 5) gene, encoding a repressor of the mTORC1 signaling pathway, has emerged as a major gene mutated in familial focal epilepsy with variable foci (FFEVF) and cortical dysplasia.

Method: Case-Report Result: A 6-year-old South-Asian girl was born at 34weeks from non-consanguineous marriage without any prenatal events. She had hyperbilirubinemia by week-1, which was successfully treated with phototherapy. She had first seizure episode at 3-months, 2-days after 'vaccination fever' subsided. It was considered as simple-febrile seizure and no treatment was given. At 3.5-months, she started having recurrent seizures. Workup including MRI/infectious/metabolic panel was non-conclusive. Despite being on multiple anti-epileptic drugs(AEDs), she is refractory epilepsy.

EEG during initial presentation showed epileptiform activity from left temporal region. Subsequently, EEG at 2.5-years showed inter-ictal bi-hemispheric epileptiform activity. EEG at 5-years showed inter-ictal spikes and wave discharges from bilateral fronto-temporal region with secondary generalization. By 3-years, MRI showed mildly deformed corpus callosum with inadequate thickening of splenium.

DNA analysis confirmed heterozygous missense mutation in exon 16 of DEPDC-5 gene, without chromosomal abnormalities. Mother is heterozygous for same mutation and father is normal.

She has grossly delayed milestones. Corrected age is approximately 1-year for Fine motor and Language, 1.5years for Gross motor, 2.5-years for Cognition, Social, and Emotional-skills. She has autism, impaired auditory/visual processing, and is hypersensitive to external stimuli. She has hypotonia (Right>Left), wide-based gait, and extrapyramidal movements.

Conclusion: DEPDC-5 gene mutation results in amino acid substitution of Histidine for Arginine at codon 389. This mutation has shown to be inherited in familial pattern. This R389H variant is not present in the 1000 genomes database and is predicted to be benign. However, It rather appears to be a sporadic mutation, which is very rarely observed phenomena. Such patients may respond well to mTOR inhibitors such as rapamycin, making prompt diagnosis and treatment.

Muhammad F. Bilal, Svetlana Famina and Miles S. Evans.

Objective: To report a case of temporal lobe epilepsy presenting with pruritic erythematous rash.

Introduction: Seizures in temporal lobe epilepsy (TLE) can cause cutaneous autonomic symptoms, including flushing, pallor, sweating and piloerection. Rash, however has never been described in the literature.

Case Summary: A 46-year-old right handed Caucasian woman presented with seizures consisting of episodes of loss of consciousness preceded by auras of excessive heat, cold, nausea and urge to defecate. Her husband observed her to flail and roll her eyes back. She was amnesic for this episode except for preserved recollection of the aura. During seizure she always developed an erythematous pruritic rash that persisted for a day. She photographically documented her rash, showing extensive erythema with raised macules and papules, especially on the buttocks. Frequency of episodes was twice or thrice yearly. Neurological examination was unremarkable. Workup prior to her initial neurology visit included echocardiography, tilt table testing, and Holter monitoring, which were all normal. Magnetic resonance imaging (MRI) of the brain showed increased signal intensity and loss of left hippocampal architecture with an en plaque meningioma over the left temporal convexity. Routine electroencephalogram (EEG) demonstrated intermittent left temporal slowing. Treatment with lamotrigine reduced seizure severity and frequency. With missed days of lamotrigine, breakthrough seizure auras with rash occured.

Discussion: Our case is one of dyscognitive seizures due to left temporal lobe epilepsy. The diagnosis of temporal lobe epilepsy was made by seizure semiology (altered behavior, amnesia), EEG (intermittent left temporal slowing) and MRI of the brain (left hippocampal abnormality and left temporal en plaque meningioma). The diagnosis is supported by her good response to antiepileptic drug therapy and reappearance of seizures with occasional medication noncompliance. She has several uncommon symptoms with her seizures, including feelings of heat and cold, nausea and urge to defecate. Her seizures also cause one symptom not previously reported in the medical literature, pruritic erythematous rash.

Many of our patient's seizure symptoms could be considered "autonomic", but rash is an unusual autonomic symptom from central nervous system disease. Autonomic instability is common after head and spinal cord injury, but rash due autonomic instability is not. The mechanism and localizing value of rash in seizures is unknown because of its rarity, but our patient has good evidence of left temporal lobe localization for her seizures.

Conclusion: Rash can also be one of the seizure symptoms in left temporal lobe epilepsy. Background: Psychiatric comorbidity occurs at a higher rate in epilepsy compared to the general population. We hypothesized that epilepsy admissions would be associated with a higher readmission risk for schizophrenia or psychosis compared to other medical causes.

Methods: The Nationwide Readmissions Database is a nationally representative dataset comprising 49% of US hospitalizations. We used validated International Classification of Disease Clinical Modification 9 codes to identify medical conditions. In 2013, there were 58,278 index admissions for epilepsy as the primary reason. This group was compared against index admissions for stroke (n5215,821) and common medical causes (pneumonia, urinary tract infection, congestive heart failure, and chronic obstructive pulmonary disease, n5973,078). Readmission rates (per 100,000 index admissions) for schizophrenia or psychosis within 90 days from discharge for index hospitalization were calculated. Cox regression was used to test for associations between admission type (defined in 3 categories as above) and readmission for schizophrenia or psychosis up to 1 year after index admission, in univariate models and adjusted for age, sex, income quartile of patient's zip code, drug abuse or alcoholism, psychiatric history, and index hospitalization characteristics.

Results: At 90 days from index admission, there were 683/100,000 readmissions for schizophrenia or psychosis in the epilepsy group, 92/100,000 in the stroke group, and 58-206/100,000 in the medical group. Unadjusted hazard ratio (HR) for readmission for schizophrenia or psychosis within 1 year in the epilepsy group compared to the stroke group was 6.58 (95% CI 5.69-7.61, p<2 3 10-16), and 4.41 compared to the medical group (95% CI 4.00-4.85, p<2 3 10-16). The adjusted HR for readmission in the epilepsy group remained elevated at 4.31 compared to the stroke group (95% CI 3.66-5.07, p<2 3 10-16), and 2.32 compared to the medical group (95% CI 2.10-2.57, p<2 3 10-16). Factors associated with readmission for schizophrenia or psychosis in all groups included documented psychiatric history at index admission and discharge to location other than home. Protective factors for readmission in all groups included age greater than the mean, female sex, higher income, and higher All Patients Refined Diagnosis Related Groups severity at index admission.

Conclusion: An epilepsy admission was independently associated with subsequent hospital readmission for schizophrenia or psychosis, even after adjustment for confounding variables. The magnitude of elevated risk, compared to stroke and common medical conditions, suggests that patients admitted with epilepsy may warrant targeted psychiatric screening. Objective: Determine the diagnostic accuracy of high-frequency oscillation (HFO) rates for localizing epileptogenic regions in the temporal lobe.

Methods: Intra-operative iEEG recordings, 2-10 minutes in duration, from 45 patients with temporal lobe epilepsy (TLE) obtained at the time of impantation, and 24 patients at the time of resection were analyzed using a custom HFO detector. During the recording some subjects received boluses of remifentanil to increase epileptogenic activity. The identified HFO events were classified and characterized as true or false ripple/fast ripple on spikes, or ripples/fast ripples on oscillations, and confirmed by visual inspection. The accuracy of HFO rates for localizing the seizure onset zone was performed using a ROC approach. The positive and negative predictive value of resected and residual HFO rates on seizure outcome were calculated using a cutoff value for the threshold HFO rate used to calculate the predictive values will be selected so as to maximize Youden's J.

Results: Preliminary analysis demonstrates that in a cohort of seven patients anesthetized using remifentanil with multiple subdural strips, and a hippocampal depth electrode, undergoing a tailored temporal lobe resection, the PPV of resected and residual ripple rates on seizure free outcome was 5 61.5% (56.5-67.3 95%CI), the NPV of resected and residual ripple rates on seizure free outcome was 5 63. . In a smaller cohort of TLE patients (n53) undergoing depth electrode implantation the area under the ROC curve for localizing the seizure onset zone using HFO rates was 82%.

Conclusions: HFO rates measured in brief intra-operative recordings can be helpful in localizing epileptogenic brain regions in the temporal lobe.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? None Movement of water and ions, including Cl -, are linked in neurons because these cells do not have aquaporins to move free water. Hyperosmolar therapy is commonly used to treat brain edema. Here we tested if hyperosmotic therapy induces a decrease in epileptiform activity using electrophysiological techniques. Acute and organotypic neocortical brain slices during early development were used to study the effect of a 20 mOsm increase in perfusion solution (by mannitol) on induced and spontaneous epileptiform activity. Epileptiform activity was provoked by omitting MgCl 2 in the artificial cerebro-spinal fluid (aCSF; Low-Mg model) in acute brain slices. Neocortical organotypic slice cultures had spontaneous seizure-like activity in regular aCSF. We observed that: 1) Induced and spontaneous epileptiform activity was decreased by 20 mM mannitol. 2) Spontaneous multi-unit activity (MUA) in the presence of excitatory neurotransmission block resulted in a decrease of MUA frequency but not amplitude. 3) A clinically relevant dose of the GABA A receptor modulator diazepam had insignificant anticonvulsant effects until potentiated by 20 mM mannitol. We conclude that an increase in the extracellular space osmolarity by 20 mOsm leads to a decrease in epileptiform activity in the neocortex in vitro during early development and enhances benzodiazepine actions. Our results suggest that mannitol decreases neuronal [Cl -] i and leads to more inhibitory actions of GABA at this early developmental age. Therapies aimed to decrease neuronal volume and [Cl -] i are another approach to treat neonatal seizures after acute brain injury.

Leah P. Gershen, Jeih-San Liow, Alison Austermeuhle and William H. Theodore. Bethesda, MD Rationale: Neuroinflammation, implicated in epilepsy, can be imaged in man with PET ligands for translocator protein 18 kilodalton (TSPO). Previous studies in patients with temporal lobe epilepsy and mesial temporal sclerosis found increased [11C]PBR28 uptake ipsilateral to seizure foci. Neocortical foci present more difficult localization problems and more variable underlying pathology.

Methods: We studied 11 patients with neocortical seizure foci using [11C]PBR28 or [11C]DPA713, and 11 healthy controls. Eight patients and all controls had concurrent arterial blood sampling during PET scans. Five had surgical resections; histopathology showed focal cortical dysplasia Type 2A or B. Brain regions were delineated using FreeSurfer and T1-weighted MRI. Additional regions of interest were drawn based on electrocorticography (ECOG) data and MRI lesions. We compared brain radioligand uptake (standardized uptake values, SUVs) in ipsilateral and contralateral regions, and calculated asymmetry indices [AIs, 200% *(ipsilateral-contralateral)/(ipsilateral1contralateral]. We compared asymmetry indices in the selected regions between epilepsy patients and controls, as well as absolute [11C]PBR28 binding as the ratio of distribution volume to free fraction (VT/fP) between patients and controls.

Results: Visual analysis showed increased signal coincided with MRI lesions. Nine of 11 patients had AIs exceeding control mean 95% confidence intervals in at least one region consistent with the seizure focus. No significant group differences were found between ipsilateral and contralateral SUVs or between patient and control VT/fP values in ipsilateral or contralateral regions.

Conclusions: Patients with neocortical foci show increased TSPO binding in some but not all ictal onset regions, suggesting the present of inflammation, particularly in patients with FCD 2A or B. Bilateral inflammation may minimize measured TSPO asymmetry. The lack of significant group differences in this sample is in contrast to significant TSPO increases previously reported in mesial temporal lobe epilepsy patients, probably due to variability in focus localization.

Acknowledgements: Drs Victor Pike, Robert Innis, Sara Inati; the NIMH PET Radiochemistry laboratory; the NIH PET Department. Background: Epileptic seizures are the most common neurologic symptoms and affect up to 80%-85% of patients with TSC. Everolimus (EVE) has been shown to improve seizures in TSC. Here we report the treatment outcomes of epilepsy in a pediatric subset of patients from EXIST-3.

Objective: To evaluate the efficacy and safety of EVE at targeted trough concentration (Cmin) ranges of 3-7 ng/mL (low exposure ) or 9-15 ng/mL (high exposure [HE] ) vs placebo as adjunctive therapy in patients with treatmentresistant seizures associated with tuberous sclerosis complex (TSC), according to age categories (<6, 6 to <12, 12 to <18, and !18 years).

Design/Methods: Patients aged 2-65 years with TSC and !16 treatment-resistant seizures on a stable regimen of 1-3 antiepileptic drugs (AEDs) were randomly assigned to receive EVE LE, EVE HE, or placebo. The primary endpoint, which was met and previously reported, was change from baseline in seizure frequency during the maintenance period, expressed as response rate (RR; !50% reduction), and median percentage reduction (PR) in seizure frequency.

Results Conclusions: Adjunctive EVE therapy improved seizure frequency across all age categories, with no new safety concerns.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? I have been paid to be a speaker by LivaNova for a training seminar.

Hamidreza Abbasi and Mona Sazgar. Irvine, CA 20-year-old girl with history of prematurity born at 32 weeks of gestation, developmental delay and regression, cerebral palsy, spastic quadripararesis, and cerebral palsy diagnosed at age 2-21/2 years. In the past 6-7 years, the patient has developed episodes of tonic posturing mostly induced by excitement, stimulation, and feeding which may occur on a daily basis and lasting about 10 seconds in duration. There is no history of infantile spasms, generalized tonic-clonic seizures, absence seizures or myoclononus. Patient admitted for long-term video EEG monitoring to characterize the patient's clinical spells and to rule rout underlying epileptic etiology for her symptoms. The patient was not on any anticonvulsant medications during this admission. During sleep, specially on second night of admission when sleep portion was obtained, there were clusters of numerous brief tonic spasms out of asleep. They lasted under 10 seconds in duration and consisted of either bilateral or unilateral (left) arm posturing when the patient raised arms above her head. EEG showed a brief burst of generalized delta activity lasting 1-2 seconds in duration (1-2 hertz, 100-120 microvolts) followed by diffuse rhythmic theta activity lasting 4-10 seconds in duration. The pattern was consistent with remnant of infantile spasms with a component of tonic seizures. The tonic seizures during sleep were not detected by the patient's family. Background: The efficacy of adrenocorticotropic hormone (ACTH) for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies (Brunson, Int Rev Neurobiol, 2002) and systematic review (Hancock, Cochrane Library, 2013) . There is a hypothesis that ACTH is not only promoting the release of adrenal steroids, but has additional direct mechanism of influence on the limbic neurons, and these combined effects may explain the robust established clinical effects of ACTH versus steroids and oral antiepileptic drugs in the therapy of IS (Brunson, Int Rev Neurobiol, 2002) .

Purpose: to assess the levels of cortisol in West syndrome children at various dates of adrenocorticotropic hormone treatment depending on the cessation of infantile spasms.

The method: Eligibility criteria for infants included: 1) having a diagnose of West syndrome made at Children's hospital according the criteria of the International League Against Epilepsy 2) an age of onset infantile spasms between 3 and 18 months;3) tetracosactide-based treatment (a synthetic adrenocorticotropic hormone). We compared the levels of serum cortisol of West syndrome patients before the treatment of tetracosactide, after the third injection of tetracosactide and 4 months after the end of the tetracosactide therapy. A child was considered seizure-free if he had no spasms for at least 12 recent months. A p value < 0,05 was considered statistically significant.

The results: We divided all patients (24 infants, 16 males, 8 females) into two groups. The first group consisted of 16 patients with full cessation of infantile spasms within 1 to 10 days of tetracosactide treatment start during at least 12 recent months. The second group comprised the remaining 8 patients with the persistent spasms despite the hormonal treatment.

We did not find significant difference level of serum cortisol between the free-seizures patients and the patients without clinical response to tetracosactide treatment: the mean level of serum cortisol before the tetracosactide treatment in the first group was 323,5 1 29,4 nmol/l versus the cortisol level of the patients in the second group -337,2 1 52,4 nmol/l, after the third injection of tetracosactide, it was 1106,9 1 118,8 nmol/l versus 1235,6 1 277,5 nmol/l, 4 months after the end of tetracosactide therapy, it was 257,0 1 62,2 nmol/l versus 220,9 1 47,4 nmol/l, respectively (P>0,05).

The conclusion: we cannot use the level of serum cortisol as a prognostic factor for cessation of infantile spasms in tetracosactide treatment.

S203. Development of an Inpatient Alert System to Improve Time to Administration of Second-Line Antiepileptic Drugs for Patients in Status Epilepticus Mauricio F. Villamar, Aaron M. Cook, Rachel K. Ward-Mitchell and Meriem K. Bensalem-Owen. Lexington, KY Objective: Status epilepticus is a neurological emergency where early treatment is essential. We evaluated whether implementation of a status epilepticus (SE) alert system can improve time to administration (TTA) of second-line antiepileptic drugs (AEDs) for patients in SE.

Methods: A quasi-experimental cohort study was performed in our institution to evaluate average TTA of second-line AEDs for patients in electroclinical SE. After establishing baseline TTA (Cohort 1), an Intervention was implemented consisting of hospital staff education and creation of an electronic order set for acute management of SE (Cohort 2). Next, a SE alert protocol was developed (Cohort 3). When a patient in clinical SE is identified, staff notify Central Monitoring. Then, Central Monitoring simultaneously pages the general neurology resident, the pharmacist, and the neurointensivist on call, in addition to the rapid response team (RRT) and the house officer. The page reads "Status epilepticus alert", followed by the patient's location. In this SE alert protocol, the neurology resident performs a clinical evaluation, enters orders for AEDs, determines need for EEG and neuroimaging, and oversees patient management. The pharmacist verifies orders and dispenses AEDs to the patient's bedside. The neurointensivist and RRT evaluate airway and perform endotracheal intubation if necessary. The house officer is notified for bed assignment purposes in the event that escalations in level of care are required. Local IRB approval was obtained. Cohorts were compared using descriptive statistics and t-test for TTA of second-line AEDs.

Results: Cohort 1 (n525) had an average TTA of a second line AED of 71 minutes (SD 59). TTA for Cohort 2 (n57) was 82 minutes (SD 32). There was no significant difference in TTA of second-line AEDs once the Intervention was implemented (p50.6414). Cohort 3 (n511) had an average TTA of a second-line AED of 15.7 minutes (SD 10.77). TTA was significantly improved when compared to the initial pre-Intervention TTA (Cohort 1, p50.0043), and to TTA following our Intervention consisting of house staff education and creation of a SE electronic order set (Cohort 2, p<0.0001). The most common second-line AEDs used in these 11 patients were levetiracetam (n55) and fosphenytoin (n54). Data collection is ongoing.

Conclusion: Our SE alert protocol has led to marked improvement in TTA of second-line AEDs, resulting in earlier initiation of therapy after benzodiazepines for patients in SE.

Neil Sondhi and Alan Hirsch. Oranjestad, Aruba and Chicago, IL Introduction: In phantosmia of Temporal Lobe Epilepsy, smell and taste of foods acquire the flavor of the phantosmia (Leopold,2002) . A patient with the opposite phenomena, wherein the phantosmia changes to the smell of the ambient aroma or food being tasted, has not heretofore been described.

Methods: Case Study: A 57 years old right handed female suffered head trauma without loss of consciousness and within a year began to experience sweet/floral, and moldy/fecal phantosmias which slowly progressed in frequency from once a day to more than 100 a day, and 8/10 in intensity lasting one minute. Both phantosmias were transiently alleviated by occluding her right nostril. The nature of these odors would change with exposure to ambient aromas, whereby the ambient smell or taste of food she was eating would transiently replace the phantosmia or change the phantosmia from sweet floral to foul. She also complained of occasional staring spells, depersonalization, derealization, and speech arrest.

Results: While experiencing sweet phantosmia, applications of nose clips reduced intensity of the smell from 6/10 to 3/10 which returned after removal of nose clip. When exposed to smell of ethyl mercaptan the sweet floral phantom changed from 3/10 to the fecal foul aroma, 8/10 intensity, for several minutes. While experiencing the sweet phantosmia, chewing a Cappuccino flavored Jelly Belly Jelly Bean changed and intensified the phantosmia from sweet floral to the aroma of Cappuccino, level 10/10. Then 90 seconds later it gradually returned to the baseline floral/ sweet smell and Cappuccino combining to be perceived equally. A half minute later, the olfactory hallucination returned to the original sweet smell level 5/10. Coincident with this, the Cappuccino smell dissipated. 24 Hour Electroencephalogram: frequent left temporal sharp waves and spikes with polymorphic slowing in left temporal region. MRI with and without contrast: normal.

Discussion: Unlike the current dogma that epileptiform hallucinations convert the perception of ambient aromas to the hallucinatory odors (Henkin, 2013) , in this case the hallucinatory odor was converted to the ambient aroma. The external sensory stimulus may be acting to inhibit the temporal lobe seizures, and thus inhibit associated phantosmias (Gowers, 1957) . A trial of hedonically pleasant aromas may be worthwhile in those with epileptiform olfactory hallucinations.

S205. Successful Implantation and Immediate Activation of Vagus Nerve 5 Stimulation (VNS) During Pregnancy in a Patient with Intractable 6 Epilepsy: A Case Illustration and Review of the Literature Noushin Jazebi, Narges Moghimi, Sara Dehbashi, Todd Masel and Juan Ortega-Barnett. Galveston, TX Seizures during pregnancy can be a challenging clinical problem to manage and may be associated with devastating consequences. Vagus Nerve Stimulation (VNS) is proven to be a safe and effective adjunctive therapy in the general population with medically intractable seizures. Studies have consistently shown the utility of VNS in treating medically refractory epilepsy, but only a few cases of women who have been treated with VNS during pregnancy have been described. Here we illustrate the case of a primigravid woman with medically refractory seizures who underwent safe and successful VNS implantation and immediate activation of the device in her pregnancy.

Case presentation: A 21 year old female in her 3rd trimester of pregnancy presented with refractory epileptic seizures since childhood. At the time of presentation she was having 3-7 clinical seizures per week, despite a regimen of 4 AEDs (gabapentin, lacosamide, oxcarbazepine, and zonisamide). In order to improve her seizure control and therefore lessen the risk of injury to the patient as well as the fetus, the decision was made to pursue VNS implantation, as adding or increasing AEDs at that point could be associated with adverse effects on the fetus or, more likely, failure to achieve seizure control. The VNS implantation procedure was performed by a neurosurgeon under general anesthesia. Due to the urgent need for seizure control, the device was activated in the OR immediately after implantation rather than implementing the usual 2-week waiting period

Results: Follow-up continuous EEG monitoring after VNS implantation did not show any seizure activity, and the patient was discharged after 3 days without any complications. After VNS placement, the patient's seizure frequency significantly decreased to one every few weeks, whereas it had been 3-7 per week prior to the procedure. She delivered a healthy baby boy at 37 weeks through an uncomplicated cesarean section.

Conclusion: Pregnant patients with refractory epilepsy have a higher incidence of obstetric complications including hyperemesis gravidarum, preterm delivery, pregnancyinduced hypertension, preeclampsia, cesarean delivery, placental abruption, and perinatal mortality. In addition, the use of antiepileptic medications (especially polytherapy) is associated with an increased risk of fetal malformations and long term adverse cognitive effects in a child.

VNS implantation and therapy for medically refractory seizures is a viable option and can be safe and effective during pregnancy.

Brian N. Lundstrom, Christian Meisel, Jamie Van Gompel, Matt Stead and Greg Worrell. Rochester and Bethesda

Background: Surgical resection is the most effective treatment for focal drug-resistant epilepsy (DRE) but is not feasible if the seizure focus is in eloquent cortex. Chronic subthreshold cortical stimulation (SCSC) is a novel brain stimulation technique that lowers seizures probability and offers an alternative therapy (Lundstrom et al., 2016) . Choosing appropriate stimulation parameters depends on estimating cortical excitability. Here, we summarize the results of patients treated with SCSC and describe several intrinsic excitability measures (IEMs) used to estimate cortical excitability during SCSC.

Methods: Intracranial electroencephalography (iEEG) data from seven patients with DRE were analyzed respectively upon admission (EpiAdm) and after the initiation of cortical stimulation (EpiStim). Patients were implanted with subdural grid electrodes. Six 15-minute blocks of EEG data for each of 16 electrodes were reviewed per patient upon admission (Epi-Adm) and during stimulation (EpiStim). Spikes were detected via a previously validated method for automated detection (Barkmeier et al., 2012) . Slow oscillation phase and synchrony were measured for oscillations in the 0.5-2 Hz frequency band. The seizure onset zone (SOZ) was defined as the contacts involved at immediate seizure onset.

Results: SCSC lowers seizure probability and focally decreases the rate of interictal spikes at the SOZ (Lundstrom et al., 2016) . Average spike rate was decreased, spike phase in relation to underlying slow oscillations (0.5-2 Hz) was later, and a global synchrony measure was decreased for EpiStim compared to EpiAdm. These same measures show increased cortical excitability for contacts in the SOZ compared to the non-SOZ in the EpiAdm group. Used in conjunction, these IEMs predicted the SOZ for 8 of 14 contacts.

Conclusions: SCSC offers a potential alternative treatment option for focal DRE. Interictal spike rate, spike phase in relation to slow oscillations, and synchrony are IEMs that potentially can be used to estimate cortical excitability. An efficient means for estimating seizure threshold would improve the efficacy of brain stimulation techniques such as SCSC.

References: Barkmeier, DT et al. (2012) . High inter-reviewer variability of spike detection on intracranial EEG addressed by an automated multi-channel algorithm. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology, 123(6).

Lundstrom, BN et al. (2016 Objective: To assess the long-term efficacy and safety of everolimus as adjunctive therapy for TSC-associated treatment-refractory seizures.

Design/Methods: Patients (aged 2-65 years) with TSCassociated refractory seizures receiving 1-3 AEDs were included. Following the 18-week core phase, patients could enter the extension phase and receive everolimus (target exposure: 3-15 ng/mL) until !48 weeks. Efficacy endpoints included change from baseline in average weekly seizure frequency (response rate [RR] , !50% reduction), and median percentage reduction (PR) in seizure frequency.

Results: 361/366 patients received everolimus in the core or extension phases. RR at week 18 was 31% (95% CI, 26.2-36.1; n 5 352) compared with 46.6% (95% CI, 40.9-52.5; n 5 298) at 1 year and 57.7% (95% CI, 49.7-65.4; n 5 163) at 2 years. Improved efficacy over time was prominent in younger patients. Median PR in seizure frequency was 31.7% (95% CI, 28.5-36.1) at week 18 compared with 46.7% (95% CI, 40.2-54) at 1 year and 56.9% (95% CI, 50-68.4) at 2 years. Early everolimus discontinuation (n 5 95) and insufficient follow-up due to study cutoff (n 5 103) contributed to fewer evaluable patients over time. Sensitivity analysis that included patients who discontinued early and were considered nonresponders showed a RR of 30.2% (95% CI, 25.5-35.2; n 5 361) at week 18 compared with 38.8% (95% CI, 33.7-44.1; n 5 358) at 1 year and 41% (95% CI, 34.6-47.7; n 5 229) at 2 years, suggesting response persisted irrespective of reducing sample size. Decreasing trend in incidence of adverse events (AEs) over time was observed (<6 months, 76.1%; 1 year, 46.8%; 2 years, 45.2%). Grade 3/4 AEs (any cause) occurred in 40.2% of patients. A total of 47 patients (13%) discontinued because of AEs including primarily pneumonia (1.7%) and stomatitis (1.4%). Two deaths (pneumonia, SUDEP) were reported.

Conclusions: Sustained reductions in TSC-associated treatment-refractory seizures over time were achieved with adjunctive everolimus. The safety profile of everolimus was consistent with the core phase, and AE frequency reduced over time.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Novartis has funded research at my institution that I am involved in and has paid my employer (CCHMC) for consulting work that I have done. Novartis has paid honoraria to me and has supported travel costs for lectures I have given. I am paid by various attorneys for legal work reviewing medical malpractice cases and occasionally giving expert testimony. Circular RNA (circRNA) is a recently recognized RNA species with covalently closed loop structures. CircRNA is very abundant in CNS, especially in synaptic components. Given that circRNAs are known to act as microRNA (miRNA) "sponge", circRNAs can regulate expression of numerous mRNAs by sequestrating miRNA and therefore inhibiting miRNA-mRNA interactions. As altered expressions of numerous miRNAs and relevant mRNAs are involved in pathomechanism underlying chronic epilepsy, we investigated the comprehensive profiling of circRNAs in relation with miRNA and mRNA in a mouse model of chronic epilepsy. The differentially expressed circular RNAs were identified by microarray analysis (Arraystar Mouse circRNA Array V2). Profiles of circRNAs from hippocampus and cortex of the four pilocarpine mouse models were analyzed and compared with those from four control mice. Among the total of 12984 circRNAs analyzed, 26 circRNAs were significantly upregulated (P< 0.05) and 17 were downregulated in hippocampus of pilocarpine mice. Potential target miRNAs that are expected to bind to those differently expressed circRNAs were obtained using bio-informatics and their expression profiles were analyzed using our experimental database. As the result, six circRNA-miRNA pairs of which expression levels were significantly regulated in opposite directions (exclusively in hippocampus of pilocarpine mouse) were further identified. 1066 mRNA targets for the six miRNAs were searched using a database (www.targetscan.org), and 105 mRNAs among them were significantly dysregulated in hippocampus of pilocarpine mouse models. Among them, 24 mRNAs with previously demonstrated role in chronic epilepsy were identified to have relevantly altered of expression profile of circRNA-miRNA-mRNA matches (up-down-up regulation or down-up-down regulation). These findings indicate that circRNAs might have a significant pathomechanistic role in chronic epilepsy. As circRNAs are resistant to RNA exonucleases therefore very stable, circRNA might possibly be a therapeutic target for epigenetic regulation of chronic epilepsy. Epilepsy is a neurological disease that affects 65 million people worldwide and 3 million in the US. About 30% of these patients do not respond to existing treatments, creating an urgent need for new therapies to address this drug-resistant population. A promising small molecule treatment that has surfaced recently is KPT-350, a Selective Inhibitor of Nuclear Export (SINE) compound. SINE compounds inhibit the nuclear export protein Exportin 1 (XPO1) that carries over 200 cargo proteins to the cytoplasm, facilitating certain proinflammatory pathways. Previous work has established antiinflammatory and neuroprotective properties of KPT-350 in various animal models. Therefore, it was proposed that inhibiting XPO1 could modulate neuroinflammation, blood brain barrier integrity and aberrant neurogenesis, which are key pathophysiological processes in epilepsy. To determine whether KPT-350 could reduce the epileptic phenotype, the compound was tested in the mouse pilocarpine model of epilepsy with spontaneous recurrent seizures (SRS). After 2week baseline SRS monitoring epileptic mice were dosed with vehicle or 0.3, 3 or 7.5 mg/kg KPT-350 PO QoD for 2 weeks. Dosing with 3 and 7.5 mg/kg KPT-350 significantly reduced SRS incidence during the treatment period (p<0.001). A significant number of mice treated with 3 or 7.5 mg/kg KPT-350 responded with a 50% decrease in SRS count when compared to vehicle-treated mice (p<0.001), and 6 out of 24 mice treated with 7.5 mg/kg became seizure free. Furthermore, mice treated with 3 mg/kg showed a sustained reduction in SRS during the 2-week drug washout period; effects at 7.5 mg/kg were not assessed in the washout phase. Additionally, the effects of KPT-350 on the seizure threshold of na€ ıve and epileptic pilocarpine mice were assessed in the acute 6 Hz test. It was found that a single dose of 7.5 mg/kg KPT-350 significantly increased the seizure threshold in epileptic mice, but not in na€ ıve mice. Based on these results, we can conclude that KPT-350 shows promising anti-seizure effects which warrant further investigation.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Sharon Tamir is a salaried employee and shareholder of Karyopharm Therapeutics S212. New Onset Gabapentin-Induced Myoclonus in Renal Failure: A Case Report Yazan Kherallah, Aaron Desai and Rohit Marawar. Detroit A calcium channel inhibitor, Gabapentin (GBP) is FDA approved for treatment of neuropathic pain associated with post-herpetic neuralgia and as an adjunctive treatment for partial seizures. It is most commonly used for non-approved indication of pain associated with peripheral neuropathy. While previous case reports have noted myoclonus as a symptom of GBP (and pregabalin) toxicity, it continues to be an under-recognized adverse drug reaction. Here, we describe the case of a 43 year old woman with end-stage renal disease on hemodialysis and without any history of seizures who developed confusion alongside multifocal myoclonic jerks involving all extremities one week after initiation of GBP at 300 mg TID for neuropathic pain. Her CBC showed a mild leukocytosis with a WBC of 12.0 as well as an anemia with a hemoglobin of 8.8 and hematocrit of 28.6 (baseline). Her basic metabolic panel that showed an elevated BUN and creatinine of 29 and 8.39 respectively (baseline). Ammonia level was normal. EEG showed generalized slow nonrhythmic activity in the delta/theta frequency range. Patient had multiple myoclonic jerks during the EEG without associated electrographic epileptiform discharges suggesting that myoclonus was subcortical. Discontinuation of the drug and hemodialysis led to improvement of the patient's clinical condition within a day. Although pathogenesis of GBP toxicity causing myoclonus is poorly understood, alterations in the serotonin neurotransmitter system have been postulated to play a role. Gabapentin has a high volume of distribution (58 L), is water soluble, not bound to protein, and renally cleared. Hemodialysis can remove approximately 35% of the drug each session. Myoclonus should be suspected as an adverse drug reaction in patients taking GBP, especially in patients with renal insufficiency. With a high index of suspicion, aggressive testing and treatment for other possible conditions like seizures or CNS infections can be avoided. In patients with renal failure and with decreased physiological renal clearance such as the elderly, GBP dose initiation and changes should be conservative. Introduction: Epilepsy affects at least 50 millions individuals worldwide. In two-third of the cases, epilepsy etiology is unknown. Investigations of suspected genetic etiology can often improve diagnostic precision and may guide therapeutic decisions. The process of molecular analysis is complex. Many eligible patients do not complete this diagnostic path. Baylor Genetic Epilepsy Clinic was established to facilitate access to genetic testing in adults with epilepsy. We analyzed our patient cohort referred to date in order to better understand the clinical utility of the genetic testing in adults with epilepsy and potential barriers to completion of testing process.

Methods: We performed a retrospective chart review of 129 adults with epilepsy referred to Baylor Genetic Epilepsy Clinic between 2013 and 2017. Epilepsy phenotype and comorbidities were defined according to the established guidelines. Testing platforms were tailored to epilepsy phenotypes and accepted practice recommendation. We analyzed the characteristics of those with available genetic results as well as the reasons behind the absence of diagnostic data in the remainder of the cohort.

Results: The diagnostic process was completed in 43/129 cases, pending completion in 23/129 cases and deferred in 63/129. In those with available genetic results, epilepsy was primary generalized in 30/43 (70%) cases and localization related in 13/43 (30%) cases. Epilepsy was refractory to treatment in 74%. Co-morbid intellectual disability was present in 48%. Genetic testing yielded clinically pertinent results in 46% and biologically plausible findings in additional 14%. Whole exome sequencing yield approached 39% while yield of chromosomal microarray was 27%. Single gene testing confirmed suspected clinical diagnosis in 3 cases. Mitochondrial gene testing uncovered variants of uncertain clinical relevance in 18%. We found that financial or health insurance considerations closely followed by outstanding questions or concerns related to genetic screening figured most prominently as the cause for delay in testing and were operative in 52% and 38% of patients, respectively.

Conclusion: In adults with epilepsy of suspected genetic etiology, genetic testing can provide meaningful results in close to 2/3 of the cases. Yet, a considerable portion of adults with epilepsy does not complete the diagnostic process, mostly due to financial considerations, insurance denials and personal reservations related to genetic investigations. Our findings warrant ongoing systematic analysis of patients and their social, cultural, and other personal circumstances. Objective: Stereoelectroencephalography (SEEG) is gaining more frequent use in presurgical planning for epilepsy patients. This refined invasive monitoring technique allows for more precise localization of seizure foci, particularly for deep cortical structures, in comparison to traditional grid/ strip electrodes. However, convergent validity between invasive monitoring technique and neuropsychological testing (also key in presurgical planning) has not been established. The current study aimed to determine the diagnostic accuracy of neuropsychological findings for lateralizing/localizing of seizures in patients undergoing invasive monitoring (i.e., SEEG or subdural grids/strips electrodes).

Methods: Patients with drug-resistant epilepsy and undergoing presurgical epilepsy workup that included invasive monitoring were recruited for this study. Neuropsychological assessment was completed no more than three months prior to invasive monitoring.

Results: Twenty patients with a mean age of 35.2 (9.93) years were included in this study. Patient characteristics included 53% male, 76% right-handed, and 44% bilingual individuals. Seizure duration ranged from 2 to 42 years. Regarding localization of seizure onset, neuropsychological data was consistent with SEEG findings 88% of the time and was consistent in 60% of individuals undergoing grid/ strip study. Regarding lateralization, neuropsychological data correctly predicted side of seizure onset via SEEG 63% of the time and was consistent in 50% of individuals undergoing monitoring via a grid/strip study. Across both monitoring techniques, neuropsychological testing was more successful at determining localization of seizure onset (72% of cases), as compared to lateralization (59% of cases).

Conclusions: Overall, neuropsychological findings were more predictive of SEEG data than grids/strips data, perhaps reflecting the more refined, precise data yielded by SEEG. The diagnostic accuracy of neuropsychological testing in candidates for epilepsy surgery, particularly in terms of localization of seizure focus, further supports its prognostic in populations with drug resistant epilepsy. S215. Vestibular Epilepsy: A Case Report Nisali A. Gunawardane, Valerie L. Sharf, James J. Young, Ji Yeoun Yoo, Lara V. Marcuse and Madeline C. Fields. New York, NY and Valhalla, NY Objective: Vestibular epilepsy is characterized by focal seizures which manifest clinically with symptoms of disequilibrium and vertigo. Information gleaned from direct cortical stimulation studies as well as stereotactic and surface EEG studies point to multiple cortical areas with vestibular representation rather than the presence of a single vestibular cortex. Vestibular cortical representation is typically localized to the right or left temporal lobe. Rarely, isolated symptoms of vertigo or disequilibrium can be the sole manifestation of epilepsy. We present a case of an elderly patient with symptoms of dizziness corresponding to a seizure during ambulatory EEG monitoring.

Background: The patient is an 80-year-old man with a past medical history of hypertension, hyperlipidemia, TIA, hypothyroidism and prostate cancer who presented with difficult to treat episodes of dizziness for the past ten years. The episodes happened suddenly and without warning and would last 1-2 minutes. During these episodes he felt as if he was going to fall and had occasional nausea. The frequency of symptoms varied from multiple times in one day to once every few months. He would return to baseline immediately afterwards. A recent MRI as part of a TIA workup was unremarkable. He had no prior history of seizure or stroke.

Methods: A four-day ambulatory EEG. Our patient was instructed to record episodes of dizziness.

Results: A seizure of right-temporal onset followed by post-ictal right-hemisphere slowing was noted during an episode of dizziness. The EEG was consistent with focal epilepsy. Our patient was started on Levetiracetam with complete resolution of episodic dizziness.

Conclusions: Vestibular epilepsy is considered to be a rare phenomenon and is often seen in association with other clinical symptoms associated with focal seizures rather than in isolation. Our patient lacked additional clinical manifestations of focal seizures such as dysmnesic symptoms, sensory changes and automatisms that may confound EEG localization and may be more indicative of cortical spread rather than rising from a primary vestibular cortical focus. Our patient had an episode of dizziness which correlated with a focal seizure on EEG of right temporal onset that resolved after starting Levetiracetam. Patients with vestibular epilepsy have a high rate of response to AED therapy. One third of localization-related epilepsy patients have normal-appearing clinical MRIs. These patients are 2-3 times more likely to have worse outcomes after surgery compared to those with lesions identified on MRI, perhaps due to an inability to accurately identify the epileptogenic focus. We previously demonstrated that the noninvasive, functional, single-slice Glutamate Chemical Exchange Saturation Transfer (GluCEST) imaging technique can lateralize and localize epileptogenic regions in the hippocampus on 7T MRI in MRI-negative patients, indicating increased GluCEST signal in the ipsilateral total hippocampus and ipsilateral hippocampal head. Here, we present confirmatory findings using the novel CEST imaging technique capable of volumetric imaging (Krishnamoorthy et al., 2016) .

Imaging was performed on a Siemens 7T MRI scanner equipped with a volume transmit/32-channel receiver array head coil. The MRI protocol included: 1) A localizer scan, 2) T1-w MPRAGE scan (TR/TI/TE 5 2800/1500/4.4 ms, FA570, GRAPPA52, 170 sagittal slices, voxel size 0.8 mm3), 3) T2w-MRI for subfield segmentation (TR/ TE 5 3000/388 ms; Matrix 5 448 3 428; in-plane resolution 5 0.4 mm x 0.4 mm; slice thickness 5 1.0 mm; 224 oblique coronal slices perpendicular to the hippocampal long axis), 4) B0 field-map for EPI distortion correction sequence (TR/TE1/TE2 5 900/10/14 ms) and 5) 3D GluC-EST scan (TR/TE 5 5.9/2.83 ms; Matrix 5 240x192; inplane resolution 5 1 mm2; slice thickness 5 1.0 mm; GRAPPA52; 60 axial slices). Raw CEST images were acquired by varying saturation offset frequencies from 6 1.8 to 6 4.2 p.p.m. with a step size of 0.3 p.p.m. B0 inhomogeneity was less than 0.15 p.p.m with localized shimming. To acquire whole brain GluCEST, a segmented elliptical center encoding strategy was used for the phase encode(ky) -slice encode(kz) plane, with ASHS segmentation to measure hippocampal GluCEST.

In 4 nonlesional (MRI-negative) left-sided TLE patients, we found increased GluCEST signal in the ipsilateral total hippocampus relative to the contralateral total hippocampus with statistical significance (p50.048, 1-tailed paired twosample t-test) using multi-slice GluCEST. Although parameters are still being optimized for high fidelity acquisitions, these results are consistent with our previous study of single-slice GluCEST in MRI-negative TLE patients. As we recruit more patients, we will further investigate GluCEST signal in hippocampal subfields and correlate these findings to electrophysiological and clinical outcomes, eventually leading to a superior understanding of epilepsy excitatory networks and improvement of surgical resection outcomes.

Abhinav Ohri and Yasir Al-Khalili. Philadelphia, PA Objective: Musicogenic Epilepsy is a reflex Epilepsy, triggered by a specific stimulus i.e music. Visual stimuli, somatosensory stimuli, hot-water immersion, reading and music are some triggers for reflex epilepsies. Musicogenic epilepsy is extremely rare with a prevalence of 1 in 10 million. Approximately 6.5% off all epilepsies are reflex epilepsies.

Background: Musocogenic Epilesy (ME) was first described by Critchley in 1977. ME usually have a focal onset and a temporal lobe epileptic region is present in 79%. 60% have right lateralization. Localization is done with the help of functional tests or EEG (Electroencephalogram) as usually no structural lesion is found.

Results: 41-year-old right handed male presented with a two-year history of blacking out spells. No seizure risk factors were reported on history. His physical exam was within normal limits. His MRI was unremarkable. A routine 20 min EEG showed rare left temporal sharps and a 24hr ambulatory EEG was normal. He followed up 4 months later with 3 episodes of LOC for 20 minutes, with headache and post ictal confusion, which occurred after listening to music. He was later brought in for an EMU(Epilepsy Monitoring Unit) admission. During the admission he started playing the song "La femme D' Argent". This was followed by pursing of his lips, chewing and lip smacking with tonic extension of the right side of his body followed by generalized tonic clonic activity. The EEG revealed left temporal onset on T1 and T3 leads. His seizures were precipitated by modern music and control music like classical or baroque style did not elicit seizures. He was started on Topiramate and discharged home.

Conclusion: The specific musical component responsible for seizure precipitation is still undetermined. Musicogenic seizures usually involve a degree of cognitive or emotional appreciation of the stimulus. In some cases, merely thinking of the atmosphere and the emotions associated with a certain stimulus is enough to induce a seizure.

S218. DASEP 15 a New Instrument to Measure Disability in Epilepsy Sanjeev V. Thomas, Sushama S. Ramachandran and P. S.

World Health Organization has defined disability as an umbrella term covering impairment, activity limitation and participation restriction. There is no validated instrument to quantify disability in epilepsy although it is the most common serious neurological disorder in the world. Our objective in this study was to develop a handy instrument to quantify disability in epilepsy.

We used Disability Assessment Schedule II -DAS II (36 items) that had been developed and validated by WHO across different societies in health and disease states to assess disability of epilepsy. We correlated DAS II scores with results of International classification of functioning (ICF), WHO well being index (WBI), Hospital Anxiety Depression Scale (HADS) and Quality of life in epilepsy 10 (QOLIE 10) schedules.

We administered the above set of instruments to 187 women and 113 men with epilepsy (age 18 -60 years, mean 32.9 1 11.8 years) attending to outpatient epilepsy service. The mean (SD) scores were: DASII: 6.19 (5.76), QOLIE 10: 16.62 (3.71), WBI: 13.44 (4.83), IQ: 93.1 (5.67), HADS anxiety: 6.99(3.88) and HADS depression: 6.69 (3.33). There was significant correlation between DASII score and lower education(p50.001) lower occupation (p50.002) and lower income (p50.31). There was significant correlation between DAS II score and QOLIE 10, WBI, IQ, HADS-Depression score, HADS anxiety score.

Based on the results we prepared a 15 item questionnaire (12 from DAS2, education, hospitalization for care of epilepsy or complications in past one year and duration of epilepsy that was tested for validity. The area under the ROC curve for the plot DASEP15 against score of DAS II score >10 was 0.65 (p50.001). A cut off value of 11 on DASEP15 had a sensitivity of 64 and specificity of 67.

Conclusion: The DASEP 15 is a handy instrument to quantify disability in epilepsy as it has good correlation with DAS II and other indirect measures of disability in epilepsy. Background: The accurate diagnosis of LGS is complex, and misdiagnosis can result in suboptimal treatment. To improve both identification and treatment of patients with this severe epileptic encephalopathy, the REST-LGS was developed using the Delphi method, and inter-rater reliability was measured as a first step in validating the tool for clinical use.

Design/Methods: Using de-identified records of patients >12 years with refractory epilepsy and !2 neurology clinic notes, 4 major and 4 minor potential diagnostic criteria were evaluated on individual case report forms by two raters (specialist, non-specialist) at two epilepsy centers. Extent of inter-rater reliability at each site was measured by Cohen's j.

Results: Of 200 records evaluated (100/site), 81%-85% patients met 1-3 major criteria. At Site 1, moderate agreement (j50.40-0.60) was reached between raters on whether patient records reflected persistent seizures despite trial of !2 antiepileptic drugs; at Site 2, both raters agreed that all patients had persistent seizures. Moderate agreement to good agreement (j50.40-0.80) was reached at each site on the following criteria: !2 seizure types; seizure onset 12 years; history of EEG with generalized slow spike-andwave discharges <2.5 Hz; other EEG abnormalities. At both sites, very good agreement (j50.80-1.00) was reached on cognitive impairment since childhood and history of VNS, ketogenic diet, or epilepsy surgery. At Site 1, very good agreement was reached on diagnosis of definite LGS, while agreement at Site 2 was good. At both sites, poor agreement (j<0.20) was found on evidence of seizurerelated helmet use/head or face injuries.

Conclusions: Overall, this first step in validation of the REST-LGS revealed moderate to very good agreement on criteria indicative of LGS among raters at two epilepsy centers.

Funding: Lundbeck. Introduction: While the burden of neurologic illness in developing countries is increasing, little is known about its true prevalence throughout sub-Saharan Africa. Mulago Hospital is Uganda's largest tertiary care referral center located in the capital city of Kampala. Mulago attends to approximately 120,000 inpatients annually. The true prevalence of neurologic illness and its association with mortality in Uganda, a country of 41 million people, is unknown.

Methods: Data was prospectively collected on 335 patients admitted to the neurology wards of Mulago Hospital from January 2009 to May 2011. Data collected included: demographic information, village of residence, admission/discharge diagnoses, HIV status, discharge disposition, and mortality data without the benefit of an electronic medical record.

Results: Patients admitted to the neurology ward were on average 48.9 6 21.8 years. Half were women and 40.6% resided in the capital city of Kampala (40.6%). At the time of admission, 33.9% received no diagnosis. Ischemic stroke (14.4%), head trauma (10.4%), seizure (9.09%), hypertension (7.7%), and psychiatric illness (6.06%) were the most common admission diagnoses. Average length of stay was 7.45 6 7.23 days. A total of 57 (18.45%) patients died during the index hospitalization, with mortality being highest among patients with admitted with: no diagnosis (33.3%), ischemic stroke (13.7%), head trauma (11.8%), cerebral malaria (9.8%), and seizure (7.8%). Death occurred equally among women and men.

Conclusions: Our data suggest there is a wide variability of diagnoses amongst patients admitted to a Ugandan neurology ward. Although a majority of patients did not have established diagnoses, ischemic stroke was the most common diagnosis and the most frequently associated with mortality. Mortality overall was high but comparable to a similar prevalence studies in another neurology ward in sub-Saharan Africa. Our study helps to identify potentially treatable conditions in which mortality rates are especially high. Future research should seek to understand how mortality relates to other factors during hospitalizations and whether interventions to improve delivery of care to patients at higher risk of mortality may affect patient outcomes. Introduction: There are $2 million HIV1 children in Sub-Saharan Africa (SSA), but <1/3rd are on antiretroviral treatment (ART). Seizures are common in HIV1 adults and new onset seizures in HIV1 adults in SSA are often associated with advanced, untreated disease and early high mortality risks. Much less is known regarding HIV and seizures in children in this setting. In developing countries most available antiepileptic drugs (AED) are enzyme-inducing agents at risk of interacting with ARTs, possibly predisposing those on AED and ART combinations to increased drug toxicity and/or the development of antiretroviral resistant strains of HIV. As a result, there is a need to balance risk and benefit of AED initiation in HIV1 children. In April 2016, we commenced a prospective cohort study of new onset seizure in HIV1 children to identify the causes for acute seizures, evaluate the long-term risk of seizure recurrence, and identify risk factors for seizure recurrence.

Methods: Since April 2016, consented HIV1 children admitted to Lusaka Children's Hospital with new onset seizure have been enrolled in this observational study which provides brain MRI, EEG, serum viral load, cryptococcal antigen test, and CSF studies including Gene Xpert, tuberculosis culture, and PCR for common opportunistic infections (OIs). Children undergo quarterly neurodevelopmental assessments and are followed for seizure recurrence, AED use and ART adherence.

Results: To date, 18 children have been enrolled. Only 4 children were on ART at enrollment, 14/18 were newly diagnosed HIV1 and 7/14 were sentinel HIV cases whose diagnosis facilitated HIV identification in other family members. Clinically, mean CD4 was 281 (CD4 14.8%). Seizure etiology was identified in 12/18 with 10/12 being HIV-related (OI, HIV encephalopathy, immune reconstitution inflammatory syndrome), one case of possible non-accidental trauma and one due to perinatal stroke. Three children were discharged on AEDs. 13/18 children have died, 7/18 children dying during the index admission. CNS infections, suspected tuberculosis, and severe malnutrition were noted to be the causes of death. The 5 survivors remain seizure free.

Conclusion: The acute case fatality rates in Zambian children with new-onset seizures is extremely high. In regions with high HIV prevalence, new onset seizures may be indicative of untreated HIV. Enrollment is ongoing and neurodevelopmental outcomes will be monitored in the years to come with the aim to identify risk factors for mortality and epilepsy in this vulnerable pediatric population. Aims: The prevalence and determinants of the DPN among a group of type 2 diabetic (T2DM) subjects, Bangladesh.

Materials and Methods: A cross-sectional study was conducted among 640 urban (M/F, 244/396; age in years, 52.23 6 11.8; BMI, 25.95 6 3.9 Kg/m2) and 560 rural (M/ F, 244/396; age in years, 50.89 6 11.9; BMI, 24.13 6 4.6) T2DM subjects, selected purposively from various health care facilities in Dhaka and Northern Districts of Bangladesh. Diagnosis of T2DM and DPN was done by WHO Study Group Criteria (following a 2-sample OGTT) and IWGDF recommendation respectively. DPN was assessed by using 5.07 (10-g) Semmes-Weinstein monofilament (applied in 10 point of the feet), 128 Hz tuning fork (for vibration sense), and two types of sensation test (fine, crude touch).

Results: DPN was present among 21.1% (95% CI, 18.8-23.4) of T2DM subjects. Regarding the sex specific, women (24.1%; CI, 21.0-27.2) showed about 1.5 times higher prevalence compared to that of men (16.0%; CI, 12.6-19.4) and the difference was highly significant (p<0.001). The prevalence of DPN was much higher among rural subjects (24.5%; CI, 20.9-28.1) compare to the urban subject (18.1%; CI, 15.1-21.1) and the difference was highly significant (p<0.001) between the two demographic locations. In Chi-square test and t-test, respondents educational status, economic status (ES), random blood sugar (RBS) and duration of wearing footwear had significant (p<0.05) difference for DPN subjects compare to counterpart in urban area; occupation, ES, household monthly income, RBS and duration of diabetes (DOD) had significant (p<0.05) difference for DPN subject compare to counterpart in rural area. On multiple regression analysis, raised RBS (p<0.001; OR52.3, CI, 1.3-3.9), long DOD (p<0.001; OR53.0, CI, 1.7-4.3 and long duration of wearing footwear (p<0.001; OR52.7, CI, 1.4-4.0) were the main predictors in urban area whereas, raised RBS (p<0.001; OR51.9; CI, 0.8-3.0), long DOD (p<0.001; OR53.3; CI, 1.8-4.8) and poor ES (p<0.001; OR52.9; CI, 0.6-14.0) were the main predictors in rural area.

Conclusions: A large proportion of T2DM subjects in Bangladesh, both men and women, irrespective of urban or rural origin, suffer from neuropathy. Raised RBS, long duration of diabetes and long duration of wearing footwear were the predictors for DPN in urban area; raised RBS, long duration of diabetes and poor economic status were the predictors for DPN in rural area. Background: Rates of stroke -the 5th leading cause of death and a major cause of neurological disability in the U.S. -are unknown among Navajo. Pooled data suggest that American Indians and Alaska Natives (AI/AN) suffer high rates of stroke, but tribes have not been examined individually despite varying levels of risk factors. Furthermore, it is known that rates of other neurological disease differ between the Navajo and the U.S. as a whole. While Navajo do possess many risk factors for stroke, few Navajo smoke cigarettes. We analyzed the occurrence of stroke overall and by subtype in the Navajo Nation between 2001-2014 and made comparisons to other populations in order to report the burden of stroke in this population, guide healthcare, and begin to assess the impact of not smoking on stroke in AI/AN.

Methods: We analyzed inpatient, outpatient, and emergency room data from the National IHS Patient Reporting System (NIPRS) between 2001-2014. The unit of analysis was the individual patient; included cases of first-time stroke were >18 years with documentation of stroke by 431, 433.x1, 434.x1, or 436 . The average number of annual patient-visits to any IHS facility was 152,901 over the study period. We determined crude and age-adjusted incidence rates overall and by sex, age, year and stroke subtype and expressed each per 100,000 population. We calculated 95% CI for each rate.

Results: Preliminary data show the average annual crude incidence rate for stroke was 81.2/100,000 (95% CI 566.9-95.5). Age-adjusted rates were 68.7, with an agespecific peak incidence of 75-84 year-olds. Overall stroke rates for men (77.5) were higher than rates for women (62.9). Stroke subtypes comprised 18.52% spontaneous hemorrhage and 53.3% ischemic, with the remainder uncategorized. Among ischemic strokes, 6.5% were large vessel or embolic, 46.8% were lacunar.

Conclusions: Despite possessing a myriad of stroke risk factors, the overall incidence of stroke among the Navajo appears to be relatively low and the pathophysiology of stroke favors small vessel over carotid artery disease or cardioembolism. Fewer and smaller strokes indicate lower morbidity and mortality in this population, and is consistent with the positive effects of widespread abstinence from cigarettes. Whether other factors in addition to not smoking also contribute awaits further study. Guillain-Barr e syndrome (GBS) is a descriptive disease entity defined by a set of clinical, electrophysiological and laboratory criteria. Various clinical phenotypes exist that may be triggered by different antecedent infectious events. Although the disease appears to affect primarily the elderly in developed countries, but, scenario is different in developing countries. Bangladesh has made an impressive progress towards the eradication of poliomyelitis. However, nonpolio AFP cases are frequently diagnosed, and the incidence rate is currently 3.25 per 100,000 children less than 15 year of age. GBS, an acute polyradiculoneuropathy, is the most frequent cause of AFP. The crude incidence rate of GBS in <15 years of age reported here appears to be 2.5 to 4 times higher than that reported in the literature. We conducted a hospital based observational study including 600 patients fulfilling the National Institute of Neurological Disorders and stroke (NINDS) criteria for GBS patients between 2010 and 2016 in Dhaka Medical College Hospital and National Institute of Neuroscience, Dhaka, Bangladesh. Detailed clinical, electrophysiological, serologic and microbiological data were obtained. GBS affected predominantly in young adults males (M/F52:1) living in rural areas. Antecedent events were recorded in 70% of patients. The most frequent events being gastroenteritis (>40%) and upper respiratory tract infection (18%). Symmetrical weakness and reduced reflexes were found in a majority of 98% patients. Disease course was monophasic in all patients. More than 60% of the patients were bed-bound at entry and about 20% patients required mechanical ventilator. GBS is associated with exceptionally higher deaths (13%) which, is related to lack of ventilator support, disease severity, longer progressive phase of the disease, autonomic dysfunction, and involvement of the bulbar nerve. About 60% of patients had an axonal variant of GBS and evidence for a recent C. jejuni infection was found in 55% of GBS patients. C. jejuni infection was significantly associated with serum antibodies to the gangliosides GM1 and GD1a, and axonal neuropathy. About 90% patients did not receive specific treatment either Intravenous Immunoglobulin (IVIg) or plasmapheresis due to high expensive treatment cost. Finally, GBS in Bangladesh is a severe, predominantly pure motor and axonal neuropathy with a high mortality rate. The majority of the patients do not receive specific and standard treatment with IVIg in view of its high price. Therefore, low-cost treatment strategies are required for GBS patients in developing countries like Bangladesh. Background: CT is often unavailable or unaffordable in low-income countries, creating challenges for patient care and impeding the understanding of neuroepidemiology necessary for policy development. Hôpital Universitaire de Mirebalais in rural Haiti houses the country's first publicly accessible CT scanner at no cost to patients, providing a rare opportunity to study neurologic disease in a rural lowincome setting.

Methods: We performed a retrospective analysis of head CT reports for CTs performed between July 2013 and January 2016 at Hôpital Universitaire de Mirebalais in rural Haiti, extracting patients' age, study indication, and radiologic findings.

Results: 3,614 head CTs were performed on 3,416 patients. Repeat scans in the same patient were excluded from subsequent analyses. The most common indications for head CTs were headache (27% of all scans), trauma (19.9%), abnormal neurological exam (12.2%), and stroke (11.3%). 44.4% of scans were normal, 4.2% were inconclusive. The most common categories of neurologic abnormalities were traumatic (31%), vascular (25.8%), and infectious (12%). Of 291 strokes, 64% were ischemic (median age at diagnosis 60.8 years, SD 17.4), and 36% were hemorrhagic (median age 52.0, SD 15.5). Evidence of neurocysticercosis was present on 11.8% of CTs (median age 42.6, SD 19.0). Atrophy was noted in 10% of CTs (median age 57.1; SD 23.8), and was characterized as atrophy out of proportion to age in 2% (median age 34.1, SD 15.3). In patients with head trauma, 22.5% had intracranial hemorrhage and 35.5% had fractures. In those scanned for seizures or epilepsy, 17.5% had evidence of neurocysticercosis. In patients undergoing head CT in the setting of known or suspected cancer, 42.7% had evidence of non-CNS tumors and 8.4% had evidence of CNS tumors. The indications with the highest proportion of normal head CTs were endocrine complaint (73.9% normal), neuropathy (71.4%), headache (69.2%), cramps (66.7%), and behavioral/psychiatric issue (60.5%).

Conclusions: Age at stroke in our rural low-income population is lower than in high-income countries and proportion of stroke due to intracerebral hemorrhage is higher. Neurocysticercosis is present in a significant proportion of patients with seizures/epilepsy in our population. These findings can inform policies for prevention and treatment of neurologic disease in low-income settings. The high proportion of normal CTs for several indications underscores the importance of ongoing education for effective use of newly introduced diagnostic tests in resource-limited settings. Background: Although evidence suggests that social supports improve functional recovery after stroke, this work has not been extended to low-and middle-income countries (LMICs) where stroke is a leading cause of death and permanent disability. LMICs account for over 87% of the global disability adjusted life years from stroke. Likewise, poststroke depression can interfere with functional outcome but is understudied, particularly in Africa, where the stroke burden is high and increasing.

Methods: We examined the relationship of social support with 90-day disability in patients with hemorrhagic and ischemic stroke at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania. Participants aged 18 or older admitted to MNH within 14 days of stroke onset were eligible if they met World Health Organization definition for stroke (August 2016-March 2017). 90-day disability was measured using the modified Rankin Scale (mRS). The Berkman-Syme Social Network Index (SNI) and the Patient Health Questionnaire (PHQ-9) measured social support and post-stroke depression, respectively. Depression was classified as 5 points or more on the PHQ-9. For predictors of depression, univariate regression analyses was used for model building, including variables with a two-tailed p-value of <0.10 or known confounding variables. Spearman's correlation coefficients were calculated to determine the degree of the correlation between 90-day outcomes. A two-tailed pvalue of <0.05 was considered statistically significant.

Results: Of 85 patients, 54% were male (n546), with an average age of 56 years (standard deviation 14.9 years). 28% of stroke survivors (n524) reported post-stroke depression. At 90 days post-stroke, more than one-third of patients (36%, n534) reported having 3-5 close friends. Group affiliations were high (66%, n562 reporting at least one affiliation). In multivariable analysis, disability at 90 days was statistically significantly associated with depression (p50.046). A history of employment (versus unemployment) showed a trend toward significance (p50.076). NIH stroke scale score at stroke presentation and age were not associated (each p>0.05).

Higher number of depressive symptoms was correlated with higher disability on mRS (r50.582, p<0.0001) and lower social engagement (r5-0.435, p50.0001). The relationship between disability and social engagement was not significant (r5-0.160, p50.156).

Conclusion: Social support is related to post-stroke depression and recovery, although a causal model is not established. In LMICs, social networks are often a principal source of resources for patients. Understanding the relationship between social networks, depression, and post-stroke recovery in resource-limited settings will help inform costeffective interventions for rehabilitation of stroke survivors. Tanzania Introduction: The incidence of stroke in Sub-Saharan Africa, particularly in Tanzania, is estimated to be three times higher than in most high-income countries; however, little is known about stroke subtype and mechanisms in this region. We examined whether vascular risk factors reported by patients admitted with acute stroke accounted for their presumed stroke subtype based on brain imaging.

Methods: Patients were enrolled at a large referral hospital in Dar es Salaam, Tanzania, when presenting with a stroke syndrome within 14 days of onset, from July 2016 to March 2017. Head CTs were reviewed at admission by the treating physicians and then confirmed by a neuroradiologist who was blinded to the clinical information. Sub-classification of ischemic stroke was based on TOAST categories with further characterization by size and arterial territory. Reported vascular risk factors were assessed for each patient compared to his/her head CT.

Results: Amongst enrolled patients (mean age 58 years, 44% female), imaging confirmation was made in 56 (46.7%) ischemic and 64 (53.3%) hemorrhagic cases. For those with ischemic strokes, 53 out of 56 (94.6%) were large vessel embolic infarcts (LVE) i.e. cardioembolic or artery-artery embolism, while 3 out of 56 (5.4%) were related to small vessel disease. Amongst those with LVE infarcts, 85% were anterior circulation and 15% were posterior circulation infarcts. Although hypertension, diabetes, dyslipidemia and smoking were reported in 82%, 30.4%, 3.6% and 12.5% patients respectively, the presence of atrial fibrillation was reported in none of the patients and no patient was on anticoagulation beforehand. 44.6% (n525) of all patients had imaging evidence of prior (non-acute) embolic infarcts.

Conclusion: Our study suggests that large vessel embolic (LVE) ischemic strokes are prevalent in this Tanzanian referral hospital. Atrial fibrillation, an independent risk factor for ischemic stroke, is significantly under-detected. Oral anticoagulation -which reduces AF related stroke risk by $64%, is almost certainly under-utilized for stroke patients in resource-limited settings. The known vascular risk factors in this population do not account for the high number of ischemic stroke burden seen. Our results highlight a critical need for cardiac monitoring to detect AF as well as neck vessel imaging to detect carotid vascular disease. These measures would improve secondary prevention for a large subset of ischemic stroke patients and decrease the overall burden of stroke in this population. To assess the quality of acute stroke care provided at a national referral hospital in Tanzania and the corresponding measures on morbidity and mortality.

Background: Stroke is a leading cause of mortality across the globe. While quality measures for acute stroke care are commonly tracked in high-income countries, less is known about the quality of care received by patients with acute stroke presenting to hospitals in low-income regions, or the effect of hospital quality of care metrics on patient outcomes.

Methods: We conducted a longitudinal study of adult patients admitted with acute stroke to Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania, between July 2016 and March 2017 (recruitment ongoing). Participants with clinical diagnosis of stroke by their treating health providers, meeting the WHO definition of stroke, were included. Stroke severity was assessed through NIH Stroke Scale (NIHSS) on admission and outcome was the modified Rankin Scale (mRS) score on discharge. To evaluate quality of care, we recorded time to admission, in-hospital management, and medications and therapies received. We assessed 90-day mortality and morbidity (mRS score) for all patients post-discharge.

Results: A total of 204 participants were enrolled, with 50% male and an average age of 58.2 years (SD 14.7). Of these, 105 (51%) were diagnosed with ischemic stroke, and 99 (49%) with hemorrhagic stroke. The majority of patients (69%) presented to MNH within one day after the onset of symptoms. Sixty-two patients (30%) presented directly to MNH, while 141 (69%) were transferred from other facilities. No patients received tPA, as this was unavailable at MNH. Similarly, DVT prophylaxis was not routinely provided to stroke patients. Of patients with ischemic stroke, 80 (76%) received antithrombotic therapy within 2 days of admission, while 84 (80%) were discharged on antithrombotic therapy. Prior to initiating feeding, 161 (79%) patients were reported to have received screening for dysphagia. There was a 23% mortality rate at discharge; at 90-day follow-up, 49% of patients had died. Among patients who were living and contacted for 90-day follow-up, 31 (34%) had moderately severe to severe disability (mRS of 4 or 5).

Conclusion: Although the majority of stroke patients receive certain recommended interventions, there are significant gaps between the care provided to patients with ischemic and hemorrhagic stroke presenting to this national referral hospital in Tanzania and the recommended guidelines for stroke care.

Headache and Pain S232. Goldilocks Phenomenon of Temperature in Burning Mouth Syndrome Khurram A. Janjua, Karam Jeet Tagore, Feras A. Shalabi and Alan R. Hirsch. Rodney Bay, Saint Lucia; Curacao, Netherlands Antilles; Kralendijk-Bonaire, Netherlands Antilles and Chicago, IL Introduction: Exacerbations of burning mouth syndrome (BMS) have been reported to occur with hot food or drinks and alleviation of pain with cold food or drinks (Forsell 2012). Pain threshold is elevated in BMS when the temperature probe is applied on the tongue. Once detected, however, the intensity of the pain is more severe, not only to hot, but also to cold temperatures (Ito 2002) . A case of a patient with BMS supported these physiologic findings of high and low temperature foods exacerbating BMS, leaving a critical temperature window in which BMS symptoms do not worsen.

Methods: A 47-year-old right-handed female presented with a 4-year history of BMS throughout her tongue, gums and palate. She is unable to drink or eat hot or cold because these markedly exacerbate her pain. Room temperature water, coffee or soup does not intensify the pain whereas cold or hot liquids intensify it from a 2/10 to a level 6/10 in severity. Popsicles and ice cream markedly increase the burning as do hot solid foods. She must wait for them to cool down to mildly cool or warm, so as not to impact her pain. The pain is so substantial, she must immerse both her hands in her food just prior to consumption to make sure the temperature is not too hot nor too cold, but rather just right, before consuming it.

Results: Abnormalities in Neurologic examination: mild left pronator drift, bilateral abductor digiti minimi signs. Reflexes: 31 throughout. Bilateral Hoffman reflexes. Chemosensory testing:

Olfaction: normosmia on: Brief Smell Identification: 11. Alcohol Sniff: 9. Pocket Smell: 3. Retronasal Smell Index: 10. Gustation: Propylthiouracil Disc Taste: 9 (normogeusia). Taste Quadrant: decreased sodium chloride and sucrose on left; decreased sodium chloride, sucrose, and citric acid bilaterally and anteriorly. Whole mouth weakness to quinine hydrochloride. Fungiform papillae count: right 33, left 34 (normal)

Discussion: The temperature extremes might have a nosogenic effect through stimulation of C-fibers, AD-fibers and Ab-fibers (Ito, 2002) . Since these nerves are already irritated due to underlying BMS, they may be more reactive to such temperature stimuli. This suggests that in management of BMS, diet with a narrow temperature range may be effective in helping to control these symptoms.

Siddharth Shankar, Anoop Nehra and Alan R. Hirsch. Oranjestad, Aruba and Chicago, IL Objective: The association between atmospheric humidity and Burning Mouth Syndrome (BMS) pain has not been reported.

Methods: Case Report: 47-year-old female presented with BMS for four years predominantly involving dorsum of her tongue, spreading to the lips, gums, and palette, level 8/10 in severity. Initially it occurred everyday, 24/7. Per patient it was noted that the following actions made it worse: sleep deprivation, stress, very hot or very cold foods, drinking water, raw onions, potato chips, spicy foods, bread, and strong odors such as perfume or cologne. It was made alleviated by crying, rest, vacationing and variety of medications including clonazepam, alpha lipoic acid, diazepam, alprazolam, buspirone, magnesium hydroxide, and marijuana. She noted that the pain would increase from baseline intensity 3/10 to 8/10 when humidity would increase or would reduce in a similar fashion when humidity subside. When humidity was 45% or less the pain would be 0-1/10, but when humidity would increase to 95% the pain would naturally intensify. When the humidity would drop down to 62% the pain would subside again to 0-1. She also noted that chronic neck pain associated with arthritis and bone spurs would be absent at low humidity and below 5/10 and would intensify at high humidity to level 5/10 or greater.

Results: Abnormalities on physical examination: General: 11 bilateral pedal edema,. Neurological examination: mental status examination: recalls 7 digits forward and 4 digits backward. Cranial nerves: CN II: anisocoria OD 4 mm OS 2 mm. Motor examination: drift: mild left pronator drift and bilateral abductor digiti minimi signs. CNS labiality test: 11. Reflexes: 3 1 throughout. Bilateral Hoffman reflexes. Neuropsych testing: clock drawing test: 4 (normal). Semantic fluency test: 39 (normal). Chemosensory testing: Olfaction: Brief Smell Identification: 11/12 (normal). Alcohol smell test: 6 cm (abnormal). Pocket smell test: 3/3 (normal). Retronasal smell testing: Jelly bean difference: 10/10 (normal). Gustatory Testing: propylthiouracil disc testing: 9/ 9 (normal). Fungiform papillae facial nerve function student: right: 32, left: 34. Taste quadrant testing: right to left difference with a decrease in the left posterior tongue to all modalities.

Conclusion: Meteorological correlation may be due to weather dependent affect, expectation effect, selective attention, recall bias, and false connection due to attempt of mastery of pain. Increased humidity induced enhanced olfactory ability with subsequent odor induced exacerbation. Further investigation into this meteorological connection is warranted. Introduction: Pain and acute ischemic stroke are associated with increased morbidity, mortality, and healthcare costs and utilization. While individuals with pain have a higher prevalence of cerebrovascular risk factors and manifest mechanisms which may promote enhanced stroke risk (e.g., baroreceptor impairment, inflammation), whether pain increases stroke risk is unknown.

Methods: We examined the relationship between pain, its intensity, and ischemic stroke among Veterans from the Musculoskeletal Disorders (MSD) Cohort. Veterans were stroke-free in the year before and after their entry into the cohort (2Á5 million Veterans). Entry in to the cohort was based upon evidence of a new MSD. MSD, as well as concurrent comorbid medical and mental health conditions, were identified via International Disease Classification (ICD)-9 codes. Persistent pain was defined as the average pain intensity numeric rating scale (NRS) score for persons with at least 3 NRS in the year following cohort entry, and categorized as: mild, moderate/severe. The primary outcome was stroke occurring in the two years following the exclusionary period. Cox regression was conducted to examine stroke risk by level of pain.

Results: The sample was 93% male and 18% Black, with a mean age of 58.5 years (standard deviation 15.1). Ischemic stroke was rare (0.56%). After controlling for sociodemographic, opioid, and vascular risk factors, persons with mild pain (hazard ratio [HR] 5 1.19, 95% confidence interval [CI] 5 1.14-1.25) and moderate/severe (HR 5 1.33, 95% CI 5 1.14-1.25) pain showed a higher hazard for stroke than those with no pain.

Conclusions: Persistent pain, a previously unreported cerebrovascular risk factor, is independently associated with a higher stroke risk; higher pain intensity is associated with increased stroke risk. Individuals with persistent pain and their healthcare providers should be aware that pain intensity may increase stroke risk in a graduated fashion.

Daniela M. Menichella, Nirupa D. Jayaraj, Bula J. Bhattacharyya, Sandra Hackelberg and Richard J. Miller.

Painful diabetic neuropathy (PDN) is one of the most common and intractable symptoms of diabetes, affecting 25% of diabetic patients. The hallmarks of PDN are neuropathic pain and small fiber degeneration, manifested by the loss of dorsal root ganglion (DRG) nociceptor axons. Neuropathic pain is associated with nociceptor hyper-excitability in the absence of physiologically appropriate stimuli. In states of neuropathic pain, DRG nociceptors become increasingly responsive to a variety of excitatory influences, including inflammatory cytokines. In particular, we have shown that stromal cell derived factor-1 (SDF-1) and its receptor CXCR4 are necessary for the generation of neuropathic pain in mouse models of PDN. However, the molecular mechanisms leading to the hyper-excitability of DRG nociceptors in PDN are unknown, as are the mechanisms leading to small fiber degeneration. This fundamental gap in our knowledge represents a critical barrier to progress in developing novel therapeutic approaches for PDN. The objective of this study is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration in PDN. DRG nociceptors can be identified by a series of molecular markers, including expression of the sodium channel Nav1.8. Indeed, >90% of Nav1.8-expressing DRG neurons are nociceptors. Feeding mice a high fat diet (HFD) for several weeks induces glucose intolerance, obesity, and mechanical allodynia, a particular pain hypersensitivity associated with PDN. Using the HFD model combined with DREADD receptor technology, we have shown that reducing excitability of Nav1.8-expressing neurons prevents and reverse neuropathic pain, neuronal calcium overload, mitochondrial dysfunction, and small fiber degeneration. Furthermore, we have shown that CXCR4 receptors are necessary for neuropathic pain and small fiber degeneration in PDN. Taken together these data demonstrate that Nav1.8 nociceptor hyperexcitability in PDN is driven through the activation of CXCR4 receptors. Inhibition of hyperexcitability can prevent and reverse the development of PDN. Furthermore, these observations will advance our understanding as to how changes in excitability, calcium influx, and mitochondrial dysfunction in nociceptors contribute to neuropathic pain and small fiber degeneration in PDN, which is a critical barrier to progression for effective and disease modifying treatment for PDN.

Kelly Harper, Emily Gittings, Max Turchan and David Charles. Nashville, TN Background: Vanderbilt University Medical Center (VUMC) provides teleneurology services utilizing low-cost tablet technology for ten community-based hospitals. Results from community physician surveys are an essential element of continuous quality improvement, yet the response rate is historically poor.

Methods: VUMC's teleneurology service is provided via iPads linked through a HIPAA-compliant secure network to allow real-time video examinations at community hospitals. Radiologic studies from the community are viewed using Jenesis, an application to share and view imaging developed at Vanderbilt. Satisfaction surveys are administered to community physicians via REDCap, a secure web application. Physicians rate the timeliness of connecting with VUMC neurologists, timeliness of receiving clinical documentation at the conclusion of a consult, whether they found the neurologists helpful in managing the care of patients, and their overall satisfaction with the consultations during a specified 30-day timeframe. In an effort to increase response rates, advanced survey methodologies including language brevity, simplified wording, and relevance to the participant were applied to redesign the physician survey. In addition, survey invitations and reminders were organized for optimal timing to generate a response.

Results: Over the 36 months beginning February 2014, 3,287 emergent teleneurology consults were completed. Seventy-seven physicians at ten community hospitals completed 90 satisfaction surveys. Physician response rates increased by 61% following the revised survey methodology. 96% reported that they were satisfied or somewhat satisfied with the speed at which they were connected with a neurologist, 83% reported that they were satisfied or somewhat satisfied with the timeliness in receiving clinical documentation, 97% reported that they were satisfied or somewhat satisfied with how helpful the neurologists were at managing patient care, and 91% reported that they were satisfied or somewhat satisfied with the service overall. Community physicians, supported by consulting teleneurologists, successfully evaluated and treated 88% of patients, while only 12% required transfer to a higher level of care. The most common diagnoses were stroke (31%), seizure (10%), headache/migraine (6%), and altered mental status (4%).

Conclusion/Discussion: Optimized survey methodology including timely reminders, simplified wording, demonstrated participant relevance, brevity, and optimized timing for survey invitations greatly improved community physician response rate. Community physicians reported high satisfaction rates for teleneurology provided via low-cost tablet technology including timeliness of consultations, patient management, clinical documentation, and overall service.

Improve Compliance with Pharmacologic DVT Prophylaxis? Christine Hessler, Kerjun Chang, Mira Parekh, Lynn Do and Megan Richie. San Francisco, CA Background: Venous thromboembolism (VTE) is a common cause of preventable morbidity and mortality in hospitalized patients and may result in significantly increased health care costs. Low molecular weight heparin (LMWH) and enoxaparin have been proven to decrease the risk of developing a VTE during hospitalization. However, VTE prophylaxis remains underprescribed; a study found that as many as 60% of patients missed at least one dose of enoxaparin and each additional missed dose correlated with increased risk of developing VTE. At our institution, pharmacologic prophylaxis with enoxaparin is typically dosed once daily in the morning, and is interrupted for a variety of clinically warranted reasons including lumbar puncture. Anecdotally, the morning dosing schedule resulted in either missed doses or delayed procedures, so our study group instituted a new protocol to administer prophylactic enoxaparin once daily at 9:00 at night.

Study Design: This was a retrospective study with historical controls, consisting of adults patients hospitalized on the neurology ward service who were eligible for enoxaparin prophylaxis at some point during their hospitalization. The primary outcome was the number of missed doses of enoxaparin, comparing pre-versus post-intervention groups. Secondary outcomes included length of hospitalization, incidence of VTE, delay to LP, and mortality.

Results: There were no differences in age, gender, or number of LPs performed in each group. Enoxaparin was more frequently prescribed on the day of admission for patients in the post-intervention group (29% vs 21%, p50.031), however there were no significant differences in the number of missed doses in each group. A non-significantly greater number of VTEs were observed in the preintervention group (5 vs 2, p50.38), and the post-intervention group tended to receive LPs later in their hospital stay. Interestingly, prescriber assessment of VTE risk was significantly different; in the post-intervention group, 62% of patients were categorized as 'intermediate risk' as compared to 36% of the pre-intervention group (p<0.0001).

Conclusions: Unfortunately, we failed to find a significant difference in missed doses of enoxaparin due to our intervention. However our data suggest that our intervention may have impacted prescribing practices in that patients were more likely to be categorized as higher VTE risk after our intervention. Background: Stroke is the leading cause of functional impairment, affecting nearly 800,000 Americans annually. Minority seniors are particularly vulnerable to stroke due to poor control of risk factors, unique cultural factors, and low levels of stroke knowledge. We designed, implemented and evaluated a community-partnered, culturally tailored intervention for minority seniors to improve walking levels and stroke knowledge.

Methods: "Worth the Walk," a randomized, single-blind wait list control study, was designed in conjunction with the Los Angeles Community Academic Partnership for Research in Aging Community Action Board (CAB), four racial/ethnic-specific mini-CABs, and 12 focus groups (N5132). Subjects at 4 senior centers (Korean-American, Chinese-American, Latino, African-American) were randomized to immediate intervention versus wait list. The intervention, a 4-week (2 meetings per week) group-based multidisciplinary stroke risk reduction walking intervention, was culturally tailored for each racial/ethnic group, rooted in social cognitive and attribution theory, integrated into existing senior center programming, and administered by trained staff to encourage sustainability. Baseline, 1-month, and 3 month measures included mean steps/day over past week (primary outcome, measured using Fitbit pedometers), and secondary outcomes collected by in-person interview/exam (stroke knowledge, self-efficacy, systolic blood pressure [SBP], bodymass index [BMI] ). (ClinicalTrials.govNCT02181052)

Results: Of 366 participants screened, 233 enrolled and were randomized to immediate intervention (N5120) or wait-list (N5113); mean age 74 years, 69% female. Between baseline and 1-month, the intervention cohort increased steps/day (4502 to 4861) while the wait-list group decreased steps/day (5197 to 4531); in a regression model adjusting for baseline, the intervention was associated with a net 750 steps/day (p50.035). By 3 months the intervention group reduced steps/day to 4176 and there was no significant difference between groups. Stroke knowledge increased in the intervention cohort from baseline to 1 month (p<0.001) and was sustained at 3 months (p<0.001), with no change in the wait-list group; similarly, self-efficacy for exercise was increased at 1 and 3 months (p<0.05) in the intervention but not the wait-list group. There were no differences in SBP or BMI between cohorts.

Conclusion: This community-partnered culturally-tailored intervention succeeded at increasing walking at 1 month, and increasing stroke knowledge and self-efficacy at 1 and 3 months. Future work should focus on how to sustain increases in walking, and whether improvements in knowledge lead to decreases in health disparities in stroke outcomes.

William G. Buxton, Verna R. Porter, Robin Clarke, Andrew Hackbarth and Meghan Nechrebecki. Los Angeles, CA Objective: To determine if a fall screening initiative in neurology practice results in fewer falls among patients with dementia.

Background: Falls are very common in patients with neurological disorders, are associated with significant morbidity, mortality, and morbidity and are costly. Prior falls, especially multiple or injurious falls, indicate a significant risk for future falls. Furthermore, strengthening and gait and balance training are the most proven fall-prevention interventions. Finally, fall-prevention interventions have not been shown to be effective among patients with dementia. Our group has previously demonstrated that a universal fallscreening program with reminders to order PT can reduce the rate of falls among neurology patients. Here, we present results of a subset with dementia.

Methods: Since July, 2013, all patients seen in our university-based general neurology practice and in selected subspecialty practices have received a screener upon check-in asking if they have experienced a single fall, multiple falls, or any fall with injury within the last 12 months. The provider was encouraged to refer any patient with serious (i.e. multiple or injurious) falls for PT. We completed a retrospective search of the electronic medical record for falls within the past 12 months, including patients with mention of dementia and excluding those with mention of mild cognitive impairment or related terms.

Results: As of August, 2015, there were 7524 patients receiving primary care through our health system who had seen a neurologist within the prior 18 months. We demonstrated a trend towards fewer falls in our proxy measure for patients with dementia, utilizing an ordinary, least-squares best fit line. In addition to this observation for the entire population, we also observed a positive trend in all patients seen in a new memory disorders clinic that began in June, 2015, in which the majority of patients carry a diagnosis of dementia.

Conclusion: A proven, successful fall-screening and prevention program in neurological practice may be able to reduce falls even among individuals with dementia. Additional time and refined electronic record-search techniques are needed to document this effect more convincingly.

S240. Cryptococcal Meningitis of 11 Years Duration in a Nonimmunocompromised Patient: Isolation of Cryptococcus Neoformans in CSF Obtained by High Cervical Puncture After Prolonged Failure to Detect C. Neoformans or Cryptococcal Antigen in Lumbar CSF Tyler J. Kaplan, Daniel T. Leung and John E. Greenlee. Salt Lake City, UT Meningitis due to Cryptococcus neoformans is commonly found in immunocompromised individuals but can also occur in patients without identifiable immune deficit. In immunocompromised patients, in particular those with untreated HIV, diagnosis is usually straightforward, with cryptococcal antigen and fungal culture being positive in over 90% of patients. In nonimmunocompromised patients, CSF may contain only small numbers of organisms, and diagnosis of cryptococcal meningitis may be more difficult: in such cases, diagnosis has traditionally relied on culture of multiple large-volume CSF samples and repeated determinations of cryptococcal antigen. Here we describe a 67 year old woman without identifiable immunodeficiency who presented in 2006 with diplopia and unsteadiness of gait and was found to have CSF containing 43 white blood cells/ml (100% lymphocytes), and protein of 71 mg/dl. Subsequent lumbar punctures revealed similar pleocytosis, but no organisms were isolated and cryptococcal antigen was not detected. The patient was lost to follow-up but in 2008 developed profound deafness requiring a cochlear implant. In 2011, she presented with progressive confusion and incontinence, and CT scan showed hydrocephalus not seen previously. CSF contained 56 white blood cells, 100% lymphocytes, protein of 238 mg/dl, and glucose of less than 20 mg/dl. The patient improved cognitively after third ventriculostomy, but all diagnostic studies of her lumbar spinal fluid were negative, including bacterial and fungal cultures and cryptococcal antigen. Seven subsequent large volume lumbar CSF collections consistently showed lymphocytic pleocytosis, elevated protein levels, and hypoglycorrachia, but cultures remained negative, as did cryptococcal antigen and all other studies for infectious organisms. Next generation sequencing of lumbar CSF and later of ventricular CSF obtained at the time of later shunt placement was also negative. In January 2017, C. neoformans was cultured from CSF obtained by C2 cervical puncture. The literature contains two additional cases in which C. neoformans was cultured from cisternal CSF after it could not be detected in CSF obtained by lumbar puncture. Culture of CSF obtained near the basilar meninges by cisternal or high cervical routes may improve detection of C. neoformans and should be considered as an additional diagnostic approach in patients with chronic meningitis in whom the organism cannot be identified in lumbar CSF.

Richa Tripathi, Sharon Cooperman and Kumar Rajamani. Detroit, MI Introduction: Baroreceptor reflex has key role in maintaining blood pressure and cerebral perfusion. Disruption of this reflex can lead to dysregulation of systemic and cerebral perfusion which could lead to syncopal episodes. We present a patient with syncopal spells post carotid revascularization procedures.

Method: 59 year old woman ex-smoker presented with recurrent loss of consciousness for 6 months. 20 years prior she was diagnosed with innominate artery stenosis causing transient right vision problems and headaches. She underwent innominate artery stenting with 4 revisions over the last 20 years. She underwent local brachytherapy for recurrent restenosis resulting from fibrosis however the innominate stenosis persisted. She underwent left internal carotid to right internal carotid (venous graft) bypass 5 years prior to presentation. She started having syncopal spells on standing with no relation to exercise of the right upper extremity. She underwent replacement of carotid bypass as there was no flow in graft. Post revision she had hoarse voice from right vocal cord dysfunction. She had nasal regurgitation of fluids and food due to palatal palsy. After her carotid bypass revision surgery syncopal spells worsened.

Physical examination revealed carotid bruits (left worse than right). Right upper extremity BP was 107/74 and left upper extremity was 160/74. She had mild dysphonia and hoarsness. Her uvula moved to left and right side of palate had decreased elevation. Rest of the neurological exam was normal. Prior EEG and MRI of the brain were normal. Angiography done 5 years ago showed right subclavian steal phenomena. Tilt Table testing revealed drop in her systolic blood pressure from 110 mmHg to 60 mm Hg without any increase in her heart rate.

Discussion: Patient underwent multiple operations for innominate stenosis to fix the "plumbing" i.e. the blood flow in the carotid arteries. The orthostatic nature of hypotension and the presence of ninth and tenth cranial nerve palsies was indicative of disruption in the baroreceptor reflex which resulted in syncopal events-"electrical failure". The multiple neck surgeries were likely responsible for the lower cranial palsy. The subclavian steal phenomenon or the innominate stenosis were not the cause of the syncope as tilt table indicates orthostatic hypotension. Fludrocortisone was administered with significant improvement in symptoms.

Conclusion: This patient highlights the importance of good clinical examination, and understanding the pathophysiology of the symptoms to correctly diagnose.

Jun Wang and Giulio M. Pasinetti. New York Stress and depression are widespread psychological conditions with broad health implications. Current available antidepressant treatments primarily target the monoamine pathways. However, they only produce temporary remission in less than 50% of patients and are also associated with low tolerability in large populations of patients. There is therefore an urgent need for new, more efficacious and tolerable therapeutics.

We report for the first time that two select phytochemicals, dihydrocaffeic acid (DHCA) and malvidin-3'-O-glucoside (Mal-gluc), derived from post-absorptive and intestinal microbiome metabolism of a polyphenol-rich preparation, promote resilience against stress-mediated depression-like phenotypes through attenuation of peripheral inflammation and normalization of synaptic plasticity in the NAc. DHCA/Mal-gluc is also effective in treating depression-like phenotypes in a model of increased systemic inflammation using mice transplanted with hematopoietic progenitor cells from stress-susceptible mice. DHCA can reduce pro-inflammation IL-6 expression through inhibition of DNA methylation at the CpG-rich sequences of the IL-6 at introns 1 and 3 while Mal-gluc can modulate NAc synaptic plasticity through reduction of histone deacetylase 2 expression and increases histone acetylation along the promoter and upstream of the Rac1. Our studies provide novel mechanistic evidence demonstrating cross-talking between the periphery and the CNS at molecular level in depression and the two phytochemicals, through epigenetic mechanisms, can simultaneously and selectively targeting peripheral inflammation and central synaptic maladaptation, the pathogenic mechanisms that are not addressed by currently antidepressants. Purpose/Aim: To study finger displacement in patients with Parkinson disease dementia (PDD) and in patients with Alzheimer disease (AD) Methods: We examined 56 patients with PDD and 35 with AD. Finger displacement was examined by asking patients to point their index fingers toward the grid ruler with the nails facing upward and to maintain the pointing position for 15 seconds. Patients were asked to close their eyes for another 15 seconds while maintaining the same position. A positive result was downward index finger displacement of !5 cm with eyes closed

Result: A total of 56 patients with PDD and 35 patients with AD with MMSE scores 24 agreed to participate in the study. The PDD group (n556) comprised 14 female and 42 male patients. Mean age was 75.0 6 5.8 years, mean PD duration was 9.1 6 7.4 years, and mean onset of dementia was 3.1 6 1.6 years. For the PDD, the mean MMSE score was 17.5 6 5.8 and the mean MDS-UPDRS score was 37 6 13.2. Results from the finger displacement test showed that among PDD patients, 53 of 56 (95%) exhibited bilateral downward drift of !5 cm and 3 (5%) exhibited <5 cm of downward drift. The mean bilateral downward finger drift was 6.8 6 2.0 cm for the entire group. AD patients (n535) included 14 female and 21 male patients with a mean age of 77.4 6 7.8 years and mean dementia onset duration of 3.9 6 2.9 years. For the AD, the mean MMSE score was 17.8 6 4.5 and the mean bilateral downward drift was 0.2 6 0.2 cm (n51). An unpaired t-test was used to analyze the difference in the number of patients in each group with bilateral downward drift of !5 cm. Finger displacement test in this study has sensitivity of 100% (93.28% to 100.00%) and specificity of 92.1% (78.62% t0 98.34%). Results showed a statistically significant difference between groups, with a lower mean finger displacement in patients with AD than in patients with PDD (p <0.0001, T518.26 with 86 degrees of freedom). The 95% confidence interval of the difference ranged from 27.309 to 25.873 (mean, 26.591).

Conclusion: There is no simple bedside test available that can measure the progression of dementia. The simple and inexpensive bedside test of finger displacement may be used to help distinguish PDD from AD and also the progression of dementia in PD.

Paradigm for Parkinson's Disease Jessica A. Karl, Dayanna Ocegueda and Leo Verhagen Metman. Chicago, IL Background: DBS of the STN using high frequency (130-185Hz) stimulation (HFS) is more effective for appendicular than axial symptoms. Low frequency stimulation (LFS) of STN may reduce gait/balance impairment, but often results in worsening of appendicular symptoms, limiting its usefulness.

Design/Methods: A novel interleaving (Medtronic-Activa) programming paradigm (interleave-interlink, IL-IL) was created. Two overlapping LFS programs are applied to each DBS lead with the overlapping area focused around the optimal electrode contact. This area receives HFS providing appendicular symptom control, whereas non-overlapping areas receive LFS to reduce gait/balance impairment and stimulation-induced-SE. Stimulation amplitude was empirically determined by the programmer and pulse width was left unchanged. This paradigm was used in all patients with optimized conventional-HFS settings who continued to have gait/balance impairment, speech impairment or incomplete symptom control. The Clinical Global Impression-of-Improvement scale (CGI-C) was completed retrospectively based on patient/caregiver feedback in patients remaining on the IL-IL program (at 3-months and most recent follow-up). The anchors of the CGI-C scale are: 1-very much improved, 2-much improved, 3-minimally improved, 4-no change, 5-minimally worse, 6-much worse, 7-very much worse. LEDDs were calculated for all patients (before the IL-IL and current time).

Results: Seventy-six PD patients were switched from optimized HFS to IL-IL. The majority was stimulated with two bi-polar overlapping programs (i.e. 0-21, 1-31) and the remainder with a combination of mono-polar and bi-polar programs at a frequency of 60-90Hz. Fifty-five (72%) patients remained on IL-IL after 18 months (range 12-47). These patients were separated into three categories: gait/balance impairment (n548); stimulation-induced-dysarthria (n517); and incomplete PD motor symptom control (n514), with some belonging to more than one group. The median (range) CGI-C for gait was 2(1-5) at 3-months and 3(1-4) currently; for stimulation-induced dysarthria 4(1-4) at 3-months and 4(1-5) currently, and for incomplete symptom control 2(1-3) at 3-months and 2(1-3) currently. In this group LEDD decreased by 32.8 6 105.5. Nine (12%) patients returned to conventional HFS after 5 days (range 1-22) mainly because of incomplete appendicular symptom control. In this group, LEDD decreased by 26.46 21.5. Twelve (16%) patients have not returned for follow up.

Conclusion: A significant number of patients chose to remain on IL-IL because of subjective improvements in gait/balance, dysarthria, or cardinal PD symptoms. Some who returned to the HFS settings did so before amplitude adjustments could be made. Formal assessment with objective/quantitative outcome measures is under way.

Nicolaas I. Bohnen, Siamak Nejd-Davarani, Melanie L. Beaulieu, Roger L. Albin, William T. Dauer and Martijn M. Muller. Ann Arbor, MI Background: Cholinergic system breakdown -or compensation -appears to affect brain regions differentially in Parkinson disease (PD) where denervation occurs initially in posterior cortical areas combined with increased activity in anterior cortices concurrently. The clinical significance of regionally decreased vs. increased cholinergic activity is not well studied in humans. The cholinergic system plays an important role in the peripheral autonomous nervous system but the role of cerebral cholinergic status is not well studied.

Objective: To investigate autonomic symptom correlates of regional hypo-, normo-and hypercholinergic activity in PD.

Methods: A total of 70 individuals with PD (sex: 52M/ 18F; age: 67.0 6 6.6 yrs.; modified Hoehn & Yahr stage: 2.4 6 0.5; duration of disease: 6.9 6 5.7 yrs.) underwent [F-18]-FEOBV vesicular acetylcholine transporter brain PET imaging to quantify cholinergic innervation. [F-18]-FEOBV was synthesized following standard methods and a short (30 minutes) dynamic scan (every 5 minutes) was obtained 3 hours after bolus injection. Distribution volume ratio (DVR) was determined for MR based volumes of posterior (parieto-occipital) and anterior (frontal) cortex (using Freesurfer) with the supratentorial white matter as the reference region. Regional cholinergic innervation status was based on values lower than the 5th percentile of normative data (hypocholinergic), between the 5th and 95th percentile (normocholinergic) or exceeding the 95th percentile (hypercholinergic) status. MDS UPDRS part 1 autonomic symptom scores were summed for autonomic symptom burden. Complete data were available for 67 subjects.

Results: There were 37 subjects with posterior cortical hypocholinergic status (group A), 22 subjects with global normocholinergic status (group B) and 8 subjects with anterior hypercholinergic activity without evidence of posterior hypocholinergic changes (group C). ANOVA shows a significant difference (F53.3, P50.044) with lowest autonomic symptom score in the hypercholinergic subgroup (1.3 6 1.2) compared to the hypocholinergic group (2.8 6 2.3). Autonomic scores in the normocholinergic group were in between the two other groups (1.7 6 1.4). Total PD group analysis shows inverse correlation between cortical VAChT binding and autonomic symptoms scores (R5-0.36, P50.002).

Conclusion: Autonomic symptom burden is lowest in cortical hypercholinergic compared to hypocholinergic status in PD.

Acknowledgements and Funding: NIH P50 NS091856.

Derek Stitt, Gavrilova Ralitza, Robert Watson and Hassan Anhar. Rochester, MN

Background: Alexander disease (AxD) is a leukodystrophy, described in infantile, juvenile and adult onset forms, due to mutations in the glial fibrillary acid protein (GFAP) gene. Adult-onset AxD (AOAD) has a range of clinical and radiographic phenotypes with the oldest reported onset in the7th decade. Case Description: We report a case of symptomatic AOAD, with onset in the 8th decade, presenting with slow variant orthostatic tremor, which has not been previously described. Magnetic resonance imaging (MRI) of the brain revealed encephalomalacia extending from the medulla to the upper cervical cord on T1 sagittal views. There was corresponding bilateral symmetric T2 hyperintensity in the ventral pons, extending inferiorly through the medulla to the level of the upper cervical cord. Genetic analysis revealed a heterozygous GFAP variant (c.1158C>A) that has not been previously reported in the Human Gene Mutation Database (HGMD).

Conclusion: Our case serves to expand the diagnostic spectrum of AOAD both clinically and genetically.

KL is a 54 year old man with hypertension and a history of a right cerebellar hemorrhage requiring hematoma evacuation via suboccipital craniotomy, and hydrocephalus requiring a temporary external ventriculostomy, who presented to the neurology clinic for a right sided tremor. The patient reported that immediately post-stroke, he developed a tremor of variable frequency and variable amplitude in the right arm, not present at rest, but worse with movement. He was previously a computer technician, and noted that he was unable to work due to this tremor, which prevented him from typing with accuracy. He was unable to write, nor grab and hold on to objects. His neurologic exam was notable for mild dysarthria, and a low-frequency, moderate-to high-amplitude right arm postural and action tremor, and ataxia on finger-to-nose assessment on the right side. The frequency and amplitude of the tremor varied with certain movements. The patient was tried briefly on propranolol, but was unable to tolerate due to bradycardia. The patient then was placed on valproic acid with minimal improvement in tremor, so he self-discontinued it. Low dose primidone was started, and the patient reported significant improvement in his tremor. He was able to feed and dress himself, he was able to better manipulate a pen when writing, and he was able to begin typing again on a computer.

The cerebellum and lesions within it can cause various types of abnormal movements. Cerebellar tremor often is classified as an intention tremor, or kinetic tremor, but can have a postural component, and it is rarely a rest tremor. Cerebellar tremors have an irregular amplitude and frequency, with the amplitude and frequency dependent upon the part of the body affected. Cerebellar tremors are difficult to treat. The most common treatment for the kinetic portion of cerebellar tremor is mechanical therapy, i.e. placing weighted objects to the wrist. Pharmacologic therapy can include clonazepam, isoniazid, and carbamazepine; one study reported improvement of cerebellar tremor with tegretol. To date, there have been no published reports of the efficacy of primidone in the treatment of cerebellar tremors secondary to cerebellar hemorrhages. This report demonstrates one case of a patient with cerebellar tremor due to a cerebellar hemorrhage who had significant improvement in his tremor with primidone, after having failed trials of propranolol and valproic acid. Objective: On group level analysis, constraint induced movement therapy (CIMT) has been shown to have moderate beneficial effect in children with hemiplegic cerebral palsy (CP). However, the individual responsiveness to therapy remains difficult to predict. CIMT is thought to modify interhemispheric inhibition between lesioned and normal hemispheres via modification of white matter connectivity. This pilot study aims at investigating the use of DTI scalars within the pontine corticospinal tracts (CST) and corpus callosum (CC) to predict functional outcomes of CIMT in a cohort of children with unilateral cerebral palsy.

Methods: Retrospective chart review of clinical characteristics and therapy protocol was conducted. Functional outcome was measured using Assisting Hand Assessment (AHA) scores pre and post CIMT. Quantitative post-processing of DTI data was performed using a region of interest (ROI)-based approach of ipsilateral and contralateral pontine CST and CC. For each ROI, fractional anisotropy (FA) and mean diffusivity (MD) was measured and the CST laterality index was calculated.

Results: Twelve children with hemiplegic CP were enrolled, including 6 males. 11 children had acquired brain injury before 2 years of age (91%). Etiologies of injury included perinatal ischemic stroke (41%), intraventricular hemorrhage (16%), Intracerebral hemorrhage (8.3%), hypoxic ischemic injury (8.3%) and others (25%). Eight children had right side hemiparesis and 4 had left side hemiparesis. Median age at time of MRI was 2.5 years [IQR 5.9] . Median age at the time of start of therapy was 2.75 years [IQR 2.05]. Mean time spent in a cast was 15.1 days [SD 1/-3.6]. Mean time of bimanual therapy was 3.6 days [SD 1/-1.8]. Range of AHA scaled scores pre CIMT was 15 to 79 points, and 25 to 81 points post CIMT. Mean change in AHA scores post CIMT ranged between 3 and 32 points.

Quantitative analysis of CST laterality index, FA and MD of CST and CC in each subject and association with clincial variables and pre and post CIMT AHA scores will be presented in the meeting.

Conclusion: Quantitative assessment of DTI scalars of ipsilateral and contralateral CST and CC may provide insight into baseline differences in brain response to unilateral injury and capacity for rehabilitation using CIMT.

Suggesting an Immunologic Mechanism Hirokazu Furuya, Hajime Arahata, Konosuke Furuta, Hiroki Shibata and Naoki Fujii. Kochi, Japan; Omuta, Fukuoka, Japan and Fukuoka, Japan

Background: Rippling muscle disease (RMD), a group of disorders characterized by the muscle involuntary movement with rippling movement cross the skeletal muscle accompanied with myalgia during exercise and percussion-induced rapid muscle contraction (PIRC). This disease is caused with the mutation of the caveolin-3 (CAV3) gene and PTRF gene. On the other hand, it is reported that the same immunological abnormality observed in myasthenia gravis (MG) is responsible for the onset of RMD in some sporadic cases.

Objective: Here we present an autosomal dominant (AD) RMD family with eight patients in three-generations without known gene mutation. We describe their clinical features, muscle pathological findings, analysis of known responsible genes, and response to therapeutic agents.

Results: The proband is 60 years old female. She had an onset of sudden muscle weakness during exercise in her adolescence and soon began to feel rippling muscle phenomenon and myalgia, which lead her to be wheel chaired at her quadragenarian. In biochemical examination, mild elevation of CK is observed and gene analysis revealed no mutation in PTRF and CAV3 coding regions. Anti-AChR antibody and thymoma were not observed. In muscle biopsy, histological examination revealed decreased expression of CAV3 in muscle tissue. Administration of pyridostigmine bromide and edrophonium chlorid decreased rippling muscle movement, myalgia and muscle weakness, which suggest the possibility that some immunological mechanism similar to that of MG leads to this type of RMD.

Conclusion: We show a unique familial RMD without PTRF and CAV3 mutation. Some kinds of immunological mechanisms are considered to participate in the onset of this disease.

Meagen Salinas, Pravin Khemani, Travis Ho, Elizabeth Chambers, DaiWai M. Olson, Sonja E. Stutzman and Shilpa Chitnis. Dallas, TX Objective: To assess knowledge of Parkinson disease (PD) and treatment among PD patients.

Background: As the 2nd most common neurodegenerative disorder, PD affects over 1 million Americans. Treatment is complex and may include pharmacotherapy, rehabilitative measures, and surgical intervention. Misconceptions about PD treatment are common among patients. A comprehensive understanding of the patient's perceptions about PD is a vital step towards improving health literacy and subsequently improving clinical outcomes. There is a paucity of tools to comprehensively assess PD patients' knowledge about the disease and therapeutic options.

Design/Methods: The "Know-PD" tool was developed using a modified Delphi approach with clinical experts in movement disorders. Initial field-testing was completed with patient and clinician stakeholders. Know-PD is a web-based survey with Likert responses for a cross-sectional, nonrandomized study to assess patients' knowledge of PD symptoms, medications, deep brain stimulation (DBS), rehabilitation, and other factors relevant to disease management. The survey consists of a multi-item electronic questionnaire that can be completed using an electronic tablet (e.g., iPadTM). We present a subanalysis of the ongoing study we believe is worthy of discussion.

Results: Of the subjects surveyed, 90% agreed they had sufficient knowledge of PD. However, of this cohort, 82% incorrectly believed levodopa stops working as the disease progresses; 77% erroneously thought DBS improves balance and reduces falls; and 55% were unaware of the Lee Silverman Voice Therapy LOUD (LSVT V R LOUD). On the other hand, 72% correctly observed DBS does not cure PD, and 63% knew about the PD rehabilitation program, LSVT V R BIG.

Conclusions: Preliminary analysis of Know-PD suggests that a significant number of patients who believe they are knowledgeable about PD are in fact ignorant of important PD facts. This knowledge gap is vital towards allocating patient education resources. We intend to continuously enroll subjects in our study and ultimately design effective educational interventions to improve patients' knowledge of PD with the objective of improving their health outcomes.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Dr. Pravin Khemani has received a consulting fee from Allergan Inc. as well as honoraria for speaking engagements from Lundbeck LLC.

Complicating Progressive Multifocal Leukoencephalopathy Robert D. Connors, Fiona Gupta and Florian P. Thomas.

Holmes tremor is a potential consequence of progressive multifocal leukoencephalopathy and may involve the head. Oral drug treatment is often of limited benefit. Improvement has been reported with a variety of other treatments, including thalamotomy and onabotulinum toxin A. We describe a patient with a Holmes tremor primarily affecting the head secondary to PML who responded very well to treatment with onabotulinum toxin A. Our patient is a 51 year old man who presented with mild cognitive impairment, dysarthria, and left upper limb clumsiness six months prior to his admission to our institution. Brain MRI revealed innumerable and variably enhancing punctate T2WI abnormalities throughout the cerebral hemispheres and the posterior fossa and CSF showed increased intrathecal IgG synthesis. A presumptive diagnosis of multiple sclerosis was made, dimethylfumarate was started and he received several courses of low and high dose steroids. A slowly progressive clinical deterioration led to the diagnosis of AIDS and PML based upon evolving, multifocal, MR lesions and the presence of JV virus DNA in the CSF. Following the initiation of HAART there was further clinical deterioration consistent with the development of IRIS and approximately two months after the initial appearance of white matter intensities in the posterior fossa the patient developed a coarse resting, postural and intention tremor, predominately involving the head. After primidone was ineffective and further compromised his level of alertness onabotulinum toxin was injected into the splenius capitus (25U) and sternocliedomastoid (75U) bilaterally. After one week there was a remarkable clinical improvement despite radiographically progressive disease. Onabotulinum toxin A may be uniquely effective for Holmes tremor and is particularly valuable in drowsy or obtunded patients.

Intermediate CTA/CTG Repeats with Those of Patients with Typically Expanded CTA/CTG Repeats in Spinocerebellar Ataxia Type 8 Makoto Samukawa, Makito Hirano, Kazumasa Saigoh and Susumu Kusunoki. Osaka-Sayama, Osaka, Japan and Sakai, Osaka, Japan Spinocerebellar ataxia type 8 (SCA8) is an autosomal dominant neurodegenerative disease characterized mainly by pure cerebellar ataxia, especially in Japan. SCA8 is associated with an unstable CTA/CTG repeat expansion in an untranslated region of the ATXN8OS gene. Previous reports described that 80 or longer repeats were pathogenic. The pathogenicity of intermediate expansions in SCA8 remains controversial, though it has been reported in other triplet diseases, such as Huntington disease, another triplet repeat disease. Thus, we compared the clinical features of a patient with intermediate CTA/CTG repeats in SCA8 gene (intermediate-SCA8) to those in three patients with SCA8 with eighty or longer repeats (typical-SCA8) to clarify the pathogenic role of intermediate CTA/CTG repeats in SCA8. A patient with intermediate-SCA8 was a 76-year-old woman who started to have progressive cerebellar ataxia at age 75 years and was found to have 74 CTA/CTG repeats. Pyramidal tract sign and parkinsonism were not observed. We ruled out other major causes of cerebellar ataxia, including autoimmune-mediated ataxia. Cerebellar atrophy on brain MRI in a patient with intermediate-SCA8 was milder than that in three patients with typical-SCA8. The onset age 75 years was older than the oldest age 73 in reported patients with SCA8 and in our three patients with typical-SCA8. These findings might suggest that aging might help develop disease in patients with intermediate repeats. We speculated that intermediate CTA/CTG repeats in our patient might be pathogenic, because she was older than reported patients with typical-SCA8, and because other major causes were ruled out. Long-term and careful observations of the clinical course and the accumulation of further patients are needed to clarify the pathogenesis of intermediate CTA/CTG repeats in the ATXN8OS gene. Background: The asymmetry of motor symptoms at diagnosis is a hallmark feature of Parkinson's disease (PD). A prospective, randomized pilot clinical trial of subthalamic nucleus (STN) deep brain stimulation (DBS) in early stage Parkinson's disease (PD) repeatedly evaluated motor symptoms after a seven-day therapeutic washout. This analysis reports changes in ipsilateral, contralateral, and axial motor symptom progression during this two year trial.

Methods: The DBS in early PD pilot trial enrolled patients age 50-75, Hoehn & Yahr stage II OFF medication, on antiparkinsonian medication between 6 months and 4 years, without a history of dyskinesias or other motor fluctuations (NCT#00282152, IDE#G050016, IRB#040797). Motor symptoms were assessed in the OFF state after a seven-day therapeutic washout by an independent, blinded neurologist using the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Based on subjects' initial side of symptom onset, UPDRS-III items were divided into three categories: ipsilateral, contralateral, and axial. Items 20 (upper and lower extremities), 21, and 23-26 were used to assess lateral (ipsilateral, contralateral) motor symptoms and items 18, 19, 20 (face) and 27-31 were used to assess axial motor symptoms. Ipsilateral and contralateral scores were totaled based on the initial side of motor symptom onset (same and opposite, respectively). Contralateral, ipsilateral, and axial scores between and within treatment groups (ODT n514, DBS1ODT n514) were compared from baseline to 24 months.

Results: Mean baseline OFF scores across all subjects were higher for ipsilateral symptoms (12.8 6 4.5) than contralateral symptoms (6.7 6 3.4), and mean baseline scores for axial symptoms were 9.3 6 3.2. From baseline to 24 months, mean change scores for the ODT group worsened by 2.0 points more than the DBS1ODT group on the ipsilateral side (ODT 5 3.6 6 3.5; DBS1ODT 5 1.6 6 4.1) and 1.2 more points for the contralateral side (ODT 5 4.4 6 3.3; DBS1ODT 5 3.2 6 4.9). Conversely, the mean change in axial scores from baseline to 24 months favored the ODT group with a 1.4 point greater worsening for the DBS1ODT group than the ODT group (ODT 5 1.5 6 2.4; DBS1ODT 5 2.9 6 2.8).

Conclusions: These results suggest that lateral versus axial motor symptoms in early stage PD may progress differently for subjects treated with DBS1ODT compared to ODT alone. These preliminary findings will be tested in the FDA-approved phase III trial of DBS in early stage PD.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Vanderbilt University receives income from grants and contracts with Allergan, Ipsen, Merz, and Medtronic for research led by David Charles. David Charles receives income from Allergan, Ipsen, Concert, and Medtronic for consulting and education services. There are no conflicts of interest for Mallory L. Hacker, Maxim Turchan, and Kathryn Cannard. Background: The spread of early motor symptoms from limbs affected at diagnosis to previously asymptomatic areas is a hallmark feature of PD. Rest tremor development in previously unaffected limbs from baseline to 24 months was evaluated in early PD subjects treated with subthalamic nucleus (STN) DBS plus optimal drug therapy (ODT) vs ODT alone after a seven-day washout (off medication and stimulation, if applicable).

Methods: Subjects in the two-year prospective, randomized, controlled, single-blind pilot trial of DBS in early PD were randomized 1:1 to receive DBS1ODT or ODT (clinicaltrials.gov NCT00282152, FDA IDE#G050016; Vanderbilt IRB #040797) [1]. Subjects with onset of rest tremor in at least one previously unaffected limb at 24 months were categorized as having developed rest tremor de novo (UPDRS-III OFF rest tremor item). The difference between treatment groups in the risk of de novo development of rest tremor (development vs no development) was evaluated using Fisher's exact test.

Results: From baseline to 24 months, 86% of ODT subjects developed rest tremor in at least one previously unaffected limb (12/14) compared to less than half of subjects receiving DBS1ODT (6/13; OR57.0, 95%CI51. 10-45.45, P50.046) . Seven DBS1ODT subjects did not develop rest tremor in previously unaffected limbs, and four of those DBS1ODT subjects had rest tremor in a limb at baseline that completely resolved by 24 months. Of note, rest tremor disappeared from all affected limbs at 24 months for one DBS1ODT subject (rest tremor OFF item score: baseline54, 24 months50).

Conclusions: These results suggest that DBS in early stage PD may slow the progression of rest tremor, prevent its spread to previously unaffected limbs, or even reverse the presence of existing rest tremor. The odds of developing new rest tremor during the pilot trial in the DBS1ODT group were 85% lower than in the ODT only group. This findings will be further evaluated in the FDA approved prospective, randomized, double-blind, placebo-controlled, multicenter, phase III, pivotal clinical trial testing STN-DBS in very early stage PD (IDE#G050016).

Reference Background: Levodopa remains the most effective and widely used treatment for all stages of PD. While the majority of patients can tolerate a slow titration of IR-CL, a modest subset of patients cannot tolerate a therapeutic dose of IR-CL, and therefore remain undertreated. Rytary, a new formulation of levodopa with immediate and extended release components, has been shown to have more sustained levodopa plasma concentrations and a significantly lower fluctuation index when compared to IR-CL. We switched patients who were unable to tolerate IR-CL to Rytaryin order to evaluate efficacy and tolerability.

Methods: PD patients who failed first exposure to IR CL due to adverse side effects were enrolled into this open label prospective study. After stopping all IR CL, patients were started on a slow titration of Rytary, starting with one 95mg capsule daily, and escalating by one capsule daily every week until a tolerated therapeutic dose was reached.

Results: 15 patients were enrolled between October 2015 and February 2017. Age ranged from 50-85 years (average 75). 73% were female. Side effects to IR-CR included nausea (93%), malaise (33%), fatigue (33%), and dizziness (20%). Prior to starting the Rytary, their average UPDRS 8 score was 8 (range 5-12). All 15 patients were escalated on Rytary and received a robust response. None of them had side effects on the Rytary. After optimization of their Rytary dose, the average UPDRS 8 score decreased to 4 (range 3-8).

Conclusion: Rytary can be used effectively to treat PD patients who are unable to tolerate IR CL. In this cohort, Rytary offers substantial improvement in motor function and subsequent quality of life for this subset of PD patients who were previously undertreated or untreated due to intolerable side effects of IR CL. Objective: Data from two Phase 3 clinical studies investigating the efficacy and safety of ADS-5102 in Parkinson's disease (PD) patients with levodopa-induced dyskinesia (LID) were pooled to summarize results for the shared primary endpoint, Unified Dyskinesia Rating Scale (UDysRS) and its sub-components.

Background: ADS-5102 (amantadine hydrochloride) extended release capsules is being developed for the treatment of LID in patients with PD. LID is characterized by involuntary movements during waking hours that are nonrhythmic, purposeless, unpredictable and occur as a result of chronic levodopa use.

Methods: EASE LID (NCT02136914) and EASE LID 3 (NCT02274766) were Phase 3, randomized, placebo-controlled trials of identical design except for longer treatment duration in EASE LID. The UDysRS was assessed by neurologists. The time points common to both studies (Baseline, Weeks 2, 8, and 12) were used for the pooled evaluations.

Results: At Week 12, the LS mean change from baseline in UDysRS total score was 217.7 for the ADS-5102 group and 27.6 for the placebo group (P < 0.0001), indicating a significant improvement in LID with ADS-5102 compared to placebo. The LS mean change from baseline for the UDysRS total historical score was 210.7 for the ADS-5102 group and 25.1 for the placebo group (P < 0.0001). The LS mean change from baseline for the UDysRS total objective score was 27.0 for the ADS-5102 group and 22.5 for the placebo group (P < 0.0001). Lastly, for any change from baseline in the UDysRS total score, a greater proportion of patients taking ADS-5102 showed a reduction compared to placebo. The most common adverse reactions (! 5%) included visual hallucinations, dry mouth, and dizziness.

Conclusion: A significant reduction in UDysRS total score was seen at Week 12 in the pooled analysis, which was driven by an effect on both the historical (patientreported) and objective (physician-assessed) scores.

Michelle Devine, Charles Herrin, Worthy Warnack and Divyanshu Dubey. Dallas, TX and Rochester, MN Objective: To present a successful and safe trial of carbidopa/levodopa therapy in an adult patient with human immunodeficiency virus (HIV) related extrapyramidal symptoms.

Background: Movement disorders, including parkinsonism, are known complications of human immunodeficiency virus (HIV) infection. While early initiation of highly active antiretroviral therapy (HAART) can help delay or prevent the onset of neurological manifestations in HIV infected patients, there is no proven management of parkinsonian features in adult patients with HIV encephalopathy.

Case Report: We report a case of a 36 year old man with a past medical history HIV infection who presented with hypomimia, hypophonia, bradykinesia, rigidity, and freezing of gait. His clinical presentation was consistent with HIV encephalopathy. Brain MRI showed diffuse leukoencephalopathy and mineralization of bilateral basal ganglia. Based on Oliver Sacks' prior use of levodopa in patients with post-encephalopathic parkinsonism, we initiated a trial of carbidopa-levodopa. The dose was escalated to a total of levodopa 1050mg daily. Amantadine was also started. Patient was closely monitored for behavioral, neurological, or systemic side effects. He tolerated therapy well without side effects. The patient's neurological exam significantly improved with levodopa therapy including increased facial expression, improved speech, reduced bradykinesia, and increased fluidity of gait. This improvement was sustained at outpatient follow up three months after discharge.

Conclusion: We safely used carbidopa-levodopa therapy in a patient with HIV induced leukoencephalopathy with significant neurological improvement. This supports the potential use of levodopa in similar adult patients. This will need to be further evaluated in the future. Objective: To determine whether smoking and alcohol use impacts the age of onset and disease course in MSA.

Methods: All patients diagnosed with MSA at Mayo Clinic, Rochester between 1998 and 2012 were retrospectively reviewed. Patients were classified by phenotype of parkinsonism (MSA-P) or cerebellar (MSA-C) based on initial evaluation. Alcohol and smoking use was obtained from standardized patient-completed questionnaires. Data was categorized as smoking (past or present use versus none), and alcohol use (none, 1-2 drinks per month, 1 per day, 2 or more per day). Heavy alcohol use was considered as consumption of 2 or more drinks per day.

Results: A total of 685 patients with MSA were included. There was no difference in subtype of MSA-P or C based on smoking (p 5 0.810) or alcohol use (p 5 0.109). Of 466 patients with alcohol data, 243 (52%) reported any alcohol use while 88 (19%) were considered heavy drinkers. The average age of onset for patients with any alcohol use was 60.0 years compared to 62.5 years for no alcohol use (p 5 0.0029). Average age of onset for heavy alcohol users was 58.4 years, compared to 61.5 years for all other groups (p 5 0.003). In MSA-C patients, average age of onset in patients with any alcohol use was 56.5 years compared to 61.5 years for those with no alcohol use (p 5 0.0001). Of 663 patients with smoking data, 335 (51%) were past or present smokers. The average age of onset for past or present smokers was 60.1 years compared to 61.9 years for non-smokers (p 5 0.019). Mean disease duration for past or present smokers was 7.2 years compared to 7.8 years in non-smokers (p 5 0.055). Mean disease duration for patients with alcohol use was similar to those with none (7.4 years; p 5 0.933).

Conclusion: Our findings suggest that current or past smoking and alcohol use hastens the age of symptom onset in MSA and the influence of alcohol use is strongest with heavy use and in patients with MSA-C. Background: Among the non-motor symptoms of PD, autonomic dysfunction significantly increases morbidity and mortality and impairs quality of life. Reduced variability of heart rate due to parasympathetic and sympathetic dysfunction has been reported in PD. HRV measurement is a noninvasive yet effective technique to assess autonomic function. Exercise therapy improves the motor symptoms of PD. Additionally, in healthy adults, exercise enhances HRV and parasympathetic activity during wakefulness and reduces parasympathetic activity during sleep. The influence of exercise on REM-related HRV in PD patients is unknown.

Methods: Five patients with idiopathic PD (Hoehn and Yahr stage 2-3) and sleep complaints underwent a high intensity, supervised exercise intervention 3 days per week for 16 weeks. This intervention has been demonstrated to improve motor outcomes and quality of life in PD patients and includes challenges to strength, power, balance, and endurance. Participants were evaluated with nocturnal polysomnography (PSG) at baseline and twice following the 16week intervention: one each on an exercise night and a nonexercise night. PSG recordings included electrocardiogram, sampled at 256Hz, which was analyzed using the Kubios HRV software version 2.1. Frequency domain parameters (low frequency (LF) power (0.04-0.15Hz), high frequency (HF) power (0.15-0.4 Hz), and LF/HF ratio were compared between the first REM period for each PSG night with repeated measures ANOVA.

Results: Participant demographics are: age: median563, range556-72; 80% female, 20% male; MDS-UPDRS total: median539, range531-78; MDS-UPDRS, part III: median523, range510-48. There were significant differences in HRV during REM sleep between sleep study nights in the LF (F55.01; p50.045) and HF (F54.83, p50.048) domains, with higher LF normalized units (representing more sympathetic activity) and lower HF normalized units (representing less parasympathetic activity) on the posttraining, non-exercise night compared to baseline. There were no significant differences between PSG nights in mean R-R interval, mean heart rate, LF/HF ratio, or total power.

Conclusion: This study suggests that exercise training increases sympathetic activity during REM sleep in patients with PD. Prior studies in healthy adults demonstrate that NREM is characterized by increased parasympathetic tone. Further analysis of HRV during non-REM (NREM) sleep and wakefulness in this cohort are needed to fully understand the effects of exercise on autonomic function in PD.

Jody Corey-Bloom, Sungmee Park, Ameera Haque, Ajay Nathan, Douglas E. Granger, Steven W. Granger and Elizabeth Thomas. La Jolla, CA; Irvine, CA and Carlsbad, CA

The objective of the current study was to assess the potential for saliva to serve as a biospecimen for biomarker identification in Huntington's disease (HD). Peripheral biomarkers are greatly needed in this field in order to anticipate onset of disease symptoms, monitor disease progression, and track potential therapeutic effects. HD is a fatal, inherited neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding the protein, huntingtin (Htt). The Htt protein is the most significant molecular target for disease modifying therapies, and several therapeutic approaches directed at its production, processing, and/or turnover are under development for impending clinical trials in HD. Since non-invasive methods to quantify Htt in the CNS do not exist, measuring Htt and other disease proteins in peripheral cells represents an essential step in biomarker discovery for HD. In the current study, we measured Htt protein in saliva from manifest HD patients, gene-positive premanifest HD patients, and age-and sex-matched normal individuals (total n5178) using ELISA methods. Stress and inflammation markers, including alpha-amylase, cortisol, Creactive protein (CRP), and uric acid, were also measured using similar methods. We found that total salivary Htt levels were significantly increased (p50.0012) in saliva from HD individuals (mean50.775 ng/ml) compared to normal controls (mean50.359 ng/ml). Total salivary Htt did not vary over time of day or over different days, nor were there age or gender effects. Salivary Htt showed significant correlations with several clinical measures, such as the total functional capacity (TFC; p50.040), motor score (p5 0.022) and the diagnostic confidence level (DCL; p50.029). In addition, salivary levels of mutant Htt protein, measured using different antibody combinations, were significantly higher in gene positive premanifest HD subjects compared to normal controls (p50.032). Of the stress/inflammation markers tested, CRP, a widely used biomarker of systemic inflammation, was found to be significantly (p50.025) elevated in premanifest HD subjects (9,548 pg/ml) compared to normal controls (3,399 pg/ml). CRP levels in saliva were also correlated with motor symptom scores (p50.022) among gene-positive patients. Levels of other markers, alpha amylase, cortisol and uric acid, were not significantly different between HD patients, premanifest subjects, or normal controls. We conclude that salivary Htt and possibly other inflammation markers, offer significant promise as relevant, non-invasive biomarkers of disease onset and progression in HD. Background: Gait disorders are common in patients with Parkinson's disease, frontal gait disorders associated with leukoariosis, or Alzheimer's disease. Episodic gait disorders, such as freezing, are particularly disabling and difficult to treat. The dorsomedial medulla forms a relay between forebrain, midbrain, cerebellar and spinal circuits that may mediate such episodic gait disorders. Indeed, in human post-mortem studies, this region contains pathological aggregates of tau and alpha-synuclein. In addition, loss of function of neurons in the dorsomedial medulla disrupts temporal patterns of gait in mice. In this study, we used temporally precise, selective optogenetic stimulation to investigate how activation of DMM neurons affects gait.

Methods: We present data from two cohorts of transgenic mice that received stereotactic injections of conditional viral vectors, resulting in expression of an excitatory opsin protein and a fluorophore in excitatory neurons expressing the vesicular glutamate transporter 2(VGlut2). Laser light (473 nm) was delivered through an optic fiber to the dorsomedial medulla. In one cohort, injections were made in the midbrain and stimuli delivered in the dorsomedial medulla targeted axons in the terminal field. In the other, injections were made in the dorsomedial medulla, and light was delivered directly to transfected neurons. We placed EMG electrodes in both tibialis anterior muscles and the gastrocnemius ipsilaterally. This allowed us to deliver stimulation not only randomly but also at precise phases of the gait cycle. We captured ambulation with high frame-rate video. Each animal served as its own control. Gait parameters were extracted from video and EMG recordings and analyzed in Matlab. Histologic analysis of injection site and fiber placement was performed and correlated with behavioral phenotype.

Results: In both experimental paradigms, optogenetic stimulation of the dorsomedial medulla disrupted normal temporal patterns of gait. We observed dysrhythmic activation of the limbs, which occurred at short latencies and with short stimuli. This response did not occur during rest and was dependent on the phase of gait at the time of stimulation.

Conclusions: Neurons in the dorsomedial medulla do not simply activate hindlimb muscles, but rather exert control over the temporal patterns of gait only when the animal is walking. Thus, abnormal circuit function affecting the dorsomedial medulla due to neurodegeneration could play a role in episodic gait disorders. Better understanding of these circuits will advance translational efforts to improve therapies for humans with gait disorders.

Deborah Raymond, Rachel Saunders-Pullman, Inge Meijer, Laurie Ozelius, Jose Cabassa and John Crary. New York, NY; Brooklyn, NY and Boston, MA Mutations in MAPT have been reported to cause diverse phenotypes, including late onset parkinsonism with frontotemporal dementia, progressive supranuclear palsy, cortico basal degeneration and aggressive early-onset parkinsonism. Herein we report a frameshift MAPT mutation in a patient with typical age of onset and progression of parkinsonism and only moderate cognitive decline, as well as a missense mutation in a woman with very mild parkinsonism initially associated with neuroleptic use.

The first patient is of Dominican descent and developed right sided rest tremor at the age of 51 years. She began ldopa therapy after 5 years of disease, and her disease progressed slowly to include motor fluctuations and dyskinesias within 12 years of onset. After 17 years of disease she had a UPDRS cognitive score of 1 and some complaints of forgetfulness. She was on 250mg of l-dopa with significant dyskinesias. She passed away at age 72, and no autopsy was available. Her parents died at age 86 and 83, and there were eight siblings, but no family history of parkinsonism or dementia. Whole exome sequencing was performed as part of a study of parkinsonism in Afro-Caribbeans. The patient had a novel MAPT P512 variant in positionn 44071315, which causes a frameshift mutation in exon 8, and was not in the ExAC database. The second patient, a 65 year old Dominican woman, developed parkinsonism while on risperidal for depression, but parkinsonism persisted after withdrawal of medication and has responded to pramipexole and selegiline alone. Her mother is also followed in movement disorders for posturing of the right arm and dementia at age 90. The daughter has a MAPT missense mutation, S427F at position 44067341, that was not in ExAC and was predicted as probably damaging or deleterious, and was previously reported in familial late-onset Alzheimer disease.

While no pathologic correlate was obtained for either mutation, the presumed pathogenic nature of the mutations suggest that the phenotypic range of MAPT mutations could include later-onset parkinsonism with rest tremor and motor fluctuations in the context of mild cognitive decline, as well as very mild parkinsonism arising in the setting of neuroleptic use. However, given that both mutations are novel, additional work is necessary to determine the pathogenicity, and hence significance, of both mutations. Clinical Summary: A 69 year-old woman with a past medical history of cervical, endometrial and ovarian carcinoma (all treated successfully without recurrence), had progressive neurological decline characterized by ataxia, spasticity, dysarthria, abnormal saccades, bilateral Babinski signs, and greatly decreased vibratory sense. The patient also had autonomic symptoms of orthostatic hypotension and mild bowel and bladder symptoms. SCA and SPG gene tests were negative. Multiple system atrophy-cerebellar type was clinically suspected.

Pathology: The brain displayed all the hallmarks of MSA. Grossly, there was marked atrophy of the midbrain, pons, and cerebellum. Microscopically, there was severe loss of neurons from all brainstem nuclei, along with degeneration of most white matter tracts. There was near total loss of cerebellar Purkinje cells and white matter. Immunostaining with antibodies to alpha-synuclein displayed the classic glial cytoplasmic inclusions (GCIs) in oligodendroglia seen in MSA. The neurons of the pontine and inferior olive displayed prominent neuronal cytoplasmic inclusions (NCIs). Supratentorially, GCIs and NCIs were identified in all deep grey structures and white matter tracts, most prominently in the subthalamic nucleus, globus pallidus, and external capsule.

Whole Exome Sequencing (GeneDx). Definitive mutations were found in 2 disease genes: one, AFG3L2, [ATPase FAMILY GENE 3-LIKE 2], p.P514S, c.1540 C>T, has been associated with spasticity and ataxia (SCA28, SPAX5). The other, PMS2, [POSTMEIOTIC SEGREGATION INCREASED, S. CEREVISIAE, 2], p.K614X, c.1840 A>T, has been associated with DNA mismatch-repair and cancers (Lynch Syndrome). Also found was a variant in a third disease gene, ITPR1 [INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1], p.S689T, c.2066 G>C, a possible contributor, this one associated with ataxia (SCA15, SCA29 and Gillespie Syndrome). Thus, AFG3L2 has been associated with spasticity, cerebellar ataxia and eye movement abnormalities, ITPR1 with cerebellar ataxia and eye movement disorders, and PMS2 with increased DNA mismatchrepair rates and cancers.

Summary: Here, we describe mutations in two ataxiaassociated genes in a patient with a clinical history and autopsy findings consistent with MSA-C.

Cases from a Single Center Angela L. Hewitt, Bryan T. Klassen, Kendall Lee, Jamie van Gompel and Anhar Hassan. Rochester, MN Background: Orthostatic tremor (OT) is a rare tremor of the trunk and lower limbs activated by standing, with progressive gait impairment and falls risk. It is often medication-refractory, or medication efficacy may be limited by tremor progression or side effects. Several case reports suggest functional improvement in OT symptoms following thalamic deep brain stimulation (DBS).

Objectives: To report a single-center experience of 5 medication-refractory OT patients treated with DBS. To review the literature and identify factors associated with successful DBS.

Methods: Five females (mean age 62.6 years, mean symptom duration 17.2 years) with electrophysiologically confirmed OT (14-19 Hz tremor) were treated with bilateral VIM thalamic DBS at Mayo Clinic from 2011 to 2017. A literature review identified 9 well-documented OT cases treated with thalamic DBS. Demographic, clinical, surgical, and DBS data were abstracted.

Results: All 5 of our cases had increased standing time, and 4 reported functional improvement post-DBS. Longterm outcomes were combined with the 9 literature cases (total n514). Surgery was effective for all, apart from 1/1 unilateral DBS and 1/13 bilateral DBS. There was clinical improvement in standing time (13/13; 100%), tremor latency onset (8/9; 89%), and ADLs (6/8; 75%). EMG findings revealed lower tremor amplitude (7/7; 100%), slower tremor onset latency (4/5; 80%), slower tremor frequency (3/6; 50%), discontinuous tremor (2/7; 29%), and slower tremor ramp-up time (2/3; 66%).

Conclusions: This is the largest single-site case series of bilateral VIM thalamic DBS for OT. DBS meaningfully improves symptoms, accompanied by measurable surface EMG parameter changes. Future larger prospective studies, with sham-stimulation and blinded patient and rater assessments, are necessary to confirm these findings.

Susan R. Criswell, Mark Warden, Susan Searles Nielsen, Joel S. Perlmutter and Brad A. Racette. Saint Louis, MO and Parktown, South Africa Background: Occupational manganese (Mn) exposure is associated with clinical parkinsonism; however, the role of the dopaminergic system remains controversial. Previous studies in Mn exposure using D2 receptor ligands have been conflicting but were limited by small sample size, relatively nonspecific tracers and tracers affected by endogenous dopamine. [11C](N-methyl)benperidol (NMB) positron emission tomography (PET) imaging is a highly selective non-invasive measure for the D2 receptor subtype (D2R) that is not displaced by endogenous dopamine. The objective of this study was to investigate the association between Mn exposure, D2R specific binding, and clinical parkinsonism.

Methods: NMB PET scans were acquired on 22 Mnexposed welders, 15 Mn-exposed workers, and 13 nonexposed reference subjects. We estimated cumulative Mn exposure from detailed work histories, and a movement disorder specialist examined all subjects. Striatal volumes of interest were identified on aligned magnetic resonance images (MRI) for each subject. We calculated D2R nondisplaceable binding potential (BPND) for the caudate, anterior and posterior putamen, thalamus, globus pallidus, and substantial nigra using the Logan graphical method with cerebellum as a reference region.

Results: Multivariable analysis of covariance demonstrated differences in D2R BPND between exposure groups by volume of interest, covarying for age (Pillai trace 5 0.44, p 5 0.04). Post-hoc descriptive discriminate analysis revealed that the substantial nigra (p < 0.01) and caudate (p 5 0.09) had the greatest discriminant power between the groups. Age-adjusted linear regression analysis demonstrated the substantia nigra D2R BPND was 0.07 greater in both the Mn-exposed welders and Mn-exposed workers compared to non-exposed reference subjects (both p <5 0.02). Caudate D2R BPND was also higher in the Mn-exposed welders (p 5 0.06) compared to non-exposed reference subjects. Cumulative welding exposure had no clear dose-response relationship to either nigral or caudate D2R BPND. Ageand examiner-adjusted linear regression revealed a positive association between substantia nigra D2R BPND and Unified Parkinson Disease Rating Scale motor subscore 3 (p 5 0.05).

Conclusions: Mn-exposed welders and workers demonstrate higher NMB D2R specific binding in the substantia nigra suggesting up-regulation of D2 receptors. Nigral D2R BPND was positively associated with clinical parkinsonism clearly demonstrating involvement of the dopamine system in human Mn neurotoxicity. Background: Evidence continues to grow for a connection between idiopathic Parkinson's disease (PD) and the gut: constipation, colonic inflammation, a-synuclein pathology in the gut, and dysbiosis of gut microbiome. PD also has a strong genetic component that includes associations with 26 nuclear genes. Host genetic variation influences the composition of the microbiome. The relationship between PDassociated genotypes and the dysbiosis of microbiome has not been studied.

Objective: To study the microbiome as a function of PD and SNCA rs356219 genotype. SNCA encodes a-synuclein. rs356219, a polymorphism at 3' of SNCA, is the strongest genetic risk factor for idiopathic PD.

Methods: 191 PD cases and 82 healthy controls were studied. SNCA was genotyped using DNA from whole blood. Microbiome composition was delineated from 16S rRNA sequences obtained from DNA extracted from stool. Operational taxonomic units (OTUs) were picked using Greengenes 16S rRNA sequence database. Dissimilarities in the microbiomes were calculated using Canberra and Uni-Frac distances. The statistical model included PD status, sex, age, SNCA genotype and SNCAxPD interaction term. The components of the model were tested first for differences in global composition of microbiome using permutational analysis of variance (PERMANOVA) with 10,000 permutations, and then for association with individual taxa using generalized linear model (GLM) with negative binomial distributions and zero inflation, and FDR correction for multiple testing.

Results: Significant differences in the microbiome composition were detected for PD case-control status (P<0.0001), sex (P50.0003), age (P50.0009) and SNCAxPD interaction (P50.006). The effects for PD, sex and age were expected and reassuring. The SNCAxPD finding was novel and indicates presence of an interactive effect that is not captured by the disease effect. Using the same model (PD1sex1age1SNCA1SNCAxPD) to test abundance of individual taxa we identified four genera whose abundance differed by the SNCAxPD interaction: Coryne-bacteriaceae_Corynebacterium (P52E-7), Enterobacteriaceae_ Serratia (P50.004), [Tissierellaceae]_WAL_1855D (P50.001), and Erysipelotrichaceae_Coprobacillus (P50.003). Corynebacterium and Serratia are opportunistic pathogens often seen in immune compromised individuals. Little is known about WAL_1855D and Coprobacillus.

Conclusions: In this exploratory study, we confirmed the known associations of PD, sex and age with the microbiome, and found new evidence for interaction between SNCA genotype and disease on the microbiome. The taxa that are altered suggest immune system may be involved in the interactive effect of SNCA and PD in the gut. Results require independent replication and functional validation.

Disease: Potential Involvement of the SLC1A2/EAAT2 System Debby Tsuang, Tiffany Greenwood, Sumie Jayadev, Marie Davis and Thomas Bird. Seattle, WA and San Diego, CA Background: Delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these psychotic symptoms are unknown, but given that the same symptoms also occur in schizophrenia, it is possible that the genetic risk factors for schizophrenia may also be relevant in the development of psychosis in HD.

Objective: We sought to investigate the role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD.

Methods: Subjects with manifesting HD were divided into those with (HD 1 P; n550) and without (HD -P; n5180) psychotic symptoms. DNA was genotyped using the Infinium Psych Array 24 v1.1 Bead Chip. We focused on single nucleotide polymorphisms (SNPs) from 23 genes that were previously associated with schizophrenia and related psychiatric disorders. We compared the frequency of these SNPs in HD 1 P subjects and HD -P subjects.

Results: There were no differences between the CAG repeat lengths between HD 1 P and HD -P groups. However, one of the highest odds ratios occurred in the Solute Carrier Family 1 Member 2 (SLC1A2) gene on chromosome 11, where we found that HD 1 P subjects had a higher frequency of the rs118186746 SNP than HP -P subjects (0.09 versus 0.02; OR 5 4.184; p 5 0.013). Results from other genes will also be discussed.

We report an association between a SNP in the SLC1A2 gene and the occurrence of psychotic symptoms in HD. The SLC1A2 gene encodes a member of a family of solute transporter proteins, which is the principal transporter that clears the excitatory neurotransmitter glutamate. This rs118186746 SNP is found in a glutamate transporter known as an excitatory amino acid transporter (EAAT2) gene that has also been associated with schizophrenia. Our finding thus suggests the potential role of glutamatergic systems in both HD and schizophrenia.

S270. Unusual Cause of Unsteadiness: Orthostatic Tremor in Cervicomedullary Teratoma Shivam Om Mittal, James Bower, Anhar Hassan and Eduardo Benarroch. Rochester, MN Background: Orthostatic tremor (OT) is a hyperkinetic disorder affecting gait and station, confirmed by surface electrophysiological recordings (SEMG) of a fast 13-18 Hz tremor in the legs, trunk, and sometimes the arms, on weight-bearing. Disruption of the cerebellothalamocortical pathway is thought to cause OT. It is mostly idiopathic but there are reports of structural lesions causing secondary OT, although rarely within the spinal cord.

Aim: To report a case of OT associated with cervicomedullary teratoma.

Case report: A 68-year-old woman presented with a oneyear history of progressive gait unsteadiness. In her 20's, she was diagnosed with a cervicomedullary teratoma, after presenting with mild left arm weakness and numbness. She underwent a subtotal resection of the teratoma with improvement of symptoms. Follow-up magnetic resonance imaging (MRI) studies showed no evidence of tumor regrowth. At age 67, she noticed progressive unsteadiness while standing, which improved with walking or sitting. She had to lean for support when standing in line. There was palpable tremor in the lower limbs while standing, but not while sitting or marching. A repeat MRI cervical spine showed an increase in the size of the cervicomedullary tumor, compared to the previous MRI study performed four years ago. A multichannel SEMG study with electrodes over leg muscles demonstrated an 18Hz orthostatic tremor. Surgical resection of the tumor was not recommended due to the high risk.

Conclusion: This is the first report of cervicomedullary teratoma presenting as OT. We postulate that the medullary portion of the lesion could disrupt the cerebellothalamocortical pathway via its connections with the inferior cerebellar peduncle, but also raises the possibility of OT generated by altered proprioceptive input.

Tanmay Parekh, Samer Riaz, Subin Mathew and Tarannum Khan. Weston, FL Introduction: Dropped Head Syndrome (DHS) is a highly disabling and perplexing condition originally reported at the end of the 19th-century in Switzerland and Japan, described in the context of endemic diseases such as Gerlier and Kubisagari disease. It has been described in a myriad of different diseases including amyotrophic lateral sclerosis, Parkinson's disease, multiple system atrophy (MSA), polymyositis, hypothyroidism, and hyperparathyroidism.

Very few cases are reported in the literature with isolated DHS. The term isolated neck extensor myopathy, coined in 1996, is used to describe isolated head drop that is present in the absence of any identifiable causes. It's pathophysiology is poorly understood but believed to be related to dysfunction of the extensor neck musculature and some component of dystonia of the flexor musculature. Electromyography (EMG) and biopsy may be non-diagnostic and portray a nonspecific myopathic disorder. Many cases of MSA and Parkinson's disease may present with late onset manifestation of DHS and respond to levodopa (L-Dopa). As a last resort, neurosurgical fixation is a therapeutic option although it is controversial at best and high risk in the elderly age group.

Case Presentation: We discuss a case of an 85-year old man, with two month history of isolated DHS presenting with neck pain. Examination demonstrated exaggerated forward neck drop, weakness of the cervical extensor musculature (3/5) more than neck flexor musculature (14/5). Cervical spine MRI was significant for multilevel spondylosis without cord compression. EMG was significant for myopathic units and fibrillation potentials predominately in the cervical paraspinalis musculature. All other laboratory studies, including thyroid studies, creatine kinase, acetylcholine antibodies (for myasthenia gravis), and inflammatory markers were essentially normal. He was treated with a trial of L-Dopa starting at 300 mg daily with gradual increase to 600 mg daily with significant improvement of his DHS over a 2 month period.

Conclusion: While the precise pathophysiology of DHS is unclear and the differential diagnosis broad, our case illustrates a remarkable improvement in an otherwise isolated DHS with no identifiable cause, treated with L-Dopa. Suggesting an underlying selective deficiency of dopamine in muscle sensitivity. To our knowledge, there are no reported cases in the literature with isolated DHS responsive to L-Dopa. While surgery remains a more aggressive approach, our findings recommend a trial of L-Dopa even in the absence of parkinsonian syndromes/parkinsonism. Slow-wave sleep (SWS) (i.e. deep sleep or non-REM stage 3 (N3) sleep) may be an important neural mechanism that supports cognitive function. However, whether SWS serves as a marker of cognitive function in PD is unknown. We examined whether differences in SWS are associated with performance on a level II neurocognitive battery, as defined by the Movement Disorders Society Task Force on PD-mild cognitive impairment.

Methods: Thirty-two PD patients underwent polysomnography (PSG) followed by completion of the Epworth Sleepiness Scale (ESS) and an objective measure of vigilance (Psychomotor Vigilance Task; PVT). At another visit, participants completed the Pittsburgh Sleep Quality Index (PSQI) and a comprehensive neurocognitive battery comprised of tests of global cognition, attention/working memory, executive function, memory, language, and visuospatial function. Raw scores for neurocognitive assessments were transformed to z-scores using normative data for statistical analysis. Participants were grouped using a median split of percent time in N3 sleep into High SWS (>10% time in N3) and Low SWS ( 10% time in N3), compared using 2-sided t-tests.

Results: There were no differences between the groups in age, education, or disease severity, but significantly more women were in the High SWS than the Low SWS group. No differences were observed between the groups' subjective daytime sleepiness (ESS) or sleep quality (PSQI). Participants in the High SWS group had significantly faster reciprocal reaction time (PVT) (p50.041). Additionally, participants with High SWS performed significantly better on measures of global cognition (Montreal Cognitive Assessment: p50.046); attention/working memory (Stroop color naming: p50.0006; word naming: p50.0025; and letter number sequencing: p50.031); executive function (Trails B-A: p50.019; and Stroop inhibition: p50.0052); and one of the two measures of language (Controlled Oral Word Association: p50.021). Results remained significant after controlling for sex. There were no significant differences between groups in performance on tests of memory or visuospatial function.

Conclusions: Increased SWS is associated with better performance on measures of global cognitive function, attention/working memory, executive function, and language in PD. The disparate results between subjective and objective measures of sleep and vigilance demonstrate the importance of objective outcomes in conjunction with selfreported measures in PD. This study demonstrates the significant influence of sleep on cognition and suggests that interventions to improve sleep might also improve cognitive function in individuals with PD. A prominent mechanism by which B cells contribute to the pathogenesis of multiple sclerosis (MS) is thought to be via antigen presentation to auto-reactive CD4 T cells. We previously demonstrated that B cells are sufficient to propagate experimental autoimmune encephalomyelitis (EAE), an established model of MS, independently of any other antigen presenting cell (APC). To explore the timing of B cell access to antigen and presentation to encephalitogenic CD4 T cells during EAE, we used genetically engineered murine reagents allowing the expression of MHCII by B cells alone in a temporal fashion. Encephalitogenic CD4 T cells facilitate initiation of EAE by B cells independent of MHCII, as the onset of EAE is accelerated with longer intervals between transfer and cognate interactions with B cells. Rapid onset of EAE was associated with prominent B cell clusters distributed throughout the length of the spinal cord within the subarachnoid space. B cell clusters were associated with vascular VCAM expression within the subarachnoid space. B cells within the meninges exhibited features of germinal center B cells but without extensive proliferation. Gr-11 cell migration to the spinal cord meninges preceded B cell accumulation, and in vivo depletion of Gr-11 cells eased the accelerated onset of EAE. Our results demonstrate that B cells are capable of rapidly accumulating within the meninges while promoting neuroinflammation during EAE. However, B cell migration to the CNS is coordinated by Gr-11 cells via signals from CD4 T cells independent of cognate interactions with B cells.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Genzyme Objective: To discuss an unusual presentation of Tumefactive Multiple Sclerosis (MS) and discuss practical approaches to the diagnosis and management of this protean condition. Background: Tumefactive demyelination describes a solitary (>2cm) intracranial space occupying lesion that may mimic a neoplasm clinically and radiographically due to contrast enhancement, mass effect, and edema. Patients may present with symptoms atypical for MS such as seizures, aphasia or cognitive dysfunction. Tumefactive lesions are common in Marburg variant, but are an uncommon manifestation of MS ($1 per 1000 cases). Distinguishing tumefactive lesions from other etiologies is necessary for appropriate treatment. Early intervention with immunomodulation is debatable. The majority of patients have relapsing remitting course, but others without attacks of demyelination.

Design/Methods: Clinical Case and Literature Review Results: A 22 year old female presented with acute onset left sided numbness and incoordination involving the upper then lower extremity without vision, bowel or bladder problems. Maternal aunt has MS. Physical exam revealed left deltoid and biceps weakness, decreased sensation of the left upper and lower extremities and unsustained clonus of left Achilles. CT Head revealed low attenuation area in right centrum semiovale. MRI Brain demonstrated an atypical 3cm lesion with contrast enhancement and restricted diffusion in right Parietal lobe. Lumbar puncture studies revealed oligoclonal bands, elevated IGG Index and myelin basic protein, no malignant cells on cytology. Vitamin D level was low. A short course of intravenous steroids was administered for clinically isolated syndrome. Subsequently her sensory loss worsened. Repeat MRI showed increase in size of the lesion without enhancement. Infectious, Rheumatological and Malignancy work up was unremarkable. She underwent brain biopsy, and pathology was consistent with demyelination and reactive gliosis. She was initiated on Dimethyl fumarate. Repeat brain imaging revealed decrease lesion size and no enhancement.

Conclusions: Tumefactive demyelination is a rare manifestation of MS which can have atypical presentation and clinical course and is frequently misdiagnosed. Although typically a monophasic disease, relapses can occur.

Strategy for Alexander Disease Berit Powers, Tracy Hagemann, Steven Wheeler, Curt Mazur, Eric Swayze and Albee Messing. Carlsbad, CA and Madison, WI Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is over-expression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. We have used mouse models with knock-in mutations corresponding to known human GFAP mutations to explore the utility of antisense suppression of GFAP expression as a therapeutic strategy for this disorder. Antisense oligonucleotides were designed to target various regions of the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for ability to reduce GFAP transcripts and protein, first in wild type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP. Nearly complete and long-lasting elimination of GFAP occurred following single bolus intracerebroventricular injections, with reversal of Rosenthal fibers and downstream markers of microglial and other stress responses. Antisense suppression therefore shows great promise as a therapeutic approach for Alexander disease.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Co-authors Powers, Swayze, and Mazur are employed by Ionis Pharmaceuticals.

Among People with Multiple Sclerosis Samantha N. Roman, Kathryn C. Fitzgerald and Ellen M. Mowry. Baltimore, MD Background: Poor diet, sleep, and physical activity are potentially modifiable contributors to fatigue in people with multiple sclerosis (pwMS). Often, these lifestyle characteristics tend to cluster; however, it is unknown whether having multiple suboptimal health behaviors is associated with greater fatigue symptoms among pwMS.

Methods: We conducted a cross-sectional assessment of dietary habits (24-hour recall over 3 consecutive days), physical activity levels (International Physical Activity Questionnaire [IPAQ] ), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), and levels of fatigue (PROMIS-FatigueMS) among pwMS. 36 participants were recruited from the Johns Hopkins MS Center, all with a body mass index (BMI) !23kg/ m2, Expanded Disability Status Scale (EDSS) score <6, disease activity in the prior 12 months, and on no MS therapy or injectable MS therapy. We classified lifestyle characteristics as sub-optimal if a person: consumed 2 servings of red meat, fried foods, and/or sugar-sweetened beverages per day, scored !5 on the PSQI, and engaged in no moderate or vigorous physical activity !3 days/week. Outcomes were scored dichotomously in each category, with 1 point assigned to sub-optimal characteristics; the sum of all three categories yielded an overall lifestyle risk factor score (LRFS) with a maximum value of 3 (i.e. sub-optimal in every category) and a minimum value of 0. Using linear regression models, we analyzed the relationship between individual survey scores and overall LRFS with PROMIS-FatigueMS score.

Results: Of the 36 participants, 18 (50%) scored suboptimally in at least two of three categories. Among all participants, each 1-point greater LRFS was associated with a 2.74-point higher fatigue score (p50.03); changes of 2-3 points have been shown to be clinically significant among other populations. Furthermore, an overall LRFS of 3 (i.e. sub-optimal in all three categories) was associated with a 10-point greater fatigue score when compared to participants with a LRFS of 0 (p 5 0.02; 95% CI 2.04-18.06). Analysis of individual categories demonstrated that poor sleep quality was strongly predictive of fatigue, with a 1.24point greater fatigue score for every 1-point higher PSQI score (p<0.001), while diet only marginally affected fatigue (p50.06), and physical activity did not appear to have a significant association.

Conclusions: Sub-optimal, but modifiable, lifestyle characteristics tend to co-occur and may lead to greater fatigue among pwMS. Poor sleep quality is a particularly strong predictor of fatigue; thus, fatigued pwMS may receive the greatest benefit from interventions targeting improved sleep quality. Background: Multiple sclerosis (MS) is treated chronically with disease modifying therapies (DMTs) to delay disease progression as well as with medications to manage a variety of symptoms and comorbid conditions. DMTs have complex pharmacodynamic effects, the potential for drug-drug or drug-disease interactions, and serious safety risks requiring baseline and periodic monitoring. There is considerable variability in practices to proactively monitor for safe use of medications. An initiative to establish a new role for a pharmacist to oversee the safe use of DMTs was successful.

Methods: The University of California San Francisco (UCSF) MS and neuroinflammation center has 14 providers who provide care for approximately 7,000 patients. On March 7, 2016, a pilot model for once weekly clinical pharmacy services was established to include performing a comprehensive review of medications and participating in quality improvement projects as part of a unit-based interprofessional leadership team. An evaluation of baseline practices was completed to identify opportunities to improve provider productivity. This included an assessment of current workflow for monitoring DMT safety, providing patient education, and documenting medication history. Solutions to issues identified were implemented as a result. The impact and value of pharmacy services was determined after 9 months.

Results: During the pilot period, once weekly clinical pharmacy services resulted in 152 interventions that prevented potential medication adverse effects in the following categories: No indication for drug/Duplicate therapy (6), Drug indicated, but not prescribed (9), Change in dose/ Dose clarified (13), Drug interaction screening (7), Drug monitoring (8), Adverse drug reaction education/Discontinued drug (18), Drug access (14), Missing medication on medication history (16), Drug information/Patient education (23), and Administrative (38). To improve quality of care and medication use work flow, the following pharmacist-led efforts are underway: revision and development of a standard DMT safety monitoring protocol; creation of a DMT registry to allow proactive safety monitoring; development of a standard format for patient education; and improvement of medication history documentation and visibility.

Conclusion: A clinical pharmacy service at the MS center has improved awareness of medication safety issues, optimized access to pharmacy resources to improve provider practices and standardize medication protocols. In the changing landscape of MS treatment, a pharmacist with expertise in MS will have an important impact on patient care and will improve MS provider satisfaction.

Knowledge and Performance in Multiple Sclerosis Jamie C. Reiter, Jan Perez, Sharon B. Tordoff and Whitney Faler. Bethesda, MD Introduction: Healthcare providers (HCPs) treating patients with multiple sclerosis (MS) are faced with a continually changing treatment landscape. As new therapeutic options become available with different mechanisms of action (MOAs) and side effects, establishing effective patient-centric treatment plans will be increasingly essential to achieving optimum patient outcomes. It is the goal of continuing medical education (CME) to keep HCPs up-to-date on the most recent developments and best practices in medicine. However, many CME providers fail to integrate the patient voice into education, which would raise awareness of challenges patients face and provide a more realistic patient perspective to HCPs. This presentation provides results from a CME activity in MS, which integrated audio responses directly from patients.

Methods: The activity consisted of a 60-minute webcast, followed by a 30-minute live Q&A. Audio from interviews with MS patient leaders (n 5 21) were integrated into the content. A survey assessing knowledge, confidence, competence, and performance was administered prior to the activity (pre-survey), immediately after the activity (post-survey), and 3 months following the activity (follow-up survey). Data from the pre-and post-or follow-up surveys were analyzed using McNemar's tests for paired data. Significance was determined at alpha 5 .05.

Results: Over 1800 HCPs participated in the activity, including 200 HCPs in the pre-activity and post-activity outcomes study, and 27 participants in the follow-up survey. A significantly greater percentage of participants post-activity versus pre-activity achieved correct responses on knowledge questions related to identifying agents effective for relapsing forms of MS (70% versus 36%, p < 001), the therapeutic agent with best impact on brain volume loss (75% versus 27%, p < .001), elements of shared decisionmaking (81% versus 39%, p < .001), and communicating risk (85% versus 59%, p < .001). For a performance question asking how often HCPs incorporate MOA into their treatment decisions, participants in the follow-up survey outperformed those in the pre-activity survey (70% versus 23%, p < .001). Confidence for identifying factors of importance to their patients was also improved following the activity (56% versus 19%, p < .001).

Discussion: Incorporating the patient voice into the educational activity was an effective format for providing insight and perspective leading to improved HCP learning and performance. HCPs are encouraged to integrate the patient perspective when developing treatment plans for patients with MS.

Miguel Melo-Bicchi, Shuja Sheikh and Gerhardstein Brian. Newark, NJ Vitamin B12 is needed for myelin synthesis in the nervous system. Its deficits causes several central and peripheral nervous system diseases due to the accumulation of methymalonyl-CoA decreasing myelin production, accumulation of abnormal fatty acids into neuronal lipids and demyelination. The neurological syndromes associated with vitamin B12 deficiency include cerebral, myelopathy, neuropathy, neuropsychiatric abnormalities and optic nerve involvement. Subacute Combined Degeneration is the most frequent clinical manifestation of vitamin B12 deficiency. Here we report a case of isolated cerebellar involvement due to critical levels of Vitamin B12.

A 32-year-old man with no past medical history was brought to the ER because he was found acting confused in a bus with unsteady gait. His laboratories revealed a B12 level of 30 pg/mL and pancytopenia. His neurological exam showed a thin encephalopathic man with a myelopathy; normal strength, spasticity and hyperreflexia with bilateral non-sustained ankle clonus in the lower extremities, impaired vibration and proprioception, diffuse ataxia and ataxic gait.

Brain MRI showed hyperintensities in the cerebellar hemispheres and vermis with associated diffusion restriction. Methyl malonic acid, homocysteine and intrinsic factors antibodies were markedly elevated, suggestive of pernicious anemia. CSF analysis was unremarkable for infectious, inflammatory or malignant process. A comprehensive neurological workup looking for infectious, vascular and neoplastic processes was also unremarkable. The patient was supplemented with cyanocobalamin and after a month of treatment he improved dramatically.

The most commonly CNS affected areas in B12 deficiency are the cervicothoracic dorsal columns, cranial and peripheral nerves. Brain involvement has been reported in B12 deficiency. To our knowledge isolated involvement of the cerebellum in B12 deficiency is extremely rare, has been documented in very few case reports and this could be a first case report of cerebellar involvement in B12 deficiency caused by pernicious anemia.

Vaibhav Goswami, Zachary A. Gray, Kriti Gupta, Michael Tenner and Brij S. Ahluwalia. Valhalla, NY Introduction: Central pontine myelinolysis (CPM) can be associated with rapid correction of hyponatremia. Seizures, dysarthria, dysphagia, oculomotor dysfunction, quadriparesis and locked in syndromes are described in CPM. Asymptomatic cases of CPM are rare, with only 7 reported cases. Babanarao et al. reported two cases of extrapontine myelinolysis that progressed to CPM within one week, where the diffusion restriction wore off by the second week. The duration of restricted diffusion in CPM is not known. We report a case of CPM in an alcoholic patient with hyponatremia that was rapidly corrected and developed pontine demyelination with no neurologic deficits. Magnetic resonance imaging (MRI) two months later showed a 1.4 cm hypointensity with persisting peripheral restricted diffusion.

Case: A 40 year old male with a history of alcoholic intoxication presented to the emergency room (ER) confused and disoriented with a forehead laceration. He had a blood alcohol level of <10 mg/dL, sodium level of 114 mEq/L, potassium level of 2.8 mEq/L, chloride of 77 mEq/ L, and mildly elevated aminotransferases. Non-contrast head computed tomography (CT) on arrival was normal. Hyponatremia correction protocol was followed as per hospital guidelines but the patient's sodium increased from 114 mEq/L to 127 mEq/L over 20 hours. His mental status improved and the patient was discharged with no neurological symptoms, and hence no neuroimaging studies were performed. Two months later, he returned to the ER with a blood alcohol level of 329.5 mg/dL. He had dysarthria, gait instability and a left leg laceration. His sodium level was 140 mEq/L, potassium of 4.7 mEq/L and chloride of 99 mEq/L. Non-contrast head CT showed a 1.4 cm focus of hypodensity in the pons. MRI of the brain showed a 1.4 cm T1 hypointense, T2 hyperintense region of signal abnormality within the central pons demonstrating peripheral restricted diffusion and T2/FLAIR hyperintensity. He was treated for alcohol intoxication and transferred to a rehabilitation facility for mild gait difficulty, which resolved in one week.

Conclusion: In this patient, CPM was associated with rapid correction of hyponatremia, but the patient remained asymptomatic. MRI of the brain two months later showed a large area of T1 hypointensity with a peripheral restricted diffusion, which is a substantially later in his disease course than previously reported in CPM literature. The duration of restricted diffusion in CPM needs further investigation.

Francesca Cignarella, Claudia Cantoni, Laura Ghezzi, Yanjiao Zhou, Anne Cross and Laura Piccio. St. Louis, MO and Farmington, CT Multiple sclerosis (MS) is a complex disease of unknown etiology involving central nervous system (CNS) inflammation, demyelination, and axonal damage. It is thought to be an autoimmune disease targeting CNS myelin. Strong evidence indicates that MS risk is impacted by environmental factors, including diet and obesity. Accumulating evidence suggest that obesity in children and young adults is a risk factor for developing MS later in life supporting the complex interplay between the metabolic state and autoimmune responses. A mechanism through which diet can influence immune responses is the gut microbiome which is emerging as a critical contributor in numerous human diseases.

Here we show that intermittent fasting (IF) was able to ameliorate clinical course and pathology of the MS animal model, experimental autoimmune encephalomyelitis (EAE), leading to less inflammation, demyelination and axonal damage. IF led to changes in the gut microbiome increasing bacterial richness. IF had direct effects on the composition of T cells in the gut lamina propria with a reduction of IL17 producing T cells and an increase in the number of regulatory T cells which could possible modulate systemic immune responses. Importantly, fecal microbiome transplantation from mice on IF was able to ameliorate EAE in immunized recipient mice, suggesting that IF immunomodulatory effects are at least partially mediated by the gut flora. We translated our findings in MS patients in a pilot clinical trial in MS patients having a relapse to test safety, feasibility and effects of IF on clinical and laboratory measures. We observed potentially beneficial effects on levels of several immune inflammatory parameters as well as gut flora that resembled the protective changes observed in mice in EAE.

In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome. Background and objective: Comorbidities impact health outcomes in multiple sclerosis (MS) and are traditionally identified using a candidate method. We comprehensively identified the comorbidity burden in severe MS using a phenome-wide association approach.

Methods: We conducted retrospective analyses of two cohorts: Partners HealthCare (Boston, USA; 1993 -2012 where we merged the electronic health records and clinic research registry data, and British Columbia (Canada; 1991 -2008 where we accessed linked population-based clinical and health administrative data. Eligibility criteria were adults, a neurologist confirmed MS diagnosis, at least one Expanded Disability Status Scale (EDSS) score, and at least one International Classification of Diseases (ICD)-9 code other than MS during study period. All ICD-9 codes were mapped to previously developed phenotype codes (i.e., comorbidities), allowing consolidation of multiple ICD-9 codes related to one condition. The MS Severity Scores (MSSS) were calculated using EDSS scores measured at each clinic visit and the corresponding disease duration. MS severity, modeled as a continuous variable, was assessed as the median MSSS based on the three most recent scores. The primary outcome was the presence of each comorbidity. We tested the association between the MSSS and each comorbidity using logistic regression and adjusting for sex, age and disease course at symptom onset and follow-up duration.

Results: 4,118 MS patients from Partners HealthCare (discovery) and 4,867 MS patients from British Columbia (replication) met eligibility criteria (both cohorts, median age of symptom onset533 years; females573%). In the discovery cohort, 37 comorbidities were significantly associated with increasing MSSS after Bonferroni correction and covariates adjustment. Genitourinary, infectious, and metabolic disorder showed the strongest correlation with the MSSS (e.g., functional disorders of bladder: p52.4x10-52, OR51.42, 95% CI 1.37 -1.47). Interesting comorbidities included epilepsy (p52.6x10-6, OR51.17) and hypertension (p53.2x10-3, OR51.07). Certain cancers are inversely correlated with MSSS (e.g., benign neoplasm of skin: p59.9x10-6, OR50.90, 95% CI 0.85 -0.94). In the replication cohort, 136 comorbidities showed significant association with MSSS after Bonferroni correction and covariate adjustment; 14 comorbidities replicate 38% of the findings in the discovery cohort (p<0.05). Overall, results in the replication cohort were generally in the same direction as the discovery cohort.

Conclusion: The phenome-wide approach may be useful to highlight clinically relevant comorbidities. Their relationship with physical disability warrants further investigation. Understanding their role will inform the management of people with severe MS. Objective To test whether the lack of an association between 25-hydroxyvitamin D (25OHD) and multiple sclerosis (MS) risk in blacks and Hispanics we previously reported is due to differences in common polymorphisms that affect 25OHD bioavailability (rs7041, rs4588).

Methods We recruited incident cases of MS or clinically isolated syndrome (CIS) and matched controls (blacks 116 cases/131 controls; Hispanics 183/197; and whites 247/267) into the MS Sunshine Study from the membership of Kaiser Permanente Southern California.

Results AA is the dominant rs7041 genotype in blacks (70.0%) whereas C is the dominant allele in whites (79.0% AC/CC) and Hispanics (77.1%). A multiplicative interaction indicating that higher serum 25OHD levels and carrying at least one copy of the C allele at rs7041 (p50.015) but not rs4588 was detected independent of genetic ancestry and lifetime ultraviolet radiation exposure (UVR). Models stratified by race/ethnicity revealed that higher 25OHD levels were associated with a lower risk of MS/CIS in whites (OR50.42, 95%CI 0.23-0.77) who carried at least one copy of the C allele at rs7041 but not in those homozygous for the A allele. No association was found in Hispanics or blacks regardless of genotype. Higher UVR was associated with a lower risk of MS independent of 25OHD levels in blacks (OR50.06, 95%CI 0.01-0.27; per 1000 KJ/m2), Hispanics (OR50.57) and whites (OR50.79) who carried at least one copy of the C allele at rs7041 but not in those homozygous for the A allele.

Conclusions Racial/ethnic variations in bioavailable vitamin D resulting from differences in dominant polymorphisms in the vitamin D-binding protein gene do not explain the lack of association between 25OHD and MS in non-whites. The protective effect of UVR regardless of race/ ethnicity may be particularly important in those who carry a specific polymorphism within the vitamin D-binding protein gene. If this finding can be replicated it would invalidate the instruments used for Mendelian randomization studies of vitamin D because it violates the assumption that the vitamin D-binding protein genotypes affect the risk of disease solely by influencing vitamin D status. Our findings challenge the biological plausibility of vitamin D deficiency as causal for MS. Background: Anti-CD20 therapy efficacy highlights the need to better understand the role B cells play in MS pathophysiology. We investigated whether B cell clonotypes persist in the CSF over time.

Design/Methods: IgM and IgG B cell receptor (BCR) heavy chain variable region immune repertoires were generated on an Ion Torrent machine using RNA extracted from CSF and peripheral blood B cells of ten MS patients at an untreated time point (a) and at a later time point (b) (1.18 years later (1/-0.28)). A custom bioinformatics pipeline based on MiXCR 1 identified CDR3 sequences. Clonally related BCRs were identified by comparing CDR3 sequences using a distance metric approach.

Results: In five of the ten patients, identical CSF B cell clonotypes were found at both time points. Persistent clonotypes were more often plasmablast/plasma cell (15/31) and switched memory (14/31) phenotype rather than unswitched memory (1/31) double negative (1/31) or na€ ıve (0/31). Persistent CSF clonotypes' CDR3s are unique to each patient.

Conclusions: To our knowledge, this is the first longitudinal B cell immune repertoire study in the CSF compartment of MS patients. CSF B cell clonotypes are more likely to be found in patients with a recent relapse, suggesting that recurring recruitment or intrathecal persistence of diseaseassociated B cells may be a marker of active relapsing disease.

1. Bolotin, D. A. et al. MiXCR: software for comprehensive adaptive immunity profiling. Nature Methods 12, 380-381 (2015) .

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? S. L. Hauser currently serves on the SAB of Symbiotix, Annexon, Bionure, and Molecular Stethoscope and on the BOT of Neurona. Dr. Hauser also has received travel reimbursement and writing assistance from F. Hoffman-La Roche Ltd. for CD20-related meetings and presentations.

At the time of submission Dr. von B€ udingen is an employee of F. Hoffman-La Roche, Basel, Switzerland and holds an adjunct faculty position at UCSF. This work does not represent the opinion of Roche. Dr. von B€ udingen has received compensation for consulting activities from Roche, Novartis, and Genzyme, and research funding from Roche, Genentech, and Pfizer. Background: Stroke is one of the leading causes of death and disability. Annually, fifteen million people suffer from stroke worldwide, out of which five million do not survive, five million are left permanently debilitated and only five million fully recover from their symptoms. Currently as per the American Stroke Association guidelines, the recommended dose of t-pa is 0.9 mg/kg, however in the Asian population, a lower dosage, 0.6mg/kg has been used and a safety and efficacy profiles comparable to the dose recommended in the Western population have been found.

Objective: To determine the safety and efficacy of intravenous t-PA at a dose of 0.6mg/kg in acute stroke patients at the Aga Khan University hospital (AKUH) and compare the results with those of 0.9mg/kg dose in the safe implementation of thrombolysis in stroke monitoring study (SITS-MOST).

Methods: This retrospective observational study was conducted at the AKUH. Hospital. Records of patients receiving intravenous t-PA for ischemic stroke thrombolysis from Jan, 2007 to Oct, 2016 were reviewed. The primary safety outcome variables included symptomatic intracerebral hemorrhage after start of thrombolysis treatment and death within three months (mRS 6). The secondary efficacy outcome variables included functional independence (mRS 0-2) at three months.

Results: Of the 79 patients included in the final analysis, 52 were male (66%) and 27 (34%) were female. Median pre t-PA NIHSS was 12 (IQR 8-15). Mean door to needle time was 96 minutes (SD 31) vs 68 minutes (SD 30) in SITS-MOST. The proportion of patients with symptomatic intracerebral hemorrhage according to the SITS-MOST criteria was 0% at AKUH vs 1.7% in SITS-MOST, whereas according to the Cochrane/NINDS definition it was 3.8% at AKUH vs 7.3% in SITS-MOST. Functional independence (mRS 0-2) was seen in 50.6% of patients at AKUH vs 54.8% of patients in SITS-MOST at three months.

Conclusion: Low dose intravenous thrombolytic therapy for ischemic stroke patients was safe and efficacious in our patient population and yielded results comparable with those of SITS-MOST. Factors associated with poor outcome after hypoxic-anoxic coma continue to be extensively studied, however literature is sparse regarding the prognostic importance of sustained vertical gaze. Four patients were followed up after hypoxicanoxic coma (Glasgow Coma Scale of < 5). Daily neuro-ophthalmological examinations (specific attention to pupils, spontaneous and reflex eye movements) were conducted. CT and EEGs were performed; the tendon response was exaggerated and all patients remained comatose with no sign of arousal elicited. EEG responses indicated moderate to severe encephalopathy of non-specific etiology while CT appeared normal with no evidence of acute damage. However, the pattern of ocular deviations did not follow any particular pattern; we noticed that the appearance of vertical eye deviation was associated with poor prognosis. Our results suggest the sustained upward gaze invariably heralds the downward spiral of the patient's clinical outcome, resulting in death.

We propose this be referred to as "Sun Rise Sign "and suggest it be used in addition to other clinical parameters to establish a prognostic timeline for patients to enable neurologists to appropriately modulate their expectations regarding final patient outcome. Upward gaze is affected far more frequently than downward gaze because some of the fibers sub-serving up gaze cross rostrally and posteriorly between the riMLF and INC nuclei and are subject to interruption before descending to the oculomotor nuclei, whereas the pathways for the down gaze apparently project directly downward from the two controlling nuclei. When Sun Rise Sign is observed in a comatose patient, it is quite telling.

Man Mohan Mehndiratta, Rajeev Nayak and Sana Ali. New Delhi, India and Jabalpur, India

Objective: Current study was conducted to study the occurrence of ventilator associated pneumonia (VAP), associated risk factors, microorganisms isolated and their antibiotic sensitivity profile among patients admitted to the Neurology and Neurosurgery Intensive Care unit (NNICU).

Background: VAP is a leading cause of intensive care unit (ICU) acquired infections. Specific neurological and neurosurgical intensive care has become significant in the last few decades. However, it is still an evolving concept in developing countries like India. Altered mental state and motor disability among these patients expose them to even greater risk of aspiration pneumonia. Knowledge of the incidence of VAP in such settings is crucial for prioritizing preventive strategies to combat its occurrence.

Methods: This prospective study included 100 patients admitted for more than 24 hours to NNICU of a tertiary care institute. After detailed history and examination, endotracheal aspirate and blood samples were collected. Complete blood count and microbiological work-up of the aspirate was done to identify causative organism and antibiotic sensitivity of the isolate. Chest x-ray was done to aid in the diagnosis of VAP.

Results: VAP was found in 24% of the subjects. Acinetobacter baumannii was the commonest pathogen (24.3%) isolated and all of these isolates were sensitive to meropenem. Duration of mechanical ventilation (p < 0.0001) and associated comorbid illness (p 5 0.005) were found to be significantly associated with VAP. Multivariate analysis revealed duration of mechanical ventilation to be the only independent risk factor (p < 0.0001) associated with VAP.

Conclusion: This study provides an overview of NNICU acquired VAP that could help clinicians while treating such patients by early identification of those at risk and wisely choosing antibiotic regimen. Background: A bibliometric uses the citation count of an article to determine its impact on the clinical world. There is a paucity of literature concerning top article citations on spontaneous intracerebral hemorrhage (ICH). The main objective of this investigation was to bridge this gap and to provide understanding of the trends on the most influential articles written on this subject.

Methods: Scopus Library database was searched to determine the citations of all published spontaneous ICH articles. Articles that focused on other forms of ICH, such as trauma-related hemorrhages, sub-arachnoid hemorrhages, hemorrhages due to anti-coagulation, vascular malformations or cavernomas were excluded from our list. Our articles were divided into two groups; 'Specific' articles, that focused specifically on spontaneous ICH, and 'Generalized' articles that were about ICH in general, including spontaneous as well as other forms of ICH. We did not apply any time or study-type restriction in our search. The top 100 cited articles were selected and analyzed by 2 independent investigators.

Results: Broderick J was the author with most publications in the list (n521). The largest subset of the spontaneous ICH articles was published in the 5-year periods from 1996 to 2000 and 2001 to 2005 (n527 each). United States had the highest number of articles (n549). The journal with the highest number of top 100 cited articles was Stroke with 39, followed by 16 in Neurology.

Conclusion: In conclusion, our study identifies the trends related to the subject of spontaneous intracerebral hemorrhage by analyzing the citation frequency of the most cited articles in the field.

Hunaid Hasan, Daniel Graf and Alok Dabi. Galveston, TX Objective: To discuss the importance of aggressive and timely prevention/management of vasospasm in cerebrovascular fibromuscular dysplasia (FMD) after subarachnoid hemorrhage (SAH)

Background: FMD is a non-inflammatory/non-atherosclerosclerotic arteriopathy with formation of intracranial aneurysms. The clinical course of vasospasm post SAH in FMD is not well understood.

Design/Methods: Case report.

Results: A 67-year-old female with history of FMD, hypertension, diabetes mellitus presented with sudden onset of headache, leg weakness, vomiting and altered sensorium. Computed tomography (CT) head without contrast revealed diffuse subarachnoid blood. Hunt Hess, Fisher and World Federation Neurological Society scores were two, four and two, respectively. CT angiogram revealed diffuse vascular beading within the anterior and posterior circulation due to vasospasm. An external ventricular drain was placed which was followed by craniotomy and clipping of the anterior communicating aneurysm. Immediate post-operatively the patient was briskly following commands bilaterally. However, subsequently the patient developed repeated episodes of left hemiparesis and right gaze deviation. Cerebral angiograms confirmed vasospasm involving the branches of right middle cerebral artery (MCA) which was followed by intraarterial angioplasty. Seven interventional angiograms were performed and three intracranial stents were placed in the MCA. A lumboperitoneal shunt was placed for the communicating hydrocephalus. Her right hemiparesis continued to improve with supportive measures and medical management. Patient was discharged to inpatient rehabilitation without further complication.

Conclusions: Our patient had an unusually protracted course of cerebral vasospasms after SAH, highlighting the need for aggressive prevention/management in the neurointensive care unit. This case demonstrates that despite a protracted course of vasospasm, a good functional outcome can be achieved if interventions are applied within a timely manner. More careful monitoring and preventative measures may avoid extensive interventional stenting and angioplasty in FMD. This case provides an extraordinary situation where post SAH vasospasm can occur unexpectedly outside of the expected therapeutic window. There continues to be a clinical gap in understanding the clinical variability of post SAH vasospasm complications. A better understanding of cranial vasospasm in FMD needs to be addressed both at the basic science and clinical stages. The discrepancy between the highly complicated clinical course of our patient and her favorable functional outcomes is likely explained by joint efforts in the neurointensive care setting with round the clock neurointerventional expertise available. Although this is an ideal clinical model with favorable outcomes, there are limited number of hospitals in the United States that can provide this optimized setting. Objective: The aim of this study is to use a human intracortical Brain Computer Interface (BCI) to investigate the neural dynamics of motor learning and motor system plasticity at the scale of single neurons and local field potentials.

Background: Recent studies employing brain computer interfaces in non-human primates have revealed fundamental insights into the neurophysiology of motor learning. The tuning properties of individual neurons evolve, and groups of neurons consolidate into stable networks. Studying the correlates of BCI learning in humans has traditionally been a more challenging task because to enable optimal BCI control of effectors, neural decoding algorithms need to adapt to non-stationary signals. Thus, real-world BCI decoders exhibit changing input features as well as model parameters making inferences about motor learning difficult to interpret.

Design/Methods: Here we present a Local Field Potential (LFP)-based decoding paradigm that allows human participants enrolled in the BrainGate2 clinical trial to learn a relatively simple and arbitrary map between LFP power in the low-gamma range and one-dimensional cursor control. Specifically, the smoothed LFP power in the low-gamma range (40 -55 Hz) from a single electrode selected from two 96-channel microelectrode arrays (Blackrock Microsystems, Salt Lake City, UT) placed in the dominant motor cortex was mapped based on threshold percentile values to constant speed leftward, resting, or rightward directional control of a cursor (paddle) during the game "Pong" presented on a computer screen.

Results: The decoder was successfully tested online with BrainGate2 clinical trial participant (T9), a 54 year-old man with amyotrophic lateral sclerosis. Our preliminary results indicate that T9 was able to improve directional control ability over the course of a single 30-minute session using this fixed decoder. We plan to analyze performance in additional participants over multiple days to assess for participant learning and subsequently analyze the evolving relationships between local field potentials and neuronal action potentials both on the control electrode and across both microelectrode arrays.

Conclusions: This study illustrates the ability to use an intracortical brain-computer interface with a fixed, LFPbased, simple decoder to analyze the spatial and temporal neural dynamics of human motor learning.

S292. Emergent Computed Tomography Angiography of Intra-and Extracranial Vessels; Ordering Patterns and Yield at a Single Institution Shannon Hextrum, Jorge Ortiz, Jonatan Hornik, Jordan Rosenblum and Barak Bar. Maywood, IL Introduction: Computed tomography angiography (CTA) of intra-and extracranial vessels is necessary for diagnosis of several emergent conditions, including acute large vessel occlusion (LVO) and acute cervico-cerebral arteries dissection (CCAD). However, CTA overuse must be avoided given radiation exposure, issues of cost, and risk of contrastinduced nephropathy (CIN). The purpose of this study was to examine CTA ordering practices at a single institution and better establish indications of high and low clinical yield.

Methods: All CTAs of intra-and extracranial vessels ordered from the Emergency Department in our institution between 07/15/2015 and 07/14/2016 were included. The resulting 410 CTA reports were analyzed by indication as written on the order and yield as documented in the final radiology report.

Results: 20 CTAs of intra-and extracranial vessels were ordered with neck pain or injury as an indication, with 75% revealing normal results and 15% showing clinically significant stenosis. Dissection was identified in 5 CTAs, none of which were associated with the indication of neck pain. Vessel occlusion was identified in 26 CTAs, associated most commonly with the indication of weakness (42.3%), followed by "rule out stroke" (38.4%), and speech or language deficits (34.6%). Weakness was an indication for a total of 89 CTAs and 55% showed clinically significant, abnormal results. CTAs ordered for vertigo and sensory changes were correlated with occlusion in 3.1% and 2.9% of scans, respectively.

Conclusion: Isolated neck pain was of particularly low yield in diagnosis of LVO or CCAD. Weakness was the highest yield indication for LVO and among the highest yield indications for likelihood of demonstrating any abnormal result. Hereditary ATTR (hATTR) amyloidosis is a rapidly progressive, life-threatening disease. Currently, the only approved medication for hATTR amyloidosis is tafamidis and such approval is limited to select countries outside the US. Recent data suggest disease progression may occur with tafamidis (Plant e-Bordeneuve et al. J Neurol 2017). Diflunisal, a NSAID shown to prevent dissociation of TTR tetramers, and doxycycline, a TTR fibril disrupter, are sometimes used off-label for hATTR amyloidosis. Patisiran, an investigational RNAi therapeutic targeting hepatic TTR production, is being studied in an ongoing Phase 3 trial (APOLLO) which completed enrollment. The objective is to evaluate the demographics of patients receiving tafamidis, diflunisal, and/or doxycycline prior to APOLLO enrollment and physician-reported reasons for discontinuation.

APOLLO is a Phase 3 multi-center, international, randomized, double-blind, placebo-controlled study (NCT01960348) to evaluate the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy. Symptomatic patients with documented TTR mutation and NIS 5-130 were eligible. Select exclusion criteria: prior liver transplantation, PND score >IIIb, NYHA class >2. Patients receiving tafamidis or doxycycline were required to discontinue those drugs !14 days before patisiran administration; patients receiving diflunisal were required to discontinue !3 days prior to patisiran administration. The primary endpoint is change from baseline at 18 months in mNIS17 composite neurologic impairment score.

225 patients with hATTR amyloidosis with polyneuropathy were enrolled in APOLLO. Among these, 119 patients were previously treated with tafamidis (62%), diflunisal monotherapy (33%), or diflunisal/doxycycline combination (5%). Mean age: 61 years (range 27-83); males: 76%, Val30Met mutation: 45%; non-Val30Met mutation: 55%. Disease severity measures: mean NIS: 58 points (6-142); mean KPS: 71 (60-100); PND I: 23%; PND II: 34%; PND IIIa: 29%; PND IIIb: 15%; NYHA Class I&II: 50% each. Physician-reported reasons captured at enrollment for patient discontinuation of these therapies prior to APOLLO enrollment: clinical study enrollment (72%), disease progression (20%), safety (1%), or other (7%).

APOLLO is the largest controlled study of patients with hATTR amyloidosis with polyneuropathy to date and is believed to be representative of the global patient population. Of patients previously treated with TTR stabilizers/disrupters, > 90% discontinued treatment for APOLLO eligibility or due to disease progression on therapy. These data highlight the significant unmet need in patients with hATTR amyloidosis with polyneuropathy.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Has received honorarium and participated in clinical trials for Alnylam Pharmaceuticals.

To date numerous patients with different mutations are diagnosed with a specific disease, in which a distinct neuron population displays early vulnerability and progressive degeneration. However, it is unclear how such a wide spectrum of gene mutation leads to similar pathologies in patients. We hypothesize that the protein products of mutated genes will not be able to maintain proper interactions with their binding partners, and thus the cellular events they take part in will be affected, and it is indeed these impaired cellular functions, and not single gene mutations, that are responsible for initiating neuronal vulnerability. In an effort to understand why upper and/or lower motor neuron populations display primary vulnerability in different motor neuron diseases, we first identified binding partners of the protein products of all mutated genes that are either associated or linked with ALS, HSP/PLS and SMA. The protein interactome map for each of these diseases had unique and shared proteins. We then studied the canonical pathways and protein networks that are common and unique among diseases that primarily affect distinct motor neuron populations. Our studies reveal that upper and lower motor neurons have their favorite cellular canonical pathways that are distinct and they share some in common. Protein interaction networks also suggest key cellular events and how they may be affected with the mutations of key proteins. At times these proteins hold interactome maps together and are the key interactors linking numerous cellular events. Therefore, their lack of function would be detrimental for numerous cellular events, and that in part explains why their mutations may lead to motor neuron vulnerability and degeneration. Our studies, which originate from human mutations, suggest presence of key cellular events that are primarily important for distinct motor neurons and implicate how their imbalance or perturbation may tip the balance towards selective vulnerability. Ongoing immunocytochemical analysis using post-mortem human motor cortex as well as Elisa assays using serum and plasma samples isolated from ALS patients, further confirm relevance and importance of protein interaction network analysis and how this imbalance lead to motor neuron vulnerability and degeneration. Our results also begin to suggest novel targets for cellular therapies, especially for upper motor neurons.

Pathways That Alter the Behaviour of Peripheral Sensory Neurons Douglas W. Zochodne, Anand Krishnan and Arul Duraikannu. Edmonton, AB, Canada

Peripheral nerve disease renders permanent neurological disability despite the assumptions that regeneration is robust or complete. For many neuropathies and traumatic nerve injuries, permanent axonal degeneration might only be reversed through new regenerative strategies. Here we summarize work identifying three pathways from tumor biology that alter the intrinsic regenerative behaviour of adult sensory neurons. PTEN (phosphatase and tensin homolog deleted on chromosome ten) is expressed in adult sensory neurons, particularly small IB4 nonpeptidergic neurons that have attenuated growth properties. As a tumor suppressor, PTEN inhibits the growth factor pathways that operate through PI3K-pAkt. Small molecule inhibition or local siRNA knockdown of PTEN ramps up the regenerative growth of sensory neurons of in vitro and in vivo injury models (Christie et al, J Neurosc 2010). PTEN expression is paradoxically increased in experimental diabetic neuropathy where regeneration is compromised (Singh et al, Brain, 2014) . Retinoblastoma 1 (Rb1) is expressed in the cytoplasm and nuclei of adult sensory neurons. Knockdown of Rb1 by siRNA increased the outgrowth and branching of adult sensory neurons in vitro, in collaboration with PPARÇ and E2F1. Local Rb1 siRNA knockdown improved outgrowth of axons beyond a nerve transection and indices of regeneration following nerve crush (Christie et al, 2014) . APC (adenomatous polyposis coli) is mutated in colon carcinomas and suppresses tumor growth by acting as a component of the b-catenin destruction complex. b-catenin is a growth promoting transcription factor. APC forms a structural scaffold to phosphorylate b-catenin to be degraded by the proteasome. APC is also particularly (but not exclusively) expressed in IB4 nonpeptidergic neurons, has a reciprocal relationship with b-catenin expression and is paradoxically upregulated by injury. APC knockdown by siRNA improves sensory neurite outgrowth in vitro and regeneration beyond a crush site in vivo (Duraikannu, submitted) .

Taken together, the findings illustrate that regenerationhesitant neurons have a number of plasticity pathways that may be manipulated. Regional and temporary knockdown of tumor suppressor pathways may encourage greater regenerative behaviour in neurons. Moreover, these studies illustrate that near nerve nonviral siRNA knockdown can impact the behaviour of the entire neuronal tree.

[ Peripheral axonal polyneuropathy is a common, potentially dose-limiting side effect of many chemotherapeutic agents despite disparate mechanisms of action, suggesting that the axon destructive properties of various chemotherapies converge on a common axonal degeneration (AxD) program. Components of such a putative program had until recently been largely unknown, until others and we discovered that genetic deletion of SARM1 dramatically protects axons from degeneration after axotomy and prevents neuropathy induced by the commonly used chemotherapeutic agent vincristine in a mouse model. It remains unknown, however, whether the same upstream regulators and downstream effectors of SARM1 act in vincristine-induced axon degeneration and axotomy, and whether the protective effects of SARM1 deletion are also realized by chemotherapeutic agents with different mechanisms of action. To address these questions, we used cultured mouse dorsal root ganglion neurons and two chemotherapeutic agents, vincristine and bortezomib (BTZ). Vincristine acts by stabilizing tubulin polymerization and interfering with intracellular trafficking, whereas BTZ inhibits the proteasome. We demonstrate that genetic deletion of SARM1 strongly decreases not only vincristine-induced neurite degeneration, but also axonal destruction following administration of BTZ. In axotomy, SARM1 is activated by a loss of NMNAT and acts through catastrophic decrease of NAD1. As in axotomy, neurite degeneration after vincristine and BTZ is preceded by loss of NAD1. Maintaining NAD1 levels by overexpressing nicotinamide riboside kinase (NRK) and supplementation with NR strongly protect from both vincristine and BTZinduced degeneration. Furthermore, as in axotomy, overexpressing cytosolic NMNAT1 in the axon prevents degeneration following both vincristine and BTZ. However, while targeting with pharmacological inhibitors the same MAPkinase pathway that regulates SARM1 in axotomy protects from vincristine-induced AxD, it does not decrease BTZinduced AxD. BTZ induced degeneration instead is transcriptionally regulated and can be blocked by over-expressing the anti-apoptotic factor BCL-XL. These findings indicate that different upstream pathways converge on a core axonal degeneration program which consists of NMNAT, SARM1 and NAD1 and which mediates both acute and chronic axonal degeneration. Excitingly, we are able to inhibit this program and, thus pathological AxD in vitro, by virus mediated expression of a SARM1-dominant/ negative mutant. We suggest that targeting the core axonal degeneration pathway either by directly inhibiting SARM1 or maintaining NAD1 through supplementation may have great therapeutic value in the prevention of multiple variants of chemotherapy-induced neuropathy and possibly other peripheral polyneuropathies. Background: Midodrine and pyridostigmine are commonly used as pharmacological treatments for orthostatic hypotension (OH). In this study, we evaluated the long-term effects of single or combined therapy with midodrine and pyridostigmine for treatment durations of up to 3 months.

Methods: This was a randomized, open-label clinical trial. In total, 87 patients with symptomatic neurogenic OH were enrolled and randomized to receive 1 of 3 treatments:

(1) midodrine only, (2) pyridostigmine only, or (3) midodrine 1 pyridostigmine. The patients were followed up at 1 and 3 months after treatment. The primary outcome measures were improvement in orthostatic blood pressure (BP) drop at 3 months. Secondary end-points were improvement of the orthostatic BP drop at 1 month and amelioration of questionnaire score evaluating OH-associated symptoms.

Results: Orthostatic systolic and diastolic blood pressure drops improved significantly at 3 months after treatment in all treatment groups. Orthostatic symptoms were significantly ameliorated during the 3-month treatment, and the symptom severity was as follows: midodrine only > midodrine 1 pyridostigmine > pyridostigmine only group. Mild to moderate adverse events were reported by 11.5% of the patients.

Conclusions: Single or combination treatment with midodrine and pyridostigmine was effective and safe in patients with OH for up to 3 months. Midodrine was better than pyridostigmine at improving OH-related symptoms. Background: Postural tachycardia syndrome (POTS) is the most prevalent form of orthostatic intolerance which frequently occurs in young people with female preponderance. Several medications are prescribed for POTS; however, the efficacy of sustained medical treatment has not been wellinvestigated. In this study, we conducted a randomized, clinical trial of a 3-month medical treatment regimen in POTS patients.

Methods: We recruited 103 patients who were diagnosed as POTS at the Neurology department of Seoul National University Hospital. Patients were randomly allocated to 4 different treatment groups (Group 1: propranolol; Group 2: bisoprolol; Group 3: propranolol1pyridostigmine; and Group 4: bisoprolol1pyridostigmine). Patients were instructed to visit the clinic at 1 month and 3 months after the initiation of medical treatments. The orthostatic intolerance questionnaire (OIQ), Beck depression inventory-II (BDI-II) and short-form health survey (SF-36) were conducted at baseline, 1 month and 3 months after treatment.

The changes of clinical scores at each visit were analysed and the efficacy of medical treatments were investigated according to the treatment regimen.

Results: Among the 103 patients who underwent randomization, 77 who completed the 3-month follow-up were analysed. In total, every clinical score improved significantly after medical treatment. The OIQ score was significantly lower than that at baseline (18.5 6 6.7) after 1 month (12.5 6 4.5, P < 0.01), which decreased further after 3 months (7.8 6 5.7, P < 0.01). The OIQ score improvements were consistent across every treatment group. In the subgroup analysis of 59 patients who did not receive antidepressants, the BDI-II score significantly decreased after treatment, regardless of the treatment regimen (paired T-test, all p < 0.05). Physical components of the SF-36 improved after 3 months in every treatment group, while mental components improved only in Group 3 (paired T-test, p < 0.05). The amount of changes in each score was similar among groups throughout the comparisons (one-way ANOVA, all p > 0.05).

Conclusions: Sustained medical treatment is beneficial to POTS patients, not only for orthostatic intolerance symptoms but also for depression and diminished quality of life, even without prescriptions for antidepressants. The efficacy of each regimen in POTS patients was comparable. Objective: To develop a low-burden clinician-completed rating scale, phenotypically anchored to the breadth of common Myotonic Dystrophy Type 1 (DM1) signs/symptoms, informed by findings of DM1 natural history studies, and capable of assessing treatment-related changes during relatively short time frames.

Background: DM1 is a rare, genetically determined neuromuscular disorder characterised by impairments in muscle functioning, cognition and quality of life. Few clinical trials have been executed in this population, and there are no gold-standard clinician-completed assessments that can characterise the DM1 phenotype. We designed a DM1-specific clinician-rated visual analog scale (VAS), following precedents established in other neurodevelopmental conditions that were subject to regulatory agencies' review.

Design/Methods: We retrieved 464 PubMed "hits" relating to "Myotonic Dystrophy" and "phenotype". Using this literature, in consultation with neuromuscular clinicians and comprehensive review of rating scales in DM1 and related disorders, as well as natural history data, we developed a 17item Domain Specific VAS allowing clinician ratings of DM1 phenotypic features such as impaired muscle functioning, fatigue, myotonia, gastrointestinal and cognitive problems. For each item the clinician makes a mark on a 10cm line representing a symptom severity spectrum from "not at all severe" to "very severe". This scale has been subject to preliminary validation, and exemplars and anchors were developed, through serial rater training exercises, ensuring rating standards consistency.

Results: The scale is piloted in an ongoing DM1 clinical trial involving an experimental medication (NCT02858908). Clinician feedback indicates that it is user-friendly and low-burden, and the scale appears to detect varying degrees of clinical benefit (or detriment) across relatively short time frames. Regulatory feedback was provided to refine the scale, which compliments preliminary psychometric data available from the clinical trial.

Conclusions: The Clinician Domain-Specific Causes for Concern: DM1 Rating Scale effectively assesses the DM1 phenotype and may be a useful tool in clinical trials.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Employee -AMO Pharma Ltd S301. Post-Injury Delivery of AAV9-SMN Accelerates Behavioral and Electrophysiological Recovery Following Peripheral Nerve Injury Christopher G. Wier, Amy R. Knapp, Kajri A. Sheth, Patrick L. Heilman, Stephen J. Kolb and W. David Arnold. Columbus, OH Background: Peripheral nerve injury (PNI) is a common occurrence, accounting for 2-3% of patients presenting to trauma centers. Weakness from damage to motor axons and incomplete reinnervation is a major source of morbidity. Strategies to improve recovery include accelerating axonal regrowth and optimizing neuromuscular junction (NMJ) reinnervation. Adult transgenic mice with SMN depletion exhibit normal axonal regrowth after PNI, but reinnervation of the NMJ is diminished. We have developed an AAV9 vector to overexpress SMN, which has been used previously to rescue animal models of spinal muscular atrophy. We developed and refined a combination of behavioral and electrophysiological assays to monitor motor unit connectivity in vivo.

Objective: To assess the therapeutic efficacy of AAV9-SMN following PNI.

Design: Two bouts of crush, 15 seconds each, were performed at the proximal sciatic nerve to model PNI. AAV9-SMN or PBS was injected into the cisterna magna immediately following the nerve crush. Outcome measures were carried out to 60 days post-injury (60dpi). Behavioral recovery was measured longitudinally using the sciatic function index (SFI). Motor unit connectivity in the triceps surae muscle was assessed electrophysiologically with compound muscle action potential (CMAP) and motor unit number estimation (MUNE) at baseline and during recovery. Pathological characterization of NMJ reinnervation was performed at the end of the study.

Results: Recovery of SFI to baseline occurred by 14dpi in mice receiving AAV9-SMN and by 18dpi in sham treated controls. In both cohorts, electrophysiological recovery was delayed compared with behavioral measures. By 14dpi, CMAP recovery in AAV9-SMN mice reached 15.5% (5.6 6 0.56mV) of baseline while sham mice had recovered to 10.6% (3.9 6 1.5mV). AAV9-SMN mice recovered to baseline CMAP measurements by 28dpi (32.3 6 5.2mV) while sham mice recovered to 65.1% (23.9 6 3.9mV) of baseline at 28 dpi and fully recovered by 32dpi (29.5 6 9.1mV). There was no significant difference between cohorts for MUNE recovery which occurred by 35dpi. Quantification of NMJ reinnervation is ongoing.

Conclusion: AAV9-SMN, administered immediately after PNI, resulted in earlier behavioral and electrophysiological recovery compared to sham. Normalization of behavioral measures occurs prior to return of motor unit connectivity, suggesting improved sensitivity for electrophysiological measures to identify functional deficits. Future directions include mapping recovery following a more severe injury paradigm that results in incomplete recovery similar to that typical of patients with PNI. Mutations in SOD1 are responsible for 20% of familial ALS. Given the likely gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. Antisense oligonucleotides (ASO) targeting SOD1 have been developed and tested in Phase I human clinical trial, yet these early ASO efforts in the CNS afforded modest protection in animal models and did not test whether ASOs may reverse disease once started. We developed next generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more 50 days in SOD1G93A rats by more than 45 days in SOD1G93A mouse. Even more striking, we demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy levels, a promising biomarker for ALS, are reversed by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle denervation and dysfunction can be reversed by therapy.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Ionis Pharmaceuticals provides antisense oligonucleotides to Dr. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type in order to elucidate underlying disease mechanisms and identify novel targets that inform on MN health during ALS disease timecourse. microRNAs (miR-NAs) are short, non-coding RNAs that can shape the expression profile of a cell and, consequently, often exhibit cell type enriched expression. To determine MN-enriched miRNA expression, we utilized Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining the in vivo miRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis, and found they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miR-NAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Thus, we have employed cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled development of a novel, drug-responsive marker of MN disease in ALS rodents.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Washington University has filed patents regarding miRNA as biomarkers and therapeutic targets for ALS. The authors declare no other competing financial interests. Objective: Assess the correlation between muscle structure, muscle function and global cerebral white matter abnormalities.

Methods: Classical DM1 subjects were compared to healthy age/sex matched controls. Disease duration (DD) and muscle impairment rating scale (MIRS) were obtained. A 3T MRI was used to acquire standardized limb images. Muscle volume was derived using T1 images. T2 relaxometry was used to assess the structural organization of biological water within the muscle. Fat fraction (FF) quantification was performed using 3 point Dixon acquisition. Established protocols using a custom force measurement apparatus were used to evaluate soleus force and fatigue. A custom design neuromuscular control evaluation system (lower extremity tracking task; LLTT) was used to perform a functional weight bearing movement assessment. Diffusion weighted imaging was used to measure global cerebral fractional anisotropy (FA). Low FA measures indicate abnormalities in white matter structure.

Results: Five DM1 subjects (34-58yo, _ X -43.8; BMI 24.4 6 4.9; DD 1-22yrs, _ X 5 12.6; MIRS 1-4, _ X 5 2.2) were compared to controls (34-54yo, _ X 5 42.8; BMI 24.9 6 4.8). DM1 subjects had lower soleus muscle volume, a higher FF, and higher T2 relaxation times (T2). Besides abnormalities in muscle force/fatigue measures of DM1 subjects, abnormalities were seen in LLTT which is considered to be governed by both peripheral and central mechanisms. Higher T2 correlated with lower muscle force and higher CTG repeats. Compared to controls, DM1 subjects had a lower FA. A lower global brain FA correlated with diminished muscle volume, increased FF, higher T2, decreased muscle force and quantitative muscle function measures.

Conclusions: Correlations between global cerebral FA and muscle structure and function suggests a CNS role in DM1 neuromuscular dysfunction.

Yotam Blech-Hermoni, Stephen Coscia, Leah Jensen, Malcolm M. Kates, Kalpana Subedi and Ami Mankodi. Bethesda, MD Myofibrillar myopathies (MFM) are rare heterogeneous neuromuscular disorders characterized by aggregation of degraded myofibrillar products in skeletal muscle. At least 6 genes including LDB3/ZASP, MYOT, DES, BAG3, CRYAB and FLNC have been identified to underlie pathology in multiple international cohorts. However, a large majority of patients with MFM still do not have a genetic diagnosis. Distal muscle weakness is often more prominent than proximal weakness. Cardiac arrhythmia, cardiomyopathy and respiratory failure can be life-threatening. Extramuscular manifestations include axonal neuropathy, deafness, diarrhea, dysphonia and cataracts, which are increasingly recognized in MFM patients. These non-muscle manifestations of MFM remain more difficult to explain in part because the expression of the MFM gene products is largely unknown in the nervous system. We demonstrate, for the first time, the expression of ZASP, Myotillin, Filamin C, and BAG3 in ChAT-positive neurons of the spinal cord in mice and humans. In contrast, we find Desmin and aB-Crystallin in glial cells under non-pathological conditions, as demonstrated previously. We show that BAG3 is expressed in motor axons ending in neuromuscular junctions, while Desmin, aB-Crystallin, BAG3, Filamin C, and Myotilin localize to the postsynaptic membranes of the neuromuscular junctions in the tibilais anterior muscle of wildtype mice. ZASP mRNA is extensively alternatively spliced in a developmental-stage and tissue-dependent manner in striated muscle. We identified distinct ZASP splice variants in the mouse brain by Single Molecule Real Time sequencing of transcripts. Exon utilization may explain distinct phenotypes seen in MFM due to ZASP mutations. The presence of different MFM gene products in lower motor neurons, terminal motor axons and neuromuscular junctions can explain non-muscle manifestations in MFM. We propose that the MFM genes should be included in the next generation diagnostic panels for the Charcot Marie Tooth diseases, motor neuronopathies, myasthenic syndromes and other lower motor unit disorders.

Adam Loavenbruck, Kevin Welk, Sit Nate, Crabb Gwen and Kennedy William. Minneapolis, MN Objective: To report two methods that quantify axon reflex sweating from individual sweat glands with nanoliter precision.

Introduction: The peripheral nerve axon reflex is useful for diagnosis of peripheral neuropathy. It can be measured using the vasomotor flare or the sudomotor axon reflex. The flare is obtained by heating an area of skin. Quantitation is limited to measuring the area of surrounding reddened skin. The sudomotor axon reflex is activated by iontophoresis of acetylcholine (ACh). It enables precise measurement of sweating of single stimulated sweat glands (SGs).

Methods: We activated the sudomotor axon reflex in healthy subjects and patients with peripheral neuropathy by iontophoresis of acetylcholine and measured sweating using starch coated plastic tape. Two methods are used for quantification: the 'sidecar' method records sweating in a 2.5cmsq skin area adjacent to the stimulation site by imaging skin with a customized high-resolution mini camera; the 'halo' method uses a starch coated film to analyze sweating surrounding the stimulated skin area.

Results: The sudomotor axon reflex is quantified in terms of sweat gland (SG) number, radius (distance from the stimulation site), sweat rate and volume per gland. Fifty normal control and twenty neuropathy subjects underwent 'sidecar' testing at the foot, calf, thigh and hand; a subset underwent halo testing at the calf and foot. Normal ranges were calculated for SG density, mean sweat rate per SG, total sweat volume, and radius. Neuropathy subjects had at least one low measurement (<5th%). Measurements differed between body sites.

Conclusions: Sudomotor sweating and the vasomotor flare both demonstrate the area of skin activated by the axon reflex. In addition, sudomotor testing includes highly precise measurements of the total and individual sweat output of hundreds of SGs in response to a standardized stimulus. 2 S309. Nicotinamide Riboside Is a Potential Therapy for Diabetic Neuropathy Pranith H. Kumar, Neda Najimi, Krish Chandrasekaran, Chen Chen and James W. Russell. Baltimore, MD Aim: To test if treatment with a precursor of NAD1, Nicotinamide Riboside (NR), would reverse diabetic neuropathy in a mouse model of type 2 diabetes mellitus (T2DM)

Methods: Adult C57BL6 mice were fed a high fat diet (HFD) for two months until they developed neuropathy. Then, 150 mg/kg or 300 mg/kg NR was added to the HFD for a further 2 mo. Neuropathy endpoints were motor sciatic-fibular nerve conduction velocities (MCV), mechanical allodynia (MA), and intraepidermal nerve fiber density (IENFD). In the dorsal root ganglion neurons (DRG) neurons, NAD1 levels were quantified by HPLC.

Results: Both MA and MCV improve in HFD mice with NR treatment (P<0.001 mice at 4 months compared to the 2 month time point). There was no change in control diet (CD) animals. HFD animals continued to develop neuropathy over the 4 mo. period. At 4 mo., the IENFD was decreased in the HFD but not the NR group (P<0.001 HFD mice at 4 months vs baseline). NR treatment did not significantly affect glucose and insulin measurements in HFD animals, but decreased HFD-induced increase in triglycerides and non-esterified fatty acids, and normalized impaired glucose tolerance test. In HFD mice, there was a parallel decrease in the NAD1 level, in SIRT1 activity, and in PGC-1 alpha levels in DRG. NR normalized these measurements.

Conclusion: Oral administration of NR can reverse neuropathy in a model of T2DM and has an excellent safety profile. For the last 2 years, researchers at the University of Tennessee Health Science Center have spearheaded a study involving patients with amyotrophic lateral sclerosis in an effort to shed light on this unpredictable disease's natural course. Utilizing expert technology analyzing metrics of metabolic diagnostics-specifically, the K4B2 machine by COSMED-we have enrolled ALS patients with various severity of disease to participate in a longitudinal study involving a six minute walk. During this exercise, a multitude of parameters are measured on a second by second basis. Metrics such as oxygen consumption and heart rate are compared with ALS functional scores, muscle resistance and reactance, and distance walked. We are in the early stages of our study but have some preliminary data which is promising as we search for predictive markers for long-term functional scores of patients with this debiliitating disease.

By the time this abstract will be presented in October, our preliminary data will be complete and will demonstrate which metrics are most predictive. Due to the timing of this abstract deadline, I am not able to present our findings as they are incomplete. We hope to have the opportunity to present our data in San Diego.

Thank you for your consideration.

Nasheed I. Jamal and Shri K. Mishra. Los Angeles, CA Introduction: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal neurodegenerative disease that affects both the central and peripheral nervous systems. Initially thought to cause purely motor neuron dysfunction, ALS has since been shown to lead to cognitive impairment. The level of cognitive impairment in Veterans with ALS is not yet known, however. Objective: To determine the level of cognitive dysfunction in Veterans with ALS, as these patients' cognitive symptoms may not reflect those found in the general civilian population.

Methods: A retrospective chart review was completed. The ALS Cognitive Behavioral Screen (ALS CBS), a validated neuropsychological assessment (Woolley, ALS, 2010), was administered to 21 ALS patients in the VA GLA ALS Multidisciplinary Clinic in Los Angeles. Each patient's initial assessment was analyzed. Patients with ALS CBS cognitive subscales scores of 10 (of 20) were categorized as frontotemporal lobar dementia (FTLD), cognitive type. Patients with ALS CBS cognitive subscale scores between 11 & 16 were considered to have ALS cognitive impairment. Patients with ALS CBS cognitive subscale scores of !17 were classified as normal. Patients with ALS CBS behavioral subscale scores of 32 (of 45) were designated as FTLD, behavioral type. Patients with ALS CBS behavioral subscale scores between 33 & 36 were labeled as having ALS behavioral impairment. Patients with ALS CBS behavioral subscale scores of !37 were marked as normal.

Results: Twenty patients completed the ALS CBS cognitive subscale. The mean score was 12. Of these patients, 35% met criteria for possible FTLD, cognitive type; 50% had ALS cognitive impairment. Only 15% were cognitively normal. Ten patients were accompanied by caregivers who completed the ALS CBS behavioral subscale. The mean score was 34. Fifty percent of patients were classified as possible FTLD, behavioral type; 10% had ALS behavioral impairment. Forty percent had normal ALS CBS behavioral subscale scores.

Conclusion: Compared to the general civilian ALS population (Murphy, Neurology, 2016), Veterans with ALS have a different cognitive profile. Veterans in our ALS cohort were over five times as likely to have possible FTLD, cognitive type. Unlike other ALS patients, Veterans with ALS were much less likely to score normally on the ALS CBS cognitive subscale. In addition, triple the percentage of Veterans with ALS met criteria for possible FTLD, behavioral type. Taken together, these data suggest that Veterans with ALS have more severe cognitive impairment than their civilian counterparts. Myotonic dystrophy type 1 (DM1) is a progressive, multisystemic, autosomal dominant genetic disease. Neuroimaging studies have discovered significant disruptions in white matter structure in the brains of individuals with DM1. In addition, patients and family members often report that the most disabling symptoms of DM1 involve cognitive and behavioral changes related to the Central Nervous System (CNS). Despite this, little is known about actual disease progression within the CNS in DM1. As clinical drug trials have already started in DM1, it will be crucial to identify biomarkers of disease progression within the CNS. Using a combination of structural MRI, diffusion tensor imaging (DTI), and neuropsychological assessment, we examined brain structure and function in a group of 30 individuals with adult-onset DM1 and 26 healthy controls (males and females, ages 18-64). Analysis of covariance (ANCOVA) was used to control for the effects of age and gender for group comparisons. In order to study disease progression we also examined the relationship of disease duration (as measured by years since onset of symptoms) to brain structure and function measures using linear regression analyses. It was found that patients with DM1 showed reduced volumes of both global (intracranial volume, white matter volume) and regional brain measures (thalamus, putamen). A similar analysis of DTI measures (fractional anisotropy; FA) revealed a significant, diffuse reduction in white matter structural integrity in the patients with DM1. Neuropsychological outcomes showed deficits in visuospatial skills, working memory, and processing speed for the individuals with DM1 (even after controlling for education level). When looking at disease progression within the DM1 group, disease duration (DD) was highly predictive of whole brain FA (r 5 -.713, p <.001) even after controlling for age and gender effects. Those who have experienced the disease the longest showed the most severely disrupted white matter (regardless of age). A similar pattern was found for volumes of the thalamus (r 5 -.496, p 5 .010), scores on the perceptual reasoning index (r 5 -.658, p <.001), and the processing speed index (r 5 -.455, p 5 .017). Results point to a progressive, measurable deterioration of brain structure and function, particularly within the white matter and thalamus. These neuroimaging measures may provide valuable biomarkers of disease progression within the CNS for DM1. Expansion of a GGGGCC hexanucleatide repat of the C9orf72 gene is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). An attractive hypothesis is that aberrant microglia might lead to neuronal loss or synaptic disruption in neurodegenerative disorders like ALS and FTD. Although recent work from our lab demonstrated that C9orf72 is required for proper macrophage and microglial function in mice, there was no appreciable neuronal death and the mechanism by which neuronal cells are eventually loss in ALS remains unknown. In order to study neuronal death in C9orf72 mice, the known and reliable MPTP model of neuronal degeneration is being utilized. Wild type, heterozygous, and homozygous C9orf72 mice were injected with lower doses of MPTP than typically used in Parkinson's models to avoid complete ablation of dopaminergic neurons. Although the preliminary data has not demonstrated a quantifiable increase in neuronal death in the mutant animals compared to controls at the tested dose, the MPTP treated C9orf72 mutants appear to develop an increase in reactive astrocytosis in areas of neuronal loss. Ongoing analyses will focus in studying older animals and further characterizing the extent of neuronal injury and the inflammatory responsea involved, including microglia. Such studies should help in understanding the link between the C9orf72 gene, microglial dysfunction, and the eventual neuronal degeneration observed in ALS.

Affected by Axon Length in a Chemical Axonotomy Model, but Is Impaired in Diabetic Patients Mohammad Khoshnoodi, Shaun Trulove and Michael Polydefkis. Baltimore, MD It is not clear if the regeneration of sensory distal axons is length-dependent. Additionally, regeneration of cutaneous unmyelinated axons is known to be slowed in DM-patients and after 3-months and the density of intraepidermal nerve fibers (IENF) does not return to baseline levels after chemical or mechanical axotomy. However, the long-term outcome of regeneration in DM or control subjects is not known. Here we measured the rate of axonal regeneration 6-months after chemical denervation using a capsaicin model in DM patients (n511/37 DM1/DM2) without neuropathy, and 5 controls. DM skin punches were performed at distal thigh at baseline, 48-hours post-capsaicin, and at 28, 90, 150 and 180 days. Blood glucose and HgbA1C were measured at baseline, 90, 150 and 180 days. Healthy controls had skin punches at both distal leg and proximal thigh at baseline, after capsaicin chemical axotomy, and days 28, 60, 90 and 180. Regeneration rate was significantly higher at the thigh in healthy controls (0.1 fibers/mm/day (95% CI: 0.04-0.18 fibers/mm/day) compared to DM (p50.043), but no difference between DM1 (0.07 fibers/ mm/day 95% CI: 0.01-0.13 fibers/mm/day) or DM2 (0.06 fibers/mm/day 95% CI: 0.01-0.12 fibers/mm/day) (p50.4). Comparing regeneration rate at different time intervals, showed that regeneration was significantly slowed between day 150 and 180 DM patients, while it continued with the same rate in controls. Blood glucose or HgA1C had no effect on regeneration rate. IENFD returned to baseline in controls by 6-months (118% of baseline) while it is did not in DM subjects, 76%/58% (DM1/DM2) of IENFD baseline, (p50.003 DM vs. controls). There was no difference in regeneration rate IENFD %-baseline by 6-months at distal leg and proximal thigh in controls (p50.61). These results suggest that the rate and outcome of regeneration is independent of the length of the axon. Additionally diabetic patient have incomplete nerve regeneration after 6 months regardless of diabetes type or the level of glycemic control. Regeneration of axons slowed down over time in patients with DM and reached a plateau after 150 days. Objective: Autosomal recessive mutations in TBCK cause intellectual disability of variable severity. Although the physiologic function of TBCK remains unclear, loss-of-function mutations are associated with inhibition of mTORC1 signaling. As mTORC1 signaling is known to regulate autophagy, we hypothesized that TBCK-encephalopathy patients with a neurodegenerative course have defects in autophagiclysosomal dysfunction.

Methods: Children (n58) of Puerto Rican (Boricua) descent affected with homozygous TBCK p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK-/-patient-derived fibroblasts by immunostaining and assayed autophagic markers by Western assay. Free sialylated oligosaccharide profiles were assayed in urine and fibroblasts.

Results: The neurologic phenotype of children with TBCK p.R126X mutations, which we call TBCK-encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy and epilepsy. Systemic features consist of coarse facies, dyslipidemia, and osteoporosis. TBCK-/-fibroblasts in vitro exhibit increased numbers of LC31 autophagosomes, and upregulation of autophagic markers LC3b and beclin-1. Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine.

Interpretation: TBCKE is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently seen in patients with the p.R126X mutation. We provide evidence that inappropriate autophagy in the absence of cellular stressors may play a role in this disorder, and that mTORC1 activation may ameliorate the autophagic-lysosomal system dysfunction. Free oligosaccharide profiles could serve as a novel biomarker for this disorder as well as a tool to evaluate potential therapeutic interventions.

Trigged by PD-1 Inhibitors: Balancing Treatment Efficacy and Side Effects Michael C. Isfort, Natalia L. Gonzalez, Neil A. Busis, David Lacomis, Sa sa A.

Z ivkovic´and Araya Puwanant. Pittsburgh, PA Objective: To define the spectrum and prognostic factors of immune-mediated neuromuscular complications triggered by PD-1 inhibitors.

Background: Severe, potentially fatal, immune-related neuromuscular complications triggered by PD-1 inhibitor therapy have been increasing reported. However, disease spectrum has not been fully evaluated.

Method: We performed a retrospective review of Cancer Database for patients receiving PD-1 inhibitors from the FDA-approval until May 2017. We identified patients who developed autoimmune neuromuscular conditions following PD-1 inhibitor treatments. We evaluated clinical, workup, pathology, immunologic studies, and prognostic factors in each patient.

Results: We identified 4 patients with neuromuscular complications. Myasthenia gravis (MG) is the most common condition (3/4), followed by Guillain-Barr e syndrome. All patients demonstrated hyperCKemia in addition to other neuromuscular conditions. Pembrolizumab and nivolumab are the most commonly used PD-1 inhibitors. Unfavorable prognosis included preexisting MG diagnosis, non-melanoma malignancy, and age. Corticosteroids and intravenous immunoglobulin led to significant improvement of symptoms.

Conclusion: Despite the rarity, it is essential that immunologic-associated neuromuscular complications should be recognized early and treated promptly to reduce iatrogenic complications. Additional studies are required to characterize the association of MG and hyperCKemia in the patients who receive anti-PD1 therapy. -PN) , a point mutation in the TTR gene destabilizes TTR protein to induce deposition of amyloid in organs including peripheral and autonomic nerves. Amyloid deposition eventually leads to multi-organ failure, with life expectancy 5-15 years from symptom onset. Inotersen is a generation 21 antisense oligonucleotide (ASO) inhibitor of TTR protein production.

We conducted a world-wide randomized, double-blind, placebo-controlled phase 3 study of inotersen in patients with hATTR-PN (NEURO-TTR, NCT01737398). Eligible patients were adults who had Stage I (ambulant) or Stage II (ambulant with assistance) disease. The primary endpoints were change from baseline in the composite modified Neuropathy Impairment Score17 (mNIS17) and patient reported Norfolk Quality of Life Diabetic-Neuropathy score. 172 patients were randomized (2:1) and received 300 mg weekly SC doses of inotersen, or placebo. Eighty percent of patients completed the 15-month treatment period. Inotersen-treated patients achieved statistically significant benefit compared to placebo for both primary endpoints. Key safety findings were thrombocytopenia and renal dysfunction. More than 95% who completed treatment have participated in the open-label extension study. Methods: ALS patients received riluzole (100mg/kg) plus either oral masitinib 4.5mg/kg/day (M4.5) (n5106) or placebo (n5114) over 48 weeks. Primary endpoint was absolute change in ALSFRS-R[W0-W48] (DALSFRS-R) in patients with baseline ALSFRS-R progression of <1.1 points/month.

Results: Masitinib showed significant benefit in DALSFRS-R over placebo with a difference of 3.4 (27% retardation) (P50.0158). Secondary analyses including time-to-event analysis (PFS), ALSAQ40, and FVC were significant. Post-hoc analysis indicated enhanced treatmenteffect (42% retardation) with early treatment (<24-month duration of illness). Common (>10%) adverse events (AEs) with masitinib in this patient cohort were rash, nausea, diarrhea, and weight loss. Frequency of AEs, serious AEs, and severe AEs (placebo versus M4.5) was respectively: 79%vs.90%, 20%vs.28%, and 18%vs.24%.

Conclusions: Masitinib 4.5mg/kg/day demonstrated significant benefit with acceptable safety in ALS patients with baseline ALSFRS-R progression rate of <1.1 points/month. Objective: To highlight choriocarcinoma as a cause of recurrent peripartum intracerebral bleeds in a normal pregnancy.

Background: Choriocarcinoma coexisting with or after an otherwise normal pregnancy is extremely rare, occurring in 1 in 160000 pregnancies. Only 3 cases of choriocarcinoma intracerebral metastases have been reported in women with viable pregnancies. Mycotic aneurysms from choriocarcinoma are rare and seldom proven angiographically.

Design/Methods: Case report.

Results: A 38-week pregnant 26-year old woman presented with an acute left frontal hemorrhage. She underwent an emergency caesarian, followed by evacuation of hematoma and resection of what morphologically appeared to be a medium-sized arteriovenous malformation. Angiogram before and after resection showed no obvious vascular pathology. One month later, she returned with status epilepticus and an acute parenchymal hematoma posterior to the surgical resection cavity. Angiogram showed a multilobulated pseudoaneurysm along the middle cerebral artery. This was completely resected and found on histopathology to have choriocarcinoma within and around the blood vessels. Serum HCG levels increased daily. Pan CT showed a left lung lobular mass. The diagnosis was stage 4 WHO score 9 high risk metastatic choriocarcinoma, requiring radiation therapy then multi-agent chemotherapy. 2 weeks later, she had another seizure. Angiogram showed an unruptured pseudoaneurysm along the right posterior cerebral artery, which was embolized.

Discussion: The diagnosis of choriocarcinoma is seldom considered during a viable pregnancy, but is almost always fatal if unrecognized and untreated. Early recognition enhances the chances of cure with chemotherapy. Arteriovenous malformations commonly cause intracerebral bleeds in young women and have higher risk of rupture in pregnant women. However, neurologists should be aware of the possibility of metastatic choriocarcinoma and mycotic aneurysms in women who experience intracerebral bleeds during and after pregnancy. Refractory prolactinomas are resistant to these treatment modalities and show rapid growth with invasion into surrounding tissue. TMZ is an oral alkylating chemotherapeutic agent primarily used in gliomas that has been given to patients with atypical prolactinomas that are refractory to medical, surgical, and radiation treatments.

Methods: Retrospective chart review was conducted for refractory prolactinoma patients treated between 2008 and 2017 at University of Texas Southwestern (UTSW). Four patients with atypical prolactinomas who had progressed through standard medical, surgical, and radiation therapies received oral TMZ at UTSW.

Result: Age at diagnosis ranged from 20 to 64 years. Two of the study patients were female and two were male. All patients had failed prior treatment with dopamine agonists, surgical resection, radiosurgery and/or radiation. The mean prolactin level of the study patients immediately prior to starting monthly TMZ was 639.4 ng/ml (normal: 4.04-15.20 ng/ml). TMZ was given at a dose of 200 mg/m2 in a 5 out of 28-day regimen. Patients were followed up every 2 months with physical and neurologic exams, brain and pituitary MRIs with contrast, and serum prolactin levels. Radiological response was determined by RANO (Response Assessment in Neuro-Oncology) criteria. All 4 patients demonstrated improvement in symptoms, markedly decreased serum prolactin levels, as well as radiographic decrease in tumor size. 3 out of 4 patients developed thrombocytopenia; however only one required platelet transfusions and the other required dose reduction of TMZ. Another patient developed neutropenia requiring Filgrastim injections. One patient completed 18 cycles of TMZ and was stable for 18 months before recurring on surveillance. Her MRI demonstrated an increase in the size of her prolactinoma and her serum prolactin again increased. She was then restarted on monthly TMZ with subsequent radiographic stabilization and lowering of her serum prolactin levels.

Conclusion: TMZ is well tolerated and is a potentially effective treatment for refractory prolactinomas. Larger prospective studies are required to confirm the efficacy of TMZ in refractory prolactinomas. Introduction: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system (CNS) disorder with particular involvement of the pons. Diagnostic criteria include a range of clinical symptoms related to the underlying brainstem pathology, visible with magnetic resonance imaging (MRI). Specifically, MRI findings include the appearance of punctuate and curvilinear gadolinium enhancement "peppering" the pons. We discuss a patient presenting with clinical and radiographic characteristics of CLIPPERS who was diagnosed with Erdheim-Chester Disease.

Case report: 52 year old male presented with two years of progressive spasticity, dysarthria, and gait instability. In the first year of symptoms, he was diagnosed with Parkinson disease at an outside hospital, based on tremor, rigidity, and gait instability; however, he failed to improve with a trial of levodopa. Brain MRI showed small enhancing parenchymal nodules coalescing in the central pons, but also affecting the cerebellum and cerebellar peduncles, with more punctate enhancing lesions in the cerebral lobar subcortical white matter. When the patient's response to steroids was inadequate, further imaging was done, revealing perinephric processes. Subsequent perinephric biopsy revealed Erdheim-Chester Disease.

Conclusion: A review of the literature for cases of CLIP-PERS demonstrated a subset of patients later found to have various malignancies involving the CNS. This case report uses the patient's unique radiographic and clinical presentation to demonstrate the importance of the exclusion criteria within the CLIPPERS diagnostic requirements and stresses red flags suggestive of alternative diagnoses. This distinction is of high importance when differentiating a relatively benign process such as CLIPPERS from comparatively more malignant diseases. Objective: To report a case of multiple myeloma with lesions extending into cavernous sinus and cervical spine presenting with isolated abducens nerve palsy and ipsilateral hemiparesis.

Background: Multiple myeloma can present with cranial nerve palsies. There are several case reports on multiple myeloma involving or extending into cavernous sinus most commonly manifesting as abducens nerve and rarely oculomotor nerve palsy. Abducens nerve is the most common nerve to be involved in various etiologies such as brainstem gliomas, diabetes mellitus, multiple sclerosis, metastases, as well as after viral illness, paget's disease, trauma and sellar/ parasellar lesions due to its long intracranial route. Diplopia due abducens nerve palsy can be a presenting symptom of multiple myeloma and has been reported in less than 10 cases. We report a case of 68-year old female presenting with inward deviation of the left eye without diplopia and left sided upper extremity weakness due to multiple myeloma lesions in left cavernous sinus and cervical spine.

Case Description: A 68-year old right handed female presented with left upper extremity weakness and inward deviation of the left eye. She had no diplopia or pain in the eye and had lost 20 lbs in 2 months with no change in appetite. Neurological examination revealed left sided weakness (flexors more than extensors) and reduced sensation in left side. CT head demonstrated multiple lytic lesion in calvarium and MRI showed enhancing lesions with 3.1 x 2.6 x 2.4 cm lesion in left paracentral clivus extending into the left cavernous sinus, sella turcica left petrous apex, sphenoid sinus, prepontine space and the left Meckel's cave. It encased the petrous, cavernous and clinoid segments of the left internal carotid artery with no vascular compression and left abducens nerve. Clinical picture along with laboratory panels and bone marrow biopsy confirmed the diagnosis of plasm cell neoplasia. The patient started radiation therapy which significantly improved her condition including left lateral gaze palsy.

Conclusion: Isolated abducens nerve palsy is the most common cranial neuropathy associated with various conditions. Multiple Myeloma of the clival region extending to cavernous sinus is a rare entity and could be a cause of isolated abducens nerve palsy.

Sinus with Prominent Cranial Nerve Involvement -Treatment and Response Over 15 Years Maliheh Mohamadpour. Brooklyn, NY Introduction: Adenoid cystic carcinoma (ACC) is a rare head and neck cancer originating in a salivary gland. Tumors originating in the major salivary glands spread locally to cranial nerves and ultimately to brainstem. Treatment includes surgical resection and radiotherapy.

Case report: A 35 y/o Iranian woman presented with a mildly painful lump on the right nasal root, diagnosed by CT imaging and later pathologically confirmed as an ACC of the right ethmoid and frontal sinuses. She was treated in Iran with surgical resection including the superior nasal concha and nasal septum, followed by fractionated Cobalt-60 radiation. A recurrence 8 years later was treated with a second surgery extending laterally to the orbital wall and posteriorly to the sphenoid sinus. At age 46 she developed a partial R CN III and CN V1 and V2 palsy with severe facial pain, and MRI also revealed perineural invasion of the optic nerve to the cavernous sinus. She was treated in Germany with neutron beam intensity-modulated radiation therapy (IMRT) which reduced the pain but led to R eye blindness within a year. One year after IMRT recurrent symptoms suggested tumor invasion of the right cavernous sinus, and imaging revealed tumor invasion of the orbit and perineural involvement of CN III, IV and VI from the orbit to near the brainstem. Now age 50, she underwent in the U.S. 39 Gy of fractionated proton beam radiation of the involved tissue including the cavernous sinus. Two months later she developed dysphagia, hoarseness and tongue deviation to the right, progressing over weeks to L frontal headache, severe nausea, dizziness and a partial L CN III palsy. MRI revealed enhancement of the R CN III as it entered the brainstem. Tumor profiling revealed 5 genomic alterations in ARID1A (G410*), CREBBP (S893*), KDM6A (splice site 975-1G>A), NOTCH1 (S2467fs*10), SETD2 (R456*). The patient is entering a research trial of an oral NOTCH inhibitor.

Conclusion: ACC can produce multiple cranial nerve and brainstem symptoms, and is difficult to cure unless it is diagnosed very early. This case illustrates both the initial indolent and later more aggressive course of the carcinoma, the difficulty obtaining a complete surgical resection, and its resistance to multiple types of radiation therapy. Methods: Cognitively-normal participants (N5189, age 66.6 18.3 years) in longitudinal cohorts at Washington University underwent 7-14 days of actigraphy in their home environment, in addition to ongoing longitudinal clinical assessment, amyloid imaging, and cerebrospinal fluid biomarker collection. Circadian rhythm analysis was performed on actigraphy data using four methods: cosinor, periodogram, non-parametric, and empirical mode decomposition (EMD).

Results: Older age, in the absence of AD pathology, was associated with a significant increase in intradaily variability (IV), a non-parametric measure of rest-activity rhythm fragmentation, as well as decreased amplitude by several measures. Amyloid plaque pathology alone did not significantly influence fragmentation when corrected for age, though non-parametric methods demonstrated a subtle advance in phase. Elevated phosphorylated tau was associated with increased IV, independent of age. Overall, non-parametric methods were sensitive for identifying circadian abnormalities in this cognitively-normal population; cosinor, periodogram, and EMD analyses were highly correlated to each other, but could not detect any changes in preclinical AD.

Interpretation: We show for the first time that circadian rhythm fragmentation is present in preclinical AD, stage 2. Amyloid pathology alone was associated with advance in circadian phase but not with changes in amplitude or fragmentation. Our data are also the first to show that aging, in the absence of AD pathology, increases circadian fragmentation and decreases amplitude.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? ESM has received consulting fees from Eisai Pharmaceutical D.M.H. cofounded and is on the scientific advisory board of C2N Diagnostics and consults for Genentech, AbbVie, Eli Lilly, Neurophage, and Denali. Introduction: Daytime napping is very common in older adults, especially in patients with Parkinson's disease (PD). Preliminary evidence suggests that self-reported napping or excessive daytime sleepiness might also precede the risk of PD. However, no study has prospectively examined whether objectively-measured napping could predict the long-term risk of developing PD in community-dwelling older adults.

Methods: We studied 1537 older men (mean age 74 years at baseline) without a history of PD who had napping habits assessed at baseline and followed up for PD over 11 years. Napping duration was measured by wrist actigraphy for a minimum of 3 consecutive 24-hour periods and was defined as the mean minutes scored as sleep (at least 5 consecutive minutes of inactivity) outside of the main sleep interval. Logistic regression was used to examine the association between napping duration and the development of any doctor-diagnosed PD reported by the participants over the follow-up.

Results: A total of 116 PD cases were identified over 11 years. After adjustment for age, Body Mass Index, smoking, physical activity, depression, diabetes, hypertension, stroke, coronary heart disease and cognitive function, the odds ratios (OR) of developing PD for men with a napping duration of 30-60min, 60-120min and >120min were 1.68 (0.79, 3.57), 2.50 (1.19, 5.26) and 3.72 (1.53, 9.02), respectively, compared to those with a napping duration of <30min. Every 30min increase in napping duration was associated with a 26% higher risk of PD (OR5 1.26, 1.10-1.44, p50.001). Further adjustment for actigraphy-measured nighttime sleep duration, sleep efficiency and apneahypopnea index did not appreciably alter the results. Sensitivity analysis excluding PD cases (n533) developed within the first two years after baseline showed similar findings (OR51.23, 1.06-1.42 for every 30min increase in napping duration).

Conclusion: Longer daytime napping was prospectively associated with a higher risk of developing PD in older men. Identification of excessive napping in the elderly might help to predict future PD risk. Further studies are needed to help understand potential mechanisms. Sleep-disordered breathing (SDB) is a common disorder in aging that is associated with cognitive decline, including significant executive dysfunction, for which the neurobiological underpinnings remain poorly understood. Using proton magnetic resonance spectroscopy (1H MRS), this study sought to assess whether dysregulations of the homeostatic balance of the major inhibitory and excitatory amino acid neurotransmitter systems of c-aminobutyric acid (GABA) and glutamate, respectively, play a role in SDB. Levels of GABA and those of the combined resonances of glutamate and glutamine (Glx), were measured by 1H MRS in the left dorsolateral prefrontal cortex (l-DLPFC) and bilateral hippocampal regions of nineteen older adults (age 6 SD: 66.1 61.9 years; 64.3% female) with moderate to severe SDB, defined as having Apnea-Hypopnea Index (AHI) greater than fifteen as assessed by polysomnography, and in fourteen older adults (age 6 SD: 62.3 61.3 years; 31.6% female) without SDB (AHI<5). In subjects with SDB, levels of left l-DLPFC GABA, but not Glx, were significantly lower than in control subjects (p < 0.0002). In addition, there was a negative correlation between left l-DLPFC GABA levels, but not Glx, and SDB severity by AHI (r5-0.68, p<0.0001), and a positive correlation between left l-DLPFC GABA levels, but not Glx, and minimal oxygen saturation during sleep (r50.62, p50.0005). By contrast, no group differences or associations with AHI or oxygen saturation were found for levels of GABA, Glx or any other metabolite in either right or left hippocampal region. Furthermore, GABA levels in l-DLPFC correlated positively with DLPFC cortical thickness (r50.41, p50.03). These findings suggest and are interpreted in terms of a pathophysiological model of SDB in which hypoxia-mediated inhibitory neurotransmission deficit in the DLPFC leads to hyperexcitability and, potentially to neuronal dysfunction and attendant cognitive decline in SDB. Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. We report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping in constant conditions and exaggerated responses to phase resetting. Remarkably, genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder. JZP-110 is a selective dopamine and norepinephrine reuptake inhibitor with wake-promoting effects. Adults with narcolepsy type 1/2 were randomized to receive placebo (n560), JZP-110 75mg (n559), 150mg (n560), or 300mg (n560) daily for 12 weeks. Change from baseline to week 12 in Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were co-primary endpoints; Patient Global Impression of Change (PGI-C) was a key secondary endpoint. Safety was also evaluated. Patients were 65.3% female, 80.1% white, mean6SD age 36.2 6 13.2 years. Least squares mean MWT change from baseline at week 12 was 9.8 and 12.3 minutes with JZP-110 150mg and 300mg, respectively, relative to 2.1 minutes with placebo (both P<0.0001); 75mg was not significant on the MWT. All JZP-110 doses significantly decreased ESS scores and increased patient ratings of improvement on the PGI-C relative to placebo at 12 weeks (75mg, P<0.05; 150mg and 300mg, P<0.0001). Treatment-emergent adverse events !5% across JZP-110 groups were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety. JZP-110 150mg and 300mg met the co-primary efficacy endpoints; safety was consistent with phase 2 trials. Support: Jazz Pharmaceuticals. Objective: To describe a pediatric case of traumatic CVST and SDH and discuss management implications. Background: CVST is a rare complication of pediatric head trauma, but is becoming more common as the incidence of pediatric closed head injury rises. Coexisting intracranial hemorrhage often confounds management, and CVST clinical trial data do not adequately address treatment decisions in children.

Case Report: A 4-year-old boy was evaluated after a generalized tonic-clonic seizure resulting in a fall with head trauma. After the event, he was drowsy and unsteady while walking. His history included developmental delay and generalized epilepsy from age 6 months, with refractory seizures. Several maternal relatives had epilepsy but there was no family history of hypercoagulable disorders.

Examination showed a developmentally delayed boy without dysmorphic features or abnormal skin findings. He was drowsy but followed simple commands. Cranial nerves, motor strength and coordination were intact. A Babinski reflex and ankle clonus were present on the left side. Noncontrast CT head demonstrated left mastoid fracture and 1.2x1.6 cm SDH near the left sigmoid sinus. MRI/MRV showed left transverse and sigmoid CVST without infarction.

He was admitted and evaluated by Pediatrics, Neurology, Neurosurgery and Hematology. A thrombophilia evaluation was negative and the mechanism of thrombosis was believed to be venous compression by SDH. Observation only was initially planned, but low-dose aspirin was started after repeat CT showed SDH enlargement. Mental status and gait abnormalities resolved and he was discharged home. He was functioning at baseline when seen three months later.

Conclusions: We describe a case of pediatric traumatic CVST and SDH in which a good outcome was achieved with conservative management. We suggest that observation is an appropriate first approach in the absence of underlying hypercoagulable states. Anticoagulation is not inherently required, and may actually be detrimental in some cases, as outcomes in pediatric cases of head trauma are generally good. Additional clinical data are needed to define specific indications for antithrombotic therapy in children with traumatic CVST. Often thought to represent gliosis, the underlying microstructural tissue and microvascular integrity within FLAIR hyperintensities are not well understood. The current study utilized a multimodal MRI protocol to assess mean diffusivity (MD), fractional anisotropy (FA), and vascular function within FLAIR abnormal regions in chronic TBI subjects. MRI was performed on chronic TBI subjects (subjects with FLAIR abnormalities, n513; subjects without FLAIR abnormalities, n58) and healthy controls (n515). Multimodal MRI included T1-MPRAGE, FLAIR, Diffusion Tensor Imaging (DTI), Arterial Spin Labeling (ASL), and Blood-oxygen level dependent imaging (BOLD) with hypercapnia challenge to assess cerebral vascular reactivity (CVR). MD, FA, cerebral blood flow (CBF), and CVR within regions of FLAIR hyperintensities were compared to normal appearing tissue. All values were converted to z-scores using the pool of healthy controls from the study. There was a significant reduction in FA, CBF, and CVR with a complementary increase in MD within regions of FLAIR abnormalities (p<0.05). TBI subjects demonstrated regions of increased MD and reduced CVR in regions of normal appearing brain parenchyma (p<0.05, compared to controls). A standardized symptoms questionnaire (RPQ-13) did not reveal differences between TBI subjects with FLAIR hyperintensities versus TBI subjects without FLAIR abnormalities (p > 0.05), consistent with prior studies indicating that FLAIR-hyperintense abnormalities do not predict clinical outcome. Grey matter CVR correlated weakly with RPQ-13 symptom score (r 5 0.457, p 5 0.018), as did global MD (r 5 20.407, p 5 0.033). These findings provide insight into the neurobiology underlying FLAIR abnormal regions in individuals with chronic TBI, and indicate that DTI metrics and measures of microvascular integrity may be more sensitive measures of chronic pathology after TBI.

CD338. Striatal Dysfunction in SHANK3 Duplication Syndrome Mice Jimmy L. Holder, Michel Weiwer, Ed Holson, Michael Lewis, Florence Wagner and Huda Y. Zoghbi. Houston, TX and Cambridge, MA

We have previously described the SHANK3 duplication syndrome and reported that mice modeling this disorder have multiple behavioral abnormalities including hyperactivity and accentuated amphetamine induced hyperactivity (AIH). SHANK3 resides in the post-synaptic density of excitatory synapses where it acts as a scaffolding protein linking neurotransmitter receptors and other transmembrane proteins to the underlying cytoskeleton. SHANK3 is most abundantly expressed in the striatum which is known to be a critical center for control of motor activity.

Shank3 overexpressing mice (Shank3 TG mice) were treated with novel D2 dopamine receptor antagonists developed as potential anti-psychotics. Two independent antagonists were able to reverse the baseline hyperactivity as well as accentuated AIH without altering other behavioral abnormalities previously observed in these mice. To further explore the necessity of Shank3 overexpression in these neurons for the hyperactivity phenotypes, we created mice with a floxed Shank3 TG allele. When this allele was disrupted by Cre recombinase expressed only in the D2 dopamine receptor expressing neurons, the accentuated AIH was rescued. Together these data suggest that dysfunction of the D2dr neurons of the Shank3 TG mice contributes to the baseline hyperactivity as well as accentuate AIH. Methods: We compared the demographics, quantitative MRI, Florbetapir-PET imaging and laboratory findings of CAA-AD (n551) to NH-AD (n585) within the ADNI database.

Results: Patients with CAA-AD had higher leukoaraiosis (0.73% vs 0.49%, p50.035) and higher occipital-to-global Florbetapir ratio (0.98 vs 0.94, p50.02) but similar demographics, mean cortical Florbetapir uptake, cortical thickness, and hippocampal volume (all p>0.2) when compared to NH-AD. APOE4 was more frequent in CAA-AD (78% vs 60%, p50.038). CAA-AD also had lower Ab-42 (127 vs 140 pg/ml, p50.038) than NH-AD. All of these associations remained unchanged in the multivariate regression models.

Conclusions: Over one-third of AD patients displayed subtle hemorrhagic lesions in a CAA-pattern, with higher posterior amyloid binding and lower CSF Ab-42 levels probably due to sequestering of amyloid in cortical vessel walls. Advanced CAA accompanying AD can be detected using imaging/lab studies, potentially affecting clinical treatment decisions. Interhemispheric interactions between the two primary motor cortices are of principal importance in understanding functional lateralization, bimanual coordination, and recovery after hemiparesis. However, investigation of these motor network interactions using human motor evoked potentials has been limited in the range of network and behavioral dynamics examined. A thorough understanding of these interhemispheric dynamics could elucidate mechanisms of bimanual coordination, its age-related loss, and more specific targets for therapy.

Network excitability and inhibition were tested across multiple stimulus-response recruitment intensities using single and paired pulse transcranial magnetic stimulation during a unimanual isometric muscle contraction. We hypothesized that resting non-dominant arm excitability would be modulated as a function of dominant arm force and that older age would impair both inhibition and dynamics.

We demonstrate that dominant-arm isometric muscle contractions cause an increase in recruitment slope of resting non-dominant arm corticospinal excitability. This increase tracks with force production rather than motor intention. We also found that older participants exhibited increased excitability but not impaired interhemispheric inhibition or behavioral dynamics. Our findings demonstrate a mechanism that may underly age-related impairments in bimanual coordination. Postmortem neuropathological examination of hemispheric lateralization of pathology in bvFTD is understudied, despite numerous neuroimaging studies showing asymmetric disease. Here we measured the severity of postmortem grey (GM) and white matter (WM) pathology using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 24 bvFTD patients (FTLD-tau59, FTLD-TDP514 or FTLD-FUS51). We calculated an asymmetry index (AI) based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of AI (i.e. degree of lateralization independent of direction) revealed highly lateralized pathology for both GM and WM in all four regions (p<0.01). Direct inter-hemispheric comparisons found higher pathology in the right orbitofrontal region compared to the left for grey matter in FTLD-Tau and for white matter in FTLD-TDP (p<0.02). We also found increased pathology in the left ventrolateral temporal lobe GM compared to the right hemisphere in the total cohort (p<0.02). Exploratory analysis using antemortem clinical and imaging data correlated with our histology data. We conclude that pathologic disease burden is not distributed symmetrically in bvFTD, and this asymmetry of disease burden contributes to the clinical heterogeneity of the disorder. Background:Neonatal seizures are common and majority are due to hypoxic-ischemic encephalopathy(HIE). Tissue clearing, transgenic mice, and advanced microscopy allow neuronal activity. Circuitry in acute HIE seizures is unknown and may shed light on relation between seizures and later behavioral deficits. Objective:Examine neuronal activity and evolution following acute HIE seizures in a neonatal mouse using tissue clearing/microscopy. Methods:Postnatal day(p)9 mice are implanted with electrodes. p10 HIE is created using unilateral carotid ligation145min hypoxia in Cre-tamoxifen transgenic mice (TRAP). 4-hydroxytamoxifen injection allows expression of fluorescent protein in active neurons. EEG is performed. Shams receive inci-sion1anesthesia only. p17 mice are processed using lipidclearing. Multiphoton imaging and Zeiss software is utilized to obtain/process images. Results: 100%(n512) exhibit seizures and burst suppression. Tissue clearing/microscopy allowed visualization of active neurons during seizures. HI mice exhibit selective neuronal activation in the dentate granule cells and CA3 compared to sham. Conclusion:Tissue clarification/advanced microscopy is feasible to examine neuronal activity during seizures in this model. Neuronal activity is present in the bilateral cortex, dentate and CA3 after HI-seizures. Ongoing work delineates seizure evolution and correlate EEG with neuronal activity in this model. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe neurodevelopmental disorder characterized by language impairment, intellectual disability, stereotyped movements, and autism spectrum behavior. Early studies into MeCP2 function demonstrated that it is enriched in neurons, interacts with methylated DNA, and represses gene expression. However, subsequent studies paint a more complex picture because MeCP2 is bound diffusely across the genome without obvious gene targets to mediate the neurological phenotypes. We recently gained insight into this problem through a meta-analysis of gene expression studies from MeCP2-mutant mice and found that MeCP2 preferentially regulates very long, highly methylated genes. Because DNA methylation patterns are cell type-specific, we hypothesized that MeCP2 regulated genes are also likely to be dependent on cell type. Using single-cell RNA sequencing, we investigated the MeCP2dependent transcriptional programs across each brain cell type in mouse and human. These data suggest that cell type-specific DNA methylation patterns largely determine the extent of gene regulation by MeCP2 within in an individual cell type. Together, these findings provide new insight into the complexity of transcriptional misregulation that occurs across multiple cell types in Rett syndrome.

Maggie W. Waung and Howard L. Fields. San Francisco, CA Imaging studies of migraine patients demonstrate changes in central pain-modulatory and reward-processing regions. How these changes contribute to headache are unknown. Using optogenetic circuit manipulation, we demonstrate a connection between the periaqueductal gray (PAG) and ventral tegmental area (VTA) and evaluate its contribution to pain processing in a rodent headache model.

Activation of PAG terminal fibers in the VTA elicits post-synaptic potentials in a subset of VTA neurons. A majority of these synaptic connections are excitatory, as light-evoked responses are inhibited by DNQX. Activation of PAG to VTA projections induces avoidance behavior in a real-time place preference assay. Furthermore, inactivation of these VTA inputs with halorhodopsin may produce a place preference in animals receiving dural inflammatory soup, but not in animals receiving saline infusion.

These studies demonstrate an excitatory glutamatergic connection from the PAG to the VTA. Activation of this circuit is aversive and appears to be active during headache-but not at baseline, as inhibition of this connection had no behavioral effect in animals without headache. This circuit may be sensitive to therapeutic targets for migraine and become refractory to treatment in chronic headache. Background: In Parkinson disease (PD), a-synuclein (asyn) misfolds to form amyloid fibrils that cause neuronal dysfunction. This process precedes clinical PD, and fibril conformation might change over time. Thus, misfolded asyn conformations are an ideal biomarker target.

Objective: We recently characterized two conformationselective antibodies to a-syn, which demonstrate distinct patterns of a-syn neuropathology in PD brain. We hypothesized that these antibodies could detect misfolded a-syn fibril conformations in PD patient biological fluids.

Methods: We optimized an enzyme linked immunosorbent assay (ELISA) using these antibodies to detect conformations of a-syn fibrils. Wild-type a-syn was expressed and purified in BL21(DE3)-RIL cells using PRK172 vectors. Pre-formed fibrils (PFFs) of a-syn were prepared in alternate conformations using serial seeded fibrilization reactions.

Results: Each antibody preferred a-syn PFFs over monomer in indirect ELISA. Conformation-selectivity was maintained in competitive indirect ELISA. However, in sandwich ELISA, each antibody detected both a-syn monomer and PFFs. Each antibody could detect a-syn in biological fluids using sandwich ELISA and dual a-syn detector antibodies.

Conclusions: Conformation-selective a-syn antibodies hold promise in detecting misfolded a-syn fibrils. Further ELISA optimization is required to minimize detection of native a-syn when both monomers and fibrils are present in mixed, biologically relevant concentrations.

Daniel O. Claassen, Adam Stark, Robert Kessler and David Zald. Nashville, TN Parkinson disease (PD) patients are frequently prescribed D2-like dopamine agonist (DAgonist) therapy for motor symptoms, yet a proportion develop clinically significant behavioral addictions characterized by impulsive and compulsive behaviors (ICBs). We identified 35 PD patients receiving DAgonist therapy, with (n517) and without (n518) ICBs, matched for age, disease duration, severity, and dopamine therapy. In the off-dopamine state, all completed [18F]fallypride PET imaging, a high affinity D2-like receptor ligand that can measure striatal and extrastriatal D2/3 binding potential. Striatal differences between ICB1/ ICB-patients localized to the ventral striatum and putamen, where ICB1 subjects had reduced nondisplaced binding potential (BPND). Self-reported severity of ICB symptoms positively correlate with midbrain D2/3 receptor binding potential. Group differences in regional D2/3 binding potential relationships were also notable: ICB1 (but not ICB-) patients expressed positive correlations between midbrain and caudate, putamen, globus pallidus, and amygdala. Compulsive behaviors seen in PD are associated with reduced ventral more than dorsal striatal D2/3 expression, similar to changes in comparable behavioral disorders. Preserved ventral midbrain dopaminergic projections throughout nigrostriatal and mesolimbic networks are unique to PD-ICB patients, and may account for differential DAgonist response. Background: As PD progresses, symptoms increase, quality of life declines, and individuals may become homebound. This causes a surge in acute healthcare utilization and excess morbidity. In 2014, we launched the Interdisciplinary Home Visit Program for Advanced PD to provide comprehensive care to homebound individuals with PD and related disorders.

Methods: PD patients meeting Medicare homebound criteria received 4 home visits over 12 months. A movement disorders neurologist, social worker, and nurse completed a comprehensive evaluation at each visit, which included medication reconciliation, psychosocial evaluation, and referrals. Neuro-QoL was measured at Visits 1 and 4.

We enrolled 27 subjects. At baseline, mean age was 81 years and UPDRS total, 65. Of those completing Visit 4, total UPDRS increased by a mean of 12 yet quality of life did not significantly decline. There was a trend toward improvement in 7/8 domains.

Conclusions: We report a unique cohort typically lost to clinical care and research-homebound patients with advanced PD. Despite the progression of disability, quality of life stabilized. Methods: We measured evoked potentials in response to low frequency DBS over the sensorimotor cortex using a temporary subdural strip electrode in patients who underwent STN or GP DBS. For each DBS setting, 100 trials were aligned with stimulus and averaged, and evoked potential peak amplitude and peak latency were calculated.

Results: We analyzed recordings from 5 patients with DBS electrode in the STN, 2 in the GP, and 1 in both. STN DBS resulted in the first evoked potential in the primary motor cortex at an average of 2.7ms (range 2.2-3.2ms), followed by responses at 7.2ms (5.0-8.9ms) and 31ms (18-40ms). For GP DBS, the first evoked potential occurred at 19.4ms (17-22ms) followed by responses at 44ms (range 41-47ms) and 61ms (58-64ms). The amplitude of the evoked potentials varied with DBS settings.

Conclusions: The very short-latency evoked potential present only during STN DBS likely represents antidromic hyperdirect pathway activation. Long-latency evoked potentials during GP and STN DBS indicate activation of a multi-synaptic pathway to the cortex.

CD368. Endogenous Recovery of Impaired Synaptic Plasticity After Juvenile Global and Focal Ischemia Robert M. Dietz, James E. Orfila, Guiying Deng, Nicholas Chalmers, Olivia P. Patsos, Richard J. Traystman and Paco S. Herson. Aurora, CO Cardiac arrest (CA) or stroke in children often leads to poor neurologic outcomes in children, including learning and memory deficits. Children often have improved outcomes compared to adults. An increase in synaptic efficiency, termed long-term potentiation (LTP), is a well-accepted cellular model for learning and memory. We have shown persistent impairment of synaptic function following CA and middle-cerebral artery occlusion (MCAO) in adult mice. Juvenile mice (postnatal day 20-25) were subjected to 8 min CA and resuscitated or had transient occlusion of the MCA. Hippocampal CA1 synaptic plasticity was evaluated using brain slices 7 or 30 days after CA/MCAO or sham controls. In control male mice, LTP was 153% (n58) of baseline (100%). In contrast, 7 days after CA, there was significant impairment, in LTP. By 30 days after CA, LTP recovered to control levels. Following MCAO, there was impairment in the ipsilateral, but not contralateral hippocampus. Similar to CA, by 30 days after MCAO, both ipsilateral and contralateral LTP had recovered LTP. This seminal discovery of endogenous recovery of LTP through development into adulthood may contribute to improved neurological outcome in children compared to adults. Exceptional neurological recoveries of post-cardiac arrest patients who otherwise expected to have uniformly unfavorable outcomes argue for presently unknown variables that may affect probabilities of neuronal survival. In search for such variables, we characterize three post-cardiac arrest patients who recovered despite remaining in coma beyond time-frames traditionally considered compatible with favorable outcome. All three patients initially had preserved pupillary, but absent corneal and motor reflexes. Importantly, all patients had prolonged burst-suppression pattern (BSP) on EEG (until days 37, 9 and 15, respectively), considered a very strong negative predictor of outcome. Neurological recovery was delayed, but progressive across the group: return of eye opening (days 17-37), motor responses (days 30-50) and command following (days 45-71), all achieved near full recovery. Based on recent modeling studies, BSP may promote cellular preservation via stabilization of membrane potentials in low energy states with each burst representing an attempt to recover circuit dynamics. Considering the current practice of early prognostic decisions in these patients, these observations call for further investigation into the physiological significance of BSP in the setting of post-anoxic brain injury. Peripheral polyneuropathy is a common side effect of many chemotherapeutic agents, suggesting that the axon destructive properties of various chemotherapies converge on a common axonal degeneration (AxD) program. Components of this program had been largely unknown, until others and we recently discovered that SARM1-/-dramatically protects axons from degeneration after axotomy and the chemotherapeutic agent vincristine in a mouse model. It remains unknown whether a) SARM1-/-protects from AxD when using chemotherapeutic agents with different mechanisms of action and b) whether SARM1 acts through the same pathway in neuropathy as in axotomy. Using the chemotherapeutics vincristine (decreases intracellular trafficking) and the proteasome inhibitor bortezomib in cultured neurons, we demonstrate that SARM1-/-inhibits both vincristine and bortezomib-induced neurite degeneration. As in axotomy, maintaining NAD1 by overexpression of NMNAT1 protects from chemotherapy-induced degeneration. While targeting the MAP-kinase pathway that regulates SARM1 in axotomy protects from vincristine-induced AxD, it does not decrease bortezomib-induced AxD. These findings indicate that different pathways converge on a core AxD program consisting of NMNAT, SARM1 and NAD1. We suggest that targeting this pathway may have great therapeutic value for different chemotherapy-induced neuropathies.

Dysfunction in Spinocerebellar Ataxia Type 1 James P. Orengo, Meike E. van der Heijden, Jianrong Tang, Harry T. Orr and Huda Y. Zoghbi. Houston, TX and Minneapolis, MN Spinocerebellar ataxia type 1 (SCA1) is characterized by adult-onset cerebellar degeneration with attendant loss of motor coordination; bulbar function is eventually impaired, and patients tend to die from inability to clear the airway. We asked whether motor neuron degeneration is at the root of this dysfunction and dissected disease progression in an SCA1 mouse model. Specifically, we assessed breathing physiology, diaphragm histology and electromyography, and spinal cord and brainstem motor neuron histology and immunohistochemistry. SCA1 mice show progressive neuromuscular respiratory abnormalities, neurogenic changes in diaphragm, and motor neuron degeneration in the spinal cord and brainstem. The latter is accompanied by reactive astrocytosis and accumulation of Atxn1 aggregates in the motor neuron nuclei. These findings confirm this mouse line as an SCA1 model with face and construct validity for this understudied disease feature. Furthermore, this model is suitable to study the pathogenic mechanism driving motor neuron degeneration in SCA1 and perhaps other degenerative motor neuron diseases. From a clinical standpoint, the data indicate that pulmonary function testing and employment of non-invasive ventilator support could be beneficial in SCA1 patients. Objective: Antiphospholipid-associated myelitis has been postulated to cause longitudinally extensive transverse myelitis (LETM). Neuromyelitis optica spectrum disorder (NMOSD) is the commonest cause of LETM and discovery of its highly specific (>99%) serum biomarker, aquaporin-4-IgG, in 2004 allowed it be distinguished from other diseases. We sought to assess the frequency of aquaporin-4-IgG-seropositive NMOSD and other diagnoses in LETM with antiphospholipid (aPL) antibodies.

Methods: We searched Mayo Clinic records (1996) (1997) (1998) (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) for patients with inclusion criteria of: 1) confirmed LETM; and 2) aPL or beta-2 glycoprotein-1 antibodies. Aquaporin-4-IgG was evaluated when sera available (n522).

Results: Twenty-seven patients were included. Aquaporin-4-IgG seropositivity was confirmed in 11 of 22 (50%) with LETM and 6 of 6 (100%) with recurrent LETM thus confirming a diagnosis of NMOSD, rather than antiphospholipid-associated LETM. Furthermore, 50% of aquaporin-4-IgG seronegative patients had alternative specific diagnoses confirmed (e.g., spinal cord infarct). Clotting disorders (deep venous thrombosis, pulmonary embolism or miscarriages) occurred in 54% of NMOSD patients.

Conclusions: Aquaporin-4-IgG should be tested in all patients with LETM and aPL antibodies as aquaporin-4-IgG-seropositive NMOSD accounts for half of all cases. Antiphospholipid-associated LETM should be considered a diagnosis of exclusion and only assigned after all other causes of LETM have been ruled out. Additionally, clinicians should be mindful that patients with AQP4-IgG-seropositive NMOSD who harbor aPL antibodies or have APS are at high risk for clotting disorders (54% in the present study).

M102. An Anti-Plexin D1 Autoantibody Is Associated with Immunotherapy-Responsive Neuropathic Pain Takayuki Fujii, Ryo Yamasaki, Kyoko Iinuma, Daisuke Tsuchimoto, Mizuho A. Kido, Shinichi Aishima, Yusaku Nakabeppu and Jun-ichi Kira. Fukuoka, Japan and Saga, Japan

Objective: A variety of sources of neural damage cause neuropathic pain (NeP), part of which is treatable by immunotherapy. We aimed to discover novel autoantibody biomarkers for NeP caused by autoimmune mechanisms.

Methods: We enrolled 110 NeP patients including 17 with neuromyelitis optica (NMO), 15 with relapsing-remitting multiple sclerosis (RRMS), 12 with Sj€ ogren myeloradiculoneuritis, 10 with neurosarcoidosis, 4 with myeloneuritis and systemic lupus erythematosus, 3 with neuro-Behçet's disease, 6 with Churg-Strauss syndrome, 22 with atopic myelitis (AM), 14 with chronic inflammatory demyelinating polyradiculoneuropathy, 2 with erythromelalgia, druginduced neuropathy, or vitamin deficiency, and 1 with anti-SGPG neuropathy, Guillain-Barr e syndrome, or cryoglobulinemia. For controls, 45 subjects without NeP comprising 20 healthy persons, 15 with neurodegenerative diseases, and 10 with collagen-vascular diseases, were used. We screened serum autoantibodies that selectively reacted with mouse unmyelinated c-fiber type dorsal root ganglion (DRG) neurons using a tissue-based indirect immunofluorescence assay (IFA). IgG purified from patients' sera positive by IFA was subjected to western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were applied to liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens.

Results: Using tissue-based IFA, autoantibodies that selectively bound to isolectin B4 (IB4)-positive and S100bnegative DRG neurons and their nerve terminals in the dorsal horns, representing unmyelinated c-fiber type sensory neurons, were detected in 11 NeP patients (10%) and no subjects without NeP were positive (P 5 0.0343). WB revealed a common immunoreactive band (approximately 220 kDa) in autoantibody-positive patients. IP and LC-MS/ MS studies identified plexin D1, a cell surface receptor for class 3 semaphorins and semaphorin 4a, as a target autoantigen. A cell-based IFA using HeLa cells, which express plexin D1, with and without small interfering RNA for PLXND1, revealed that the patients' IgG signals were significantly decreased after PLXND1 knockdown, confirming plexin D1 as a relevant autoantigen. NeP patients with anti-plexin D1 IgG showed relatively young onset ages, a relapsing or fluctuating disease course, burning pain, thermal hyperalgesia, and abnormalities of current perception threshold for cfibers, possibly reflecting c-fiber type DRG neuron damage. Comorbidities included atopy (n510 patients), collagen-vascular disease (n54), demyelinating disease (n53), and malignant neoplasm (n51). Immunotherapies such as plasma exchange ameliorated NeP in all treated cases.

Interpretation: An anti-plexin D1 antibody is a novel diagnostic biomarker for immunotherapy-responsive NeP. Objective: This a case report to illustrate the importance of early diagnosis and treatment of Takayasu Arteritis (TA).

Background and Method: TA is an idiopathic vasculitis mainly involving the aorta and its branches1. It was first described in 1908 in a Japanese patient2 and predominantly affects young Asian women. There is a 15.8% prevalence of stroke/TIA among TA patients3. TA is commonly overlooked due to low clinical awareness.

24 year old female with a history of headaches and newly diagnosed DM type 2 presented with headaches, transient right quadrant visual loss, right arm tingling with numbness and word finding difficulties to an outside facility. MRI brain demonstrated a stroke and the vessels studies were concerning for RCVS vs vasculitis. She was started on Verapamil 40mg TID, Solumedrol 40 mg TID and transferred to West Virginia University Hospital for further care.

Results: MRI brain demonstrated multiple areas of subacute and acute infarcts in the left occipital, frontal and temporal lobes in the MCA and PCA territory. MRA chest demonstrated subtle focal narrowing of the proximal right subclavian and right common carotid artery. MRA abdomen was unremarkable. Cerebral angiogram demonstrated contour irregularity involving multiple extra and intracranial vessels, including the proximal right common carotid artery, right subclavian artery, distal left common carotid artery, proximal left internal carotid artery and left external carotid artery trunk, and intra-cranially involving the left M1 (MCA) and left P2 P3 (PCA) segments.

Hypercoagulable panel was unremarkable; except for mild elevation of factor 8 and protein C. The Vasculitis panel was unremarkable except for positive C-ANCA and MPO antibody. ERS was 17 and CRP was mildly elevated at 21. TEE was negative for thrombus or shunt.

Etiology for strokes in multiple vessel territory was secondary to TA, confirmed by cerebral angiography. It's type 1 TA per Hata classification4. She was started on ASA 325mg and 5 days of high dose Solumedrol, there after prednisone 50mg BID. She will be starting on an immunosuppressive medication.

Conclusion: There are multiple challenges with TA. A cohort study of 126 patients demonstrated a median delay in diagnosis of 17.5 months5. Assessing disease activity is further challenging requiring serial imaging. Clinical awareness is essential in early diagnosis of TA given the stroke prevalence.

Controlled HIV1 Patients Beau Ances, Jeremy Strain, Tricia Burdo, Sheng-Kwei Song and Beau Ances. Saint Louis, MO and Philadelphia, PA Introduction: Inflammation is present in HIV infected (HIV1) individuals immediately following seroconversion and in the virologically suppressed. Elevated inflammation is not always indicative of cognitive decline but can relate to anatomical damage. Diffusion tensor imaging (DTI) metrics are significantly confounded by the presence of inflammation losing its sensitivity and specificity to brain pathologies. Utilizing Diffusion basis spectral imaging (DBSI) we will examine restricted diffusion patterns associated with cellularity and neuroinflammation, in a cohort of virally suppressed and medically stable HIV1 patients. Methods: Ninety-two HIV1 patients on highly active anti-retroviral therapy and 66 HIV uninfected (HIV-) controls underwent neuropsychological testing, and neuroimaging. Cognition was assessed utilizing standardized T-scores on the domains of memory, psychomotor speed, and executive functioning. Tract based spatial statistics was utilized and comparisons between cohorts were conduced for both DTI and DBSI metrics. An ANCOVA was perform across the age spectrum on skeletal averages of cellularity and HIV status stratified for gender. Within the HIV1 cohort, cellularity was evaluated for CD4 recovery and correlations were performed (nadir CD4 <250 and current CD4 >500; CR). Results: There were no significant differences in cognition between the two groups. Voxel-wise analysis revealed fractional anisotropy as defined by DTI was lower in aviremic HIV1 compared to HIV-(p<0.05 corrected) but no differences were observed between groups for FA when estimated with DBSI. However, diffuse increases for cellularity were observed in HIV1 individuals compared to HIV-controls (p<0.05 corrected). Age was inversely associated with cellularity in HIV1 participants (p50.003, r5-0.31) but not controls. Significant differences in cellularity were only observed for the voung CR group (< 50) compared to either the older non-CR (> 50; p<0.001) or older CR group (p50.001). Conclusions: This data shows that DBSI is more sensitive at detecting alternate etiologies that are beyond the limitations of DTI. Elevated levels of cellularity were diffusely observed in aviremic HIV1 patients and persist in lieu of cognitive impairment. The biological correlate of cellularity is unknown, however elevated levels of cellularity were seen in younger individuals with CR, implying an active immune response. This is one of the first non-invasive approaches at quantifying low-level neuroinflammation in virologically suppressed HIV individuals without cognitive impairment. Objective: To report a patient with common variable immunodeficiency (CVID)-associated granulomatous disease with neurological complications including cervical dystonia with tremor and optic neuropathy.

Background: CVID is the most common severe primary antibody deficiency in which humoral immunity is compromised, leading to low levels of IgG, IgA and/or IgM. Diagnostic criteria for CVID include decreased serum levels of IgG along with a reduction IgA or IgM, history of persistent or frequent infections, and poor or no response to pneumococcal vaccine challenge. Autoimmunity occurs in approximately 25-30% of patients with CVID and roughly 8-22% of CVID patients develop granulomatous disease or "atypical sarcoid-like lesions" which can often be misdiagnosed as sarcoidosis. Neurological diagnoses in CVID patients with and without granulomatous disease are likely under-reported.

Design/Methods/Results: A 41-year-old previously healthy male presented for evaluation of facial swelling. He denied a history of frequent infections. A chest computerized tomography (CT) demonstrated lymphadenopathy and subsequent biopsy revealed "non-necrotizing granulomas consistent with sarcoid." Within one month of the onset of the facial swelling, he developed a postural tremor of the right upper extremity and phasic craniocervical dystonia predominantly involving the platysma, sternocleidomastoid, and orbicularis oris. Within two months of symptom onset, he noticed visual changes and was diagnosed with bilateral optic neuropathy. He also subsequently developed tinnitus with mild hearing loss and atrial fibrillation. From the time of biopsy, the patient was treated with a six month course of prednisone. At the time of neurological consultation, he had been off prednisone for over 5 months. Screening prior to consideration of further immunotherapy revealed a markedly low serum IgG at 153 mg/dL (normal >700 mg/dL) and IgA at 17mg/dL (normal >44mg/dL), consistent with a diagnosis of CVID.

Conclusions: We report craniocervical dystonia and tremor in the setting of CVID-associated granulomatous disease. Neurological manifestations of CVID and CVIDassociated granulomatous disease are underappreciated. Granulomas associated with CVID are indistinguishable from sarcoidosis, and thus patients with presumptive sarcoidosis should have serum immunoglobulins measured as part of their initial evaluation -and prior to initiation of immunotherapy -to rule out CVID as an etiology of the granulomatous disease. Further study of CVID patients to determine the neurologic phenotypes and frequency of neurologic involvement is needed.

Alexandra Weller and Alan Hirsch. Curacao, Netherlands Antilles and Chicago, IL Introduction: Multiple antidepressant have been reported to induce hyposmia including sertraline, fluoxetine, lamotrigine, clonazepam, and vilazodone. A single case with multiple antidepressants independently inducing hyposmia has not heretofore been described. Such a case is presented.

Method: Case Study: A 52 year old right handed female presented with head trauma with loss of consciousness seven years ago, followed by reduced ability to smell except for monthly olfactory windows. Coincident with this she also experienced impaired taste with ability to taste only sweet and salty foods. She denied dysgeusia, phantosmia, cacosmia and palinageusia. She also suffered from chronic depression and anxiety with complaints of easy fatigability, worry, continuous racing thoughts, obsessions and panic attacks every other day. For this she was started sequentially and independently on a variety of antidepressants. Each one induced hyposmia which resolved with discontinuation of the antidepressant.

Results: Abnormalities Neurologic Examination: Premedication olfactory ability: subjective smell 2100%, subjective taste -100%. On sertraline: subjective smell-0%, subjective taste-0%, Pocket Smell Test-2 (hyposmia), Alcohol Sniff Test 20 (anosmia), Propylthiouracil Disc Taste Test-5 (hypogeusia); On paroxetine: subjective smell 20%, subjective taste-50%, Pocket Smell Test-2 (hyposmia), Alcohol Sniff Test-0 (anosmia); On lamotrigine: subjective smell-0%, subjective taste-10%, Pocket Smell Test-2 (hyposmia); On vilazodone: subjective smell-0%, subjective taste-30%, Alcohol Sniff Test-0 (anosmia). One antidepressant had no impact on chemosensation -vortioxetine: subjective smell-100%, subjective taste 2100%.

Discussion: The antidepressants may have acted on neurotransmitters in the olfactory bulb, since serotonin, dopamine and acetylcholine are present in this region. Possibly, because of a preexisting mild deficit in this region, she may has been more susceptible to such changes. Alternatively, nasal mucosal engorgement may have been effected, reducing air flow to the olfactory epithelium, and thus smell. The mucosal lining of the nasal epithelium may have been altered, reducing ability of odors to dissolve and thus perceived smell. The taste deficit may have been a retronasal smell deficit, which is a result of synesthesia, misperceived as a taste loss. Why vortioxetine did not have similar effect is unclear. However, it has multimodal serotonergic actions including a 5-HT3, 5-HT1D, and 5-HT7 antagonist, a 5-HT1A agonist, and a 5-HT1B partial agonist property. Possibly these bypass the olfactory pathway and thus the smell is not effected. In those with depression and olfactory deficits, it may be prudent to initiate therapy with vortioxetine. Background: ANEC affects infants and children and is characterized by multiple, symmetrical lesions in the thalami, putamina, cerebral and cerebellar white matter, and brain stem tegmentum. ADEM is an inflammatory demyelinating disease. WHS is a fulminant variant of multiple sclerosis. These disorders can be difficult to differentiate due to overlapping clinical and neuroradiologic findings.

Case Report: A 15 year-old female of Vietnamese origin presented with sudden onset coma but without other lateralizing signs and low grade fever with Glasgow Coma Scale 8. MRI brain revealed symmetric bilateral T2 hyperintensities with restricted diffusion and tiny hemorrhagic foci in thalami, left occipital gray and white matter, tegmentum and bilateral cerebellar white matter lesions. Patient's fever selfresolved in 2 days. CSF analysis was normal with 3 WBC and normal protein count. Further work up was unrevealing for risk factors for stroke, infections, malignancy, demyelinating disease such as MS, vasculitis and metabolic disorders. Patient received IV and oral steroids and IVIG treatment with improving awareness but was noticed to have developed right sided hemiparesis with supranuclear gaze palsy. With rehabilitation patient achieved independent status with resolution of hemiparesis and minimal speech apraxia and supranuclear gaze palsy after 45 days. 3 month and 6 month follow up did not reveal any new findings on MRI.

Discussion: Patient presented with coma and unusual MRI findings including white matter as well as deep gray matter involvement with hemorrhagic foci. Radiologic reads were obtained independently from 6 certified neuro radiologists favoring possible diagnoses of ANEC, ADEM, and stroke. Symmetrical lesions, decreased apparent diffusion coefficient values, lack of edema and normal CSF with lack of inflammatory cells are features that differentiate ANEC from these diagnoses. Usually this is a fulminant diagnosis and rapid administration of steroids and IVIG have played role. This case supports that a favorable outcome may be reached despite grave imaging and clinical presentation if aggressive therapies are considered in timely fashion. It is crucial to identify differences to achieve accurate prognosis in patients with confusing neuroradiologic presentation. Objective: To report a case of diagnostic uncertainty in a young patient with isolated unilateral oculomotor nerve dysfunction (IUOND).

Background: Oculomotor nerve dysfunction is a clinical sign of an underlying neurological or systemic disease. IUOND is a rare entity with 1 to 15 percent incidence. Published findings have reported IUOND in association with other neurological processes such as hydrocephalus and after severe head trauma. Magnetic resonance imaging (MRI) brain is an important diagnostic tool in determining secondary causes of oculomotor nerve dysfunction. Positive MR brain findings of IUOND have not yet been reported in literature. We present an atypical case of IUOND in a young patient with no other clinical findings, but positive MR brain findings, posing to be a diagnostic dilemma.

Methods: Case report.

Results: Twenty-four year old male presented with sudden onset right eye ptosis and binocular diplopia. In 2005, patient experienced similar complaints, resolving after 2 weeks without treatment. Neurological exam demonstrated right eye ptosis with impairment in adduction. Right pupil was 4 millimetres, sluggishly reactive. Left pupil was 2 millimeters, reactive. Stroke workup was negative. MR brain contrast showed enhancement of the cisternal portion of the right oculomotor nerve with discrete nodular thickening at the nerve root entry zone, unchanged since 2005. These findings prompted a differential of chronic inflammatory demyelinating polyneuropathy (CIDP) versus schwannoma. CIDP serology was negative. Neurosurgery recommended no acute surgical intervention. CSF demonstrated proteins 39, glucose 113, WBC 3, cytology with lymphocytes, neutrophils, and monocytes. Serum and CSF electrophoresis were normal. Initial treatment with Solu-Medrol resulted in no improvement. After 5 days of intravenous immunoglobulin (IVIG) therapy, ptosis and right eye adduction improved slightly. IVIG therapy will continue as outpatient every 3 weeks for 2-3 months.

Conclusion: In this atypical clinical presentation of IUOND, an exhausting list of differentials were considered. Paucity of associated clinical features and diagnostic findings, in addition to limitations in neurosurgical interventions and other diagnostic modalities have not yet allowed us to reach a diagnosis. Positive MRI brain findings of intrinsic IUOND, as seen in our patient, have not been reported in literature. Congenital, vascular, neoplasm, autoimmune, and infectious causes have been entertained. Slight clinical improvement after IVIG therapy may suggest an autoimmune or idiopathic process. However, the diagnostic workup has been indeterminate. This diagnostic dilemma poses a challenge in initiating appropriate timely management without a definitive diagnosis. Objective: To report a case of diagnostic uncertainty in a patient with primary angiitis of the central nervous system (PACNS) with metastatic prostate cancer.

Background: PACNS is a rare entity with an unclear etiopathogenesis. It presents with a wide array of neurological manifestations. PACNS is a diagnosis of exclusion. Secondary causes of CNS vasculitis such as malignancies, infections, autoimmune disorders, and reversible cerebral vasoconstrictive syndrome must be ruled out. PACNS can be diagnosed with cerebral vessel angiogram (CTA) and conventional angiography with only 60 percent sensitivity. PACNS, with predominant small vessel involvement, can have negative imaging. Biopsy of the brain and meninges remains gold standard study. Published literature has demonstrated testicular cancer cases in association with PACNS, likely through a vascular paraneoplastic process, but no prostate cancer cases.

Methods: Case report.

Results: Sixty-six year old male with metastatic prostate cancer presented with right lower facial spasms and hands paresthesias. He later developed dizziness followed by dysarthria, word finding difficulties, confusion, agitation, and behavioral changes. Initial exam revealed right facial droop, weakness and atrophy of distal hand muscles, head tremors, altered postural reflexes, and bilateral cogwheeling. Initial magnetic resonance imaging (MRI) brain demonstrated T2 signal abnormalities in the right basal ganglia and temporal region, progressing to diffuse infiltrative process over the right temporal and left posterior parietal lobe, suggestive of leptomeningeal enhancement. Repeat MRI brain demonstrated scattered punctate areas of restricted diffusion, progressing to diffuse perivascular with numerous foci of acute ischemia in multiple vascular territories. Lumbar puncture showed lymphocytic pleocytosis, protein 238, glucose 79, and reactive histiocytosis. CTA and conventional angiography were normal. Patient was treated with intravenous immunoglobulin (IVIG) followed by intravenous and oral steroids with clinical improvement. Patient was subsequently started on Cytoxan. Brain biopsy revealed granulomatous angiitis.

Conclusion: Our case illustrates the diagnostic difficulty of PACNS. Small-sized vessel involvement, often present in PACNS, has negative imaging, but positive biopsy. The nonspecific clinical and imaging findings create a diagnostic dilemma in deciding appropriate timing for brain biopsy and immunosuppressive treatment. Given the poor outcome of PACNS in untreated patients, the need for early biopsy in MR negative patients is crucial. Additionally, to investigate the etiopathogenesis of PACNS, we recommend searching possible association between genitourinary malignancies and PACNS in future studies. Background: Autoimmune encephalitis (AE) is a diverse group of neuro-psychiatric disorders recognized recently, which can be treated with immune modulating therapies. Distinguishing AE from infectious meningoencephalitis at early phase is very important because each of them requires different type of treatments. However, AE and viral meningoencephalitis (VME) can present with similar symptom at the early phase of the disease. The elevated blood level of a protein called TNF-related apoptosis-inducing ligand (TRAIL) has been reported to be useful for distinguishing viral infection from bacterial infection or non-infectious patients. Here, we investigated if the CSF TRAIL level can be useful for distinguishing VME from AE or non-infectious neurological disorders.

Methods: A total of 30 patients were included in the analysis. Ten patients were diagnosed as AE supported by autoantibody detection, 5 Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis and 5 Anti-leucine rich glioma inactivated 1 (LGI1) encephalitis; 10 patients were confirmed as VME by cerebrospinal fluid (CSF) PCR, 5 Japanese encephalitis virus (JEV) and 5 Herpesviridae; and 10 patients were non-infectious neurological patients, including dizziness, orthostatic hypotension, and vasovagal syncope. CSF was obtained from the patients before the initiation of any treatment and were stored in -808. CSF TRAIL levels were measured by ELISA (R&D system).

Results: The CSF TRAIL level in the VME group was elevated to 49.4 6 18.8 (mean6SEM) while those in AE and control group were 5.1 6 1.0 and 2.0 6 0.6, respectively. When the optimal cut-off value was selected, the sensitivity and specificity for detecting VME from total patients were 90% and 95%, respectively. On receiver operating characteristic (ROC) curve analysis, the area under curve (AUC) was 0.975. Among the 20 encephalitis patients, sensitivity and specificity for detecting VME were all 90%, and the AUC was 0.950.

Conclusions: Our result demonstrates that CSF TRAIL level can be used for distinguishing VME patient from AE or other neurological diseases at early phase. This can be extremely useful in the clinical practice for helping the physicians to make an early decision of proper treatment for the encephalitis patients.

Objective: To report a rare, mixed, autoimmune disorder with overlapping features between Multiple Sclerosis (MS) and Neuromyelitis Optica Spectrum Disorder (NMOSD), complicated by a recent diagnosis of multiple myeloma (MM) Introduction: Multiple myeloma (MM) is a clonal malignancy of plasma cells characterized by an overproduction of monoclonal antibodies. Multiple myeloma (MM) and its precursor, monoclonal gammopathy of undetermined significance (MGUS), have been linked with several autoimmune conditions in the medical literature. Yet, significance of these associations is not well understood.

Presentation: 73 years old right-handed African American woman diagnosed with relapsing-remitting multiple sclerosis and yet had seropositive NMO IgG antibody. Her disease started back in 2000 and diagnosis was supported by Magnetic Resonance Imaging (MRI) scan of the brain that showed multiple supratentorial and infratentorial T2 signal changes and Dawson's fingers. MRI of the cervical spine showed multiple T2 signal changes. MRI T spine didn't reveal any abnormal cord signal. Over the years, she has been aggressively treated with disease modifying agents, several courses of cyclophosphamide, high dose corticosteroids, and plasmapheresis.

After undergoing a bone marrow biopsy in 2015, she was diagnosed with multiple myeloma, with IgG of 3010 and IgM of 54. Currently, she is receiving chemotherapy and she is clinically stable.

Conclusion: We present a rare autoimmune disorder with overlapping features between multiple sclerosis and NMOSD, seropositive for NMO IgG antibody who had Multiple myeloma diagnosed later in the course of illness. Further research is required to explore the link between MGUS/MM and autoimmune disorders. Inflammation in the setting of autoimmunity may serve as a trigger for MM. In addition, a common genetic susceptibility for developing both an autoimmune disease and MM might also exist. On the other side, the question of the potential causative role of monoclonal proteins in MS and in CNS demyelination generally cannot be answered. It is necessary to establish whether these proteins bind to some known or unknown neural antigens and if they do, to investigate whether this binding plays a causative role in the disease or is a result of a general immune disequilibrium.

References 3) Cho SY, Int. J Rheum Dis 2014 July; 17 (6) 635-9. A case series of autoimmune diseases accompanied by incidentally diagnosed monoclonal gammopathy.

Introduction: Neuromyelitis optica is an antibody-mediated disease, commonly associated with autoantibodies directed against the astrocytic water channel aquaporin-4 (AQP4). These antibodies can often persist for many years, even decades. AQP4-antibodies are higher in the periphery than in CSF. The peripheral B-cell subset secreting AQP4-antibodies and the conditions which modulate their production are poorly understood although one study suggested plasmablasts are the source of AQP4-antibodies.

Methods: We studied unfractionated PBMCs and sorted plasmablast populations from 12 patients with widely-varying serum levels of AQP4-antibodies (1:20 -1:12800) to investigate the source of AQP4-antibodies. All patients had been treated with immunotherapies prior to sampling. Culture conditions utilised selected combinations of CD40L, IL-2 (50 ng/ml), IL-1 (1 ng/ml), TNFa (1 ng/ml), BAFF (200 ng/ml), IL-21 (50 ng/ml), IL-6 (10 ng/ml) and APRIL (300 ng/ml). IgG levels were measured by ELISA. AQP4antibodies were determined by live cell based assay, followed-by flow cytometric quantification.

Results: In vitro culture of patient plasmablasts (CD3-CD14-CD191CD2711CD3811) generated modest quantities of IgG, but no AQP4-antibodies. The lack of AQP4-antibodies was also observed from unfractionated PBMCs cultured under plasmablast-maintainance conditions (IL-61/-APRIL). By contrast, conditions which promoted B-cell proliferation (IL-2, CD40L, TNFa, IL-21) generated large quantities of IgG (mean 12lg/ml, IQR 1.8-19), and often high levels of AQP4-antibodies. The number of plasmablasts and total-IgG generated per well in vitro showed little variation across the wide-range of supernatant AQP4antibody levels, suggesting the baseline frequency of AQP4-specific B-cells determined the AQP4-antibody levels in culture. Furthermore, the AQP4-antibody supernatant levels correlated well with the serum levels from the 12 patients (Spearman's r50.81, p 5 0.0023).

Conclusions: AQP4-antibodies can be derived in large quantities from circulating B cells rather than circulating plasmablasts. The robust correlation between in vitro AQP4-antibody levels and serum AQP4-levels suggests a mechanism of action for CD20 depletion and does not implicate long-lived CD20-negative cells in the pathogenesis of NMO.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? SRI is a coapplicant and receives royalties on patent application WO/2010/ 046716 (U.K. patent no., PCT/GB2009/051441) entitled 'Neurological Autoimmune Disorders'. The patent has been licensed to Euroimmun AG for the development of assays for LGI1 and other VGKC-complex antibodies. He has received consulting fees from MedImmune.

Jun-ichi Kira, Ryo Yamasaki, Hayato Une, Mei Fang, Yinan Zhao, Guanrui Li, Kyoko Iinuma, Katsuhisa Masaki, Kouji Shinoda and Hiroo Yamaguchi. Fukuoka-Shi, Fukuoka, Japan

Objective: We previously reported that astroglial connexin (Cx)43 and oligodendroglial connexins Cx32 and Cx47 are frequently lost in the acute and chronic lesions associated with multiple sclerosis and neuromyelitis optica spectrum disorder. However, the roles of glial Cxs in these demyelinating diseases remain to be established. Therefore, in the present study, we aimed to examine the roles glial Cxs play in demyelination using an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), in Cxs-deficient mice.

Methods: Tamoxifen was administrated to Plp1-CreERT;Cx47 fl/fl mice and Glast-CreERT2;Cx43fl/fl mice to generate tamoxifen-inducible oligodendroglia-specific Cx47 knockout (Cx47 iKO) mice and tamoxifen-inducible gray matter astroglia-specific Cx43 knockout (GM Cx43 iKO) mice, respectively. Cx30 knockout (Cx30 KO) mice, Cx47 iKO mice, and GM Cx43 iKO mice were used together with their control littermates for induction of EAE by myelin oligodendrocyte glycoprotein.

Results: EAE was markedly attenuated in the chronic but not acute phase of EAE in Cx30 KO mice, which showed less demyelination and diffuse activation of microglia. These microglia displayed down-modulation of Toll-like receptor 4 and an M2 macrophage phenotype as assessed by microarray analysis and immunohistochemistry. In GM Cx43 iKO mice, acute and chronic EAE were significantly ameliorated, with less inflammatory cell infiltration and less demyelination. By contrast, Cx47 iKO mice showed more severe EAE at the acute as well as chronic phases.

Interpretation: The absence of astroglial Cx30 and Cx43 ameliorates EAE, whereas the absence of oligodendroglial Cx47 exacerbates EAE, suggesting that astroglial and oligodendroglial Cxs differentially modulate EAE severity.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? JK is a consultant for Biogen Idec Japan, Novartis Pharma AG, and Medical Review. He has received speaking fees and/or honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical, Novartis Pharma KK, Takeda Pharmaceutical Company, Nippon Rinsho, and Medical Review. He has received grants from Pfizer, Eizai, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, and Bayer Healthcare.

Nidaullah Mian, Lokesh Rukmangadachar and Ali Choucair. Springfield, IL Objective: We describe a case of Nivolumab induced autoimmune-encephalitis. With the more common use of this drug, early recognition and treatment of this supposedly rare side-effect is important.

Background: Immunotherapy is becoming more widely used in the treatment of cancers. Drugs in a new class of immunotherapy called, Immune checkpoint inhibitors (anti-CTLA4, and anti-PD1), are approved for the treatment of metastatic melanoma, non-small cell lung cancers, and renal cell carcinoma. Nivolumab is an anti-PD1 monoclonal antibody that enhances anti-tumor immunity by targeting the T-cell inhibitory receptors. Adverse events might occur through immunologic activation and can involve any organ system. Neurological adverse events although rare, require prompt recognition and treatment to avoid substantial morbidity.

Description: 59-year-old female with history of a treated laryngeal squamous cell carcinoma status post resection and radiotherapy with tracheostomy in place; adenocarcinoma of the lung with liver metastases status post chemotherapy, was started on palliative immunotherapy with Nivolumab. A week after her first infusion, she was admitted to the hospital with a 2 day history of generalized weakness, worsening of her respiratory status and changes in sensorium. Her neurological status worsened with rapid progression into quadriparesis and coma, followed by status epilepticus. MRI brain revealed scattered T2 flair hyperintensities in the subcortical white matter in the bilateral parietal and posterior frontal regions, the body and splenium of the corpus callosum, and right brachium pontis. None of these lesions enhanced with contrast. Lumbar puncture revealed 70 white cells with lymphocytic predominance, 70 protein; normal glucose, IgG index and oligoclonal bands. Cytology revealed pleocytosis but no malignant cells. CSF myelin basic protein was >1050 ng/ml. No infectious source was identified. Mayo clinic autoimmune encephalitis panel on CSF was negative. The patient was started on Keppra and Vimpat for seizures. Also she was started on methylprednisolone 1gm IV daily for 5 days, followed by IVIG given at 0.4mg/kg daily for 5 days. Seizures abated and patient's neurological status improved gradually. At one month she was able to move all four extremities and follow simple commands.

Conclusion: Autoimmune-encephalitis is a rare but significant neurological adverse event of immune checkpoint inhibitors and can rapidly progress to necrotizing encephalitis. Early recognition and prompt treatment with steroids and plasmapheresis or IVIG is important to prevent significant morbidity and mortality.

Are Associated with Poor Treatment Outcome Hye-Rim Shin, Seon Jae Ahn, Yoonhyuk Jang, Tae-Joon Kim, Jin-Sun Jun, Jangsup Moon, Soon-Tae Lee, Keun-Hwa Jung, Sang Kun Lee and Kon Chu. Seoul, Republic of Korea Objective: Anti-LGI1 (Leucin-rich glioma inactivated 1) encephalitis is the second most common autoimmune encephalitis, and has several distinct clinical manifestations such as memory impairment, fasciobrachial seizure (FBDS), and neuropsychiatric symptoms. We investigated the detailed profile of psychiatric symptoms in anti-LGI1 encephalitis, and analyzed whether the presence of neuropsychiatric symptoms affects the prognosis of the patients.

Methods: We enrolled consecutive patients diagnosed with anti-LGI1 encephalitis from Jun. 2012 to Mar. 2017 in Seoul National University Hospital, the tertiary hospital. The neuropsychiatric symptoms were classified into four categories related to anxiety, mood, psychosis, and impulsivity according to the psychiatric symptoms and behavior checklist of the Vanderbilt-Kennedy center. The time to immunotherapy was defined as the time from symptom onset to the first line immunotherapy such as steroid or immunoglobulin.

Results: Of 16 patients diagnosed with anti-LGI1 encephalitis, 10 (62.5%) showed psychiatric symptoms as the initial manifestations. All 10 patients experienced moodrelated symptoms, and the depressed mood was the most common (n56, 60%). Four patients (40%) had anxiety and five (50%) had psychotic symptoms such as hallucination. Six patients (60%) initially visited psychiatric clinic before visiting the neurology clinic. The time to immunotherapy was longer in those with initial psychiatric symptoms compared to those without them (Median 3.5 months vs 1.5 months, P50.049). In addition, the follow-up modified ranking score (mRS) at 2 months after the first immunotherapy was significantly higher in the patients with psychiatric symptoms compared to those without them (Median 2 vs 0.5, P50.014). Multivariate linear regression of factors affecting mRS at 2 months showed that both the presence of initial psychiatric symptoms and the delayed immunotherapy could be significant contributors to the poor mRS score. (P 50.023 Co-efficiencefficienct 0.92, P5 0.026 Coefficiencent 0.07, respectively)

Interpretation: Initial manifestation of psychiatric symptoms in patients with anti-LGI1 encephalitis has a negative impact on early recovery in two aspects; the presence of psychiatric symptoms itself implies the severity of the illness, and the mood-related symptoms often leads to misdiagnosis with psychiatric illness such as senile depression, delaying the timing of immune treatment. Methods: We conducted a retrospective study of epilepsy cases at Mayo Clinic (Rochester-MN; Scottsdale-AZ, and Jacksonville-FL) in whom autoimmune encephalopathy or autoimmune epilepsy or autoimmune dementia autoantibody testing profiles were requested (06/30/2014-06/30/ 2016). Antibody prevalence in epilepsy (APE) score, based on clinical characteristics, was assigned to each patient. Among patients who received immunotherapy, Response to Immunotherapy in Epilepsy (RITE) score was assigned. Favorable seizure outcome was defined as greater than 50% reduction of seizure frequency at the first follow up.

Results: Serum and CSF from 1736 patients were sent to the Mayo Clinic Neuroimmunology Laboratory for neural autoantibody evaluation. Three-hundred eighty-seven of these patients met the diagnostic criteria of epilepsy. CNS specific antibodies were detected in 44 patients.

Certain clinical features such as new-onset epilepsy, autonomic dysfunction, viral-prodrome, facio-brachial-dystonicseizures/oral-dyskinesia, inflammatory CSF profile and mesial temporal MRI abnormalities had significant association with positive antibody results. A significantly higher proportion of antibody positive patients had an APE score greater than 4 (97.7% versus 21.6%, p<0.01). Sensitivity and specificity of an APE score greater than 4 to predict presence of specific neuronal auto-antibody were 97.7% and 77.9% respectively.

In the subset of patients who received immunotherapy (77), autonomic dysfunction, facio-brachial-dystonic-seizures/oral-dyskinesia, early initiation of immunotherapy and presence of antibodies targeting plasma membrane proteins (cell-surface antigens) were associated with favorable seizure outcome. Sensitivity and specificity of a RITE score greater than 7 to predict favorable seizure outcome were 87.5% and 83.8% respectively.

Significance: APE and RITE scores can aid diagnosis, treatment and prognostication of autoimmune epilepsy. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune synaptic encephalitis caused by autoantibodies directed against GluN1 subunit of the NMDAR, resulting in psychosis, memory loss, seizure, speech problems, dyskinesia, autonomic dysfunction, central hypoventilation, and loss of consciousness. Although antibodymediated mechanism of disease pathogenesis driven by immunoglobulin-induced receptor internalization was proposed, the exact pathophysiology of NMDAR has not been clearly defined. In this study, we investigated the expression profiles of miRNAs and mRNAs in the in vitro model of anti-NMDAR encephalitis to understand the underlying molecular mechanism.

Hippocampal neurons of rat pups were cultured for 14 days and then were and incubated for 48 h with CSF (cerebrospinal fluid) from 4 anti-NMDAR encephalitis patients, and 4 negative controls,. After incubation, the RNAs were extracted from the cells and Genome-wide miRNA and mRNA expressions were analyzed by Agilent Rat miRNA microarray 8 X 15K v21 and quantitive mRNA sequencing using Illumina NextSeq500, respectively.

Following the multiple comparison corrections by false discovery rate of 0.05, we identified 4 miRNAs differentially expressed in NMDA encephalitis in vitro model: All 4 miR-NAs (miR-465-5, miR-6216, miR-139-3p, miR-135a-3p) were upregulated (fold change > 1.5). A total of 17,509 mRNAs were analyzed: 134 mRNAs were upregulated and 57 mRNAs were downregulated (!2.0-fold, p < 0.05). The most abundant functional category of genes was 'cell differentiation' including 38 mRNAs.

Our results demonstrate that dysregulation of miRNA and mRNA expressions occurred during the early in vitro NMDAR encephalitis model. This information might help understanding the pathogenesis and performing future studies on therapeutic application of miRNAs in NMDAR encephalitis. Background: Anti-leucine rich glioma inactivated 1 (LGI1) encephalitis is a rare autoimmune condition presenting mainly with altered mentality, cognitive dysfunction and seizure. Antiepileptic drugs (AEDs) are usually initiated to control faciobrachial dystonic seizure and other seizure manifestations, but the clinicians often change AEDs during the treatment course and drug side effects are among the main cause. We investigated the types and frequency of side effects of AEDs in patients with anti-LGI1 encephalitis.

Methods: We screened the patients who were diagnosed with anti-LGI1 encephalitis and treated with AEDs for seizure control from October 2012 to September 2016. Medical records were reviewed to identify the AEDs and their side effects in these patients.

: Among the 20 patients who were treated with AEDs, 10 (50%) changed their AEDs due to adverse cutaneous drug reaction (ACDR). Eight of them presented with maculopapular eruption, one with drug rash with eosinophilia and systemic symptoms syndrome, and one with eczema. AEDs that were discontinued in association with ACDR include oxcarbazepine (7 patients), lamotrigine (2 patients), phenytoin (2 patients), carbamazepine (1 patient), and levetiracetam (1 patient). Oxcarbazepines were discontinued in two additional patients due to hyponatremia. Six patients (30%) discontinue or reduce the dose of levetiracetam for psychiatric manifestations including irritability/ aggressive behavior (4 patients), insomnia (1 patient) and depressive mood (1 patients).

Conclusions: ACDR was a highly frequent side effect leading to the discontinuation of AEDs in patients with anti-LGI1 encephalitis and the causative drugs were mostly consist of aromatic AEDs. Clinicians should consider ACDR, psychiatric side effects, and hyponatremia when selecting AED for the treatment of anti-LGI1 encephalitis.

Sarah Berth, Paula Barreras, John C. Probasco, Lilja B. Solnes, Carlos A. Pardo and Lyle W. Ostrow. Baltimore, MD

A 53 year old previously healthy man was admitted to an inpatient psychiatry service with confusion, decreased interaction, hypersomnia, and episodes of agitation, following an upper respiratory prodrome. He developed urinary retention and was transferred to our institution on day 12 of his hospitalization.

On examination, he exhibited persistent memory defects, a moderate nonfluent transcortical motor aphasia, cerebellar dysarthria, dysdiadochokinesia, and a mildly broad-based gait. Urinary retention persisted and he also developed a bowel pseudo-obstruction. MRI brain and spinal cord were unremarkable, and EEG showed only diffuse slowing. Infectious workup was unremarkable. CSF studies demonstrated lymphocytic pleocytosis, oligoclonal bands, and an elevated IgG index. His mental status, somnolence, and language deficits steadily improved without intervention.

Given concern for an autoimmune and potentially paraneoplastic encephalitis, he underwent workup for an underlying malignancy. CT chest/abdomen/pelvis showed hilar lymphadenopathy, and brain and whole body FDG-PET/ CT demonstrated (1) FDG-avid hilar lymph nodes and (2) marked hypometabolism in both occipital lobes. Biopsy of a mediastinal lymph node revealed an atypical B cell Lymphoma. NMDA Receptor (NMDAR) antibody was detected in the CSF, but negative in serum. Immunostaining for the NR1 subunit of the NMDA receptor was strikingly positive in the lymph node neoplastic B-cells. He underwent a 5 day course of IV-immunoglobulin therapy, and after discharge underwent 8 cycles of chemotherapy with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone. His mental status continued to improve, though he was left with residual memory deficits and impaired fluency.

A repeat FDG-PET/CT one month after discharge showed resolution of the prior occipital hypometabolism.

Anti-NMDAR paraneoplastic encephalitis most commonly affects young women with ovarian teratomas, though atypical and protean presentations are increasingly being recognized. This case was unusual given the patient's age, sex, tumor type, and monophasic course (i.e. gradual improvement prior to initiating treatment). We could not find any prior published cases of anti-NMDAR encephalitis associated with non-Hodgkin's lymphoma. Additionally, this case illustrates the utility of brain FDG-PET in diagnosis of autoimmune encephalitis, while demonstrating resolution of occipital hypometabolism in the setting of clinical improvement. Puzzlingly, there was ectopic onconeural antigen expression by mediastinal lymphoma cells at a time when NMDAR antibodies were detected in CSF but not in serum. This might suggest serum dilution contributes to the negative test, and/or blood-brain-barrier dysfunction might play a role in pathogenesis.

Usama Tariq, Paola Trejo, Alicia Parker, Doty Leilani and Kenneth Heilman. Gainesville, FL Objective: To report a patient with posterior cortical atrophy found to have quadrantic spatial neglect.

Background: Spatial neglect has been rarely reported as horizontal or vertical neglect in association with neurodegenerative disease, and quadrantic neglect has not been described.

Methods: A case report. Case Report: A 68 year-old right-handed man presented with a four years of progressive cognitive decline, starting with disturbances in visual perception. He gradually developed difficulty with facial recognition, naming, memory and visual hallucinations. On testing for visual neglect, he demonstrated decreased attention to stimuli presented in his right inferior egocentric visual space. When asked to detect hand movements he could detect stimuli on both sides but with bilateral simultaneous stimulation he extinguished (neglected) stimuli in his right lower visual field. In addition, he demonstrated visual simultanagnosia, visual object agnosia, alexia with apraxic agraphia and ideomotor apraxia. On motor examination, he was found to have bilateral cogwheel rigidity and mirror movements. Labwork for reversible causes of dementia were unrevealing. Although the MRI showed cortical atrophy that was most prominent in the posterior region of his left hemisphere, the pathological basis of this patient's disorder has not been determined.

Discussion: This report describes quadrantic neglect in a patient with posterior cortical atrophy. The brain mechanisms accounting for this patient's quadratic neglect are not known; however, studies of stroke patients suggest that the parietal lobe appears to be important in the allocation of contralateral and inferior vertical spatial attention. Our patient had atrophy in his parietal lobe. The interaction of lateral and vertical inattention may have induced this patient's quadrantic neglect. Spatial neglect is disabling and can be dangerous, particularly if unrecognized. Brief cognitive screens such as the Mini-Mental Status Exam and the Montreal Cognitive Assessment do not assess for neglect. This case illustrates the importance of evaluating patients for neglect for diagnosis and management.

Clinical Presentation of AIDS Farinaz Safavi, Ling Pan and Steven Frucht. NYC, NY Introduction: The following case report describes a patient presenting with subacute, progressive global aphasia and central face palsy as the first symptom of newly diagnosed AIDS.

Case description: Patient is a 53 year-old male, with no PMH, who presented complaining of speech difficulty, and drooling from the right side of his mouth. Two weeks prior to presentation, he initially noticed slurred speech with difficulty pronouncing words. Symptoms progressively worsened to confusion, inattentiveness, forgetfulness and inability to perform routine daily tasks. His wife noticed that he was misplacing objects, not following commands and had severe word finding difficulty. On admission,general exam:unremarkable. he was alert,awake and oriented to own name, but not to place, time or examiner. Naming for low frequency objects,attention, concentration and calculation were impaired. Immediate recall was intact, but recall after 5 min was 0/3. Could follow simple and two step commands, but required prompting to perform complex commands passing the midline. lower Rt nasolabial fold flattening with decreased activation with otherwise normal neuro exam. Routine labs: wnl; U-Tox: Neg. CT head showing nonspecific areas of parenchymal hypodensity in the bilateral frontal regions. MRI w/wo contrast showed multiple bilateral cerebral non-enhancing white matter lesions with peripheral diffusion restriction. HIV rapid antigen test came back positive, HIV viral load was 49284, and CD4 count was 60, which confirmed a diagnosis of AIDS. CSF analysis showed Glu:53, Pro:73, WBC:5 and RBC:27. CSF JC virus PCR was positive with negative HSV1-2,EBV,CMV,VZV. CSF cytology showed atypical B cells suspicious for chronic lymphocytic leukemia vs chronic atypical lymphocytosis. However, blood cytopathology was not confirmatory for neoplastic process. To differentiate between neoplastic process and PML, patient underwent brain biopsy of a Lt frontal lesion, which confirmed PML with JC virus reactivity.

Discussion: fundamental importance of including systemic etiologies on the differential even in the setting of what appear to be isolated neurological symptoms or signs. This patient appeared well-nourished and well-developed with no other systemic signs or symptoms of AIDS, aside from progressive, focal neurological deficits. Interestingly, both brain imaging and CSF analysis were insufficient in differentiating infectious and neoplastic processes. Final diagnosis of PML required brain biopsy of a frontal lesion seen on MRI. For clinicians, this case emphasizes the importance of considering HIV and PML on the differential for patients who present with subacute, progressive neurological deficits and atypical lesions on brain imaging.

Farwa Ali, Jennifer Whitwell, Joseph Y. Matsumoto, Cliff R. Jack, Jr., Val Lowe and Keith A. Josephs. Rochester, MN Corticobasal syndrome (CBS) can result from a number of different pathologies, including Alzheimer's disease. We performed tau-PET imaging with [18F]AV-1451 in a patient with CBS, asymmetric frontoparietal hypometabolism on [18F]fluorodeoxyglucose (FDG) PET and positive brain beta-amyloid imaging, to determine whether the underlying pathology was indeed Alzheimer's disease. 70 year old righthanded man presented with an eighteen month history of resting tremor, bradykinesia, speech problems and paranoid delusions. Without cognitive impairment, REM sleep behavior disorder, falls, or hallucinations. On examination he had normal cognition, mild torticollis and upper extremity myoclonus. There was bilateral parkinsonism; decremental small amplitude rapid alternating movements in all limbs, tremulousness, and reduced asymmetric arm swing. There was marked hypokinetic dysarthria and apraxia of speech. Asymmetric limb and orofacial apraxia was noted. Strength, sensory and cerebellar exams were normal. There was no gaze palsy or postural instability. Investigations revealed normal complete blood count, paraneoplastic antibody levels, ceruloplasmin, liver, renal and thyroid function. Multichannel surface electromyography confirmed cortical myoclonus affecting the upper extremities but no evidence of tremor. MRI brain revealed left greater than right parietal lobe atrophy. This correlated with left lateral fronto-parietal and bilateral medial fronto-parietal hypometabolism on FDG-PET scan. I-123 ioflupane DAT/SPECT scan confirmed pre-synaptic dopaminergic deficit, with asymmetrically left > right reduced putaminal uptake. Pittsburgh compound B (PiB) PET was positive for significant betaamyloid deposition throughout the cerebral cortex, standard uptake value ratio (SUVR) of > 2.0 (normal<1.42). The patient underwent [18F]AV-1451 tau-PET imaging. Regional [18F]AV-1451 uptake was calculated for 49 cortical and subcortical regions-of-interest across the brain and median uptake in each region was divided by median uptake in cerebellar crus grey matter to create SUVRs. Regional SUVRs were compared to median SUVRs across a healthy control cohort. The CBS patient showed no regions with greater SUVR values than controls, with only slight uptake observed in the left inferior temporal gyrus.

[18F]AV-1451 has been proven to be able to detect paired helical filament tau, this case did not represent Alzheimer's disease pathology despite beta-amyloid positivity. Hence, beta-amyloid positivity in the context of CBS should not be considered diagnostic of Alzheimer's disease. Tau-PET scan can provide additional diagnostic data on underlying pathology in CBS, in this case suggesting pathology other than Alzheimer's disease, such as 4R tauopathy or TAR DNA binding protein 43 accumulation. Background: This study explores the unusual musical processing skills of a professional ragtime pianist. This musician claims that he can simultaneously hear several complex pieces of music, such as symphonies, in his mind while playing the piano. He describes superior audiation abilities which are associated with complex multi-sensory and visual imagery. Studying the neuronal effects of music may allow us to better understand higher cognitive function and provides us with insight into the neuronal networks that are activated during complex cognitive tasks.

Methods: This is a case-control study of a musician with exceptional audiation skills. His abilities were tested and compared to those of an age, gender, and educationally matched professional musician control. Behavioral data from neuropsychological testing, audiation tasks and working memory tasks were collected and analyzed. Functional MRI based whole brain activation patterns and functional connectivity models during each task were sampled and analyzed.

Results: The pianist and the musician control showed a superior working memory index and superior matrix reasoning. Both study subjects had higher than average scores on multiple standard neuropsychological subtests. Neurobehavioral testing confirmed that only the pianist could mentally listen to up to four complex pieces of music simultaneously. He described intense multi-sensory experiences and visual imagery accompanying these audiations. FMRI showed rather circumscribed brain activation during his audiations. Data from fMRI studies also suggest that the pianist utilizes different neuronal networks to successfully complete various cognitive tasks compared to the control. Conclusion: The activation of multi-sensory integration areas may play an important role for the execution of complex cognitive tasks such as audiations or during musical composition in the study subject. The utilization of alternative functional networks during standard cognitive tasks suggests that interventions aiming at the recruitment of a such alternative networks could have implication for the recovery from brain injury and requires further study.

Ideomotor Apraxia: A Programing or Perceptual Disorder Rocio Polanco Fern andez, Alicia Parker, Kenneth Heilman, Umberto Castiello and Elisabetta Ambron. Padova, Italy; Santorso, Vicenza, Italy; Gainesville, FL and Trieste, Italy

Objective/Background: Patients with ideomotor apraxia (IMA) from a stroke will often make postural errors when imitating an examiner's posture. The possible mechanisms that may account for this deficit include a perceptual disorder and a programming disorder. To discriminate between these two possibilities patients with IMA, as well as healthy control participants were asked to reproduce postures using their own upper limb as well as to manipulate a manikin.

Methods: Ten right-handed patients with left hemisphere infarction and 10 age and education-matched controls were recruited. Patients were diagnosed as apraxic or non-apraxic by performance on the STIMA test. The experimental IMA task required subjects to reproduce meaningless hand postures displayed on a monitor, in 2 conditions: 1) using the subject's own upper limb and 2) moving a manikin.

Results: The apraxic patients performed more poorly than the controls using both the subject's own body (p50.003) and the manikin (p50.042). The apraxic group's performance was more impaired making postures with their own body than using the manikin (p<0. 005).

Discussion: The finding that patients with IMA, when using a manikin, made fewer errors than when using their own bodies suggests that these patients' motor programming impairment is greater than their perceptual impairment. However, when compared to controls their performance on the manikin was also impaired suggesting they also have a perceptual impairment. The brain is a distributed network that operates at small and large spatial and temporal scales to meet the needs of the task at hand. Certain tasks generate conflict by requiring attention to relevant stimuli among distractions. Engagement in conflict-based tasks elicits network activity that differentiates these tasks from other behavior. Brain states associated with conflict in experimental behavioral contexts may be an important marker of dysfunction related to neuropsychiatric illness, yet there are no documented decoders that predict engagement in conflict-based tasks through invasive, large scale local field potential recordings. In addition, there is evidence that precisely timed Deep Brain Stimulation (DBS) could restore normal behavioral task dynamics in neuropsychiatric patients, however these findings were limited to within task features. In the present study, we have developed a decoding strategy to accurately predict task engagement by harnessing canonical correlation analysis (CCA), a measure of functional connectivity between regions, in tandem with a Support Vector Machine (SVM) classifier. Cortical and sub-cortical invasive local field potential recordings were collected in patients engaged in one of two Stroop-like tasks, including the Multi-Source Interference Task (MSIT), and the Emotional Conflict Resolution Task (ECR). Canonical correlation coefficients were extracted by performing Singular Value Decompositions on windows of data across all channels within each region, and transforming the resulting singular vectors in a way that maximally correlates activity between each region pair. These CCA features were used as inputs to an SVM classifier to differentiate functional connectivity between task engagement and free behavior. A mean classification accuracy of 95.3% (MSIT med: 96.7 6 2.3%, ECR med: 95.0 6 3.2%) was achieved for both tasks across 14 patients, and a subset of features per patient were isolated that are required to maintain high accuracy (MSIT: med 3 6 3.4 region pairs, ECR: med 4 6 6.6 region pairs). The reduced feature set can be used to reduce the computational complexities of the algorithm moving forward, which points to potential tractability for driving a simple algorithm to detect task engagement on existing systems. While decoder stability was not achieved over two recordings, classification accuracy improved when trained on both recordings. This increase in accuracy suggests that training the classifier on many temporally separated data could improve its stability. Detection of task-associated brain states could ultimately be a closed-loop strategy for delivering real-time therapy to patients with neuropsychiatric illness. Background: Social cognition and interaction are indispensable in everyday life. Nonetheless, the social brain network and its dysfunction after brain damage remains little understood, in particular in regard to non-verbal social communication.

Methods: Functional MRI and diffusion tensor imaging (DTI) on a 3T MR scanner (Siemens Medical Solutions, Erlangen, Germany) were recorded in 17 healthy righthanded male participants during recognition of emotions (happy, neutral and angry) conveyed by a point-light arm seen knocking on a door. Data pre-processing, functional MRI analysis and dynamic causal modelling (DCM) were performed with Statistical Parametric Mapping (SPM12; The Wellcome Trust Centre for Neuroimaging, London, UK, http://www.fil.ion.ucl.ac.uk/spm). The FMRIB Software Library (FSL4, Oxford Centre for Functional MRI of the Brain, UK, http://www.fmrib.ox.ac.uk/fsl) was used for probabilistic tractography.

Results: The integrated structural and effective connectivity data reveal functional architecture of this network indicate that the social brain consists of a distributed and differentiated network. Happy as compared to neutral body motion activates the right superior temporal sulcus (STS) and caudate nucleus, while angry versus neutral knocking elicits activation in the left inferior insula, perigenual anterior cingulate cortex (ACC) and posterior midcingulate cortex (MCC). The cerebellar vermis (lobule IX) and right amygdala appear to signal a lack of emotional content.

Conclusion: Revealing the components, structural connections and functional interactions of the social brain network in the context of reading emotional body language, the data may contribute to better understanding socio-cognitive deficits after brain damage. In addition, the developed approach for integration of structural with effective connectivity may open a window for neurobiologically more valid assessment of task-related brain networks in normalcy and neurological disease.

Leila Saadatpour, Usama Tariq, Alicia Parker, Mohammadhossein Alimardani, Kenneth Heilman and Leilani Doty. Gainesville, FL Objective: To describe a patient with a novel form of primary progressive aphasia (PPA).

Background: Mixed transcortical aphasia is a rare speech disorder characterized by reduced spontaneous speech and decreased comprehension with intact repetition. This type of aphasia has been reported in patients with an infarction of watershed areas which isolate Broca's area, Wernicke's area, and the arcuate fasciculus from remainder of the brain. To our knowledge mixed transcortical aphasia has not been reported as a form of PPA.

Design/Methods: A case report. Results: The patient was a 55 year-old right-handed woman who gradually developed language difficulties over two years. Symptoms began with difficulty finding and producing words. On neuropsychological testing, she demonstrated a dramatic decrease in spontaneous speech, impaired comprehension and naming. Her repetition, however, was in intact. Her MRI showed atrophy in the left frontal, parietal and anterior temporal lobes, without evidence of ischemia.

Conclusions: Primary progressive aphasia (PPA) is a progressive decline in language-speech associated with neurodegenerative disorders. To date, three major forms of PPA have been described including, semantic aphasia, nonfluent/ agrammatic PPA and logopenic PPA. To our knowledge, this is the first report of a patient with mixed transcortical aphasia as the presenting symptom of a neurodegenerative disease. Further research is needed to learn the underlying pathology as well as possible treatments.

Giang Dang Ngo and Alan R. Hirsch. Chicago, IL Introduction: Historical aspects indicating chemosensory malingering have been ignored. A patient who is malingering, with a strangely detailed history of chemosensory functioning, is reported.

Case history: A 47 years old right handed female housekeeper presented after chemical exposure to PerCept (Peroxyacetic Acid, Hydrogen Peroxide, Acetic acid, Sulfuric Acid) at work. She feft the smell was overwhelming and sour and soon changed to the aroma of fish. She observed her taste was reduced at work, but normal at home. She described that dark chocolate all her life was bitter, now is not bitter and tasted like milk chocolate. Despite not having been exposed to PerCept for four months, she feels that she still was being exposed because a coworker used it and this coworker was contaminating her, just by being in her presence.

Results: Abnormalities Neurological Examination. Motor exam: mild right pronator drift with bilateral abductor digiti minimi signs, right more than left and right Holmes phenomenon. Reflexes: 31 brachioradialis and biceps bilaterally, 0-11 quadriceps femoris bilaterally. 0 ankle jerks bilaterally. Positive Hoffman bilaterally. Neuropsychiatric Testing: MMPI -2: invalid, consistent with malingering. Validity Electric lighting is one of the greatest technological advances in human history, and until recently it was assumed to be innocuous. In contrast, chronic exposure to light at night has been linked to poor clinical outcomes in a variety of serious health conditions, including cancer, heart disease, and obesity. Many of these negative effects of night shift work or chronic exposure to light at night have been attributed to disrupted sleep. By comparison, very little is known about the physiological and behavioral consequences associated with short-term exposure to light at night. We hypothesized that light at night has rapid effects on physiology and behavior and predicted that even a few nights of exposure to dim light would precipitate depressive-like behavior and associated neurological changes. We studied nocturnal mice so that light at night would not interfere with daytime sleep. Adult male and female mice were acclimated to a standard light/dark cycle [14h light (150 lux)/10 h dark (0 lux)] and then either maintained in this light/dark cycle or transferred to dim light at night [14h light (150 lux)/10 h dim light (5 lux)] conditions for four consecutive evenings. Mice exposed to dim light at night for just four nights displayed increased floating in a forced swim test relative to mice exposed to dark nights (P<0.05), indicative of increased depressive-like behavior. There was a concomitant reduction in hippocampal vascular endothelial growth factor (VEGF) protein concentration (P<0.05) and hippocampal blood vessel staining with tomato lectin (P<0.05) among the mice exposed to dim light at night relative to the mice housed in dark nights. Reduced VEGF expression has previously been implicated in the pathogenesis of depression, however, this study provides the first evidence that VEGF expression is modulated by night-time light exposure and that this fairly subtle environmental cue precipitates depressive-like behavior. Furthermore, the responses of both male and female mice to dim light at night were similar. Together, these data indicate that even short-term exposure to light at night has physiological and behavioral consequences.

Peter Tsai, Fantao Meng, Elyza Kelly, Jennifer Gibson, Jacob Ellegood and Jason Lerch. Dallas and Toronto, Canada

Autism spectrum disorders are prevalent neurodevelopmental disorders with great societal cost; however, treatment options remain parsimonious due to limited understanding of the underlying molecular, cellular, and circuit mechanisms. We have recently demonstrated in a mouse model of Tuberous Sclerosis Complex, that cerebellar specific dysfunction is sufficient to generate autistic-like behaviors. To better understand the cerebellar topography governing the cerebellar regulation of these ASD-relevant behaviors, we identified abnormalities in a clinically-implicated region in our cerebellar ASD mouse model. In addition, we have demonstrated that inhibition of this cerebellar domain is sufficient to generate social deficits and repetitive behaviors. Moreover, we have demonstrated that stimulation of this domain is sufficient to rescue abnormal behaviors in our cerebellar ASD mouse model, even into adulthood, thereby demonstrating the potential for cerebellar neuromodulation-based therapies in the treatment of abnormal ASD behaviors. We further explore the cerebellar -cortical circuits regulated by this domains to better understand the circuit networks involved in ASD behaviors and to identify additional therapeutic targets for neural circuit-based therapeutic development.

Christopher J. Lamb, Alfonso S. Lopez, David Sotello, Julio C. Mendez and Maisha T. Robinson. Jacksonville, FL Introduction: HIV has been implicated in a broad spectrum of neurologic dysfunction at virtually every locus along the neuraxis. Before the advent of antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) were the most common. HIV CSF viral escape syndrome is a recently-recognized, rare manifestation defined by discordant viral load between plasma and CSF compartments. It is proposed that a distinct HIV clonality arises and matures in the CSF space after initial infection. We present one such case of a 46-year-old man who presented with acute, persistent hiccups and subacute executive dysfunction.

Case Presentation: A 46-year-old, right-handed African-American man with HIV, compliant on ART, presented to the emergency department after a week of persistent hiccups. His sister noticed that he had been experiencing righthand tremor and gait imbalance for the last three months.

The patient's co-workers remarked that he came to work at the wrong hours.

Physical examination revealed frequent hiccups; decreased short term recall; fine tremor of the right hand worse with activation; appendicular and gait ataxia. The remainder of the physical examination was normal. The patient's hiccups resolved after administration of chlorpromazine. MRI of the brain and with and without gadolinium revealed nonenhancing T2/FLAIR hyperintensities involving the right frontal cortex, cerebral white matter, right external capsule, right caudate nucleus, left midbrain, area postrema, and bilateral peri-dentate cerebellum. Cervical and thoracic spine MRI demonstrated non-enhancing, right-sided T2 hyperintensity from C4-T1. Plasma CD4 count was 724 cells/mliter, and plasma HIV RNA viral load was 406 copies/mL. Lumbar puncture revealed lymphocytic pleocytosis and elevated protein. Herpesviridae, gram stain, JC virus, toxoplasma, Cryptococcus, and VDRL were negative, but CSF HIV RNA PCR was 2520 copies/mL. Discordance between plasma and CSF HIV confirmed HIV CNS viral escape syndrome; antiretroviral regimen was changed to abacavir, lamivudine and dolutegravir based on resistance testing. Neurocognitive symptoms had resolved at 6 month followup. Repeat MRIs demonstrated interval improvement.

Discussion: We present a case of HIV CSF viral escape syndrome causing subacute HAND and acute HIV encephalomyelitis with area postrema syndrome. In other reported cases of CSF HIV escape syndrome, patients presented with variegated focal or non-focal neurologic symptoms with insidious onset despite longstanding antiretroviral therapy. High clinical suspicion despite plasma viral suppression is the key to diagnosis and management. Treatment is contingent upon modification of ART to incorporate higher CNS penetration targeting the susceptibilities of the CSF HIV population.

John D. Papatriantafyllou, Efstratios Karavasilis, Theodore Parthymos, George Kaspas, Ioannis Seimenis, Andrew C. Papanicolaou and Sokratis G. Papageorgiou. Athens, Greece; Athens, Greece; Alexandroupolis, Greece and Memphis Objective: It is well known that a considerable proportion of Alzheimer's patients also present with depression. We herein conducted a large-sample study to address the question of what pattern of gray matter abnormalities differentiates depressive from non depressive Alzheimer's patients.

Methods: We included 201 Alzheimer's patients who underwent MRI and complete neuropsychological assessment, that enabled their unequivocal categorization into depressive and non depressive groups based on the Geriatric Depression Scale. We conducted whole-brain authoritative volumetric analysis using 3d high resolution T1 weighted anatomical images and applied between-group comparisons and regression analysis models to analyze the volumetric data.

Results: Depressive Alzheimer's patients had extensive gray matter volume loss mainly in the paracentral region, specifically in the post-and pre-central gyrus, the supplementary motor areas and the thalamus compared to non depressive Alzheimer's patients. Similar findings were observed using regression analysis; gray matter loss in the post-and pre-central gyrus, the supplementary motor areas and the thalamus was correlated with the Geriatric Depression Scale score controlling for dementia severity and other relevant factors.

Interperation: We provide the first clear demonstration of a unique pattern of gray matter atrophy that characterizes Alzheimer's patients with depression who show greater gray matter loss mainly in the sensory and motor areas as well as in thalamus. This pattern is consistent with the phenomenon of psychomotor retardation that characterizes depression. Background: Strokes involving the AOP, an anatomic variant of thalamic vascular supply, are rare. In an era of directed therapeutics, such as thrombolysis and embolectomy, prompt stroke recognition greatly reduces post-stroke disability. Little is known about the clinical presentation, time to diagnosis and hospital course for patients with an AOP infarct. Further research is needed to help better guide clinicians and patients.

Design/Methods: We retrospectively identified 18 consecutive patients who underwent neuroimaging and had the keywords "artery of Percheron" in their imaging reports. After radiographic inclusion criteria were applied, 10 patients were included. A chart review then identified demographics, presenting signs/symptoms, time to diagnosis, and tPA use. Data on the severity of a patient's presentation were collected, including use of emergency medical services (EMS) before hospitalization; use of intensive care unit (ICU) services; intubation, tracheostomy or PEG tube use; length of stay (LOS); and discharge location.

Results: Of the total 10 patients, there were 5 men and 5 women, and the mean age 6SD 5 67 6 15. Mental status changes and ocular disturbances were present in all patients. Language disturbances, such as dysarthria, were the most common other neurologic finding. Seven patients used EMS prior to their hospitalizations. Time to diagnosis, from last known normal, averaged 3.9 days (range 4.25 hours to 15 days). One patient received tPA. Six patients spent time in the ICU, with an average stay of 2.1 days. Two patients were intubated during their stay. No patients required tracheostomy or PEG tube placement. The average LOS was 9 days (range 3 to 29 days). Five patients were discharged home, and five entered sub-acute/skilled nursing facilities.

Conclusions: In our study it took an average of 3.9 days to diagnose AOP infarction from the initial onset of symptoms. This may reflect the disconnect between the symptomatology of an AOP infarct and other more typical presentations of stroke. Despite relatively common EMS use, only one patient with an AOP infarct received tPA. A high level of suspicion may assist in rapidly identifying these patients for thrombolysis treatment.

Christina Canzoneri, Andrew Schroeder, Gerson Cedeno Suarez and Nicole R. Gonzales. Houston, TX Background: Eagle Syndrome is a condition characterized by elongation of the styloid process secondary to ossification of the stylohyoid ligament. The elongated styloid process (ESP) can come into contact and interfere with adjacent anatomical structures. Rarely, an ESP comes into contact with the extracranial internal carotid artery (ICA), giving rise to the "Vascular" form of Eagle Syndrome. Vascular Eagle Syndrome has been implicated as a cause of both carotid artery compression and dissection. Until recently, ESP has not been appreciated as a significant contributor to carotid artery dissection (CAD) leading to ischemic infarction and, to our knowledge, has only been reported in three previous cases. We report a rare case of CAD leading to stroke in a patient with radiographic evidence of ESP.

Design/Methods: Case Report.

Results: The case follows the course of a 55-year-old man who presented to our institution within two hours of being found unconscious at home. The patient had no past medical history and no reported trauma. He presented with left-sided weakness and hemisensory loss. The patient presented outside the window for intravenous alteplase or endovascular therapy. Imaging revealed right middle cerebral artery ischemia resulting from a right ICA dissection and right M1 embolic occlusion. CT reconstruction revealed bilaterally elongated styloid processes, measuring 50.8 mm on the right and 51.5 mm on the left. The right ICA was irregularly opacified with severe narrowing and string-like patency in close proximity to an ESP.

Conclusion: Vascular Eagle Syndrome may be an understated and potentially treatable cause of CAD leading to ischemic stroke, particularly in young patients without significant vascular risk factors. Our patient had no evidence of vascular risk factors, arteriopathy, connective tissue disorder, or recent history of a significant traumatic event; his only identifiable predisposing factor to CAD was abnormal elongation of the styloid processes bilaterally. The potential association between Eagle Syndrome and CAD may account for previously unexplained cases of spontaneous CAD, warranting further investigation into the correlation between ESP, CAD, and ischemic stroke.

Justin Long, James Giles, Lynn Zhang, Peter Kang, Laura Baldassari, Kristin Andruska (Gehrking), Carey-Ann Burnham, Craig Wilen, Beau Ances and Robert Bucelli. St Louis, MO Background: Vasculopathy due to varicella zoster virus (VZV) infection is a secondary cause of stroke in patients with zoster reactivation, with or without rash. A limited number of studies in patients with VZV vasculopathy have demonstrated significantly increased sensitivity when testing for presence of CSF anti-VZV IgG as compared to CSF VZV DNA via PCR. However, there is limited independent verification of this finding and lack of evidence as to the specificity of anti-VZV IgG antibodies in CSF of patients without VZV, most crucially in those with strokes unrelated to VZV infection.

Goal: To assess sensitivity and specificity of CSF anti-VZV IgG and CSF VZV DNA testing by PCR, both in isolation and in combination, in patients with suspected VZV vasculopathy.

Methods: We prospectively identified and collected blood and CSF specimens from 9 control subjects without stroke, 20 disease control subjects with stroke unrelated to VZV infection and 6 subjects with stroke due to suspected VZV vasculopathy (i.e. stroke either with active or recent history of zoster rash). Prior to CSF analysis, patients were assigned to these groups on clinical grounds using pre-defined criteria. Specimens were analyzed for VZV DNA copies by PCR and anti-VZV IgG and IgM levels.

Results: Among 6 patients with suspected VZV vasculopathy, 3 (50%) had CSF VZV DNA and 4 (67%) had CSF anti-VZV IgG. Among 20 patients with stroke due to other causes, 0 patients had CSF VZV DNA and 1 had CSF anti-VZV IgG. Among 9 patients without stroke, 0 had CSF VZV DNA or anti-VZV IgG. For presence of CSF VZV DNA alone, sensitivity/specificity for detection of VZV vasculopathy was 50%/100%. For presence of CSF anti-VZV IgG alone, sensitivity/specificity was 67%/97%. For presence of either CSF VZV DNA or anti-VZV IgG, sensitivity/specificity was 83%/97%. The difference in sensitivity for presence of CSF VZV DNA alone as compared to presence of either CSF VZV DNA or anti-VZV IgG was not statistically significant by McNemar test (p50.2482), although sample size for this comparison was quite small (n56).

Conclusions: The presence of either CSF VZV DNA or CSF anti-VZV IgG is highly specific for VZV vasculopathy. Sensitivity is improved by testing for both VZV PCR and anti-VZV IgG, although sample size was too small in this study to demonstrate statistical significance.

Study supported by: The Paula C. and Rodger O. Riney Fund.

Vijayalekshmi V. Nair, Wyssem Ramdani, Elena Schmidt and Julius G. Latorre. Syracuse, NY Introduction: Endovascular intervention in the treatment of CVT(cerebral venous thrombosis) is an alternative strategy in patients who deteriorate despite best medical management or develop refractory intracranial hypertension. CVT is uncommon and lack of consensus in management leads to disparities in outcome.

We present a patient with CVT due to heparin-induced thrombocytopenia(HIT) complicated with intraparenchymal hemorrhage(IPH) and refractory intracranial hypertension, who was managed with concurrent systemic anticoagulation with Argatroban, continuous intra-venous sinus infusion of rTPA and Mechanical Thrombectomy(MT) resulting in an excellent outcome.

Case Report: A 50-year-old woman with left parafalcine meningioma s/p cyberknife radiosurgery, was started on subcutaneous heparin for radiation necrosis 5 days prior to admission. She presented to the hospital with complains of new onset headaches and nausea. CT head showed increased edema with midline shift around the meningioma, for which steroids were started. Within 2 days her headaches worsened and repeat imaging demonstrated right temporal IPH. Emergent hematoma evacuation was performed. Following surgery, as part of repeat imaging MRI brain showed right cerebellar infarct and MRA head showed extensive cavernous sinus thromboses, from right internal jugular vein and into sigmoid and transverse venous sinuses. She was transferred to our hospital for further management. She tested positive for HIT and was started on Argatroban drip. Patient however continued to deteriorate with development of refractory intracranial hypertension. Intracavernous rTPA injection and MT was done with partial success but the thrombosis was noted to recur on repeat angiogram 24 hours later. An intra-sinus catheter was left in place and continuous infusion of rTPA at 1 mg/hr. for 12 hours was done while Argatroban drip was continued. The patient's intracranial pressure returned to normal. Repeat venogram showed resolution of CVT. Patient tolerated the therapies well, without any further hemorrhagic complications. Modified Rankin score at 6 month follow up was 1.

Conclusion: This case features successful aggressive endovascular interventions including in-situ rTPA infusion and MT in addition to concomitant systemic anticoagulation for CVT due to HIT, complicated by intracranial hemorrhage and refractory intracranial hypertension. The paucity of high quality evidence related to safety, efficacy and modality of endovascular treatment lead to making therapeutic decision on individual basis. Further study is needed to determine the timing of endovascular intervention, the duration of in-situ fibrinolysis and safety of combined systemic and in-situ anticoagulation.

Yuan Ye Beh, Bonnie Breining, Rajani Sebastian, Sadhvi Saxena, Amy Wright, Donna Tippett and Argye Hillis. Aberdeen, United Kingdom and Baltimore, MD Background: Impaired naming is the most common poststroke language disorder. Previous research has shown that damage to left inferior frontal gyrus, posterior superior temporal gyrus (pSTG) and posterior middle/inferior temporal gyrus are critical for naming. In this longitudinal study, we investigated naming recovery by identifying i) areas of the brain damage responsible for low naming ability immediately after stroke and whether ii) different/additional areas of damage are associated with persistent low naming scores at 4 27 months post-stroke.

Methods: We included 19 patients with acute left hemispheric ischemic stroke, who were enrolled within 48 hours of symptom onset and returned for follow-up 4-7 months later. All participants had MRI with DWI acutely and naming evaluations at both acute and chronic (4 -7 months) time points. None had recurrent stroke in the interim. Boston Naming Test was used to quantify naming ability. We performed atlas-based lesion-symptom mapping using the MRIcron software and MATLAB to associate damaged brain regions with naming scores. Of the 189 regions of interest on the JHU atlas, 9 were considered in our analysis. Analysis was run using the general linear model (least squares' linear regression), corrected for lesion volumes and multiple comparisons (Bonferroni correction) at a level of significance of 0.05.

Results: No region was associated with lower naming scores at acute time point after controlling for lesion volume and corrected for multiple comparisons. Two regions, when damaged acutely, were associated with impaired naming at 4-7 months: left pSTG (Z5 22.540) and superior longitudinal fasciculus (SLF; Z5 22.660).

Discussion/Conclusion: Findings are consistent with those from previous studies regarding the importance of pSTG in naming. Further, a lesioned SLF acutely is associated with long-term naming deficits (i.e., failure to recover naming). This suggests that both regions, when damaged acutely, contribute to naming recovery. As they are only associated with low naming scores at 4-7 months, but not acutely, this could mean that they independently/synergistically contribute to naming deterioration, or failure to improve, from acute to chronic stage (4 patients had worse naming at 4 27 months). Naming involves many cognitive processes and SLF and pSTG have been proposed to be part of language pathways. Results show that grey matter regions, as well as the status of white matter tracts (e.g. SLF) that connect components of language cortex can influence language recovery in stroke survivors. Introduction: Intracerebral hemorrhage (ICH) is the second most common cause of stroke and one of the leading causes of death and disability worldwide. There are multiple ICH scores for prediction of 30 day mortality in those with spontaneous ICH, but limited studies evaluating the predictive values of these various scores or comparing their accuracy.

Methods: 354 Patients presenting to our stroke center over a four year period with spontaneous ICH, confirmed with neuroimaging, were evaluated retrospectively. Patients who were alive at hospital discharge and did not have a recorded date of death were assumed to be alive at 30 days, and patients discharged to hospice were considered deceased. Subjects were rated using established ICH scoring systems: original ICH score (oICH), original modified ICH (MICH), modified ICH A (mICH-A), modified ICH B (mICH-B), ICH grading scale (ICH-GS) and Essen ICH (ICH-E). Correlation analysis was used to assess the relationship between 30-day mortality and each of the ICH scores. The ROC (receiver operating characteristics) was used and AUC (areas under curve) was calculate for each ICH score using 30-day mortality as the binary outcome measure to estimate the discrimination of each ICH score.

Results: The overall 30-day mortality was 35.9% (127 of 354). The Spearman correlation coefficients between mortality and oICH, MICH, mICH-A, mICH-B, ICH-GS and ICH-E were 0.643, 0.612, 0.673, 0.675, 0.658, and 0.625, respectively. All P values were <0.001. All ICH scores significantly predicted the 30-day mortality with the AUC of 0.878, 0.861, 0.901, 0.902, 0.890, and 0.874 for oICH, MICH, mICH-A, mICH-B, ICH-GS and ICH-E. All P values were <0.001.

Conclusion: The mICH-B and mICH-A scores are the most predictive of 30-day mortality based on our data, followed by ICH-GS, oICH, ICH-E and MICH. Objective: This study summarizes intracerebral hemorrhage (ICH) volumes and patient characteristics among cases of deep, lobar, cerebellar, and brainstem ICH in a populationbased study.

Methods: Genetic and Environmental Risk Factors for Hemorrhagic Stroke (GERFHS III) was a population-based study of spontaneous ICH among residents of the fivecounty Greater Cincinnati/Northern Kentucky region from July 2008 through December 2012. Information regarding subjects' history of hypertension, diabetes, hypercholesterolemia, frequent alcohol use, smoking, and anticoagulant or antiplatelet use was collected from the hospital charts. Initial non-contrast computed axial tomography images of the head were reviewed; the presence of intraventricular hemorrhage (IVH) was determined; and ICH volumes were calculated using the ABC/2 formula.

Results: There were 1082 cases of ICH among white (76.1%) and black (23.9%) residents of the study region during the study period. Among these cases, 51.4% were female, 81% had history of hypertension, 24.4% had diabetes, 37.4% had hypercholesterolemia, 12% used alcohol frequently (>2 servings per day, or noted on hospital chart as heavy drinker), 43.5% had history of smoking (19.8% current smokers and 23.7% former smokers), 19.2% were taking anticoagulants, and 41.5% were taking antiplatelet agents. In terms of ICH location, 495 hemorrhages were deep, 418 were lobar, 101 were cerebellar, and 68 were in the brainstem. The median volumes of ICH varied by location: 9.9 cubic centimeters for deep ICH, 28.9 for lobar, 10.9 for cerebellum, and 3.5 for brainstem. The median volume of all ICH was 14.2 cubic centimeters, with interquartile range of 4.0 to 44.9. Lobar cases tended to be older (mean574.9 years) than deep, cerebellar, or brainstem cases (67.7, 70.5 and 65.0 years, respectively, p < 0.0001). White cases tended to be older (mean573.5 years) than black cases (mean561.4 years). Intraventricular extension of hemorrhage was present in 51.7% of deep, 36.8% of lobar, 46.5% of cerebellar, and 42.6% of brainstem cases.

Conclusions: ICH volume was largest in lobar hemorrhages, followed by cerebellum, deep, and brainstem. Patients with lobar hemorrhages were older, likely due to the different mechanisms of hemorrhage. Further analyses could investigate the prognostic implications of patient characteristics, mechanism of hemorrhage, and ICH features. To our knowledge, there has not previously been a populationbased study to determine the average volume and range of ICH.

Zafer Keser, Gerson Suarez-Cedeno, Ram Saha, Quynh Huong V. Pham, Amanda Jagolino and Tzu-Ching Wu. Houston, TX Background: VZV vasculopathy in immunocompetent or immunocompromised individuals can be unifocal or multifocal involving likely both anterior and posterior circulations in the brain. It can cause ischemic stroke, subarachnoid and intracranial hemorrhages, and carotid dissection in central nervous system (CNS).

Methods: Single Case Report Results: We report a 65 year-old immunocompetent female with past medical history of hypothyroidism, anxiety, depression, who presented with two day of generalized weakness accompanied with new onset thunderclap headache for a week. She just returned from cruise trip to South America and she had non-specific neck/shoulder pain prior to her presenting symptoms. At the presentation, she was afebrile, non-toxic appearing with normal alertness and orientation, had 4-/5 proximal left lower extremity, 4/5 right upper extremity proximal and distal weakness with normal skin exam. We performed head computerized tomography (CT) which was unremarkable, head and neck CT angiography positive for diffuse narrowing in both anterior and posterior circulations. Her magnetic resonance imaging (MRI) of the brain was positive for bilateral anterior cerebral artery (ACA)-middle cerebral artery (MCA) and MCA-posterior cerebral artery watershed infarcts in the gray-white junction without any gadolinum enhancement. At that point, RCVS was our working diagnosis given the presentation and imaging however we performed LP to rule out infectious, inflammatory, malignant causes of CNS vasculopathy. Initial and repeat LP results were suggestive of bacterial/fungal meningitis; RBC in 7500s(non-traumatic), WBC 300s(70% neutrophil dominant), glucose 30s(mg/dl), protein:300s(mg/dl), however only VZV PCR was positive; bacterial and fungal cultures and the rest of viral studies were negative. Of note the patient had serum VZV IgG and IgM were positive. The patient was put on acyclovir intravenously for 14 days with improvement of her symptoms.

Conclusion: Patients' non-toxic appearance with no signs of infection might be falsely reassuring for patients presenting with CNS vasculopathy and RCVS can be diagnosed prematurely. Our case raises awareness of the need of CSF studies to rule out an underlying infectious etiology in these cases. Also our case is unique due to VZV meningitis presenting with a CSF profile similar to bacterial/fungal meningitis. In case of abnormality in CSF profile, patients with intracranial diffuse vasculopathy should be treated empirically until for VZV CSF studies have been completed. Additionally as in our case, previous studies revealed that not all patients with VZV vasculopathy have a history of zoster or varicella rash.

Marina Yu Khodanovich, Alena A. Kisel, Andrey E. Akulov, Dmitriy N. Atochin and Vasily L. Yarnykh. Tomsk, Russian Federation; Seattle, WA and Novosibirsk, Russian Federation Introduction: Myelin damage in ischemic stroke has attracted a significant interest over past decade. It is commonly recognized that demyelination occurs in both white and gray matter after ischemic injury due to apoptosis of oligodendrocytes. A recently developed quantitative MRI method, fast macromolecular proton fraction (MPF) mapping has shown a promise as a quantitative biomarker of myelin in human and animal studies.

Purpose: Histologically validate the accuracy of MPFbased myelin density measurements in the rat stroke model.

Methods: 15 Sprague-Dawley rats were used in experiments. Stroke was induced by the middle cerebral artery occlusion (MCAO) during 1 hour followed by reperfusion. MPF mapping and histological processing were performed at three time points after surgery: 1 day (n55), 3 days (n55), and 10 days (n55). MPF maps were obtained using the single-point synthetic reference method on a Bruker BioSpec 11.7T small-animal MRI scanner. Brain sections were stained histologically using Luxol Fast Blue (LFB) for myelin quantification in the ischemic lesion. The differences between the ischemic lesion and contralateral hemisphere in MPF and LFB optical density (OD) were assessed using paired t-test. Relationships between MPF and histology were examined using the Pearson's correlation coefficient (r).

Results: Absolute values of MPF and LFB OD were significantly reduced (P<0.05) in the ischemic lesion on days 1, 3 and 10 after surgery as compared to the anatomically symmetrical regions of the contralateral hemisphere. A percentage decrease of LFB OD relative to the contralateral hemisphere on the 10th day was significantly larger (around 35%, P<0.05) as compared to the 1st and 3rd days (15-20%). Percentage decrease of MPF was similar to LFB OD on the 3rd and 10th days but larger on the 1st day (around 30%). The values of percentage decrease in LFB OD and MPF were strongly correlated across all animal groups (r50.81, P<0.001). Comparison of dynamic changes in MPF and LFB confirms that demyelination is a major determinant of the MPF decrease, though an additional reduction of MPF in acute stroke may be associated with edema.

Conclusions: Demyelination is detectable in the acute phase of ischemic stroke by both MPF and histology. Quantitative estimates of the myelin loss by MPF in acute stroke may be confounded by edema. In the chronic stroke phase, MPF provides a reliable quantitative marker of demyelination.

Grant support: Russian Science Foundation (project @ 14-45-00040).

Background: Hypertension, diabetes and smoking are known risk factors for vascular disorders and are commonly present in coronary artery disease (CAD). CAD is associated with an increased likelihood of cognitive impairment, including impairments in memory, processing speed and executive function. This study aimed to assess associations between vascular risk factors and cognitive performance in a CAD population.

Methods: Participants were recruited from the University Health Network Toronto Rehabilitation Institute. Cognition was assessed using a battery of neuropsychological tests including the California Verbal Learning Test, Brief Visuospatial Memory Test (BVMT), Stroop test, Trail-Making Tests A and B, Digit-Symbol Substitution Test, Controlled Oral Word Association Test and Animal Naming Test. Presence of hypertension, diabetes and smoking history were obtained through patient interviews.

Results: 83 CAD patients (71.1% male, mean (SD) age 5 62.8 (11.1)), were included in the analyses. In a linear regression model (controlling for age, sex and total years of education), hypertension, diabetes and smoking history accounted for 31% of the variance in BVMT total recall scores (p 5 0.00007) and diabetes was independently associated with lower BVMT scores (b 5 20.297, p 5 0.004). In the same model, the three vascular risk factors accounted for 25% of the variance in digit symbol substitution test score (p 5 0.001) and diabetes was associated with lower digit symbol scores (b 5 20.220, p 5 0.037).

Conclusion: The presence of vascular risk factors are associated with poorer scores on tests of executive function and visuospatial memory in a CAD population. Diabetes was most strongly associated with lower scores on both tests compared to hypertension and smoking history. Early prevention and detection of these risk factors may aid in improving cognition, as well as decrease the incidence of vascular disorders in this population.

Mona N. Bahouth, Argye E. Hillis and Rebecca F. Gottesman. Baltimore, MD Background: Accumulating evidence suggests that hydration at the time of stroke may impact functional outcome. We sought to investigate the relationship between blood pressure, hydration status, and stroke severity in a population of acute ischemic stroke patients.

Methods: In this observational study, we recruited acute ischemic stroke patients from a single, comprehensive stroke center. Subjects were studied within 12 hours from onset of ischemic stroke confirmed by MRI. Patients with renal disease or active infection at the time of stroke were excluded. Hydration status was determined by BUN/creatinine ratio, as in prior studies, with a volume contracted state defined as BUN/creatinine ratio >15. Mean arterial pressure (MAP) was calculated based on initial blood pressure measurement and analyzed as a nonlinear continuous variable using a linear spline with a knot at 90 mmHg. Baseline stroke severity was defined by admission NIH Stroke Scale scores (NIHSSS). To investigate the relationship between hydration status and blood pressure at the time of stroke, we used linear regression models, adjusted for potential confounders (age, sex, atrial fibrillation, diabetes), evaluating the effect of MAP on baseline NIHSSS, and considered models stratified by hydration status, along with formal testing for interaction between MAP and hydration status.

Results: Of the 109 subjects recruited, 56 (51%) were in a volume contracted state at the time of presentation. In adjusted models, in the total sample, for every 10 mmHg higher MAP up to 90mmHg, NIHSSS was 4.2 points lower (p50.01), without further statistically significant association between MAP above 90 and NIHSSS. This relationship was entirely driven by volume contracted individuals: MAP was not associated with NIHSSS in individuals who were euvolemic. For individuals in a volume contracted state, however, each 10 mmHg higher MAP, up to 90 mmHg, was associated with 9.1 points lower NIHSSS (95% CI 4.9, 13.3). The formal test for interaction between MAP and dehydration status for MAP values below 90 mmHg was statistically significant (p50.001), although there was no difference statistically in dehydrated versus euvolemic patients in the relation between MAP and NIHSSS at MAP values above 90 mmHg.

Conclusions: Lower MAP contributes to more severe stroke in patients who are volume contracted but not those who are euvolemic. These results suggest a potentially modifiable risk factor to improve functional outcome with a low cost, broadly available intervention like rehydration.

Sadhvi Saxena and Argye E. Hillis. Baltimore, MD Background: Hemispatial neglect is a common and disabling consequence of stroke. Some patients neglect the contralesional side of space with respect to the viewer; others neglect the contralesional side of each stimulus in the view (independent of the location with respect to the viewer). There is a paucity of data on the variables that influence the risk and severity of viewer-centered (VC) and stimulus-centered (SC) neglect.

Methods: This retrospective analysis of prospectively collected data included 248 patients with a unilateral (235 right, 13 left hemisphere) acute ischemic stroke, tested within 48 hours of hospital admission on a neglect battery that included: oral reading of 30 words and 5 sentences; scene copy; horizontal line bisection (presented at midline, 458 to the left and 458 to the right of the viewer); line cancellation; and gap detection. The presence of VC and SC neglect were defined dichotomously. Severity of VC neglect was measured by percent errors on line cancellation. SC neglect severity was measured by line deviation. We evaluated the influence of age, lesion volume, sex, handedness, and hemisphere on the risk of each type of neglect with logistic regression, and evaluated the influence of age and lesion volume on severity of neglect with linear regression. We compared groups using ANOVA.

Results: A total of 108 patients had VC neglect; 75 had SC neglect; 50 of had both. There were no differences between groups (defined by hemisphere and handedness) in age or lesion volume. Frequency of VC neglect was significantly associated with age (p50.004) and lesion volume (p50.007). Frequency of SC neglect was marginally associated with handedness after controlling for other variables (p50.1), but was not associated with age, lesion volume, hemisphere, or sex. SC neglect was more common in left handers (42.1% vs 29.3%), but the number of left handers was small (19). Age and lesion volume were associated with severity of VC neglect (r25 0.67; p50.03) only in right handed patients with right hemisphere stroke, but only lesion volume independently predicted severity (p50.02). Neither type of neglect was more severe in left handers or right hemisphere stroke.

Conclusion: Incidence of VC and SC neglect were influenced by different variables. Risk and severity of VC neglect increased with age and lesion volume. Risk of SC neglect was marginally higher in left-handers but not influenced by age or lesion volume. Background and Purpose: False negative neuroimaging in acute posterior-fossa stroke is a known pitfall. This is particularly relevant for diagnostic decision-making in emergency department (ED) presentations of common, acute symptoms that might be due to posterior-circulation stroke (e.g., dizziness, vertigo, or headaches). Absent focal neurologic findings, neuroimaging (particularly NCCT) is often used to differentiate strokes from stroke mimics. We sought to estimate diagnostic accuracy of magnetic resonance imaging with diffusion-weighted imaging (MRI-DWI) and non-contrast computerized tomography scan (NCCT) to detect early brainstem and cerebellar infarction.

Methods: This was a systematic review with meta-analysis. We conducted a systematic literature search using Pubmed (MEDLINE) and Embase to identify articles from modern era of neuroimaging describing MRI or CT test properties (sensitivity, specificity) in patients with imaging-confirmed acute infratentorial stroke (<72 hours). Two independent raters determined eligibility for abstracts and full-text articles. Articles were rated for bias risk on primary outcomes (sensitivity/specificity) using the QUADAS-2 scoring system.

Results: Of 6083 abstracts, 186 full-text articles were reviewed and 14 articles with test property data (MRI58, NCCT55, both51) were included. Included studies were at low bias risk except in patient selection, where directional bias was mixed (some focused on minor or hyperacute strokes, potentially underestimating sensitivity; others did not routinely perform follow-up MRI-DWI, potentially overestimating sensitivity Conclusions: In current ED practice, NCCT is often used to "rule out" stroke in patients with potential posterior circulation symptoms like dizziness or vertigo. However, our results indicate that NCCT is inadequate for detecting acute posterior-fossa ischemic stroke. MRI-DWI outperforms NCCT for detecting infratentorial strokes, but false negative MRI-DWI is seen in roughly one in four brainstem strokes in the first 48 hours after stroke onset. For patients presenting acute, non-specific, potentially posterior circulation symptoms (e.g., dizziness/vertigo), providers should consider alternative diagnostic strategies shown to have higher sensitivity (e.g., eye-movement-based physiologic diagnosis). When such strategies are unavailable, high-risk patients may warrant repeat, delayed neuroimaging by MRI-DWI. Introduction: Patients with obstructive sleep apnea (OSA) have a higher burden of cardiovascular disease (CVD), including stroke. Sleep apnea severity is defined by apnea hypopnea index (AHI). We aimed to describe the associations between demographics, medical comorbidities including Charlson Comorbidity Index Score, and sleep apnea characteristics and being prescribed an optimal CVD treatment regimen in veterans with OSA treated with positive airway pressure (PAP).

Methods: We conducted a retrospective study of existing PAP users at a Veteran's Affairs Medical Center. Data were collected on demographics, current medications, medical comorbidities and sleep apnea characteristics. Medications were corroborated using the electronic medical record. Optimal CVD medication regimen was defined by prescription of antiplatelet, antihypertensive, and statin medications. Using multivariable logistic regression adjusting for demographic variables, social behaviors, medical comorbidities and sleep apnea characteristics, we explored factors associated with optimal medication prescription.

Results: The sample comprised 499 veterans (95% male, 38% Black, mean age of 58 611 years). The sample had severe OSA (AHI 40 6 31 events per hour) and had been treated for 2.0 6 2.5 years. Two hundred seventy-three veterans (55%) were prescribed an optimal medication regimen for prevention of CVD, while 226 (45%) were prescribed a suboptimal regimen. Seventy-two percent of patients with hypertension (273/379) were on an optimal regimen. Eighty-five percent of diabetics, 93% of patients with coronary disease, 95% with history of myocardial infarction, 93% of those with heart failure and 75% of those with stroke were on an optimal regimen. In adjusted logistic regression analyses, older age (OR 1.06, 95% CI 1.04-1.09), Black race (OR 1.82, 95% CI 1.13-2.91), higher BMI (OR 1.11, CI 1.07-1.17), and higher Charlson Comorbidity Index Score (OR 1.32, 95% CI 1.17-1.49) were significantly associated with being prescribed an optimal medication regimen.

Conclusions: Various factors influence the use of an optimal medication regimen for prevention or treatment of CVD in this high risk patient cohort. Charlson comorbidity index predicted likelihood of being prescribed and optimal regimen.

Background: Systemic lupus erythematosus (SLE) may affect the central and peripheral nervous system by formation of immune complexes and auto-antibodies (auto-Ab). Neuro-vascular complications of SLE may include headache, vascular cognitive impairment, immune-mediated cerebral arteritis, thrombo-embolic stroke, cortical venous sinus thrombosis, and intracerebral or subarachnoid hemorrhage. We conducted a single-center, retrospective survey of neurovascular complications of SLE admitted to a university hospital-based stroke service.

Methods: Consecutive hospital admissions and consultations were surveyed over a 5-year interval. Diagnosis of SLE followed American College of Rheumatology (ACR) criteria supplemented by laboratory studies that revealed auto-Ab to double-stranded DNA. ACR criteria and laboratory studies showing anti-cardiolipin auto-Ab supported diagnosis of anti-phospholipid Ab syndrome (APAS).

Results: Between 2012 and 2017, 10,953 cases of ischemic or hemorrhagic stroke, transient ischemic attack, or stroke mimic were admitted or consulted. Known SLE, APAS, or positive lupus anticoagulant occurred in 175 cases (1.6%). Female:male ratio favored women over men (2:1). The most common causes of stroke were aseptic brain emboli (44%), septic emboli associated with meningitis or endocarditis (22%), arteritis (11%), large-vessel vasculopathy (11%), and ischemic white matter injury (11%).

Conclusions: Lupus spectrum disorders occur commonly in hospitalized stroke patients and are associated with higher frequency of cerebral emboli caused by arterial coagulopathy or infection.

Seemant Chaturvedi, Diane L. Levine, Neeli Thati and David Pieper. Miami, FL and Detroit, MI Background: A previous systematic review found that women with diabetes mellitus were at increased risk for stroke compared to men. Within the United States, women residing in urban areas with a higher Black population have higher rates of DM compared to suburban areas with a higher White population. The quality of primary vascular disease prevention in women with DM is unclear.

Objective: To determine the utilization of various pharmacologic therapies in urban and suburban women with DM. We also assessed whether use of aspirin was done in accordance with American Diabetes Association (ADA) recommendations.

Methods: Women age 40 and above were eligible for the study. A data mining tool was used to abstract information from the medical record from five primary care practices, including internal medicine, family medicine, med-pediatrics, and geriatrics. Data pertaining to use of statins and antiplatelet medications were collected. We also obtained information related to use of estrogen in women with DM. Chi square statistics were calculated to compare urban and suburban patients.

Results: From the five practice sites, data on 1815 women were available. The overall rate of DM was 27%, with urban patients having higher rates of DM (30.0% vs. 21.8%, p<0.0001). Urban patients were also more likely to have hypertension (82% vs. 66%, p<0.001) and hyperlipidemia (52% vs. 44%, p<0.01). The use of statins across all sites was 70.6%, with no difference between urban vs. suburban patients (70.8% vs. 69.9%). Urban diabetics were more likely to be treated with aspirin (57.8% vs. 41.5%, p50.002). The rate of estrogen use in diabetics was 5.1%. For patients with an ADA recommendation to take aspirin, the rate of aspirin use 57.8%.

Conclusions: This study shows that across a variety of primary care locations, the use of statins and aspirin for women with DM was suboptimal. Aspirin prophylaxis was used less commonly than statins, with higher rates of use in urban women. The suboptimal use of preventative therapies in women with DM could be one factor in the higher risk of stroke observed in women with DM. Given the overall greater combination of vascular risk factors in urban women, this group in particular should receive more vigorous primary stroke prevention.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Grant support: Boehringer-Ingelheim Levetiracetam(LEV), a second generation antiepileptic drug, is structurally related to the neuroprotective pyrrolidone compound, picaretam. It is well known that NMDA antagonist have not only antiepileptogenic effects, but effect against deuronal death associated with cerebral ischemia. There are a few animal studies about LEV and its neuroprotective effects in brain ischemia induced by middle cerebral artery cocclusion(MCAO) or neonatal hypoxia, but because these studies inject LEV before ischemic insult, it is difficult to apply the result in clinical setting. In this study, we hypothesized that LEV injected after ischemic insult also showed neuroprotective effect in MCA occlusion animal model.

All the experiments were performed in 6-week old. Male, Spraque Dawley rats weighing 200g. Rats were anesthetized with ketamine (30mg/kg) xylazine (4mg/kg) intraperitoneal injection. Neurovascular bundle of the neck was exposed through a ventral midline incision of the neck and extracarotid and pterygopalatine arteries were ligated with a 4-0 silk suture. 3-0 nylon monofilament was introduced in the internal carotid through an arteriectomy near the carotid bifurcation. The length of filament introduced in the carotid was 15mm. LEV (50mg/kg) was administered i.p. 60 minutes after occlusion. To allow reperfusion, the occluder was gently retracted 90 minutes after its insertion. All the brains was TTC stained 72 hours after ischemic insult. The surface areas of the slice and ischemic lesion were measured using the image analysis software Image J in all the slices.

In LEV injected group, the percentage of infarcted brain was similar to saline injected group (23.8%65.0 and 19.0%613.2 of the whole brain, n55 in saline group, n56 in LEV group, p50.432). We found that LEV injection after ischemic insult doesn't show any neuroprotective effect in MCA occlusion model. Previous experiments with cerebral ischemia model have shown that LEV before ischemia reduce infarction size, but after the ischemic insult couldn't reduce infarction. Pharmacokinetics of LEV and decreased perfusion status after MCA occlusion could lower the LEV concentration of infarcted area, prevent LEV neuroprotective effect. Background: Lowering systolic blood pressure (SBP) below 140 mm Hg is a clinical recommendation to reduce the risk of cardiovascular events, such as stroke and myocardial infarction (MI). Intensive intervention to lower SBP below 120 mm Hg resulted in reductions in both fatal and nonfatal cardiovascular events as well as mortality in the Systolic Blood Pressure Intervention Trial (SPRINT). However, this study reported higher rates of hypotension in the target group for SBP < 120 mm Hg, which could have resulted in decreased cerebral perfusion pressure and increased stroke risk. Using the SPRINT data, we investigated whether stroke and syncope risk was affected by changes in mean arterial pressure (MAP) and pulse pressure (PP).

Methods: Blood pressure measurements from 8,844 participants enrolled in the SPRINT study were analyzed. MAP [DBP1(SBP-DBP)/3] and PP (SBP-DBP) values were derived from SBP and diastolic blood pressure (DBP) measurements. The lowest MAP and PP values across the followup period for each participant were used in the analyses. Data from participants who withdrew consent were excluded. The risk of stroke and syncope was modeled with survival analysis, taking account of competing risk of death and the time-varying effect of MI and heart failure (HF), non-MI cardiac events, and hypotension events. The models were also adjusted for race, age, gender, intensive treatment assignment, statin use, and history of bradycardia events.

Results: There were 132 stroke cases (1.49%) and 187 syncope cases (2.1%) over a median follow-up of 3.26 years. The mean minimal MAP was 78.21 mm Hg and mean minimal PP was 45.10 mm Hg. Although there was an increased risk for hypotension and syncope with lower MAP and PP, neither increased the stroke risk. With every 5 mm Hg increase in MAP or PP, the stroke risk increased about 31% [adjusted hazard ratio (HR): 1.31, 95% confidence interval (CI): 1.18-1.45] and 30% (HR: 1.30, 95%CI: 1.19-1.42), respectively. Additionally, we observed a 39% (HR:1.39, 95% CI: 1.27-1.51) and 14% (HR: 1.14, 95% CI: 1.06-1.23) increase in syncope risk with every 5 mm Hg increase in MAP and PP, respectively.

Conclusion: Intensive SBP lowering does not increase risk of stroke in hypertensive patients even in the setting of lower MAP and PP values.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? I receive royalties as the editor of a book on mild traumatic brain injury and a book on teleneurology. I own stock in Illumina, Biogen, and Amgen.

Bakhtier Nurmukhamedov, Vishal Shah, Aiga Rakhesh, Elena Schmidt and Antonio Culebras. Syracuse, NY Introduction: Pourfour du Petit syndrome (PdP) is an extraordinarily unusual clinical condition produced by oculosympathetic hyperactivity. Typically it is characterized by the unilateral appearance of mydriasis, lid retraction and exophthalmos. It is named after a French anatomist and ophthalmologist who was also the first one to identify clinical symptoms of what is now known as Horner's Syndrome. He noticed that soldiers who had suffered head wounds sometimes manifested symptoms of sympathetic hyperactivity in ocular system and upper extremity which is known as PdP. Typically, PdP occurs following irritative cervical injury/irritative compression of the sympathetic fibers. We describe a case which suggest similar symptoms in the setting of a basilar artery stroke whereby loss of parasympathetic response led to PDP syndrome.

Case Report: Patient was a 70 year old female who presented to hospital after being found unresponsive by staff at rehabilitation facility. Neurologic exam was significant for obtunded patient with bilateral ptosis, unreactive pupils with intact brain stem reflexes and withdrawing to painful stimulus. MRI brain revealed acute infarcts in bilateral thalami with extension to the cerebral peduncles and central midbrain along with right cerebellum and right occipital lobe. Patient was managed with appropriate medical care for her top of the basilar artery symptom presentation. During hospital stay, she was noticed developing symptoms of sympathetic storming. This was particularly vivid on physical stimulation-the patient had episodes of dilatation of bilateral pupils along with hyperhidrosis and agitation with upper extremity movements. These episodes of sympathetic storming were controlled with addition of clonidine with good outcome.

Discussion: PdP syndrome has previously described in injuries to cervical sympathetic chain and brachial plexus, post-traumatic syringomyelia, aortic malformation, thoracic, esophageal and lung carcinoma and maxillofacial surgery. Our patient presented an interesting dilemma where she had bilateral complete third nerve palsy from a basilar artery stroke affecting the midbrain. She was noted to periods of sympathetic hyperactivity and this seemed to be extremely pronounced especially as the parasympathetic activity was lost due to bilateral complete third nerve palsy. Our hypothesis is that the occurrence of periods of sympathetic overactivity associated with bilateral mydriasis and hyperhidrosis is similar to picture observed with PdP syndrome albiet now being caused by a central lesion. Neurologists should be aware about PdP syndrome which is a reverse Horner's Syndrome and its etiologies to help localize the lesion. Background: Stroke remains the leading cause of disability worldwide with the only acute treatment, reperfusion, being critically time-dependent. The odds of a favorable outcome decrease with every additional minute of delay. Mobile ambulance-based telemedicine presents a novel solution to improving both the accuracy of prehospital stroke diagnosis and the timeliness of treatment. Implementation and sustainability of such innovative technology can be made difficult by the complexities of healthcare organizations, work practices and physical environments. Before implementing a new mobile prehospital telestroke program, we conducted a retrospective study to evaluate the characteristics of our prehospital acute stroke care in an urban setting.

Methods: De-identified data was obtained from a local urban EMS agency transporting suspected stroke patients to VCU Health over twelve months. Data included EMS dispatch and provider stroke protocols, suspected stroke patients' date and time stamps of the following: time of 911 Call, dispatch, ambulance/EMS arrival, initial patient contact by EMS provider, departure from scene, and arrival to hospital. Using the above de-identified data, we matched patients transported on the corresponding date and time with a discharge stroke diagnosis.

Results: From October 1, 2015 to September 30, 2016, 409 suspected stroke patients were transported to 10 local hospitals within the city limits of Richmond, Virginia. Of the 409 patients transported, 216 patients (53%) were transported to VCU Health. The average dispatch to arrival to scene was 5 minutes and 41 seconds and the average arrival to departure from scene was 18 minutes and 15 seconds. The average time from departure to hospital arrival was 10 minutes. Of the 216 prehospital suspected stroke patients, 99 (46%) had a final diagnosis of stroke with 19 patients (1%) having a final diagnosis of hemorrhage. Of the 80 patients with a final diagnosis of acute ischemic stroke, 36 (45%) received tPA and 18 (23%) received thrombectomies. The average door to needle time is 35 minutes.

Conclusion: Prior to implementation of a mobile prehospital stroke program, a strong collaboration with local EMS agencies and training will need to occur to prevent exhaust of the system and improve sustainability. There is adequate time during transport to conduct a mobile telestroke rapid stroke assessment via the NIH stroke scale. Mobile prehospital telestroke can potentially improve prehospital stroke diagnosis.

Vermian Stroke Due to Vertebral Dissection in a Patient with Factor VIII Deficiency Vaibhav Goswami, Kriti Gupta, Zachary A. Gray, Sudeep K. Rajpoot, Michael Tenner and Brij S. Ahluwalia. Valhalla, NY Introduction: Chiropractic manipulation of the cervical spine is an established cause of craniocervical arterial dissection. They account for up to 20% of strokes in patients younger than 45 years of age, who are five times more likely than other age groups to have neck manipulation performed within 30 days prior. 55% of patients present with symptoms associated with vertebral dissection within 12 hours of neck manipulation. In a prospective study, Albuquerque et al. reported 13 patients with symptoms of vertebral artery dissection due to chiropractic manipulation. Eight of these patients presented within two days. The longest interval between manipulation and presentation was 14 days in one patient. 31% of patients were permanently disabled or died. Prolonged symptoms of vomiting approximately every hour for 24 hours associated with dizziness and balance difficulty has been described by Jaynes et al. in a 9 year old girl with a vertebral dissection and vermian stroke of unknown origin.

Case: A 34 year old woman with neck stiffness underwent chiropractic cervical spine manipulation on January 4 and 6, 2017. On January 22, 2017 she had mild a headache. Fifteen minutes later while showering, she bent down and experienced severe dizziness, unbalance and vomiting that lasted 36 hours. On January 26, 2017 she felt dizzy again and presented to the ER at an outside hospital where magnetic resonance imaging (MRI) showed a focus of restricted diffusion and T2 hyperintensity indicating an infarct in the cerebellar vermis. CT angiogram was read as hypoplastic right vertebral artery. On February 10, 2017 neurologic evaluation at our hospital was unremarkable. MRI brain with and without gadolinium on February 26, 2017 was normal. Magnetic resonance angiogram (MRA) in T1 weighted sequence showed wall hemorrhage at the site of dissection at C5-C6 level in the right vertebral artery. Retrospective review of the CTA on January 26, 2017 was found to have a dissection at the C5-C6 level. Patient's coagulopathy workup showed a factor VIII deficiency and von Willebrand disease.

Conclusion: This patient developed a delayed vermian stroke after chiropractic manipulation. Factor VIII deficiency and von Willebrand disease could have contributed to the hemorrhage at the site of the dissection. Nature and presence of vertebral dissection can be missed in a CT angiogram especially in a hypoplastic artery and MRA may be a more sensitive study. Background: Disruption of extracellular matrix integrity is associated with both intracranial aneurysm (IA) and bone fragility. In addition, both IA and osteoporosis have a female predominance and this hormonal factors are considered to affect this predominance. We aimed to evaluate the relationship between bone mineral density (BMD) and IA.

Methods: This cross-sectional study was conducted on 12,785 subjects who underwent brain magnetic resonance angiography and bone densitometry as a part of a health examination between December 2004 and November 2015. Menopausal women and men aged !50 years were assigned to an at-risk population for bone mineral loss. The BMD tertile and T scores were analyzed for comparison with the presence of IA and its characteristics.

Results: Lower BMD was associated with an increased risk of harboring IA. It was also associated with larger IA size in patients with IA. The associations were more definite in the at-risk population. A low T score (<-1 SD) was significantly associated with the presence of IA, and large and multiple aneurysms after adjusting for age, sex, and vascular risk factors. In the sex-specific analysis, a low T score was associated with increased risk of harboring IA in men and increased aneurysm size in women.

Conclusions: Bone mineral density was associated with the presence, size, and multiplicity of IA. The strength of the association between BMD and IA varies according to sex and population group (at-risk versus general population).

Causing Isolated Ptosis: Recovery After Embolization of Fistula Sara Dehbashi, Noushin Jazebi, Prashant K. Rai and Xiang Fang. Galveston, TX Introduction: Cavernous carotid aneurysm often causes diplopia due to compression of CN III, IV, and VI. Isolated CN III palsy is less common. We report a unique case of cavernous ICA aneurysm with fistulization into cavernous sinus that caused only isolated ptosis without any other extraocular muscle and papillary involvement.

Aim/Objective: Retrospective review of a case of partial CN III palsy caused by cavernous ICA aneurysm with fistulization and clinical outcome with urgent embolization of the carotid cavernous fistula.

Case Report: A 79 year old Caucasian female with past medical history of hypertension, hypothyroidism, A-fib (on warfarin), and cataract surgery presented to the local emergency room for four days history of left ptosis and constant left temporal pounding headache. There were no recently histories of head trauma or any other precipitating events. She denied retro-orbital pain, diplopia, and weight loss. On exam, she had near complete left ptosis. Her pupils were equal and reactive to light, range of eye movement was within normal limit, and there were no facial sensory deficits suggestive of intact CN IV, V, and VI function. Funduscopic exam was normal. Laboratory tests and CXR were unremarkable. Brain MRI (orbital protocol) showed a fusiform dilatation of the cavernous segment of the left ICA. Additional findings including prominent vascular channels in the left clival dural venous plexus, and enlargement of the left superior ophthalmic vein and left optic nerve sheath raised the possibility of a carotid cavernous fistula. Conventional angiogram revealed left cavernous ICA aneurysm with fistulization into the left cavernous sinus and predominant venous drainage. The patient was undergone stent-assisted coil embolization of the carotid cavernous fistula which was noted to be due to rupture of a cavernous ICA aneurysm into the left cavernous sinus. Two-months later, her left eye ptosis was almost resolved.

Conclusion: Isolated unilateral ptosis could be an only unique manifestation of cavernous ICA aneurysm with fistulization. Timely recognition of this unique presentation and initiation of appropriate work with urgent intervention could significantly ameliorate the neurological deficit associated with this vascular abnormality.

Hemorrhage and Negative CT Angiography Stan Naydin, Yasir Al Khalili and Leonel Estofan. Philadelphia, PA A 68-year-old male with sudden onset headache that started with nausea and vomiting, which resolved in 30 minutes. However, headache was severe and persisting which brought him to his primary care doctor where an outpatient MRI was done, and showed subarachnoid hemorrhage with intraventricular extension. Patients was transferred to our hospital. His physical and neurological examinations remain stable. CT scan of the head (figure 1) was done and also a CT angiography with contrast which did not show any aneurysm. Patient then underwent a catheter-based angiogram. Figure 1 shows moderate hemorrhage within the fourth ventricle and a small volume of blood in the occipital horn of the left lateral ventricle with mild obstructive hydrocephalus with dilatation of the third and lateral ventricles. There are scattered small foci of subarachnoid blood. Based on the distribution of the bleed, a PICA aneurysm was suspected which was confirmed with a catheter-based angiogram, which revealed presence of a distal right PICA aneurysm. The aneurysm was embolized successfully and patient remained in the neurological intensive care unit for monitoring. Patient examination was stable and headache subsided within days.

Distal PICA aneurysms are rare and account for less than 1% of all cerebral aneurysms.1 Surgical and endovascular treatments of PICA aneurysms are challenging due to the proximity of the brainstem and cranial nerves which limit operative working space and make microsurgical treatment technically challenging.2 The pattern of hemorrhage associated with ruptured PICA aneurysms is unique. 93% of patients presents with both IVH and hydrocephalus. 86% of patients with IVH have 4th ventricle involvement.3

In conclusion, despite the failure of CT angiography to reveal any aneurysms, the distribution of the bleed and the hydrocephalus supported by the history of the patient all pointed toward a PICA aneurysm which was diagnosed and treated by the vascular neurosurgery team. Background: A prior meta-analysis and meta-regression revealed that higher doses of transcranial direct current stimulation (tDCS) have a better post-stroke upper-extremity motor recovery. While this finding suggests that currents greater than the typically used 2 mA may be more efficacious, the safety and tolerability of higher currents have not been systematically assessed in stroke patients. We aim to assess the safety and tolerability of single session of up to 4 mA current in stroke patients. Methods: We adapted a traditional 3 1 3 study design with a current escalation schedule of 1 > 2>2.5 > 3>3.5 > 4 mA for this tDCS safety study. We administered one 30-min session of bihemispheric montage tDCS and simultaneous customary occupational therapy to patients with first-ever ischemic stroke. We assessed safety with pre-defined stopping rules(clinical seizure; second degree skin burn; brain ischemia; discontinuation from the study due to any reason above) and investigated tolerability through a questionnaire. Additionally, we monitored body resistance and skin temperature in real-time at the electrode contact site. Results: Eighteen patients completed the study. The current was escalated to 4 mA without meeting the pre-defined stopping rules or causing any major safety concern. 50% of patients experienced transient skin redness without injury. No rise in temperature (range: 26 235 C) was noted and skin barrier function remained intact (i.e. body resistance >1 kX). Conclusion: Our phase I safety study supports that single session of bihemispheric tDCS with current up to 4 mA is safe and tolerable in chronic stroke patients. A phase II study to further test the safety and preliminary efficacy with multi-session tDCS at 4 mA (as compared with lower current and sham stimulation) is a logical next step. (ClinicalTrials.gov Identifier: NCT02763826).

Ansley Stanfill, Brandon Baughman, Adam Arthur, Ryan Foley, Tyler Speaks, Beth Piraino and Lucas Elijovich.

Introduction: Aneurysmal subarachnoid hemorrhage (aSAH) carries high mortality and disability rates; however, little large-scale follow-up is available to examine the union of clinical, demographic, and social variables that could impact long-term mortality outcomes for this population.

Methods: This study is a retrospective data review from a neurosurgical clinic EMR and the matching death certificates of aSAH patients (selected by ICD-9 code) seen from 2004-2016. Additional patient baseline characteristics and treatment-related variables were collected, including admission Glasgow Coma Scale (GCS), Fisher Group Score (FGS), Hunt and Hess Grade (HHG), side and vascular site of aneurysm, treatment method, marital status, smoking history, education, and employment status. Mortality data were collected at 1 and 3 months post aSAH admission. Variables were independently analyzed for significant (p 0.05) associations with mortality outcomes at 1 and 3 months post aSAH using correlations, chi squares, and ANOVA as appropriate. Variables found to meet the significance threshold were then analyzed for multicollinearity, and variables with a vif<10 were removed before placing in a backwards multiple regression model.

Results: These patients (N51,412) were 55 (614.6) years old, 54.7% Caucasian, 43.2% African American, and 65% female. Higher mortality rates at 1 and 3 months were independently associated with African American race, female gender, treatment by aneurysmal clipping, and higher admission GCS, HHG, and FGS (p 0.05). More highly educated patients experienced lower mortality rates at both time points (p< 0.00001), as did those that were employed at the time of aSAH (p<0.04). Age at time of aSAH, side and vascular site of aneurysm, and smoking history were not found to impact mortality at 1 and 3 months for this population. A model built using the significant characteristics above found that African American race, female gender, and higher HHG at admission were predictive of 1 (R 2 522.1, p55.049 x 10 215 ) and 3 month mortality (R 2 524.7, p53.714 x 10 214 ) for this sample.

Conclusions: This work demonstrates that social factors such as race, gender, educational status, and employment status should be included in addition to clinical variables in a comprehensive predictive model of mortality post aSAH. X-linked adrenoleukodystrophy (ALD) is a debilitating neurological disorder caused by mutations in the peroxisomal half transporter, ABCD1. ABCD1 transporters are essential for the import of very long chain fatty acids (VLCFAs) such as C26:0-CoA, C24:0-CoA, and C22:0-CoA from the cytosol. ALD patients are marked by the accumulation of VLCFAs intracellularly as well as in blood plasma. Building on our previous studies demonstrating upregulationof TGFBeta1 in human brain microvascular endothelial cells (HBMEC) following ABCD1 silencing here we studied its downstream molecular and functional contribution to endothelial permeability to inflammatory cells. Silencing of ABCD1 leads to an increase in SMAD3 phosphorylation and an approximate 2-fold increase in pSMAD3/SMAD3 ratio and downregulation of claudin-5, a brain specific tight junction protein. By comparing HBMEC to mouse brain microvascular endothelial cellls (MBMEC), we also found that MBMEC do not display ABCD1 dependent changes in TGF-b1 activation or claudin5 levels. The lipid analysis also confirmed that the expression and distribution of tight junction protein and adhesion molecules occurs even before the elevation of VLFCA in ABCD1 deficient HBMEC but not in MBMEC. A transcriptome analysis confirmed an upregulated TGF-b and extracellular matrix pathways and downregulated Nf-kB signaling pathways in HBMECs lacking ABCD1. These molecular changes corresponded with a 2 fold increase in the adhesion and 1.5 fold increase in transmigration of peripheral blood mononuclear cells (PBMCS) selectively in human ABCD1-deficient brain endothelium. Notably, medium supplementation of recombinant TGFBeta1 to MBMEC led to downregulation of Claudin5 levels. Our results strongly suggest that brain microvascular endothelial dysfunction following ABCD1 silencing is mediated by upregulation of the TGFBeta1 pathway. Cerebral white matter hyperintensity (WMH), an important marker for vascular and Alzheimer's dementia, is frequently noted in patients with chronic heart disease. However, the dynamic link underlying cardiac hemodynamics and the progression of WMH has not been elucidated. We hypothesized that chronically altered cardiac hemodynamics may have a major influence on various mechanisms of cerebral WMH progression and investigated comprehensive cardiac hemodynamic markers in relation with the severity of WMH in patients with chronic valvular heart disease. We included 232 consecutive individuals with a valvular heart disease (!1 year from the initial diagnosis) who were !50 years of age, and had undergone cardiac catheterization, echocardiography, and brain MRI as pre-surgical evaluations. Patients with a history of territorial stroke or other demonstrated CNS diseases were excluded. Cardiac catheterization parameters such as right atrial (RA) mean pressure, right ventricular mean pressure, and aortic mean pressure, and echocardiographic factors such as left ventricular ejection fraction, left ventricular mass index, and E/e' ratio were obtained. WMH burden was measured using volumetric analysis. The mean WMH volume was 5.93 6 7.14 mL, and mean RA pressure was 10.0 6 4.7 mmHg. From the catheterization data, 147 (63.4%) patients had a disease involving mitral valve, ninety-three (40.1%) involving aortic valve, thirty-seven (15.9%) involving tricuspid valve, and two (0.9%) involving pulmonary valve. In the multivariate linear regression analysis adjusting the type and mechanism of valve disease and clinical, echocardiographic, and other catheterization parameters, WMH volume was linearly associated with mean RA pressure (P<0.001), along with age (P50.023), and mean aortic pressure (P50.019). Our findings indicate that mean right atrial pressure is independently associated with the WMH volume in patients with chronic valvular heart disease. Chronically elevated mean RA pressure may influence the various pathomechanism underlying the cerebral WMH progression.

Ana G. Cristancho, Arastoo Vossough, James R. Treat, Daniel J. Licht and Jenna L. Streicher. Philadelphia and Phildelphia PHACE syndrome (posterior fossa defects, hemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities) is a constellation of findings of unknown etiology. Diagnosis of this condition requires presence of large segmental hemangioma with at least one major criteria, including posterior fossa brain anomalies (such as Dandy-Walker anomalies) or other hypoplasia or dysplasia of the mid or hind brain. Early diagnosis of this condition is critical to minimizing long term effects of these congenital abnormalities. We report nine patients with ultimate diagnosis of PHACE syndrome who had abnormal brain findings on prenatal ultrasounds. Patients were seen in our Center for Fetal Diagnosis and Treatment from 2007 to 2017. Intracranial abnormalities were characterized by fetal MRI. Electronic health records were reviewed to determine the additional evaluation for PHACE syndrome, including postnatal imaging, management, and postnatal outcomes. Fetal MRI studies were significant for unilateral cerebellar hypoplasia or cystic lesions in all patients. Other intracranial findings included asymmetric Meckel's cave and ventricular abnormalities. These findings should prompt further evaluation in utero, including fetal echocardiogram. In addition, early postnatal evaluation by Dermatology, Cardiology, Neurology, and Ophthalmology are critical for effectively managing patients with PHACE syndrome. It is now clear that aquaporin-4 (AQP-4) mediated glymphatic flow (GF) is responsible for b-amyloid clearance and GF disturbance plays a significant role in the pathogenesis of Alzheimer disease (AD). AQP-4 is known to be blocked by higher extracellular pH (acidosis) and, therefore, AQP-4 functionality and, hence, GF can be facilitated by an alkaline shift in the extracellular fluid. Guanidinoethyl sulphonate (GES) has been shown to be an effective alkaline shifter in vivo, and exhibits virtually no significant adverse effects (NeuroReport 1993; 4:1035) . Accordingly, we investigated the preventive effects of orally administered GES on senile plaque (SP) formation in transgenic APP-PS1-Tg AD model mice. Male B6SJL-Tg (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas/Mmjax AD model mice and age matched wild type (WT) mice were raised in our laboratory. AD model and WT mice were divided into two groups (experimental vs. control). Experimental mice received water containing 1% GES from 4 months of age for 12 weeks. Senile plaque (SP) formation was assessed immunohistologically using Aquacosmos (Hamamatsu Photonics) (Ann Neurol. 2016 80:554-565) . AD model experimental mice showed significantly reduced SP formation compared to control AD model mice. No adverse effects of GES were detected in either of the experimental mouse groups. The study unequivocally demonstrated that the GF facilitator GES, given orally, significantly retards SP formation. Considering that there were virtually no identifiable adverse effects of oral GES, this agent appears to be a realistic agent for AD prevention and/or treatment.

Improve and Impair Learning and Memory in Streptozotocin-Induced Rat Model of Sporadic Alzheimer's Disease Zeinab Charmchi, Mohammad Esmaeili and Behnaz Heidari. Qazvin, Islamic Republic of Iran Introduction: It is well established that benzodiazepines and their related agonists at the benzodiazepine site of GABA receptor present anxiolytic and amnesic properties, whereas b-carboline alkaloids exert anxiogenic and learningenhancing actions. The goal of the present study was to investigate the therapeutic efficacy of Norharmane (NO) as a benzodiazepine receptor inverse agonist on learning and memory of the Streptozotocin (STZ) rat model of Alzheimer's disease (AD).

Methods: Eighty male Wistar rats were divided into control, STZ, Saline, STZ1 vehicle and STZ1 NO groups. For induction of AD, rats were administered with STZ (3 mg/kg) bilaterally into the lateral ventricles. Administration of either ethanol (0.2 ml) or NO (1, 2, 3, and 4 mg/ kg, Intraperitoneal) started one weeks post-STZ injection on a daily basis for a duration of 10 days. Learning and memory performances of the rats were evaluated using Morris water maze (MWM) and shuttle-box, respectively.

Results: Escape latency was significantly increased in STZ groups compared to the control and saline groups (P<0.01). Low doses of NO (1 and 2 mg/kg) protected learning against STZ-induced impairment, whereas treatment with high doses of NO (3 and4 mg/kg) led to further learning impairment in the STZ rat model of sporadic AD. The percentage of time spent, the swimming distance in the target quadrant and the step-through latency (STL) in the STZ1 NO (2 mg/kg) group were significantly higher than those in other STZ-induced AD groups (P<0.001).

Conclusion: The findings of the present study suggest that administration of low doses of NO(1 and 2 mg/kg) improves learning and memory, whereas high doses of it (3 and 4 mg/kg) worsened both learning and memory in the STZ rat model of AD. Over the past decade there have been variable reports of decreased thicknesses of the retinal nerve fiber layer (RNFL) and/or ganglion cell layer (GCL) in Alzheimers disease (AD) and Mild Cognitive Impairment (MCI), putatively reflecting axonal loss and neuronal cell death. We explored changes in these retinal layers in subjects at high-risk for preclinical AD over 27 months, and we compared retinal cell layer volume changes to PET amyloid binding in the neocortex.

Fifty-six older adults (mean age 5 62.7 years), with subjective memory complaints and first-degree family histories of AD, were followed for 27 months. Florbetapir amyloid PET scans was obtained at 27-month time point. Neocortical PET standardized uptake value ratios (SUVr) for six regions were summed and normalized to the whole cerebellum. Participants underwent spectral-domain optical coherence tomography (SD-OCT; Heidelberg SPECTRALIS system) at baseline and 27 months. The volumes for both the RNFL and GCL were obtained separately, across the entire macular region extending 3.45 mm from the center of the fovea. Mean volumes (mm3) for each layer (right and left eyes averaged) were computed for both the baseline and the 27-month time points. The difference between these two exam time points was obtained for each subject and for each layer.

A multivariable linear regression model was performed with neocortical SUVr as a dependent variable, and retinal layer measures and age as the explanatory variables. For the RNFL, the model accounted for more than 10% of the variance (Adj R2 5 0.103, q 5 0.02) and both variables were significant. For the GCL, the model accounted for 12% of the variance (Adj R2 5 0.123, q 5 0.011) but only age was significant (q50.004), not SUVr (q50.582).

To our knowledge this is a first attempt to explore within-subjects change in retinal cell layer structures in the preclinical stage of AD. Our findings suggest that a decrease in the RNFL macular volume reflects the earliest detectable structural retinal changes to be observed in AD. Moreover, this axonal loss in the RNFL is related to neocortical amyloid-beta accumulation in very early AD. By comparison, the observed decrease in GCL volume over the same time period appears to be more strongly related to the effects of normal aging, rather than due to cortical amyloid-beta aggregation.

Mark H. Tuszynski, Krystof Bankiewicz, John Bringas, Imre Kovacs, Alan Nagahara, Jacob Koffler and Ken Kadoya. La Jolla, CA and San Francisco, CA Nervous system growth factors have extensive effects on neuronal function and survival. Brain-Derived Neurotrophic Factor (BDNF) influences the survival and function of entorhinal and hippocampal neurons in several animal models of Alzheimer's disease (AD), including transgenic mutant APP-expressing mice, aged rats and lesioned rats, and aged and lesioned primates. Accordingly, BDNF represents a potential treatment that could both reduce the rate of neuronal loss in AD and improve the function of remaining neurons. Beneficial effects of BDNF in animal models appear to occur independent of detectable alterations in beta amyloid load, representing an alternative treatment strategy to amyloid-modifying approaches under development for AD. However, BDNF does not appreciably cross the BBB, and exhibits potential off-target effects when broadly spread through the CNS; therefore it must be directly administered intracerebrally and its spread must be restricted to regions of cell degeneration. Gene therapy is one means of achieving practical and safe BDNF delivery in AD. We have now developed methods for accurate targeting and regionally-restricted AAV2-BDNF gene delivery in the non-human primate brain using real-time MRI guidance and co-infusion of the MRI contrast agent gadoteridol. AAV2-BDNF gene delivery to the entorhinal cortex and hippocampus is safe and well-tolerated in rhesus monkeys for up to 18 months. This program is on a translational path, aiming to test the hypothesis that BDNF will exhibit neuroprotective and functional-enhancing properties in AD.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Scientific Advisory Board, Acorda Therapeutics Introduction: Alzheimer's disease (AD) is a progressive brain disorder with several genetic risk factors identified. With increasing scientific advances in the ability to detect preclinical AD at earlier stages, and clinical trials targeting individuals based on genetic information before symptoms develop, engagement in genetic research is critical. Volunteers are needed for AD genetic research to help identify new approaches to prevent and treat the disease. However, relatively little is known about the public's understanding of genetic research or willingness to engage. The purpose of this study was to explore understanding and acceptance of genetic research for AD among the public.

Methods: Surveys were mailed to 1,205 individuals either actively engaged in the Alzheimer's Disease Center longitudinal program (ADC) or from an aged-matched voter registration list (VLS) of older adults in the community. Surveys included a mock AD genetic research consent form with modified Quality of Informed Consent scale. The survey also included opinion questions focusing on many aspects of genetic research including privacy concerns and use of data as well as basic demographics.

Results: 502 surveys were returned. An overwhelming majority believed it was important to participate in genetic research (92.3%) and wanted to know the details of any genetic information that could affect their risk for disease (82.4%). Older individuals, those of a minority status, and those with less than a college education scored significantly worse on the informed consent knowledge questions, p < 0.001. ADC participants were more favorable than VLS participants towards having their genetic information used more openly although they preferred single gene studies than multiple genes.

Discussion: The public recognizes the importance of genetic research and would like to learn about their own risk for developing disease. Extra efforts to bring awareness of research participation opportunities to the public should be made to capitalize on this interest. Clinical trial design should consider individuals' desire to know about their own risk factors when making decisions about disclosures. Finally, to promote diversity in research studies, educational efforts about genetic research may need to focus on older individuals, those with lower levels of education, those who are not married, and those from minority groups. Background: The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for sporadic Alzheimer's Disease (AD). It has been reported to combine with traumatic brain injury (TBI) to increase the risk of developing AD. However, the underlying mechanism(s) by which ApoE4 genotype influences the development of neurodegeneration after TBI remain elusive. Our recent findings suggest that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process.

Aim/Hypothesis: We test the hypothesis that ApoE proteins regulate changes in brain phospholipid homeostasis in response to TBI and that ApoE4-associated phospholipid dysregulation may promote development of TBI-associated amyloid and Tau pathologies.

Methods: Using well-established experimental models of human ApoE knock-in (KI) mice and a battlefield-relevant mouse model of blast-induced TBI, we investigated the effects of ApoE isoforms on brain phospholipid composition (PIP 2 ), amyloid accumulation and Tau hyper-phosphorylation (pTau) after blast-induced repetitive neurotrauma. Total 38 blast-exposed and 40 sham control male mice were used in this study. Levels of brain PIP 2 , synaptojanin 1 (synj1, the PIP 2 degrading enzyme), pTau, total Tau, Ab 40 and Ab 42 were quantitatively determined by western blot and ELISA assays. The standard analysis of variance (ANOVA) followed by post-hoc Tukey tests were used to determine group differences for multiple comparisons.

Results: ApoE3 brain PIP 2 levels are increased with reduced synj1 protein levels after blast TBI exposure, whereas ApoE4 brain PIP 2 and synj1 levels are resistant to any changes. In parallel, total Tau levels are elevated with no changes in pTau levels in ApoE3 mouse brains in response to blast TBI exposure, whereas pTau levels are increased with no changes in total Tau levels in ApoE4 blast-exposed mice. We further demonstrated that down-regulation of synj1 can reduce Tau hyper-phosphorylation in vitro, and abolish blast TBI-induced pTau elevation in ApoE4 mouse brains in vivo. We also found that the effects of synj1 reduction on ApoE4-induced Tau hyper-phosphorylation after TBI are mediated, at least partially through inactivation of glycogen synthase kinase-3b (GSK3b).

Conclusions: In mouse models, ApoE4 genotype-specific changes in brain phospholipid homeostasis in response to blast exposure contribute to ApoE4-increased susceptibility to develop AD pathology after TBI. These findings implicate dysfunction of brain phospholipid homeostasis as a mechanism for the known synergistic effects of ApoE4 genotype and TBI on the development of Tau-related neurodegenerative processes.

Synaptic Injury as Dynamic Correlates of Whole Brain and Regional Amyloid Load in a Longitudinal Study of Alzheimer's Disease Rawan Tarawneh and Juan Peng. Columbus, OH Background: While amyloid plaques and neurofibrillary tangles are early pathological substrates of Alzheimer's disease (AD), it is only after significant synaptic and neuronal loss has occurred in vulnerable brain regions that the first signs of cognitive impairment appear. Synaptic and neuronal injury is the best surrogate for disease progression and cognitive decline in AD. We here investigate associations between cerebrospinal fluid (CSF) markers of neuronal injury (visinin-like protein-1 [VILIP-1] and tau), synaptic loss (neurogranin [Ng] and SNAP-25), neuro-inflammation (YKL-40), and tau pathology (p-tau181), and estimates of whole-brain and regional amyloid deposition using florbetapir in a cross-sectional and longitudinal study of individuals with pre-symptomatic (CDR 0) and symptomatic AD (CDR 0.5-2).

Methods: Data used in the preparation of this abstract were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu and www. adni-info.org). Participants included cognitively normal controls (CDR 0, n523) and individuals with symptomatic AD (CDR 0.5-2, n542) (mean age, 77.3 years). All participants had clinical, CSF biomarker, and positron emission tomography using florbetapir (PET-florbetapir) (Avid Pharmaceuticals) assessments at baseline. A subset of individuals had longitudinal CSF biomarker and PET-florbetapir assessments (CDR 0, n519; CDR 0.5-2, n527) over follow-up. CSF biomarker and PET-florbetapir assessments were performed as described (adni.loni.usc.edu). Partial correlations and linear mixed models examined adjusted cross-sectional and longitudinal correlations, respectively, between CSF biomarkers and PET-florbetapir measures.

Results: CSF VILIP-1 (r50.39, p<0.0001), Ng (r50.41, p<0.0001), SNAP-25 (r50.32, p50.002), tau (r50.53, p<0.0001), p-tau181 (r50.47, p<0.0001), and Ab42 (r5-0.65, p<0.0001), but not YKL-40, levels correlated with whole-brain amyloid load, adjusting for age, gender, and APOE4 genotype. Similar correlations were observed between CSF biomarker levels and amyloid deposition in the frontal, cingulate, parietal, and temporal regions. In individuals with positive amyloid deposition who had follow-up PET-florbetapir assessments (CDR 0-2; n531), longitudinal changes in CSF VILIP-1 (p50.002), Ng (p50.002), SNAP-25 (p50.03), tau (p50.004), and p-tau181 (p50.001) levels predicted changes in whole-brain amyloid deposition over time (mean follow-up, 3.2 years).

Conclusion: Ongoing amyloid deposition is associated with dynamic changes in CSF markers of neuronal and synaptic injury in symptomatic and pre-symptomatic AD. These findings support the value of CSF VILIP-1, Ng, and SNAP-25 as longitudinal markers of neuronal and synaptic injury, respectively, in AD and highlight their utility as outcome measures in clinical trials of disease-modifying therapies that target amyloid pathology.

Rakez Kayed, Julia Gerson, Kathleen Farmer, Diana Castillo-Carranza and Urmi Sengupta. Galveston, TX Objectives: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by the deposition of alpha-synuclein (A-syn) and hyperphosphorylated tau (P-Tau). In addition, phosphorylated tau aggregates have been reported in all synucleinopathy mouse models suggesting a possible synergistic interaction between A-syn and tau. Increasingly, research focuses on the prefibrillar aggregates (oligomers) of various pathogenic amyloidogenic proteins that are now considered to initiate toxicity and spreading. Previous work from our lab and others has shown that oligomeric tau and a-syn accumulate in disease and in mouse models. Here we directly investigate the toxic relationship of the oligomeric species of both proteins with each other.

Methods: We have evaluated brain tissue and isolated oligomers from human and mouse tissues using biochemical and immunohistochemical analysis with novel antibodies for A-syn and tau oligomers. We investigated the toxicity in vivo and performed injections of brain-derived (BD) oligomeric and fibrillar A-syn in Tau-expressing and tau knockout mice (KO tau) mice. Finally, we targeted tau oligomers in immunotherapy in A53T mice.

Results: We found that (a) Both A-syn and tau oligomers are elevated and in disease and in A53T mice compared to age-matched controls. Tau-expressing mice are significantly impaired following application of recombinant and brainderived (BD) oligomeric A-syn when compared to tau knockout mice (KO tau), while a-syn fibril injections do not induce the same level of impairment. (b). A-syn seeded tau is more toxic and slower to form fibrils; (c) Targeting tau oligomers in mice with mutated a-syn decreases toxicity

Conclusions: Our results suggest that tau and a-syn oligomers may have a synergistic relationship, tau and A-syn interact in disease and a-syn toxicity is attenuated in the absence of tau. These studies suggest that tau and A-syn oligomeric structures represent main targets for therapeutic agents.

Mohammad Shahnawaz, Nicolas G. Mendez Dinamarca and Claudio Soto. Houston, TX Background: To date, there is no definite, sensitive and predictive laboratory test available for Alzheimer's disease (AD) and Parkinson's disease (PD) that can identify individuals well before they show clinical manifestations. The extensive and irreversible brain damage has already occurred by the time the disease is clinically diagnosed. The availability of early diagnosis of these diseases would be of utmost importance for the development of disease-modifying or preventive therapies. The central event in AD and PD is misfolding, aggregation and accumulation of amyloid beta peptide (Ab), Tau and alpha-synuclein (a-Syn). Compelling evidence suggests that misfolding and oligomerization of these proteins begins years or decades before the appearance of clinical symptoms. Most importantly, these oligomers have been found circulating in biological fluids, such as cerebrospinal fluid (CSF) and blood. Thus, detection of these circulating oligomers in biological fluids holds promise for early and specific diagnosis.

Methods: We have devised a sensitive method to detect tiny amounts of these oligomers present in the biological fluids adapting our protein misfolding cyclic amplification (PMCA) technology. PMCA has been widely used for the detection of misfolded prion protein (PrPSc) implicated in prion diseases that share similar molecular mechanisms of protein misfolding with AD and PD. PMCA exploits the functional properties of these oligomers to seed soluble monomers used as substrates thus facilitating their detection.

Results: Using CSF, PMCA amplification of Ab and a-Syn oligomers allowed us to distinguish AD patients with an overall sensitivity of 90% and specificity of 92%, whereas PD patients with 88.5% sensitivity and 96.9% specificity from control individuals affected by other neurodegenerative disorders or nondegenerative neurological diseases. Importantly, PMCA results for different PD patients correlated with the clinical severity. Furthermore, PMCA was adapted to detect oligomers in blood plasma that led us to differentiate AD patients from individuals suffering from other neurodegenerative disorders and healthy controls.

Conclusion: These findings laid the foundation towards the development of a highly sensitive and specific biochemical test for the diagnosis of AD and PD and monitoring disease progression. Introduction: Delirium is an acute, often preventable, cognitive disorder characterized by fluctuations in attention and consciousness that affects as many as 30% of elderly hospitalized patients. While screening tools have improved delirium recognition, identification of its cause is often expensive and elusive.

Objective: To identify differences in whole genome mRNA gene expression between hospitalized patients who develop delirium due to a known etiology -urinary tract infection (UTI) -from patients with delirium of an unknown etiology, as well as from patients without delirium.

Methods: Patients with or without delirium were identified on the neurology consult and inpatient services at a tertiary care hospital. Delirium was diagnosed by a board certified neurologist. Blood samples from cases and controls were obtained. Transcriptomic profiles from RNA-sequencing of peripheral blood mononuclear cells were analyzed for differential gene expression and disease-specific pathway enrichment patterns, correcting for presence of systemic inflammatory response syndrome (SIRS). Genes and pathways with significant differential activity based on Fisher exact test (p<0.05, |Z-score| >2) are reported.

Results: Thirty hospitalized patients with delirium (8 with UTI) and 21 hospitalized age-matched controls without delirium (11 with UTI) were enrolled from July 2014 through March 2015. Mean age of patients with delirium was 71 6 12 years (50% women); mean age of patients without delirium was 61 6 17 years (38% women). Patients with delirium and UTI, compared to patients with delirium but no UTI, exhibited a significant activation of interferon signaling, as well as upstream cytokines and transcription regulators. Between these two groups, there was significant inhibition of actin cytoskeleton, integrin, paxillin and glioma invasiveness signaling and upstream growth factors. For all patients with delirium, compared to patients without delirium, there was significant activation of the complement system. Among delirious patients without UTI, there was significant activation of regulation of elF4 and p7056K signaling.

Conclusions: There are differences in gene expression between patients with delirium due to UTI compared to those without UTI, as well as between patients with and without delirium. RNA sequencing may be further studied as a means of differentiating between causes of delirium, and as a tool to provide insight into the transcriptomic footprint underlying its pathophysiology.

Oligomers Through Intravenous Immunoglobulin (IVIG) Antibodies and the Anti-Inflammatory Role of Sialylated IVIG in Alzheimer's Disease Tasneem F. Hasan, Urmi Sengupta and Rakez Kayed.

Objective: To determine if intravenous immunoglobulin (IVIG) contains antibodies against neurotoxic tau oligomers and to identify the potential role of sialylated IVIG in combating toxicity and inflammation caused by tau oligomers in AD.

Background: Alzheimer's disease (AD) is one of the most common causes of dementia. Approximately 5.4 million Americans are currently diagnosed with AD, which is expected to rise to 6.7 million by 2025. The three hallmarks of AD are inflammation, senile plaques, composed of amyloid-beta protein, and neurofibrillary tangles (NFTs), comprised of hyperphosphorylated tau protein. Clinically, tau aggregation has been reported in AD, in addition to many other tauopathies such as frontotemporal dementia and Pick's disease. An intermediate form of NFT formation, known as tau oligomers, is pivotal in the pathogenesis of AD and other tauopathies, causing toxicity and degeneration of brain cells. Couple pilot studies, investigating the use of IVIG as passive immunotherapy, demonstrated promising results in AD patients.

Methods: Three IVIG preparations were used: Gamunex, Gammaguard, and Privigen. IVIG preparations were tested against tau oligomers through biochemical analysis using recombinant and brain derived tau oligomers. Tau oligomers from AD brain homogenates were immunoprecipitated using total IVIG and sialylated IVIG fractions, extracted through purification using agarose bound columns.

Results: Our results demonstrate for the first time that IVIG preparations contain antibodies detecting neurotoxic recombinant and brain derived tau oligomers. Results were confirmed using primary antibodies specific for tau oligomers and generic tau antibodies. Therefore, the limited beneficial effects of IVIG can be attributed to the presence of anti-tau antibodies, demonstrating an anti-inflammatory effect against tau oligomers, in addition to anti-amyloid antibodies.

Conclusion: IVIG is a well-known therapeutic for various autoimmune diseases. Previous studies have demonstrated the presence of anti-amyloid antibodies in IVIG. Our results demonstrate the presence of antibodies that recognize neurotoxic tau oligomers in IVIG. Apart from the presence of these antibodies, IVIG preparations demonstrate antiinflammatory effects at high doses mediated in part via the Fc receptor uptake of IgG by inflammatory cells. High doses of IVIG are required due to the limited active component present on IVIG. The Fc-sialylated IgG fraction is responsible for mediating the anti-inflammatory effect of IVIG. Thus, we propose IVIG to be a novel supplementary therapeutic agent in combating both toxicity and inflammation in AD patients.

Sara C. LaHue, Vanja C. Douglas, Teresa Kuo, Carol Conell, Vincent X. Liu, S. Andrew Josephson, Clay Angel and Kristen B. Brooks. San Francisco, CA; Oakland, CA and San Rafael, CA Introduction: Delirium is an acute change in mental status affecting more than 7 million hospitalized patients in the United States annually. While prior studies suggest an association between delirium and worse clinical outcomes, these investigations have not focused on post-discharge health care utilization.

Objective: To determine differences in health care utilization post-discharge among hospitalized patients with delirium compared to those without.

Methods: The study population included all adults at least 65 years old hospitalized from September 2010 to March 2015 at a Kaiser Permanente (KP) hospital and discharged alive. Subjects with a diagnosis of alcohol withdrawal were excluded. A hospital-wide program screened hospitalized patients for delirium using the Confusion Assessment Method (CAM) with follow-up by a staff psychiatrist for those who screened positive and required psychiatrist intervention. Patients seen by a psychiatrist with confirmed delirium were compared to patients who were hospitalized without diagnosis of delirium. Study data were derived from the KP electronic medical record, which uniquely detailed hospitalization and post-hospitalization data due to integration of insurance coverage and medical care for KP members. This study included only one hospitalization per subject. To account for differences between groups that might affect outcomes, we calculated propensity scores for delirium based on patient demographics (age, sex), and admission clinical characteristics (admission type, urgency and ward, illness classification and severity indices), for the primary analyses, which involved inverse propensity of treatment weighted (IPTW) logistic regression.

Results: The cohort included 718 delirious patients (mean age 83 6 7 years, 57% women) and 7927 non-delirious patients (mean age 77 6 8 years, 57% women). Delirium during admission was significantly (p<0.001) associated with the following outcomes: hospital readmission within 30 days of discharge (9.7% versus 3.4%; relative risk, RR, 2.9), emergency department visit within 30 days of discharge (28.1% versus 14.7%; RR 1.9), discharge to skilled nursing facility or hospice rather than home (42.6% versus 8.4%; RR 2.3), as well as death within 30 days (1.9% versus 1.3%; RR 1.4) and within one year of discharge (13.7% versus 8.6%; RR 1.6). Delirium was not associated with death during hospitalization.

Conclusion: Delirium is a significant predictor of hospital readmission and emergency department use within 30 days of discharge, as well as discharge to nursing facility and post-hospitalization mortality. Delirious patients are a vulnerable group that should be targeted to reduce post-discharge health care utilization.

Filippa Lo Cascio, Urmi Sengupta, Jiulia Gerson and Rakez Kayed. Galveston, TX Alzheimer's disease (AD) is most common neurodegenerative disorder associated with age. The amount of people living with neurodegenerative diseases continues to rise with the increasing life expectancy. Thus, finding effective prevention and therapeutic strategies is becoming extremely important. AD is one of over 18 different disorders known as tauopathies, characterized by pathological aggregation and accumulation of tau, a microtubule-associated protein.

Functional tau is important in stabilizing microtubules. However, during disease tau detaches from the microtubules and misfolds forming aggregates and inclusions such as the intracellular Neurofibrillary Tangles (NFTs). Tau oligomers are small, dynamic and soluble structures that have shown to be more toxic and efficient seeds for the propagation of pathology, compared to the large metastable NFTs. It has been demonstrated that tau oligomers manifest in different conformations, termed tau oligomeric strains. Importantly, different strains could explain how the aggregation of the same protein causes different diseases, progression rates and phenotypes, even between individuals within the same disorder. We hypothesize that small molecules able to bind and modulate tau aggregation pathways thus neutralizing their formation and toxicity and preventing the spread of pathology. Herein, we used in vitro techniques such as Western Blot and direct ELISA as well as biophysical assays to characterize tau oligomeric strains and their reactivity with tau oligomer specific polyclonal antibody T22, in the presence and absence of newly synthetized curcumin derivatives. Our data shown that curcumin related compounds are able to modulate tau aggregation pathways, thus neutralizing their formation and toxicity and preventing the progression of the pathology. The successful completion of this proposal will deliver compelling data that will move the tau field forward both in the development of novel therapeutic approaches for AD and other tauopathies. Furthermore, small molecules that target oligomeric tau strains associated with different neurodegenerative tauopathies can be used in the diagnostic field as imaging agents for the early detection of toxic tau oligomeric strains. Neurodegenerative diseases are disorders of impaired protein homeostasis. The mechanistic target of rapamycin (mTOR) plays a key role in protein homeostasis and metabolism by dictating whether a cell engages in anabolic growth and protein synthesis or catabolic protein degradation via lysosome biogenesis and autophagy. TSC1/hamartin is an upstream inhibitor of mTOR with mutations that were previously associated with juvenile-onset tuberous sclerosis (TS). TSC1 has not previously been implicated in neurodegenerative disease, although a new entity, adult-onset tuberous sclerosis associated neuropsychiatic disorder (TAND), has recently been described.

We have identified a new loss of function mutation in TSC1 in an individual presenting with the adult-onset behavioral variant frontotemporal dementia (bvFTD). The mutation segregated with family members with late-life cognitive disorders. To investigate the relevance of this link between TSC1 and bvFTD, we utilized CRISPR-Cas9 genome editing to generate a TSC11/-line of SH-SY5Y cells. These cells can be differentiated with retinoic acid into neuron-like cells. As expected, TSC11/-cells exhibited increased mTOR activity compared to controls. Interestingly, they also accumulated total tau and phospho-tau, suggesting a relatively specific impairment in tau metabolism with disrupted mTOR signaling. Neuropathological evaluation of resected temporal lobe tissue from a TSC1 mutation carrier also demonstrated increased phospho-tau without accumulation of TDP-43, alpha-synuclein, Abeta or ubiquitin.

These studies suggest that TSC1 could represent a new neurodegenerative disease gene, although additional genetic, pathological and experimental studies will be needed to definitively establish this relationship. However, this potential link between mTOR signaling and impaired tau metabolism provides a novel site of impairment in protein homeostasis that could result in a neurodegenerative tauopathy. It also suggests a potentially treatable mechanism for age-associated, tau-related neurodegeneration. Heterozygous mutations in APP, PSEN1 and PSEN2 cause autosomal dominantly inherited Alzheimer Disease (AD). Whether PSEN mutations lead to a toxic gain of function, dominant negative or loss of function leading to neurodegeneration is not well established. We previously reported a 56 year-old woman with early onset AD found to have a novel heterozygous PSEN2 2-base pair deletion leading to a frame shift and premature termination codon in exon 5 (PSEN2 115Fx). The variant is predicted to result in a truncated PS2 peptide or lead to nonsense mediated decay. Given the uniqueness of the case, pathogenicity of the mutation could not be strongly confirmed. Here we report the identification of a second and unrelated early onset AD case carrying the PSEN2 115Fx heterozygous mutation discovered during a targeted exome screen of 150 early-onset dementia cases. The subject had a maternal family history of AD, was diagnosed with dementia at age 51 and died 3 years later. Autopsy confirmed diagnosis of AD showing amyloid angiopathy, Braak Stage V, and numerous neuritic plaques. To begin to understand the pathogenic mechanism of PSEN2 115Fx in AD we assessed its expression and function in primary patient tissue. Stability of the PSEN2 115Fx transcript was measured through RNA analysis of frozen cortex and fibroblasts. To investigate the impact of mutation on PS2 protein we performed Western blot analysis on fibroblasts and lymphocytes isolated from control subjects and AD patients carrying PSEN2 115Fx or PSEN2 N141I mutations. We found that cells isolated from a PSEN2 115Fx carrier showed decreased PS2 C-terminal fragment suggesting insufficient compensation for PS2 levels by the wildtype allele. We assessed APP processing capacity of PSEN2 115Fx by measuring Ab40 in conditioned media from fibroblasts. We observed decreased Ab40 in both PSEN2 115Fx and PSEN2 N141 compared to controls, demonstrating that like PSEN2 N141I, PSEN2 115Fx results in a biochemical loss of function as measured by Ab40 extracellular release. In conclusion, we report evidence demonstrating loss of normal PS2 levels and function in the PSEN2 115Fx that strongly suggests pathogenicity of this novel mutation. Further, the biological and genetic features associated with this type of variant underscore the complexity of PSEN2 mutation mechanisms of action causing AD.

Zachary deCant, Dzintra Celmins, Jiang Qian and Earl Zimmerman. Albany, NY Introduction: This report describes a patient with a phenotype of corticobasal syndrome and frontotemporal dementia who showed Alzheimer's disease on neuropathological examination at autopsy. Alzheimer's disease is the most prevalent type of dementia affecting at least 48 million people worldwide. There are typical amnestic variants commonly seen in practice and atypical variants, with a diagnosis made only through neuropathologic confirmation. Corticobasal degeneration is another neurodegenerative disease in the group of frontotemporal tauopathies, with a four repeat isomer tauopathy on pathology. It has a clinical syndrome of extrapyramidal signs, cognitive loss, and parietal lobe function impairment, termed corticobasal syndrome because it may not always correspond to the correct pathologic diagnosis.

Case: The patient was a 74 year old woman who initially presented with two years of progressive cognitive impairment, depression, parkinsonism, and personality change. On cognitive testing, she displayed deficits involving short-term memory, executive functioning, verbal fluency, organization/ planning, and visual-spatial abilities. She was impulsive, disinhibited, and anxious, and notably abulic. Her motor exam showed axial, as well as predominantly left sided rigidity and apraxia, which progressed to an alien hand on the left. She was trialed on Aricept, but did not tolerate it due to increased anxiety and nausea. While her episodic and visualspatial memory deficits pointed to elements of typical amnestic Alzheimer's disease, her parkinsonism, apraxia, and alien hand suggested corticobasal degeneration and her disinhibition, abulia, and frontal release signs suggested frontal lobe involvement. Her MRI showed mild diffuse cortical atrophy and small vessel ischemic disease, and a PET scan was not done as the patient refused. Neuropathological exam at autopsy revealed amyloid plaques and neurofibrillary tangles severe in the amygdala and entorhinal cortex, moderately in the hippocampus and limbic system, and minimally in the neocortex, confirming the diagnosis of Alzheimer's pathology, Braak stage III-IV.

Discussion: Cognitive decline in the elderly can present as a challenging diagnosis with unclear etiology. Despite clinical presentation and history, pathologic correlates on autopsy ultimately may reveal an unexpected result. While there are a growing body of case studies showing corticobasal syndrome that later reveals Alzheimer's pathology on autopsy, this case also has elements of frontal lobe symptoms, which in some discussions are more prevalent in corticobasal degeneration pathology. The case allows practitioners to appreciate the fluidity within the spectrum of neurodegenerative disorders as well as the importance of confirming a pathological diagnosis. Rationale: There is a critical role for tau in transducing Ab-linked neurotoxicity and tau pathology is temporally and regionally-related to neurodegeneration in Alzheimer's disease (AD). Reducing the synthesis of tau should decrease all isoforms, post-translational modifications and conformational states of tau in all compartments. In mice, homozygous and hemizygous knockout of endogenous tau expression is protective against many Ab insults (Morris M, et al. Neuron 2011; 70; 410-26) . In transgenic mouse models, antisense oligonucleotide (ASO) mediated binding and degradation of human MAPT gene pre-mRNA reversed pre-existing tau pathology and seeding activity, prevented neurodegeneration and functional deficits and extended survival (DeVos SL, et al. Science Translational Medicine 9, 2017) . Based on these findings, an ASO that would bind and degrade the pre-mRNA transcribed from the MAPT gene and thereby reduce synthesis of tau protein was identified suitable for human clinical trials.

Methods: ASOs were designed and tested in cell cultures and in transgenic mice to identify the optimal drug candidate. Toxicology studies were performed in rodents and non-human primates (NHPs) to determine the candidate's safety, pharmacokinetic and pharmacodynamic profiles. The results from the toxicology studies informed the design of the early clinical program.

Results: Ionis-MAPTRx, a second generation 2'-Omethoxyethyl chimeric ASO, was documented to reduce tau expression in transgenic mice and was tested in INDenabling toxicology studies in rodents and NHPs. Intrathecal administration of the highest dose in NHPs resulted in a mean MAPT mRNA reduction of 77% in frontal cortex and 74% in hippocampus without dose-limiting side effects. The first clinical trial, Ionis-MAPTRx-CS1, is a multi-center, randomized, double-blind, placebo-controlled study assessing multiple ascending doses of intrathecally administered Ionis-MAPTRx in patients with mild AD. The study endpoints, which include CSF biomarker, neuroimaging, and clinical outcomes, serve both as safety measures and as exploratory measures of pharmacodynamic effect.

Conclusions: Ionis-MAPTRx is a potent ASO with specificity for human MAPT pre-mRNA to suppress translation of tau protein. This promising therapeutic approach for primary and secondary tauopathies is about to enter clinical investigation in patients with mild AD.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Employee of, and stock owner in, Ionis Pharmaceuticals M180. Denosumab Given Subcutaneously Twice Yearly for 1 Year was Associated with an Increase BMD of the Lumber Spine but Not Femoral Neck in Patients with Osteoporosis and Dementia Yasuhiro Yoshii and Taisuke Yatomi. Kawasaki, Kanagawa, Japan and Shinjuku-ku, Tokyo, Japan

Objective: Optimal treatment of osteoporosis for patients with dementia is not completely established. In this study, we assess the effectiveness, adherence and safety of the denosumab treatment in patients with dementia.

Background: Fracture due to falling is one of the main causes for people becoming bedridden. Fractures also lead to decrease activity of daily living, increase burden of care and increase cost of care. Since osteoporosis is common among patients with dementia, treatment of osteoporosis to prevent fractures are very important. Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kB ligand (RANKL), which blocks its binding to RANK and prevents osteoclast activation and bone resorption, and increases bone density. Denosumab given subcutaneously twice yearly is expected to have high adherence and effectiveness in the treatment of osteoporosis.

Method: We enrolled 46 patients who were already diagnosed as dementia and had a bone mineral density (BMD) young adult mean (YAM) of less than 70% at the lumber spine or femoral neck, who agreed to join this study, and we obtained written documents. Patients are newly received 60mg of denosumab twice yearly or switched to denosumab from weekly bisphosphonate. Every patients have daily alfacalcidol (vitamin D3) 0.5 microgram. We measured BMD with DEXA (dual-energy X-ray absorptiometry) before and 1 year after the treatment of denosumab. We assess the effectiveness, adherence and safety of the denosumab treatment.

Result: Denosumab increased BMD at the lumber spine from 0.86 to 0.91 (g/cm2) (p<0.001), however it did not statistically increase BMD at the neck of the femoral bone from 0.582 to 0.588 (g/cm2) (p50.55). 41 patients (89%) successfully continued denosumab for one year. Adverse events which required treatment were not detected.

Conclusion: Denosumab given subcutaneously twice yearly for 1 year was associated with an increase BMD of the lumber spine but not femoral neck in patients with osteoporosis and dementia. Introduction: Carotid disease is a significant risk factor for cerebral ischemia and has been associated with altered brain structure and cognitive decline. Here, we investigated the relationship between carotid disease and cerebral cortical thickness, and examined their association with cognition.

Methods: We assessed 554 community-dwelling elderly subjects from the Lothian Birth Cohort of 1936 (LBC1936) study with available brain MRI and carotid Doppler ultrasound studies. The relationship between carotid disease markers (carotid stenosis, intima-media thickness, pulsatility, and resistivity indexes) and cerebral cortical thickness was examined at age 73 years, controlling for extensive vascular risk factors (VRFs), including white matter disease burden, and IQ at age 11 (IQ-11). In 347 individuals, we investigated the association between carotid disease at age 73 and progression of cortical thinning between the age of 73 and 76. In addition, we determined the association between carotid stenosis and a composite measure of fluid intelligence at age 73, and employed a mediation model to examine if the relationship between carotid disease and cognition was mediated by cortical thickness alterations.

Results: A widespread negative association was identified between carotid stenosis and cerebral cortex thickness at age 73 years, independent of other carotid measures, VRFs and IQ-11. This association was not present for other carotid disease markers. The relationship between the degree of carotid stenosis at age 73 and longitudinal cortical thinning over a 3-year period was not statistically significant. Interestingly, at age 73, a negative association was noted between carotid stenosis and fluid intelligence. This appeared to be partly mediated by carotid stenosis-related cortical thinning.

Conclusion: Asymptomatic carotid stenosis is related to cortical thinning and lower fluid cognitive abilities later in life, independent of VRFs and IQ at age 11. The presence of this association in individuals with mild carotid stenosis suggests that interventions to reduce the burden of carotid disease should be considered even for individuals with milder disease.

Chelsea Sherman, Myuri Ruthirakuhan, Eleenor Abraham, Nathan Herrmann and Krista Lanctôt. Toronto, Canada

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder marked by cognitive deterioration. Nutritional status (NS) is important in those with AD, as risk of malnutrition has been found in up to 80% of individuals. Poor NS has been associated with increased cognitive, behavioural and functional impairments, as well as increased frailty and morbidity. The goal of this study is to investigate the association between NS, agitation and other neuropsychiatric symptoms in AD patients.

Methods: Patients were recruited from a clinical trial in AD patients with clinically significant agitation. Patients were dichotomized based on nutritional status into 1) normal/at risk, or 2) malnourished as defined by the Mini Nutritional Assessment Short-Form. Baseline medication history, cognitive and behavioural measures (neuropsychiatric inventory (NPI) and Cohen Mansfield Agitation Inventory (CMAI) scores) were compared between groups.

Results: To date, 28 patients (n518 normal/at risk, n59 malnourished) have been recruited (71.4% male, mean (SD) age586.9 (10.74), NPI532.7 (14.99), CMAI567.3 (18.10)). Malnourished patients had significantly greater scores on the CMAI/physical aggressive subscore (t(25)5 1.94, p50.03) and NPI irritability subscore (t(25)50.61, p50.02) and significantly lower scores on the NPI anxiety subscore (t(25)56.68, p50.02) compared to patients who had normal nutritional status/risk of malnutrition.

Conclusion: Compared to normal/at risk patients, malnourished AD patients had greater physical aggressive symptoms and irritability, but lower anxiety. Greater levels of agitation in AD patients may result in increased energy expenditure or a decrease in daily food consumption, putting patients at risk for malnutrition. Conversely, weight loss and malnutrition in AD are associated with an increased risk of falls and poorer quality of life, both of which may contribute to greater agitation and aggression. By identifying the link between NS and neuropsychiatric symptoms such as agitation, efficacious interventions may be established to manage these symptoms such that an improvement in one may benefit the other. Background: The apolipoprotein E (APOE) E4 allele is associated with an increase in Ab pathology; yet, E4 is suspected to have additional Ab-independent effects on AD pathophysiology. Here, we aimed to assess potential Abindependent effects of E4 on tau pathology using PET imaging with [18F]AV1451 and [11C]PIB.

Methods: Two cohorts were studied: i) a group of 71 cognitively normal elders (78 6 5.7yo, 23 (32%) e4 carriers), ii) a group of 44 clinically impaired PIB-positive patients (mix of patients with MCI or at the dementia stage, age 65 6 8.3yo, 24 (55%) carriers). PET data were processed using Freesurfer 5.3 and SPM12 to compute Standardized Uptake Value Ratio (SUVR) images normalized to cerebellar gray matter (PIB and AV1451). Statistical analyses were performed separately in the two cohorts, assessing both E4-related differences on global cortical uptake and conducting voxelwise analyses.

Results: In the whole cognitively normal group, E4 was associated with higher cortical PIB (Cohen's d50.94, p<0.001) but not AV1451-SUVR (d 5 0.22, p50.26). Voxelwise analyses showed that E4 was associated with higher PIB-SUVR in the entire cortex. AV1451-uptake was increased in E4 carriers in the temporal lobe, but this effect was not significant after controlling for PIB status or SUVR. In patients, the presence of the E4 allele was not associated with significant differences in global measures of AV1451 (d50.13, p50.7) or PIB-SUVR (d50.31, p50.34). Voxelwise analyses showed no difference on PIB-PET, while E4 carriers had higher AV1451-uptake in the anterior medial temporal lobe (MTL); that difference remained unchanged when controlling for PIB-SUVR. In E4-carriers patients, AV1451-uptake in the MTL was associated with lower performances in delayed recall (California Verbal Learning Test 10 min recall, rho5-.66, p<0.001; Rey figure 10 min recall, rho5-0.36, p-0.09), but not other cognitive tests (Stroop: rho50.2, p50.92).

Conclusion: In cognitively normal individuals, the effect of APOE E4 on tau pathology seems to be mediated by the effect of E4 on Ab deposition. However, when assessing amyloid-positive symptomatic AD patients, E4 was associated with increased AV1451 binding in the MTL. This suggests that, in addition to its effect of Ab pathology, E4 might influence the topographical distribution of tau pathology, and potentially the cognitive symptoms in patients. Rationale: Pathogenic mutations in Presenilin (PSEN) 1, 2 or amyloid precursor protein (APP) lead to autosomal dominant Alzheimer's disease (ADAD) by altering beta-amyloid production and deposition. Though these mutations are all highly penetrant, in vitro studies suggest that there is substantial molecular diversity in the amyloid species produced by each mutation. Using data from the Dominantly Inherited Alzheimer Network (DIAN), we examine inter-genotypic variance in the temporal pattern of amyloid burden assessed using both Pittsburgh Compound B (PiB) PET and cerebrospinal fluid (CSF) Ab42. In the context of prior literature suggesting amyloid deposition in ADAD may begin in the striatum as opposed to the cortex, intergenotypic variance in cortical mean and striatal PiB PET binding was separately assessed.

Methods: CSF Ab42 and PiB PET were assessed in 244 individuals (138 mutation carriers, 106 non-carriers, 338 visits). Fifty-four unique genotypes were categorized into groups based on the topological domain affected by the mutation. We used linear mixed-effect regression models to examine interactions between genotype and estimated years to symptom onset (EYO) and genotype, and between genotype and cortical vs. striatal amyloid burden.

Results: Significant genotype-by-EYO interactions were observed in mean cortical PiB binding. Significant genotype-by-region interactions were also observed, indicating intergenotypic variance in the balance of striatal and cortical amyloid burden. Intriguingly, significant inter-genotypic variance was not observed in CSF Ab42 in the same sample. CDR sum of boxes also did not show significant genotypeby-EYO interactions, suggesting grossly similar clinical progression across genotypes.

Conclusion: These results suggest that the nature of particular ADAD mutations can lead to differential temporal and regional patterns of amyloid burden as measured by PiB PET. The same effect was not observed in CSF Ab42, suggesting greater inter-genotypic variance in fibrillar, insoluble amyloid as compared to amyloid species measured in CSF. These results are relevant for the use of PiB PET and CSF Ab42 in ongoing ADAD prevention trials, and, more broadly, in understanding how CSF-vs. PET-based amyloid measurements may relate to AD-related cognitive decline. Background: Delirium is an underrecognized, highly morbid, potentially preventable condition among hospitalized neurological patients. Multimodal interventions have been shown to be effective at preventing delirium. Residents are in a unique position to implement these changes. Despite this, delirium is underrepresented in medical school and residency curricula.

Methods: Post-graduate year 2 (PGY-2) neurology residents in a single program underwent a 15 question online survey, including 12 multiple choice and 3 free text questions.

Results: Of the 18 neurology residents, 10 completed the survey (56% response rate). None of the residents rated their delirium knowledge as "excellent" (6/10 -"fair," 4/10 -"good"). None of the residents reported "a great deal" of delirium knowledge (9/10 -"some" knowledge). 9/10 residents reported feeling unsure about how to appropriately manage delirium at some point in their training.

All residents responded correctly that delirium extends length of stay and increases risk of falls. Most residents knew that delirium increased hospital costs (9/10) and recognized the link between delirium and increased mortality (8/10). Fewer residents correctly estimated the prevalence of delirium on stroke services to be 15-50% (6/10), knew that delirium leads to worse cognitive outcomes (7/10) and can increase the risk of nosocomial infections (5/10). 8/10 residents recognized the confusion assessment method as a validated scale used to determine a patient's delirium status.

All residents reported managing delirium on their night shifts in the 2 weeks preceding the survey (5/10 -50-75% of the time, 2/10 -75-100%, 2/10 25-50% of the time). Most residents also reported having at least one delirious patient on their service (5/10 >50% of the time).

All respondents were interested in learning more about delirium. 9/10 respondents had never completed a delirium simulation. Residents requested education around delirium prevention and management. Interestingly, when asked what service was best equipped to manage delirium, 7/10 residents said psychiatry, 3/10 said geriatrics. None said neurology.

Conclusions: Neurology residents recognize that delirium is prevalent on neurology inpatient services and report frequently managing delirious patients. They do not feel that they have gained the skills necessary to manage delirium and are motivated to learn more about it. We will discuss these findings and the simulation-based delirium curriculum that we developed in response to these concerns. Purpose: The objective was to evaluate the effects of stroke codes on neurology residents at a Comprehensive Stroke Center with the goal of describing code stroke fatigue (CSF). We hypothesize by recognizing CSF as a distinct entity; we will be able to target and reduce contributing factors to mitigate resident burnout.

Introduction: Stroke codes require the immediate cessation of the normal work routine and are considered disruptive. Neurology residents are frequently the first responder to stroke codes. Prior literature has examined burnout among physicians. Research examining the direct effects of stroke codes on residents is lacking.

Methods: Eighteen neurology residents (attending 838 stroke codes) completed an anonymous 27-item survey regarding CSF. The variables included: residents' demographic, patients' clinical information, and burnout measures (emotional-exhaustion, depersonalization and personalaccomplishment). Differences in these measures were analyzed with a partial chi-square and T-test. While controlling for confounding variables, the fractional outcome regression estimated the association between the measures.

Results: Of the eighteen residents, six moderately (33.3%), and twelve highly (66.7%) experienced burnout. More female PGY II and PGY IV residents exhibited burnout than their male counterparts. Residents who experienced high burnout reported high emotional-exhaustion, high depersonalization, and low personal-achievement. Out of the 838 stroke codes, 19.7% (n5153) were considered legitimate stroke codes. The average door-to-code time was shorter for residents who received prior EMS notifications (9.7 minutes) relative to residents who did not (14.1 minutes). The average resident-arrival-time was shorter for residents who received prior notification of a potential code stroke (arrived 6.3 minutes prior to code stroke called) compared to residents who did not (arrived 10.5 minutes after code stroke called). The regression results found PGY III (OR:9.76, q50.000), PGY IV (OR:6.94, q50.000) residents were associated with higher odds of burnout relative to PGY II.

Conclusion: CSF is a distinct entity that has an impact on residents. Senior residents are more susceptible to burnout than are junior residents, and certain characteristics of stroke codes may affect the risk of burnout. Stroke codes add stress to the resident's training. Many indeed wish that a stroke code would not be called during their shift. Further research is warranted to investigate contributing factors resulting in CSF to reduce resident burnout and dissatisfaction.

Hazem Shoirah, Achillefs Ntranos, Rachel Brandstadter, Yangbo Liu, Elisha Medina, Jamie Kwan and Stephen Krieger. New York, NY Objective: To enhance residency education by implementation of the six principles of adult learning theory (ALT) in a large academic neurology residency program.

Methods: We implemented a set of curricular interventions based on the principles of ALT; including curricular reform, increasing resident-as-teacher activities and enhancing residents' interaction.

Outcomes: Knowledge acquisition was evaluated with Residency In-service Training Examination percentiles and was compared between the cohort before and after REAL Neurology implementation, adjusting for USMLE step 1 and 2 score. Other outcomes included evaluating the impact of the program on the distribution of performance categories.

Results: 134 RITE score reports were evaluated (87 before and 47 after implementation). The mean RITE score percentile post-intervention was 11.7 points higher than pre-intervention (adjusted, longitudinal analysis: fit linear mixed model, p5<0.0001). The adjusted odds of better performance with REAL Neurology were 5.77 (ordinal logistic regression, 95% CI: 2.366-14.072).

Conclusions: To the authors' knowledge, this is the first study evaluating the efficacy and feasibility of implementation of ALT-based curricular programs in neurology education. The results show robust and sustainable benefit without imposing a financial or logistical burden on programs. REAL Neurology could serve as a model for curricular reform in other programs across sub-specialties. Projects (2006 Projects ( -2012 Rohit Das, Krithika Suresh and Cynthia Hingtgen.

Background: The Accreditation Council for Graduate Medical Education mandates scholarly activity for residents including research. There is limited evidence on the quality, characteristics and outcomes of neurology resident research projects.

Aim: We aim to report the characteristics and outcomes of 6 years of a mandatory resident research project conducted by adult and child neurology residents at Indiana University School of Medicine.

Methods: All neurology residents complete a Ross Research Project which is presented at the end of their training. We reviewed all Ross projects submitted between 2006-12. We abstracted information regarding type of study, sample size, neurology subspeciality area of the project and of the faculty mentor and finally determined using PUBMED whether the project was published.

Results: A total of 36 residents submitted projects between 2006 and 2012; 5 of these were child neurology residents. Retrospective data collection (13) and prospective data collection (11) were the most common research designs. Other designs included patient/provider surveys (7), literature reviews (4) and education (1). Sample size ranged between 4-434 (mean:65). 11 (30%) studies captured statistically significant results; 5 (13.8%) were published. The most frequent subspecialty areas were epilepsy (7), stroke (6) and neuromuscular (6). Sixteen residents (44%) went to take academic positions following residency Discussion: A review of resident research demonstrates that clinical research, whether prospective or retrospective, was the most type of research project undertaken during residency. Less than a fifth of projects were published suggesting a limited utility of these projects.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Cyberonics: Honoraria for Promotional Speakers Bureau Neurotech EEG: technical consultant

Benjamin S. Cunningham, Shanna Patterson and Stephen Krieger. New York, NY Background: Physician burnout is a significant problem in modern medicine, and neurologists show significantly higher rates of burnout compared with other specialists (1). This problem begins early in training, and burnout among neurology residents has been associated with decreased professional development (2). There is a clear need for programs which can reduce neurologist burnout, beginning at the residency phase of training, to lay the groundwork for reversing this crisis among practicing physicians. Methods: The Mental Health Comes First Program (MHC1) was developed by neurology residents as a quality improvement initiative designed to foster meaningful connections between residents, with an emphasis on previously validated topics of mindfulness, burnout, meaning in medicine, and self care (3). Each neurology resident was partnered for the duration of an academic year with two other residents (these are their MHC1-Links, one individual from each of the other two PGY levels). Monthly, each resident has a brief discussion with their two MHC1-Links. The distributed list of suggested topics for discussion focuses on the validated wellness-enhancing themes indicated above (3). Once all residents have completed the monthly program, the chain of support across the entire residency is completed. Efficacy of the program is measured using the Maslach Burnout Inventory (MBI). A baseline survey was administered at the beginning of the program, and on an ongoing basis three times annually (4) .

Results and Discussion: Formal results are forthcoming later this year. We will show data on burnout rates stratified by PGY year, season (given the potential influence of significant reduction in light exposure during the winter months in the northeastern United States), and clinical rotation. Comparison will be made to the pre-MHC1 MBI baseline. This type of burnout prevention and wellness program can be replicated across any other residency program, and also furthers the aims of the ACGME Physician Well-Being initiative (5).

References Objectives/Background: When the Renaissance brought new perspective in the study of neurology, the academic discipline of neurology and institution were established from Europe and Northern America, ever since other medical field had achieved big steps to both technique and diagnosis and made the history of neurology. In Taiwan, western medicine was not officially introduced until 1865, after that foreign communities and presbyterian missionaries worked as volunteers to build western-style hospitals and to educate for better health of Taiwanese people. The diseases and weather reports were their regular job and usually reported every 3 months or semi-annually providing the historical records.

Material and Method: Documents covered from 1865 to 1910 in the Missionary Medical Reports and Official Customer Medical Reports were reviewed, analyzed and concluded in the history of neurology in Taiwan before Japanese occupied period.

Results: These documents covered from 1865 to 1910 in the Official Customer Medical Reports and Missionary Medical Reports, the data showed that common neurological diseases and documents in details might proceed to the study of neurology later. In the beginning of 20th, senior medical missionaries helped to train the junior neurologists and published Textbook in Taiwanese language and gradually make different to the neurological practice in Taiwan, especially led the neuropsychiatric practices into psychiatry and neurology two distinct specialties.

Discussion: This study reviews the history of neurology development both in the world and Taiwan and neurological diseases documented in the late 19th till 20th century, also discusses the contribution of missionaries toward neurology in Taiwan.

Raising Awareness About Bedside Medicine Nakul Katyal and Raghav Govindarajan. Columbia, MO Background:With over reliance on technology, there has been waning interest among faculty to teach the art of Bedside Medicine(BM) to medical students.

Objective of this pilot study is to assess the perception of BM and feasibility of using historical articles in Neurology as a tool for raising awareness about importance of BM among medical students.

Methods: This is a prospective,single-blinded,scaled questionnaire study of consecutive third year medical students. A 6 item-3 factor Likert scale questionnaire was conducted at beginning of rotation. Articles were chosen by study authors and students were given a week to review. Articles were then reviewed in small groups. At the end of rotation, 3 item-3 factor Likert scale questionnaire survey was conducted.

Results: 30 participants,14 males and 16 females responded.73.3% were interested in learning BM. 76.6% responded BM was relevant to their future practice. At the end of rotation 53.3%responded positively for learning historical aspects as compared to 23.3% at beginning (p<0.01). 20% initially felt, including historical aspects in curriculum was a good idea which increased to 63.3% at end of rotation (p <0.01).

Conclusion: There is a strong interest among medical students in learning about bedside medicine.

Neurology Resident Attitudes and Self-Efficacy with Leading Stroke Codes Sara C. LaHue, Elif G. Sozman, Fern Cudlip, Denise M. Connor and Wade S. Smith. San Francisco, CA Introduction: An acute stroke is a neurological emergency involving the coordination of a multidisciplinary team of providers and the rapid determination of eligibility for timesensitive therapies. This high acuity situation can be unfamiliar and stressful for novice neurology residents, which may lead to treatment delays. We sought to incorporate simulation into our training of stroke code procedures as simulation has been shown to enhance medical knowledge and improve performance.

Objective: To determine if clinical simulation improves neurology resident levels of comfort, self-efficacy, and attitudes toward leading a stroke code.

Methods: All first-year adult neurology residents at the University of California, San Francisco (UCSF) took part in this exercise. All residents received an NINDS NIH Stroke Scale booklet and became certified on NIH Stroke Scale implementation using a video tutorial prior to the simulation. The exercise took place at the UCSF Kanbar Center for Simulation and Clinical Skills Education. We implemented one 30-minute lecture on the fundamentals of acute stroke management and a 90-minute simulation incorporating three clinical cases based on different stroke syndromes acted out by standardized patients. Residents were randomly assigned to play different roles, including neurology resident, emergency medicine resident, and family member, or completed a checklist while actively observing. Participants completed anonymous self-assessments prior to, and at the conclusion of, the activity. Numerical test scores and a 5-point Likert scale (5 -not at all, 1 -very) were analyzed with paired t-tests. Free responses were aggregated.

Results: A total of 9 first-year adult neurology residents at UCSF took part in the activity. There was a statistically significant increase in subjective level of self-efficacy as measured with a Likert scale inquiring about "level of preparedness" before and after the simulation (3.27 6 0.57 versus 3.94 6 0.63; p50.016). Prior to the exercise, all residents reported feeling "anxious,""nervous," or "scared," when "thinking about a Code Stroke," but only two expressed this concern after the simulation (p<0.001), suggesting development of a more positive attitude toward stroke codes. There was no statistically significant difference in performance on factual assessment or in subjective level of "comfort" pre-versus post-simulation (p>0.05).

Conclusion: Simulation significantly improves neurology resident self-efficacy and attitudes toward leading stroke codes. Future directions include determining whether simulation decreases time to treatment administration for novice residents.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? I do not have any disclosures, but my co-author, Dr. Wade Smith, is a consultant for Stryker for Data Safety Monitoring Board activity. Background: Ictal and interictal single photon emission computed tomography (SPECT) is a perfusion-based imaging modality that can demonstrate seizure foci based on ictal perfusion changes. The diagnostic yield of ictal SPECT can be increased by applying statistical parametric mapping (SPM) to the study. Here we demonstrate and validate a means of automated lobar localization of SPM-SPECT abnormalities using a modified version of the automated anatomic labeling (AAL) atlas.

Methods: 54 patients who had undergone SPM ictal SPECT and subsequently received intracranial EEG (iEEG) monitoring were identified, of whom 35 had SPECT studies that were considered at surgical epilepsy conference to have had localizing value. Information was abstracted from medical records pertaining to the presence and/or presumed lobar localization of abnormalities based on MRI and PET lesions, interictal and ictal scalp findings, intracranial EEG localization, and resection localization (where applicable). The lobar localization of the SPM-SPECT hyperperfusion abnormality was obtained automatically using a modified version of the AAL atlas. The 116 regions of interest (ROIs) in the AAL atlas were aggregated by their lateralization (left or right) and lobe (frontal, temporal, parietal, occipital or subcortical). White matter voxels in the atlas were aggregated with the nearest gray matter ROI. Lateralization and localization of the SPECT hyperperfusion abnormality were determined by the atlas ROI containing the greatest mean SPM SPECT intensity.

Results: In the cohort of 54 patients, automated lateralization of SPM-SPECT hyperperfusion was concordant with iEEG 69% of the time, and concordant 73% of the time with scalp EEG seizure onset. Lobar localization was concordant with iEEG 45% of the time, and concordant with scalp EEG seizure onset in 43% of cases.

Conclusions: These results provide support for the use of automated localizing techniques for SPM-SPECT. Such an approach may have a role in the multimodality evaluation of surgical epilepsy patients. Electrical brain stimulation has been used as a therapeutic intervention for some neurological disorders, including refractory epilepsy. Deep brain and vagal nerve stimulation treatments have proven effective in suppressing interictal spikes, which are transient electrographic events linked with impaired cognition in epileptic patients. Interictal spiking correlates negatively with behavioral performance in a word list memory task during both encoding and recall periods in several brain regions (Horak, Epilepsia, 2016). Electrical stimulation applied during this cognitive task could modulate interictal spiking and impact behavioral performance.

We investigated the modulatory potential of targeted electrical stimulation on interictal spiking across 97 stimulated free-recall memory task sessions collected for the Restoring Active Memory (RAM) project. We used an automated detector to identify interictal spikes in the electrocorticograms of 47 patients undergoing clinical monitoring. Spike rates were compared across matched pairs of stimulated and unstimulated segments from those sessions. Bipolar electrode pairs were most often stimulated in medial (n 5 43), superolateral (n 5 22), and inferior (n 5 14) temporal lobe structures. Stimulation frequencies were 10, 25, 50, 100, and 200 Hz. Our results suggest that a closed-loop stimulation paradigm more consistently suppresses interictal spiking than does an open-loop approach and that the modulatory effect of electrical stimulation depends on the parameters of stimulation.

Kelsey M. Smith, Paul E. Youssef, Elaine C. Wirrell and Lily C. Wong-Kisiel. Rochester, MN Background: Jeavons syndrome (JS), also known as eyelid myoclonia with or without absence (EMA), is an underreported epileptic syndrome characterized by eyelid myoclonia, eyelid-closure induced seizures or EEG paroxysms, and photosensitivity. JS commonly persists throughout a patient's lifetime and is associated with drug resistant epilepsy (DRE).

Methods: The EEG database at the Mayo Clinic in Rochester, MN was searched from January 1, 2000-December 15, 2016 using the following search terms: Jeavons, Jeavon's, eyelid myoclonia, and eyelid myoclonus. Patients were then identified who met the diagnostic criteria for Jeavons syndrome. Through a retrospective chart review process, clinical information was extracted in order to describe the clinical features, medications trialed, and response to treatment.

Results: There were 30 patients (24 females) identified who met the inclusion criteria. The mean age of seizure onset was 7.3 years old (IQR 3.9-11) with a clinical diagnosis of Jeavons syndrome not made until a mean age of 17 years old, with 4 patients never having a clinical diagnosis of Jeavons syndrome. Seizure types other than absence were noted in 22 patients. All patients had a trial of at least 1 AED, with the mean number of AEDs tried being 5.9 (IQR 4-9). Only 6 patients (20%) were managed successfully with 2 or fewer AEDs. Ethosuximide and levetiracetam were both noted to be effective monotherapy for two patients. Among the patients initiated on dietary therapy for epilepsy, >50% seizure reduction compared to baseline was achieved in 4 of 8 patients. DRE was common among the cohort. Patients with seizures other than absence and with generalized tonic-clonic seizures were more likely to have DRE.

Conclusions: These results support that Jeavons syndrome is a commonly missed or delayed diagnosis and is also frequently associated with DRE. Seizure types other than absence and generalized tonic-clonic seizures may be possible predictors for DRE among patients with JS.

Seizure-Associated Neuronal Injury Lucie Suchomelova, Jerome Niquet, Daniel Torolira, Roger Baldwin and Claude Wasterlain. West Los Angeles, CA and Los Angeles, CA Status Epilepticus (SE) is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. GABAergic drugs, the standard treatment for neonatal seizures, can have excitatory effects in the neonatal brain, by depolarizing immature neurons with low intracellular chloride. It is not known whether this could worsen seizures and their long-term consequences. GABAergic drugs appear to stop behavioral seizures, but adverse effects might occur in a subpopulation of immature neurons which have little behavioral expression at that age.

We developed a model of SE in P7 rats that resulted in high survival rates and widespread neuronal injury (Torolira et al 2016). Using this model, we studied the effect of treatment of SE with the GABAA agonists phenobarbital and midazolam. The doses used were too low to cause apoptosis by themselves (phenobarbital 10 mg/kg, midazolam 3 mg/ kg). Neuronal injury was assessed with Fluoro-Jade B (FJB), 24 hours after seizure onset. We found that treatment with either phenobarbital or midazolam significantly increased status epilepticus-associated neuronal injury in many brain regions.

In thalamus, midazolam increased the number of FJB1 cells by 128% (p<0.01), phenobarbital by 131% (p<0.001). Both midazolam and phenobarbital treatment significantly increased neuronal injury In caudate-putamen (1279%, p<0.01; 1211%, p<0.01), globus pallidus (1128%, p<0.01; 1150%, p<0.001), and substantia nigra (1350%, p<0.001; 1825%, p<0.0001) compared to untreated SE. However, only midazolam treatment increased neuronal injury in nucleus accumbens (154%, p<0.05). Phenobarbital treatment increased neuronal injury in hypothalamus and septal nuclei (1988%, p<0.0001; 1293%, p<0.001), but midazolam increased it only in septal nuclei (137%, p<0.001). Both midazolam and phenobarbital increased neuronal injury in lateral entorhinal cortex (1171%, p<0.0001; 1114%, p<0.01), but not in pyriform cortex. Neuronal injury in parietal cortex was significantly increased by midazolam (154%, p<0.05), but not phenobarbital. Hippocampus showed only mild injury, which was not altered by treatment except in ventral CA1/ Subiculum after midazolam (185%, p<0.05). In thalamus, 79 6 10% (SE 1 midazolam group) and 73 6 16% (SE 1 phenobarbital group) of FJB1 cells expressed active caspase-3a, and many of these cells had fragmented nuclei, suggesting an active and probably irreversible form of neuronal injury.

Our results suggest that more research is needed into the possible deleterious effects of GABAergic drugs on neonatal seizures and on excitotoxic neuronal injury in the immature brain.

Kapil Gururangan, Babak Razavi and Josef Parvizi. Stanford, CA Objective: Standard 18-channel scalp electroencephalography (EEG) is used to detect a wide range of cerebral pathology, from subtle asymmetries to seizures. However, its utility in emergent and resource-limited settings may be limited by delays in setup and interpretation. Past studies have investigated reduced channel configurations as screening tools, but have inferred a lower utility for these restricted montages in detecting epileptic abnormalities. The current study aims to measure the utility of reduced, 8channel montage (rm-EEG) covering the lateral hemispheres compared to full, 18-channel montage (fm-EEG) for detecting seizures and seizure-like patterns based on brief samples.

Methods: Forty-four, 15-second long samples of continuous EEG recordings were presented as both fm-EEG and rm-EEG to 23 epileptologists (from 7 institutions) and 42 medical students at Stanford University. Ten samples represented seizures or status epilepticus, 10 represented seizurelike activity (e.g., lateralized or generalized periodic epileptiform discharges), and 24 represented non-rhythmic, nonperiodic patterns as determined by agreement between 3 epileptologists. Both epileptologists and students were asked to determine whether each sample represented seizure activity (yes/no), and epileptologists were further asked to specify any and all pathological activity represented in each sample (samples of seizures judged to have seizure-like activity were scored as correct). We calculated the sensitivity and specificity of fm-EEG and rm-EEG for seizures and seizure-like activity with 95% confidence intervals [CI] .

Results Conclusion: Despite the demonstrated utility of full montage EEG, it remains difficult to employ as a screening tool for seizures or epileptiform activity, and its large number of channels may be more than sufficient to provide diagnostically important information. Our study demonstrates that a reduction from 18 to 8 channels provides highly specific information for ruling in epileptic activity, even when shown to inexperienced readers. A restricted channel configuration can significantly reduce EEG setup time, thereby expediting diagnosis and lowering health care costs.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Kapil Gururangan and Babak Razavi report no relevant financial disclosures. Josef Parvizi is the co-founder and chairman of Ceribell, an early-stage startup company that is developing a new technology to acquire EEG in the evaluation of patients with altered mental status. Introduction: In a large, multicenter genome-wide-association study (GWAS), a significant association was reported between an intronic variant (rs7587026) at the sodium channel gene, SCN1A, and mesial temporal lobe epilepsy with hippocampal sclerosis and febrile seizures [(MTLE1HS1FS); odd ratio (95% confidence interval) 5 1.59 (1.35-1.87)]. The impact of rs7587026 on brain structure is unknown. Here, we investigated the neuroanatomical correlates of this variant by comparing subcortical structures' volumes and cerebral cortex geometric measures in risk allele (A) carriers and non-carriers.

Methods: We studied 597 members [mean age 6 (SD): 23.5 6 (3.1), male/female: 236/361] of the Queensland Twins Imaging Study (QTIM) with available genotype and brain MRI data (acquired on 4-Tesla scanner). The genotype of the SCN1A single nucleotide polymorphism, rs7587026, was extracted for each individual. FreeSurfer was applied to process MR images to generate geometric measures for the subcortical structures and cerebral cortex surfaces. Differences in subcortical structural volumes between risk allele carriers (AA or AC) and non-carriers (CC) were examined using multivariate ANCOVA, and generalized linear models were applied to test for vertex-wise variation in cerebral cortex morphology. Intracranial volume (ICV), sex, and age were included as covariates in all models.

Results: Individuals homozygous for the rs7587026 minor allele (AA) displayed significant bilateral hippocampal and amygdalar volume reductions, compared to those with AC (P < 0.01) or CC genotypes (P < 0.01). No significant group differences were noted for the volume of the thalamus, caudate, putamen, or globus pallidus. Using a vertexwise cerebral cortex analyses, surface area reduction was noted in individuals with AA compared to AC or CC genotype in an extended area that spread over the left insular and orbitofrontal cortices, surviving correction for false discovery rate. Similar cortical surface area pattern was also noted over the right hemisphere, however, this did not survive correction for multiple comparisons. No cortical thickness differences were noted between risk allele carriers and noncarriers.

Conclusion: Hippocampal atrophy and altered limbic structure are common in MTLE1HS patients with and without febrile seizures. Here, we show that a common variant in SCN1A (rs7587026) is associated with altered mesiotemporal and limbic structures in a large cohort of healthy young homozygous risk allele carriers. Further replication and histopathology work are ongoing to explore this association.

Tanmay Parekh, Subin Mathew, Chantal Goudreau, Amanda Lonergan, Pirouz Piran and Chetan Malpe. Weston, FL

Objective: The objective of this study was to assess the knowledge and level of public awareness on epilepsy risk factors and treatment options.

Background: A Pubmed search for literature investigating general knowledge and awareness about epilepsy reveals a paucity of studies. A lack of knowledge about epilepsy may lead to misunderstanding and inadequate treatment. Identifying the gaps in epilepsy awareness and improving community knowledge about the disease may help to reduce the social stigma associated with epilepsy and improve access to appropriate treatment.

Design/Methods: This is a cross-sectional study involving 200 respondents randomly selected from an outpatient department of a community-based hospital in Weston, Florida. With the aid of a structured questionnaire, data was collected from each respondent regarding his or her general knowledge about epilepsy as a disease, the risk factors for developing epilepsy, and the treatment of epilepsy. We provide a descriptive analysis of responses.

Results: Of the 129 respondents who stated that they feel they have a good understanding of epilepsy risk factors, the following inaccurate responses were noted: 24% considered hot weather a risk factor, 7.75% considered excessive use of cellphone as a risk factor, 37% considered psychological stress as risk factor. The most common correct risk factors identified were brain tumor (81%) and a history of head trauma (81%). Among the treatment options that are available, 80% of respondents chose medication, 33.5% chose surgical management, 22% chose marijuana, and 20.5% responded "I do not know". Only 32.5% chose both medication and surgical management as available treatment modalities. 93.5% correctly responded that epilepsy can present at any age.

Conclusions: Despite significant efforts made to increase public awareness about epilepsy, moderate deficits and misconceptions still exist. A larger educational campaign that involves health-care providers and community leaders should be undertaken to improve awareness about epilepsy, its risk factors, and treatment. Background: Three age-specific quality of life (QoL) measures were included as secondary endpoints in EXIST-3 (CRAD001M2304), a three-arm, randomized, double-blind, placebo-controlled phase 3 study to assess the efficacy/safety of two trough ranges of everolimus as adjunctive therapy in patients with TSC.

Objective: Examine psychometric properties of three QoL epilepsy measures in TSC.

Design/Methods: Intellectual ability was reported using Wechsler Non-Verbal Scale of Ability (WNV). QoL measures included QoL in Childhood Epilepsy (QOLCE) aged 10, QoL in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48) aged 11-17, and QoL in Epilepsy Inventory-31-Problems (QOLIE-31-P) aged !18. A post hoc analysis examined psychometric properties of three QoL instruments and generated minimally important difference (MID) values. Results: A majority of patients had intellectual disability (IQ <70) at baseline, with WMV mean (SD) of 54.6 (32.3) in the 4-7 year age group, and 55.6 (25.4) in the 8-21 year age group. Psychometric analyses of the three epilepsy instruments (including reliability, validity, and ability to detect change) supported the appropriateness for use in TSC. The ability to detect change analysis demonstrated that the overall QoL score on the QOLCE improved by 15.8 points in responders versus 11.7 points for the nonresponders. QOLIE-AD-48 mean total QoL change was 18.2 for responders and 12.6 for nonresponders, and QOLIE-31-P total QoL score change was 115.2 for responders versus 20.6 for nonresponders.

Conclusions: This is the first known evaluation using trial data to determine psychometric properties of these three epilepsy QoL measures for use in TSC. Reliability, validity, and ability to detect change have been established in a TSC population with treatment-refractory seizures, supporting the appropriateness of use of these measures in this population.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Novartis has funded research at my institution that I am involved in and has paid my employer (CCHMC) for consulting work that I have done. Novartis has paid honoraria to me and has supported travel costs for lectures I have given. I am paid by various attorneys for legal work reviewing medical malpractice cases and occasionally giving expert testimony. Objective: The objective of this analysis was to explore the long-term efficacy and safety of everolimus in a subset of children under 6 years of age.

Methods: Patients aged 2-65 years with TSC and treatment-refractory seizures receiving a stable dose of 1-3 antiepileptic drugs were included. Following completion of the core phase, all patients were permitted to enter the extension phase and transitioned over 8 weeks to everolimus 6-10 ng/mL followed by investigator-led titrations to achieve everolimus target exposure range of 3-15 ng/mL until 48 weeks. Efficacy endpoints included change from baseline (start of everolimus) in average weekly seizure frequency in children <6 years old, defined as response rate (RR; patients with !50% reduction) and median percentage reduction (PR) in seizure frequency (cutoff date, 2 September 2016).

Results: Of the 361 patients receiving everolimus either in core or extension phases, 102 (28.3%) were aged <6 years. Median duration of everolimus exposure was 1.6 years, and median dose intensity was 8.29 mg/m 2 /day. The median PR (95% CI) in seizure frequency increased from 40% (30.8%-47.7%) at week 18 (end of core phase) to 48% (34.3%-73.6%) and 78.3% (59.3%-97.7%) after 1 and 2 years of everolimus, respectively. Among patients still on study in the respective timeframe, RR also improved from 39% (29.7%-49.7%) at week 18 (N 5 99) to 49% (38.1%-59.8%) and 75.7% (58.8%-88.2%) after 1 (N 5 88) and 2 years (N 5 37), respectively. The most frequent (>25%) adverse events (any grade/any cause) reported were pyrexia (47.5%), diarrhea (38.6%), stomatitis (35.6%), mouth ulceration (33.7%), upper respiratory tract infection (31.7%), nasopharyngitis (26.7%), and cough (25.7%).

Conclusions: Adjunctive everolimus therapy led to sustained reductions in seizure frequency over time in children <6 years old with TSC-associated treatment-refractory seizures. The safety profile of everolimus was consistent with previous reports, with no new safety concerns identified.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Novartis has funded research at my institution that I am involved in and has paid my employer (CCHMC) for consulting work that I have done. Novartis has paid honoraria to me and has supported travel costs for lectures I have given. I am paid by various attorneys for legal work reviewing medical malpractice cases and occasionally giving expert testimony. Background: Current practice often involves trial and error when choosing an effective anti-seizure medication for a child with epilepsy. Recent whole-exome sequencing studies have revealed hundreds of epilepsy-related genes, setting the stage for precision therapies. One genetic childhood epileptic encephalopathy, Dravet Syndrome (DS), is typically caused by de novo loss-of-function heterozygous mutations in SCN1A, which encodes the voltage-gated sodium channel (VGSC) Nav1.1.

Objective: We hypothesize that neurons from DS patient-specific induced pluripotent stem cells (iPSCs) are a faithful model to screen for effective anti-seizure medications.

Methods: We obtained fibroblasts from multiple subjects with Dravet Syndrome caused by heterozygous mutations in SCN1A and generated multiple iPSC lines. We performed directed differentiation of the iPSCs into excitatory corticallike neurons using dual-SMAD inhibition. We also generated induced excitatory neurons from SCN1A-patient iPSCS using forced expression of neurogenin 2 (NGN2). We performed longitudinal multi-electrode array recordings on these neurons over 1 month to examine for differences in firing properties between the patient and control cells.

Results: When differentiated with dual-SMAD inhibition, DS patient cells with SCN1A mutations appeared to have a higher mean firing rate than controls. While burst frequency was similar, the burst duration was longer and the interspike interval within bursts was shorter in SCN1A patient vs. controls at later time points. In contrast, with NGN2 induced neurons, the mean firing rate was similar between patient and control, and the burst frequency was higher in patient cells. However, the burst duration was shorter, and the interspike interval within a burst was longer in the patient cells.

Conclusions: SCN1A DS patient neurons derived from dual-SMAD inhibition may be hyperexcitable, as manifested by bursting properties. NGN2 induced DS neurons appeared to have more frequent bursts of shorter duration and longer interspike interval. The difference in properties may relate to differential developmental windows for compensatory changes or the generation of different neuronal subtypes between differentiation protocols. Further definition of these potential phenotypes will be necessary for drug screening. We will also generate interneurons from DS and control iPSCs to explore whether altered firing properties leading to network hyperexcitability are present.

Grant support is provided by NIH 5 K12 HD 028820 (LTD), and NIH (NINDS) NS088571 (JMP and LLI).

Activity in a Patient Undergoing Wada Testing While Implanted with Bilateral SEEG James J. Young, Megan E. Young, Thomas Oxley, Lara V. Marcuse, Christina Palmese, Fedor Panov, Saadi Ghatan, Johanna Fifi and Peter Rudebeck. New York, NY Evidence from animal models have implicated the role of synchronous and nested oscillations in the local field potential in the organization of neural systems, yet evidence that these oscillations are necessary is largely correlative. Here we describe a case report of an individual undergoing an intracarotid amobarbital test (Wada test) while implanted with bilateral stereo-EEG. Changes in the synchronous and nested oscillatory activity are described in relation to the patient's manifested deficits during the procedure. Background: The symptoms in witnessed Sudden Unexplained Death in Epilepsy (SUDEP) suggest a breakdown of the central autonomic control. We, previously, reported preliminary evidence for structural mesencephalic and lower brainstem abnormalities in two SUDEP cases affected by a focal epilepsy. Since the mesencephalon and medulla oblongata are involved in autonomic control, we set out to validate our preliminary findings in a uniquely large cohort of SUDEP cases and to analyze suspected association between the observed brainstem abnormalities and reduced heart rate variability (HRV) as a proxy of autonomic control.

Methods: Two populations were studied: 1. Autonomic population (18 patients with focal epilepsy, 11 controls) with HRV measurements and standardized 3T MR exams. 2. SUDEP population (27 SUDEP epilepsy patients) with clinical MRI 1-10 years before SUDEP. Deformation-based morphometry of the brainstem was used to generate profile similarity maps from the resulting Jacobian determinant maps that were further characterized by graph analysis to identify regions with excessive expansion (sigExcROIs).

Results: The total sigExcROIs counts in the autonomic population were negatively correlated with HRV (r5-0.37, p50.03), sigExcROis counts in periventricular gray/medulla oblongata autonomic nuclei explained most of the HRV associated variation (r/r25-0.82/0.67, p<0.001). The total sigExcROIs counts in the SUDEP population were negatively correlated with TimeLastMRIToDeath (r5-0.39, p50.03), sigExcROis counts in the raph e/medulla oblongata autonomic nuclei explained most of the TimeLastMRITo-Death associated variation (r/r25-0.60/0.35,p50.001).

Conclusion: These findings confirm our previous findings and suggest that MRI can detect potentially life threatening brainstem damage before SUDEP onset and ought to be further studied as a clinically useful biomarker to identify patients at risk for SUDEP.

Sarah A. Mandelbaum, Fawad Viqar, Lara V. Marcuse, Madeline C. Fields, Jessica Spat, Kelly Coulehan, Ann DeSollar and Heidi Allison Bender. New York, NY Objective: The neuropsychological assessment of Deaf and hard of hearing populations presents unique challenges to assessment of candidacy for epilepsy surgery. Potential issues include: a) unclear hemispheric specialization of language in individuals fluent in American Sign Language (ASL); b) neuropsychological test measures which are not developed for, and standardized in, this population; and c) multiple procedural confounds limiting more invasive procedures, such as the intracarotid amobarbital procedure. This case study describes a comprehensive assessment of surgical candidacy in a 28-year-old, right handed, Deaf male with medically refractory epilepsy s/p spinal meningitis in infancy. EEG revealed both generalized and localized seizure types and neuroimaging was remarkable for left mesial temporal sclerosis. Prior surgical intervention included VNS implantation two years ago, which did not offer adequate seizure control. His most recent pre-surgical work-up via stereo-EEG indicated a bitemporal seizure onset. Additional comorbidities included intellectual disability, learning differences and psychiatric diagnoses.

Methods: A modified neuropsychological assessment was administered as an additional method of localizing and lateralizing seizure onset; data were compared to testing prior to VNS implantation two years ago. All tests were administered with the assistance of an ASL interpreter.

Results: The results of the evaluation indicated that there has been a significant decline in cognitive and behavioral functioning from estimated premorbid functioning. Though his premorbid intellectual abilities were initially found to be in the Borderline to Low Average range, the patient's current functioning fell into the Impaired range. With regards to specific neurocognitive domains, the patient had relatively more advanced skills in visually mediated tasks, as compared to verbally mediated tasks. Relative weakness was also appreciated on a measure of fine motor coordination in his dominant (right) hand. Weaknesses included learning and memory, language, attention and selective aspects of executive functioning.

Conclusions: Neuropsychological test findings suggested frontotemporal neuropathology in the patient's left hemisphere (>right). The reason for the discrepancy between neuropsychological testing and sEEG findings (bilateral temporal onset) is likely multifactorial in nature, owing to neuroanatomical, psychometric and methodological differences. Less conventional evaluation techniques, such as fMRI and/ or MEG, may be useful in establishing hemispheric specificity in Deaf or hard of hearing candidates for epilepsy surgery. Doing so may facilitate improved cognitive outcomes post-surgically.

Architecture with High Resolution Multiple Image Co-Registration and Averaging (HR-MICRA) Lawrence Ver Hoef, Joel Cure and Richard Kennedy. Birmingham, AL Loss of hippocampal internal architecture clarity has long been known as a radiographic feature of hippocampal sclerosis (HS) in patients with temporal lobe epilepsy, along with the other hallmark features of HS -hippocampal atrophy and signal abnormality. While hippocampal atrophy and signal abnormality are easily recognized in conventional MR imaging, detection of loss of hippocampal internal architecture clarity is directly related to the ability of the MRI sequence in use to depict hippocampal internal architecture clearly in the normal hippocampus. While the internal architecture, specifically the gray matter of Ammon's horn and the intervening white matter, may be seen clearly in isolated hippocampal slices, it is difficult to image consistently in most slices through the hippocampus. Because internal architecture is not seen consistently in normal hippocampal slices, it is difficult to assess its absence with confidence in potentially abnormal hippocampi. This is due to volume averaging effects with the thick slices used in highresolution MRI. We overcome this challenge using a MRI technique we refer to as HR-MICRA to generate high-resolution images with thin slices using a conventional 3T scanner, and compare the clarity of these images with conventional T2w MRI.

MR images of 20 healthy controls were acquired on a Philips Achieva 3T platform. Conventional T2w images had a resolution of 0.25mm in the coronal plane with 3mm thick slices using a standard 2D turbo spin echo sequence. The HR-MICRA scans were acquired with a resolution of 0.5mm in the coronal plane and 0.75mm thick slices using a commonly available variable flip-angle turbo spin echo sequence (BrainView) optimized for minimum acquisition time at the expense of SNR. Multiple whole brain images were acquired and then co-registered and averaged to improve SNR, and compared to the conventional images. Clarity of hippocampal internal architecture was quantified using a published 4-point rating scale, and scores in the head, body, and tail were considered together and separately. Rating scale: 15none, 25poor, 35good, 45excellent; a score of 3 or 4 in a given slice means subfields CA1-4 can be visualized directly.

Clarity scores of good or excellent were seen with the HR-MICRA method in 73%, 90%, and 79% of slices through the head, body and tail, versus 0%, 50%, and 0% with conventional MRI, demonstrating that HR-MICRA images show hippocampal internal architecture with greater clarity (O.R. 8.26, p<0.0001).

Calcium Channel alpha1 Subunits Employing Biochemical Criteria Established for Voltage-Gated Sodium Channels (NaV) Maureen W. McEnery, Anne Marie R. Yunker, Ya Chen and Alan H. Sharp. Cleveland, OH Voltage-dependent Ca21 channels (VDCC) are key mediators of Ca21 influx, with low-voltage activated (LVA) VDCC contributing to developmental processes and modulation of adult neuronal excitability. Three distinct gene products, CaV3.1 (alpha1G), CaV3.2 (alpha1H), and CaV3.3 (alpha1I), give rise to LVA VDCC (T-type) currents. While their electrophysiological properties are well characterized, the biochemical properties of LVA VDCC are unknown. In this study, we take guidance from the observation that the primary sequences of CaV3 alpha1 subunits predict structural homology to both high-voltage activated (HVA) VDCC alpha1 and voltage-dependent sodium channel (VDSC) alpha subunits (NaV). Both families have welldefined biochemical features that offered valuable insight into their post-translational modification and assembly into complexes. With these defining features in mind, we explored the biochemical properties of all three recombinant LVA VDCC alpha1 subunits stably expressed in HEK293 cells and rat cerebellar CaV3.1. Using a panel of isoformspecific antibodies, we determined that LVA VDCC alpha1 subunits possess a unique subset of biochemical features that distinguishes them from both HVA VDCC and VDSC. Specifically, all recombinant CaV3 isoforms and endogenous CaV3.1 are highly glycosylated, similar to alpha subunits of VDSC and distinct from HVA VDCC alpha1. The presence of N-linked glycosylation on recombinant and endogenous CaV3 isoforms was exploited to partially purify the proteins on a lectin column. Another property that distinguishes VDSC from HVA VDCC is the covalent attachment of a beta2/beta4 subunit to the VDSC alpha subunit via a disulfide bond. Under conditions that recapitulate the increased mobility of a VDSC alpha subunit following disulfide-bond reduction, neither recombinant nor endogenous CaV3.1 shifted in electrophoretic mobility suggesting that LVA VDCC alpha1 do not associate with a VDSC beta2/beta4 homologue. This study presents the first characterization of the biochemical properties of LVA alpha1 subunits and suggests novel strategies for approaching their assembly, maturation, and purification. Background: Perampanel, one of the most recently introduced anti-epileptic drugs, is unique in that it inhibits AMPA receptor. With the novel mechanism distinct from the previous drugs, perampanel as an adjunctive treatment successfully reduced generalized tonic-clonic seizure (GTCS) in epilepsy patients. Moreover, 5-10% of patients became seizure-free. However, perampanel showed some adverse effects (AEs) including psychosis such as aggressiveness and suicidal attempt. Here, we investigated the efficacy and AEs of perampanel in Korean adult patients.

Methods: We prospectively recruited adult epilepsy patients from May 2016 to March 2017, and planned to follow them for six months. Perampanel was initiated in 2 mg per day and carefully titrated up to 4, 6, 8, 10 or 12 mg gradually with two-week interval. Before starting perampanel, baseline frequencies of GTCS and non-GTCS were calculated during last follow-up and Buss-Durkee Hostility Inventory (BDHI) questionnaire was evaluated. After six months, the same scales were obtained and compared with the baseline scores using paired t-test.

Results: Total 197 epilepsy patients (100 males, mean age 38.7 6 13.5) were enrolled. Baseline GTCS was 1.88 6 6.10 and non-GTCS was 17.87 6 54.80. Up to date, 45 patients (37.5% of total followed 120 patients) quitted the study. Seventy-five patients, who completed the six-month followed up, were subjects to the following analyses, and the remaining 77 patients are supposed to visit soon. The mean dosage of perampanel at six-month was 7.12 6 2.66 mg. Both GTCS (mean 2.00 6 4.84 vs. 0.67 6 1.84, P 5 0.016) and non-GTCS (mean 23.21 6 75.21 vs. 12.35 6 48.83, P 5 0.047) was significantly reduced after six months. Seizure-free was obtained in 16 (13.3%) patients and GTCS-free was in 11 (9.2%). Fifty percent reduction of seizure or GTCS was achieved in 12 and 8, respectively. BDHI questionnaire exhibited no significant change (P 5 0.390). AEs were noted in total 42 (21.3%) patients; 22 with dizziness, 17 with psychosis, and 10 with other complaints. A subgroup with AEs demonstrated no difference in perampanel dose or six-month outcome compared to a subgroup without AEs.

Conclusions: In conclusion, perampanel showed appreciable efficacy in Korean adult patients, however, AEs represented by dizziness and psychosis were not inconsiderable. Therefore, careful monitoring of AEs is needed when treating epilepsy patients with perampanel.

Tae-Joon Kim, Han Sang Lee, Jin-Sun Jun, Jangsup Moon, Soon-Tae Lee, Keun-Hwa Jung, Kyung-Il Park, Ki-Young Jung, Manho Kim, Kon Chu and Sang Kun Lee.

Background: Oxcarbazepine is a widely used anticonvulsant drug to treat focal seizure as monotherapy or adjunctive therapy. The mono-hydroxylated derivative (MHD) is the main metabolite which is responsible for most of the anticonvulsant activity. The objectives of this study are to develop a pharmacokinetic model of oxcarbazepine in Korean population, and to analyse the relationship between trough concentrations of the drug and occurrence of adverse event (AE) or seizure.

Methods: To develop a pharmacokinetic model of oxcarbazepine, the data from two studies were used; the data of 447 patients who had been enrolled in from Epilepsy Registry Cohort of Seoul National University Hospital since Feb 2011 and the data of pharmacokinetic study involving 40 patients evaluating oral loading of oxcarbazepine. Plasma concentrations of MHD were analysed using nonlinear mixed-effect modelling in NONMEM (ver 7.3). The firstorder conditional estimation with interaction method was used to fit the plasma concentration-time data. Trough concentrations of each patient were calculated using the final pharmacokinetic model. The relation between trough concentrations and occurrence of AE or seizure were analysed using Students' t-test.

Results: A one-compartment model with first-order absorption, and a proportional error model describes oxcarbazepine pharmacokinetics adequately. The body weight was significant covariate for the clearance and the volume of distribution of the drug and the use of concomitant drugs including carbamazepine, phenytoin, and phenobarbital which are known to be enzyme-inducers increased the clearance 1.38-fold. The trough concentrations of the drug were slightly higher in the patients group with AEs (mean 6 SD; 13.4 6 7.8 ng/mL) or with seizure episodes more than once (13.9 6 7.6 ng/mL) compared to the non-AE group (12.4 6 6.8 ng/mL) or non-seizure group (12.7 6 7.2 ng/ mL) but the differences were not statistically significant.

Conclusions: The population pharmacokinetic model developed in this study adequately described oxcarbazepine pharmacokinetics in patients with epilepsy. The covariates selected in this study including body weight and the use of concomitant drug are expected to be used to choose appropriate dosage regimen in the patients. Tae Background: After genome project, network analysis of genes or proteins is being actively performed and generated fruitful insights. Parameters and characteristics of the networks revealed important pathways or genes associated with the target diseases, such as cancers. However, whole genes related to epilepsy have not been evaluated with network analysis previously. Here, we analyzed the epilepsy related genes using network analysis methods.

Methods: We collected lists of genes related to seizure or epilepsy by searching OMIM. Total 793 genes were obtained and subject to STRING analysis (http://stringdb.org/). Threshold of STRING analysis was set to 0.4. Resultant weighted network including 663 genes (nodes) and 3904 connections (links) were analyzed using R program with tnet package. Network parameters comprises strength (sum of connections), betweenness centrality (degree of inclusion to shortest pathway between other two nodes), global clustering coefficient (triplet nodes), and local clustering coefficient (connections between two connected nodes). We defined hubs as upper 10% by strength.

Results: Epilepsy related genes produced small-world network characteristics. Genes in STRING analysis showed more interactions among themselves than what would be expected for a random set of proteins of similar size, which indicates that the proteins are at least partially biologically connected, as a group. The associated gene groups in STRING analysis were proved to be related to nervous system development, ion transmembrane transporter activity, and so on. Degree distribution of genes demonstrated smallworld model, rather than scale-free model. Average strength was 7.69 and global clustering coefficient was 0.278. When we sorted the genes by strengths and collected the hubs, familiar genes including KCNQ2, GRIN2B, MTOR, CAC-NA1C, GRIA1, GRIN2A, KCND2, GRIN1, KCNA1, and KCNA2 were lined when we removed common enzymes or cancer markers.

Conclusions: Epilepsy related genes by gene network showed small-world network featured by nervous system development and ion transporters. STRING analysis and weighted network analysis can be useful for investigating connections between epilepsy related genes.

Abhinav Ohri and Yasir Al-Khalili. Philadelphia, PA Objective: To determine reasons for non-compliance with Anti Epileptic Drugs (AEDs) in patients with Epilepsy and measures to improve compliance.

Background: Epilepsy affects approximately 2.5 million Americans and has a prevalence rate of 6 to 7/1000 and 65 million people globally and costs about $15.5 billion dollars in healthcare cost. Adherence to medication therapy is critical because it improves prognosis. However, in practice it is very difficult to achieve efficacy and the main reason being non-compliance to AEDs.

Methods: Outpatient charts of 50 patients seen at the Drexel Neurology Epilepsy clinic between 01/01/2013-04/ 30/2015 and aged 20 to 77 years were reviewed. Any patient missing one or more doses of their AEDs was considered non compliant.

Results: 15 out of the 50 (30%) were non compliant with their AEDs. Of the non-compliant patients 60% were females (9 patients) and the remaining (6 patients) were males. All the 15 patients were not employed compared to 21/35(60%) in the compliant group (P 50.003). 9 out of the 15 (60%) patients had underlying depression or other mood or behavioral problems compared to 14 out of 35(40%) in the compliant group. (Although this did not reach statistical significance P50.193). 7 patients (46%) were non compliant because of adverse effects while 5 patients (33%) reported non compliance due to failure to remember to take the medications. 1 patient (6.6%)was non compliant because they ran out of medications.

Conclusion: Failure to comply with medication regimen puts patients at increased risk for breakthrough seizures, increased number of hospitalizations, increased health care cost and SUDEP. Failure to tolerate the drug due to adverse effects, cognitive deficits and mood/behavioral issues are common reasons for non-compliance and measure to treat or fix them is the goal for better seizure control.

M214. Comparing the Diagnostic Accuracy of Neuropsychological Testing to Invasive Monitoring in Non-Native English-Speaking Candidates for Epilepsy Surgery Heidi A. Bender, Jessica S. Spat, Kelly Coulehan, James Young, Lara V. Marcuse, Madeline Fields, Ji Yeoun Yoo and Sarah Mandelbaum. New York, NY Objective: Procedural and psychometric confounds often limit the reliability and validity of neuropsychological testing in non-native English-speaking candidates for epilepsy surgery. Beyond the increased probability of atypical language representation in bilinguals and/or tonal language speakers, the use of medical interpreters with varying degrees of fluency and expertise, and the use of tests which were neither developed for, nor standardized with, nonnative English-speaking neurological populations, are all clearly immutable sources of test bias. The prognostic value of neuropsychological testing in localizing and lateralizing underlying neuropathology is perhaps most critical in presurgical contexts; however, the diagnostic accuracy of cognitive metrics is highly variable in culturally-and linguistically-diverse patient populations. The present study sought to compare the localizing and lateralizing value of neuropsychological testing to invasive monitoring in non-native English-speaking candidates for epilepsy surgery.

Methods: Patients with drug-resistant epilepsy undergoing invasive monitoring as part of a pre-surgical work-up were recruited for this study. We compared the data yielded from 'gold standard' invasive monitoring techniques (i.e., stereoelectroencephalography and grids/strips electrodes studies) to the seizure localization and lateralization derived from a neuropsychological evaluation completed no more than three months prior to implantation.

Results: Nineteen patients with a mean age of 34.1 years (8.88) were included. Patients were 47% male, 88% righthanded, and had a duration of seizures ranging from 2 to 31 years. Monolingual English-speakers (n511) were compared to non-native bilingual or monolingual non-native English-speakers (n58); languages spoken include Spanish (n56), Cantonese (n51) and Korean (n51). Neuropsychological test data correctly predicted the localization of seizure onset in 82% of monolingual English-speakers, but only 50% of non-native English-speaking patients. Lateralization of seizure focus was also more accurately predicted in U.S.born, English-speaking patients (70% monolingual Englishspeaking and 50% non-native English-speaking).

Conclusions: Findings underscore the limitations of neuropsychological testing in non-U.S. born, non-native English-speakers. While this method of assessment possesses well established prognostic value in evaluating the risk of post-surgical cognitive decline, its accuracy in establishing localization and lateralization of seizure focus in culturallyand linguistically-diverse populations should be interpreted with considerable caution. Future studies should aim to more rigorously standardize assessment practices, including meaningful improvements in neurocognitive test development, and more appropriate and applicable normative samples.

M215. Long-Term Safety and Efficacy of Intracerebroventricular Enzyme Replacement Therapy with Cerliponase Alfa in Children with CLN2 Disease: 2

Year Results from an Ongoing Multicenter Extension Study David Jacoby, Angela Schulz, Nicola Specchio, Emily de los Reyes, Paul Gissen, Heather Cahan and Temitayo Ajayi. Novato, CA; Hamburg, Germany; Rome, Italy; Columbus, OH and London, United Kingdom Background: CLN2 disease, a rare, inherited, pediatric, neurodegenerative lysosomal storage disorder caused by TPP1 deficiency. Clinical course is characterized by progressive seizures, ataxia, language and motor loss, blindness and early death. A 48 week treatment study (NCT01907087) demonstrated that intracerebroventricular (ICV) infusion of 300 mg cerliponase alfa, a recombinant human TPP1 enzyme, every other week was associated with significant attenuation of CLN2 disease progression. All subjects continued into an extension study (NCT02485899) to assess the long-term safety and efficacy. Results after 2 years of treatment are reported.

Design: Cumulative data from both studies were used to evaluate long-term safety (assessed by analysis of adverse events (AEs)) and efficacy (assessed by changes in the CLN2 clinical rating scale).

Results: 24 subjects were initially treated with cerliponase alfa in the original 201 study (9 male, 15 female, mean (SD) age 4.3 years (1.24)); 1 subject withdrew consent after first dose, the remaining 23 subjects completed 201 and enrolled in the 202 extension study (median exposure 116 weeks total exposure). All had AEs; most were Grade 1-2. Common AEs included pyrexia, hypersensitivity and convulsion. Nineteen (79%) subjects had at least one serious AE, which were mostly consistent with neurodegenerative disease in a pediatric population. External observational natural history cohort declined in CLN2 score by 2.1 points per 48 weeks. Significant attenuation was observed in treated subjects in the rate of decline in ML score (mean (95% CI): 0.32 (0.13, 0.52) points/48 weeks, p<0.0001). Similar treatment effect observed in responder rates, change from baseline and categorical analysis.

Conclusions: These data suggest that enzyme replacement therapy with ICV-administered cerliponase alfa has an acceptable safety profile and a sustained, clinically meaningful therapeutic effect over time.

Human Sleep: Dependence on Frequency-Specific Metrics Giridhar P. Kalamangalam and Ioan M. Chelaru. Houston, TX A major challenge in the field of brain connectivity is relating connectivity metrics to the brain state of interest. An influential view describes the unconsciousness of sleep arising from fragmentation of integrated cortical modules. Yet the propensity for focal seizures to occur -and generalize-in the sleep state implies a hyperconnectedness (hypersynchrony). Electrocorticography (ECoG) from six patients undergoing prolonged video-EEG telemetry with subdural grid electrodes was analyzed. Segments of wakefulness and sleep were comb-filtered into the canonical Berger EEG bands. Using a novel method for modeling ECoG spectra, the sleep-wake state of the ECoG was assigned a continuous numerical score over sliding windows of 30s duration. Correlations between the score and concurrently computed graph-theoretic connectivity metrics were drawn. We found that the coherence network modularity in the beta and gamma bands -relevant to high-frequency seizure-onset rhythms -correlated positively with wakefulness, while alpha modularity correlated negatively. Thus, ECoG-based brain connectivity metrics are both state (sleep-wake) dependent and waveform frequency dependent. It is possible for the cortex to be 'disconnected' with respect to conscious wakefulness in the sleep state, yet 'hyperconnected' with respect to transmission of epileptic seizures.

M217. The Importance of Screening the Twin of a Known Patient with Epilepsy for Subclinical Seizures Neeraj Singh and Karen Powers. Albany, NY M.S. and D.S. are 8-year-old twin sisters born at 31 weeks gestation without complications, and met all developmental milestones. At age 7, M.S. had a 20-minute event during which she stood still, without response to verbal or physical stimuli, and without convulsions, tongue bite, or urinary incontinence. She then vomited and seemed more tired than usual. She was brought to an emergency department, where an emergent electroencephalogram revealed several 5-10 second runs of 3-Hz generalized spike-and-wave activity correlated with lack of response to verbal stimuli, consistent with absence epilepsy. She was started on ethosuximide, and tolerated this well with no breakthrough seizures in fourmonth follow-up. Although D.S. had no episodes concerning for seizures, she underwent a screening electroencephalogram over 48 hours given her sister's diagnosis. D.S. had multiple periods of 3-Hz spike-and-wave discharges, but no clinical events. Based on these findings, she was also started on ethosuximide, and tolerated this well with no clinical seizures in two-month follow-up. This case illustrates an important example of screening a twin of a known patient with epilepsy, as it can reveal abnormalities that warrant treatment despite lack of clinical events.

Continuing Education Results in Improved Performance in Developing Seizure Action Plans for Patients with Epilepsy Jamie C. Reiter, Whitney Faler, Jan Perez and Sharon B.

Introduction: Research has shown gaps among healthcare providers (HCPs) in best practices for identifying and treating seizures. We previously identified gaps in shared-decision making and developing Seizure Action Plans (SAPs) for adult patients with epilepsy. It is the goal of continuing medical education (CME) to keep HCPs up-to-date on the most recent developments and best practices in medicine. However, many CME providers fail to integrate the patient voice into education, which would raise awareness of challenges patients face and provide a more realistic patient perspective to HCPs. This study aimed to determine whether integrating the patient voice into an educational intervention could assist HCPs in achieving best practices related to identifying and treating various seizure types as well as working with patients with epilepsy to make decisions and put SAPs in place.

Methods: The activity consisted of a 60-minute webcast, followed by a 30-minute live Q&A. Audio from interviews with epilepsy patient leaders were integrated into the content. A survey assessing knowledge, confidence, competence, and performance was administered prior to the activity (presurvey), immediately after the activity (post-survey), and 3 months following the activity (follow-up survey). Data from the pre-and post-or follow-up surveys were analyzed using McNemar's tests for paired data. Significance was determined at alpha 5 .05.

Results: Over 4,500 clinicians participated in the activity, including 200 HCPs in the pre-activity and post-activity outcomes study, and 30 participants in the follow-up survey. A significantly greater percentage of participants post-activity versus pre-activity achieved correct responses on knowledge questions related to risk factors for seizure clusters (74% versus 35%, p < .001) and the therapeutic agent FDA-approved for out-of-hospital treatment for acute repetitive seizure or seizure clusters (88% versus 48%, p < .001). For a performance question asking how often HCPs develop SAPs with their patients, participants in the follow-up survey outperformed those in the pre-activity survey (77% versus 14%, p < .001).

Discussion: Incorporating the patient voice into the educational activity was an effective format for providing insight and perspective leading to improved HCP learning and performance, especially with regard to developing SAPs. HCPs are encouraged to integrate the patient perspective when developing treatment plans for patients with epilepsy.

Introduction: In median neuropathy associated with carpal tunnel syndrome, rapid movement of the hand at the wrist ("the flick sign") is such a reliable reducer of paresthesia that it has been designated as a clinical test for this disorder (Krendel 1986) . Similarly, in Restless Leg Syndrome (RLS), movement of legs reduces pain and is part of the diagnostic criteria (Allen 2003). Alleviation of phantogeusia by tongue movement has not heretofore been described.

Methods: A 60 year old right handed female with chronic history of RLS was nasute until one year prior to presentation whereupon she fell on the ice with loss of consciousness. Within a few days she noted taste problems which have not recovered since onset. Every few days she is able to detect the first bite of a food, otherwise her ability to taste is limited to pickles and sweets and she perceives her taste as being 20% of normal. She complains of dysgeusia whereby spaghetti sauce and raspberry jelly taste metallic and chocolate and water taste salty. Peanut butter and peppermint taste so terribly salty and bitter that she cannot tolerate them. She complains that her tongue feels awkward in her mouth. Furthermore, she also noted a constant salty phantogeusia, level 8-9/10 in intensity. When she would protrude her tongue anteroposteriorly or rapidly side to side, the phantogeusia would vanish from a level 8-9/10 in intensity to a level 0/10. She denied problems of smell.

Results: Abnormalities neurological examination: Scalloped tongue. Motor: mild left pronator drift, left cerebellar spooning, left abductor digiti minimi sign. Gait: heel walking with decreased right arm swing. Sensory exam: decreased vibratory sense in bilateral lower extremities. Chemosensory testing: Brief Smell Identification test: 11 (normosmia). Retronasal Smell Index: 2 (abnormal). Gustatory: Propylthiouracil Disc Taste Test: 9 (normogeusia). Taste threshold: Mild hypogusia to sodium chloride. Taste quadrant testing: posterior tongue and palate: reduced ability to taste citric acid. Whole mouth taste weakness to sodium chloride and sucrose. Other: MRI of the brain: mild small vessel ischemic changes. Fiberoptic endoscopy: negative. Sjogren antibodies SSA, SSB: negative.

Discussion: This could represent a lingual extension of RLS. Possibly movement induced large fiber discharge, reducing phantogeusia, wherein the phantogeusia may be considered a pain variant. In those with intractable phantogeusia, a trial of tongue movement and query as to presence of phantogeusia in those with oral-facial-lingual-dyskinesia is warranted. Objective: Cerebral malaria (CM) remains a common cause of death in African children. The pathologic hallmark of pediatric CM is sequestration of parasitized red blood cells in the cerebral microvasculature. Recent Malawi-based research utilizing a 0.35T MRI has established that severe brain swelling is associated with fatal CM, but the etiology of brain swelling remains unclear. Autopsy and clinical studies suggest several potential etiologies, but technical limitations of 0.35T MRI precluded optimal investigations into swelling pathophysiology.

Methods: Using 1.5T MRI, Zambian children with retinopathy-confirmed CM underwent imaging with susceptibility weighted imaging (SWI), T2, T1 pre-and postgadolinium, DWI with ADC and T2/FLAIR sequences. Images were reviewed independently by two radiologists (MJP; neuroradiologist, and SDK; MRI fellowship trained radiologist). We hypothesized that imaging retinopathy-confirmed pediatric CM would identify pathophysiological mechanisms underlying cerebral edema in pediatric CM specifically seeking evidence of blood brain barrier breakdown, impaired perfusion, parasite sequestration, autoregulatory dysfunction and microhemorrhages.

Results: Sixteen children including two with moderate/ severe edema were imaged. All survived. Gadolinium extravasation was not seen. Cerebral perfusion was intact with DWI abnormalities sparing the gray matter. SWI findings consistent with microhemorrhages and parasite sequestration co-occurred in white matter regions where DWI changes consistent with vascular congestion were seen. Findings consistent with posterior reversible encephalopathy syndrome as a cause of swelling were also present.

Interpretations: High field MRI findings indicate that vascular congestion associated with parasite sequestration, local inflammation from microhemorrhages and autoregulatory dysfunction contribute to brain swelling in CM. No gross radiological blood brain barrier breakdown or focal cortical abnormalities were evident in this cohort of children with non-fatal CM. Background: Pediatric cerebral malaria (PCM) affects 200 million children worldwide, causing 625,000 deaths annually mostly in children under five in Sub-Saharan Africa. Increased brain volume and subsequent herniation are strongly associated with fatal outcomes in PCM. More accurate non-invasive measures of increased brain volume are needed for optimal clinical trial design.

Objective: To examine the receiver-operator-characteristic (ROC) curve characteristics for six different MRI brain volume quantification methods for predicting mortality in PCM and review the pros and cons of each method.

Materials and Methods: MRIs from children admitted to the Pediatric Research Ward at QECH in Blantyre, Malawi from 2009-2014 with retinopathy-positive PCM were reviewed. Fatal CM cases were matched to the next available non-fatal case. Using the admission MRIs, the ROCs were assessed for six brain volume measures. (1) A radiologistderived edema score from 1-8, (2) a single, midsagittal linear prepontine anterior-posterior (AP) measure of the cerebrospinal fluid (CSF) space, (3) the SamKam ratio of the right parietal lobe height/(prepontine AP dimension14th ventricle AP dimension) and (4) a global assessment of the cerebrospinal fluid space ascertained manually via Clear Canvas. Only a subset of children survive long enough and remain in coma long enough to allow serial imaging. For those with serial imaging, we evaluated the ROC for (5) the global assessment of CSF space on the second MRI. Finally, the ROC for a (6) recovery factor variable comprised of the global CSF space on the second divided by the initial MRI was evaluated.

Results: A total of 78 MRIs from children 5 months-13 years (mean 4.0 years), 44.8% male, were included in the study. AUCs with 95% CI on measures from the initial MRIs were as follows: the radiologist-derived score 0.69 (0.58-0.79; p50.0037); prepontine cistern AP dimension 0.70 (0.56-0.78; p50.0133); SamKam ratio: 0.74 (0.63-0.83; p50.0002), and global CSF space 0.67 (0.55-0.77; p50.0137). For patients with serial MRIs (n5 37), the global CSF space AUC was 0.87 (0.71-0.96; p<0.001) and the recovery factor was 0.91 (0.76-0.98; p<0.0001).

Conclusion: All the noninvasive measures of brain volume performed well in terms of predicting death and providing a noninvasive proxy measure for increased brain volume. Assessments on the initial MRI may inform future clinical trials for subject selection, risk adjustment or stratification. Measures of temporal change may be used to stage PCM. Objective: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next-generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients.

Methods: We present the case of a 34 year-old man with X-linked agammaglobulinemia from Australia suffering from three years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next-generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen.

Results: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next-generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue.

Interpretation: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in three immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a selflimiting meningitis to a rapidly fatal meningoencephalitis with multi-organ failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Indeed, our research subject returned from a trip to North Carolina two days prior to the onset of his illness. This report demonstrates that metagenomic next-generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes.

Melissa A. Elafros, Gretchen L. Birbeck and The Epilepsy-Associated Stigma in Zambia Study Team. Baltimore, MD; Rochester, NY and Mazabuka, Zambia

Epilepsy-associated stigma (EAS) continues to be a substantial barrier for people with epilepsy (PWE) worldwide. EASZ is a 15-year study examining stigma consequences, determinants, and interventions in Zambia.

Initial cross-sectional work quantified stigma and its sequelae. Focus groups with PWE and parents of children with epilepsy provided insight into the context of EAS. Findings led to knowledge, attitude and practice (KAP) studies of 'power' groups that moderate/mediate EAS (teachers, clerics, healthcare workers (HCWs), employers, and police). Mediating factors distinct for each group were identified-e.g. among clerics identifying epilepsy as a biomedical condition was critical, whereas personal proximity to PWE was important among teachers. Instruments measuring stigma were further developed. Structural aspects of care (e.g. drug availability and cost) were also examined.

Observational data confirmed the extreme impact of EAS. EAS was associated with poorer education and housing quality, and increased vulnerability to sexual assault. For mothers of children with epilepsy, courtesy stigma resulted in diminished social support. Greater epilepsy-related knowledge among PWE and their family was associated with less EAS. Multifaceted, locally facilitated interventions aimed at reducing EAS and its morbidity were developed for targeted groups and evaluated.

For PWE, monthly PSGs were held for 103 men, women, and youth with epilepsy at three urban and rural clinics for one year. Participants determined meeting content, focusing on problem-solving and coping techniques related to EAS. EAS decreased among youth attending >6 meetings (p50.02) with a non-significant decrease among adults (p50.20). Among power entities, 60 urban and rural teachers attended a symposium on epilepsy knowledge, including seizure management and appropriate attitude modeling. 131 additional rural teachers participated in quarterly pupil-oriented sessions imparting epilepsy knowledge and attitudes via discussions and skits. Both interventions involved PWE as trainers. Symposium participation improved epilepsyassociated knowledge (p50.0003), tolerance (p50.02), and practices (p50.0001) even one year later. School advocacy participation increased epilepsy tolerance (p50.0007). Interventions for clerics and HCWs showed mixed results. A HCWs' intervention uncovered health systems challenges requiring additional interventions to improve care, including inappropriate referral patterns. EASZ leadership are now working with grassroots community organizations for PWE and the Ministry of Child Health and Community Development to scale up successful interventions nationally.

EAS is a sociocultural phenomenon with far-reaching effects. Low-cost interventions utilizing local expertise decrease EAS among PWE and stigmatizing KAPs among 'power' groups, which may improve outcomes among this vulnerable population. Purpose: Research conducted in Malawi utilizing MRI has identified increased brain volume as the likely cause of death in pediatric cerebral malaria (CM). Detailed review of Malawi imaging shows that Posterior Reversible Encephalopathy Syndrome (PRES) was also present in a significant subset of children with CM. The pathophysiology of PRES is thought to be related to hyperperfusion and/or endothelial injury. Histologically, the hallmark of CM is parasite sequestration in the cerebral vasculature due to parasitized red blood cell adherence to microvascular endothelium. We investigated clinical risk factors and outcomes associated with PRES in pediatric CM with particular attention to possible markers of endothelial injury.

Methods: Our study population consisted of children admitted to the Pediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre, Malawi from 2009-2014 with retinopathy positive CM who underwent imaging. Two radiologists independently interpreted images with data captured via NeuroInterp, a web-based, structured reporting system that prompts radiologists to explicitly describe brain regions on each sequence. A relatively strict case definition of PRES was developed based on well-established patterns of imaging findings within the literature. Images were reviewed and further stratified on the presence/absence of other CM-related imaging abnormalities, those with PRES abnormalities alone being termed "Pure PRES". Clinical and demographic factors assessed as potential risk factors for PRES included hypertension, lactic acid level, HIV status, seizures, blood glucose, and plasma Histidine Rich Protein-2 (a quantitative marker of parasite burden). Mortality rates in PRES vs. non-PRES groups were examined.

Results: 91/269 (34%) CM children demonstrated PRES with 20/198 (10%) having Pure PRES. There was no difference between the PRES and non-PRES groups in age, gender, weight or height. Children with higher lactic acid levels were less likely to have PRES (OR 0.9, 0.83-0.96) and Pure PRES (OR 0.8, 0.68-0.94). Among those with PRES, 75 (82%) recovered, 8 (9%) had neurologic sequela at discharge, and 8 (9%) died. In the Pure PRES group, 16 (80%) recovered, 2 (10%) had neurologic sequela, and 2 (10%) died. There was no statistically significant difference in mortality between the PRES and non-PRES groups.

Conclusion: Posterior reversible encephalopathy syndrome is less likely in CM children with hyperlactatemia, a marker of severe malaria and a well-established risk factor for death in CM. Future investigation will address the potential role of endothelial cell injury (Angiopoetin-I and II) in malaria-associated PRES. Methods: We conducted a retrospective, mixed methods analysis of 60 cases referred by MSF field doctors to consultant neurologists within the MSF telemedicine platform (2010) (2011) (2012) (2013) (2014) (2015) (2016) . Variables of interest included logistical (e.g. geographic location of field site and consultant, language of communication) and clinical features (e.g. patient symptoms/signs, time course of presentation, laboratory tests performed). Outcomes were (1) whether diagnostic or treatment advice was provided, and (2) whether a final diagnosis was reached.

Results: Most cases were from Africa (75%) and transmitted in English (60%). The median age of all cases was 8 years old (mean 13.4 years, interquartile range 18). Ten neurologists from 6 high-income countries provided consultations to 17 low and lower-middle-income countries. The main countries of case origin were Central African Republic (17%), South Sudan (15%), and Niger (12%). There was a trend towards more consults over time (p50.08).

Overall, 68% of patients were pediatric and 47% were male. The most common symptoms among patients were fever (n529; 48%), seizures (n518; 30%), and paraparesis (n514; 23%). Less than 1% (n52) involved traumatic brain injury. Patients presented predominantly with acute symptoms (n523; 38%), although care-seeking for chronic diseases also occurred (n517; 24%).

In about half of cases (n531; 52%), images or videos were sent by the referring clinician with the consultation. 73% (n544) of neurologists provided both diagnostic and therapeutic advice, but the ability to fulfill diagnostic recommendations was constrained. A lumbar puncture was performed infrequently (n511; 18%); likewise with CT scans (n510; 17%). Only 12 cases (20%) involved a final diagnosis. In these cases, the diagnosis was made prior to consultation, with the consult question asking for confirmation or management advice. The majority of diagnoses involved chronic conditions (67%), the most frequent being epilepsy (25%).

Conclusion: Early experience with telemedicine in complex humanitarian emergencies suggests that neurologists, and especially pediatric neurologists, have a role in supporting neurological care for complex cases in the field. This may require a shift from establishing a final diagnosis towards managing complications of unknown primary illness, adding empiric therapy, and providing education in neurological care.

M226. Barriers to Lumbar Puncture in Zambia: Insights into the 'Tap Gap' Melissa A. Elafros, Clara Belessiotis, Gretchen L. Birbeck, Virginia Bond, Izukanji Sikazwe and Michelle P. Kvalsund. Baltimore, MD; London, United Kingdom; Rochester, NY; Mazabuka, Zambia; Lusaka, Zambia and East Lansing, MI Background: Data from resource-limited settings suggests a substantial gap between the number of patients who could benefit from CSF analysis and the number undergoing lumbar puncture (LP). Caregiver/patient and provider understanding of LP and barriers to LP completion was studied at the University Teaching Hospital in Lusaka, Zambia in 2016.

Methods: A cross-sectional questionnaire of inpatients with meningitis symptoms, their caregivers, and providers was conducted to assess knowledge, attitudes, beliefs, and sources of LP information. Patients/caregivers were asked about patient symptoms, LP requests, procedure acceptance, and justification. Associations between respondent sociodemographics, patient characteristics, LP knowledge, and completion were assessed.

Results: 63 child caregivers, 36 adult caregivers, and 24 adult patients (86% female, 36 6 12.5yrs) were interviewed (total patients5123). While 93% of patients/caregivers had heard of LP and 65% knew someone who had an LP, 76% reported knowing little about LP. 67% said LP could be replaced with CT/MRI, 47% said with a blood test. Perceived LP consequences included death (63%), paralysis (39%), and infertility (10%). Sources of information included doctors (71%), family (55%), and community (38%). 20 physicians (15% female, 31.9 6 7.8yrs) and 30 nurses (77% female, 34.1 6 7.8yrs) participated. Only 18 knew a non-patient who had an LP. 60% believed LP causes paralysis and 42% indicated it can lead to death. While LP was considered generally safe, 55% of physicians believed it could make a patient worse. Patients/caregivers and providers agreed Zambians do not understand LP (96%). Increased provider knowledge was associated with greater wealth (p50.03) and personal proximity to someone who had an LP (p<0.001). There were no predictors of patient/ caregiver knowledge.

LP was ordered for 118/123 patients (96%) and completed on 67/118 (57%). Adult patients were more likely to undergo LP (75% versus 39%, p<0.001). Refusals were attributed to fear of death (42%), poor understanding (27%), fear of paralysis (8%), and waiting for additional family discussion (8% Conclusions: Reservations about LP are pronounced across patients, caregivers, and providers. Fear of adverse outcomes combine with low knowledge and, thus, 43% of patients with meningitis symptoms did not undergo LP. Multifaceted interventions to reduce the 'Tap Gap' are warranted. Objective: To encompass the history of Neurology in Mexico since its inception to its current stage.

Background: Neurology in Mexico can be traced to the prehispanic era, when it was influenced by Mayan medicine, Egyptian medicine and Chinese medicine. Over the years, the contributions of Mexican neurologists have been paramount.

Materials and Methods: The information was gathered from review of various articles on Pubmed, USC and UCLA libraries and historic texts.

Results: In 1500 B.C., during the prehispanic era, Mayan people believed that mental illness was the consequence of demons inside the patient's head. They performed trepanations, which caused relief in these people, who most certainly suffered from migraine and traumatic head bleeding. Documents dating from 1400 B.C. describe epilepsy as a "divine disease", and make a distinction between GTC ("Huapahualitzzi") and myoclonic seizures ("Hixcayotl"). In 1551, the Royal and Pontifical University of Mexico (now, Universidad Aut onoma de M exico) was founded. In 1833, at the University of Mexico, Manuel Carpio became the first neuro-physiologist in Mexico, while Casmirio Liceaga became the first expert in mental illness of the continent. In 1882, Miguel Alvarado became the first Neurology Chairman at the University of Mexico. In 1910, first public and private mental institutions started to treat patients. In 1925, there was a boom in nervous physiology thanks to Harvard researchers Walter Cannon and his Mexican collaborators Arturo Roseblueth and Jose Joaquin Izquierdo, who described the function of the autonomic nervous system. In 1936, Teodoro Flores Covarrubias built his own EEG machine and started electrophysiological studies. In 1960, first Neurology service was started by J Hernandez Peniche at Hospital de La Raza of Instituto Mexicano de Seguro Social (IMSS). In 1964, National Institute of Neurology and Neurosurgery (INNN) was established with Manuel Velasco Suarez as its director. INNN comprises of 3 main divisions: Neurology, Neurosurgery and Psychiatry. The division of Neurology offers specialized training to postgraduate students in various neurological sub-specialties. In 1971, the Board of Mexican Council of Neurology was born within the Mexican Academy of Neurology. They all seek for international recognition, with quality standards established by the National University of Mexico (UNAM).

Conclusion: The history of Mexican Neurology is vast and complex, and dates from the ancient prehispanic cultures. Even today, Neurology in Mexico is constantly evolving, so that they can provide better care for patients, based on evidence and clinical expertise.

Strains Drive Strain-Specific CNS-Immune Responses Anita A. Koshy, Shraddha Tuladhar, Yarah Ghotmi, Apoorva Bhaskara and Joseph Lagas. Tucson, AZ Toxoplasma gondii is an intracellular parasite that latently infects the brain of up to 1/3 of the world. Though asymptomatic in most, in immunocompromised individuals, Toxoplasma can cause symptoms ranging from focal neuroinflammation to death. While the determinants of disease variability are poorly understood, recent human data suggest that the genotype of the infecting strain may influence outcomes. In vitro and in vivo work suggest that Toxoplasma strain-specific polymorphic effector proteins injected into host cells can lead to different innate immune responses. Thus, we hypothesized that different Toxoplasma strains provoke distinct, strain-specific CNS immune responses, which in turn would affect disease outcomes. To test this hypothesis, we used quantitative immunohistochemistry to compare CNS immune responses in mice infected with either type II or type III parasites. At 3 weeks post infection (wpi), we found that despite having similar parasite burden, the CNS of type III-infected mice had a more pro-inflammatory immune response (macrophages and T-cell response, and cytokines/chemokines) as compared to type II-infected mice. Our flow cytometry analysis of immune cells isolated from the spleen and brain of 3 wpi mice also showed that type III-infected mice had a significantly lower numbers of alternatively activated macrophages (AAMs) and regulatory T cells as compared to type II-infected mice. However, early in infection (0.5 wpi) type III-infected mice had higher numbers of AAMs. Taking these data together, we propose that by inducing a robust pro-inflammatory response early on, type II infection provokes a tempering anti-inflammatory response that will ultimately hinder the host from eliminating CNS parasites. Conversely, early in infection type III parasites elicit a less inflammatory response which converts to a stronger pro-inflammatory response as parasites expand and disseminate, ultimately resulting in a highly effective immune response capable of clearing CNS parasites. Consistent with this model, at 16 wpi, we find that type IIIinfected mice have a much lower CNS parasite burden compared to type II-infected mice. Current work is identifying the parasite and host factors that determine these strain specific differences in the CNS outcomes. Background: The neurologic complications of EVD are not well-known and are still being characterized. The recent EVD epidemic in West Africa resulted in more than 10,000 reported cases with over 5,000 survivors in Liberia alone.

Design/Methods: Self-identified EVD survivors (n5164) and close contacts of EVD survivors (n592) enrolled in the ongoing PREVAIL III EVD natural history study underwent a detailed neurological evaluation. A standardized assessment was used at the 6-month study visit to collect information on neurologic symptoms during and after EVD and to document neurologic examination findings. The cohort underwent follow-up neurological assessment at the 12-month study visit. Based on disparate serology testing, 11 self-identified survivors and 11 self-identified close contacts were excluded from the analysis.

Results: The 153 EVD survivors had a mean age of 34.1 years (SD511.0) and the 81 close contacts had a mean age of 35.3 years (SD512.7). 70.6% of survivors were admitted to an Ebola Treatment Unit (ETU) for more than 14 days. The most commonly recalled new neurologic symptoms during or after the ETU admission were: headache, depressed mood, myalgia, weakness, and memory loss. Severe neurologic manifestations included seizures, stroke, meningitis, and coma. The most commonly reported ongoing symptoms were headache, depressed mood, and memory loss. The majority of survivors had abnormal neurological exams. The most common neurologic findings were abnormalities of eye pursuits and saccades, tremor, pathological reflexes, and mild dysmetria. These findings were all significantly different from the control population. Asymptomatic peripheral neuropathies were seen in a significant proportion of both survivors and close contacts. On follow up 6 months later, 144 survivors and 76 close contacts were seen. Many survivors reported improvement in some of their symptoms; however, a significant proportion of survivors have ongoing complaints, most notably headaches and memory loss.

Conclusion: Acute manifestations of Ebola infection include a meningoencephalitis, seizures, and strokes. The chronic sequelae involve both diffuse and focal neurological findings as well as depression and post-traumatic stress syndrome. Follow up evaluations of survivors are ongoing and will allow for additional insight into the neurologic burden of EVD. Background: NS is an epileptic encephalopathy with head nodding and other seizure types, developmental delay, and behavioral changes. Described in Tanzania in the 1960s, epidemics of NS occurred in South(ern) Sudan (from 1991) and Uganda (2000-13) , with affected children more heavily infected with nematodes (Onchocerca volvulus, Mansonella sp.) than controls. Our 2014 case-control study of NS revealed a case association with prior measles infection, and a clinical course consistent with a postviral disorder akin to subacute sclerosing panencephalitis, suggesting nematode infection is a bystander that capitalized on prior viral infection (Spencer et al., J. Neurol. Sci. 369:191, 2016 & 372:441, 2017 . Onset of head nodding was associated with poor nutrition, food dependence on moldy maize, the associated mycotoxins (aflatoxins, fumonisins) potentially activating a latent neural virus or changing the epileptogenic threshold. Given the absence of new NS cases in 2014 and resumption of a usual diet across the community, we tested the hypothesis that mycotoxin load, a reflection of contaminated food intake in the past few days, would currently not differ between NS cases and controls.

Design/Methods: Plasma and urine samples from 50 Ugandan NS cases and 50 age-matched Community Controls (CC) were subjected to liquid chromatography-mass spectrometry multi-mycotoxin analysis.

Results: For urine, mycotoxins were detected in 14%/ 12% of NS/CC. Most frequently detected was the fumonisin immunotoxin deoxynivalenol (DON), seen in 4/50 NS and 4/50 CC (mean values 21.3 and 3.1 mg/L, respectively). Oxidized luol was present in 3 NS and 2 CC. Trace amounts of the quantitative transition for zearlenone-4-glucoside were detected in 17 NS and 22 CC and, for deepoxy-DON, in 4 NS and 1 CC. Only oxidized luol contaminated plasma in 2 NS and 2 CC samples. The qualitative transition for DON was seen in many plasma samples (28 NS, 23 CC) but without the quantitative signal, this mycotoxin was not confirmed. The same qualification applied to DON-3-glucoside (9 NS, 11 CC), 3-acetyl- DON (22 NS, 17 CC) .

Conclusion: Children in post-NS epidemic Uganda are exposed to mycotoxins and the toxic burden is similar in established cases of NS and CC. Study supported by R01 NS079276. Background: There are limited data on mortality and disability following stroke in Sub-Saharan Africa (SSA). We characterize factors associated with 90-day mortality and disability post-stroke in patients admitted to the Muhimbili National Hospital (MNH), Tanzania's largest referral hospital.

Methods: Patients with acute stroke were enrolled within 14 days of symptom onset (July 2016-January 2017). Upon admission, demographic and clinical variables were assessed. Outcomes of interest were mortality and modified Rankin Scale (mRS) at hospital discharge and at 90-day telephone follow-up. Multivariable models were constructed using variables that were significant on univariate exploratory analyses (p<0.10): age>50 years, sex, unconsciousness, systolic blood pressure (SBP)>180mmHg, and NIH Stroke Scale (NIHSS).

Results: Of 206 patients (average age 58.5, SD 14.8), 107 were ischemic (53 male) and 99 were hemorrhagic (52 male). At hospital discharge, mRS among patients with ischemic stroke was 0 (n52), 1 (n54), 2 (n512), 3 (n58), 4 (n554), 5 (n57), and 6 [death] (n520). At 90 days, mRS among 93 patients was 0 (n55), 1 (n55), 2 (n57), 3 (n58), 4 (n514), 5 (n55), and 6 (n549). At 90 days, statistically significant predictors of death included NIHSS (p50.004) and unconsciousness (p50.014). At 90 days, predictors of mRS 4-5 compared to 0-3 included NIHSS (p50.020) and unconsciousness (p50.034). For hemorrhagic stroke, mRS among patients was 0 (n50), 1 (n53), 2 (n57), 3 (n510), 4 (n541), 5 (n510), and 6 (n528) at discharge. At 90 days, mRS among 87 patients was 0 (n58), 1 (n54), 2 (n511), 3 (n511), 4 (n512), 5 (n50), and 6 (n541). At discharge, predictors of death included sex (p50.046), NIHSS (p<0.0001), SBP>180mmHg (p50.016), and unconsciousness (p50.002). At 90 days, predictors of death included NIHSS (p<0.0001) and unconsciousness (p50.003). At 90 days, predictors of mRS 4-5 compared to 0-3 included NIHSS (p50.069) and unconsciousness (p50.006).

Conclusion: There is a higher 90-day mortality and disability from both stroke types at this large referral hospital in SSA as compared to reports from high-income countries with a high proportion (48%) of hemorrhagic stroke. NIHSS and unconsciousness at the time of admission each independently predicted mortality and worse disability. While not predictors of 90-day mortality from hemorrhagic stroke, sex and SBP>180 were predictive of in-hospital mortality. Clinically useful predictors that require little expertise or infrastructure could devise meaningful bedside interventions and prognostication in SSA.

Jiang Wu, Bihua Bie, Joseph F. Foss and Mohamed Naguib. Cleveland, OH Introduction: Paclitaxel-induced neuropathy is associated with morphologic and biochemical alterations in dorsal root ganglia satellite cells, hyperplasia/hypertrophy of macrophages in the peripheral nervous system, and microglial and astrocyte activation within the spinal cord. This neuroinflammatory process causes central sensitization, leading to the persistent pain states. There is, therefore, a critical need to determine how paclitaxel alters pain sensation due to microglia activation and central sensitization. Cannabinoid receptor type 2 (CB2) is expressed primarily in the immune system including microglia in the CNS. MDA7 is a novel selective CB2 agonist that has shown efficacy in ameliorating microglial activation and preventing allodynia in rodent models of neuropathic pain. Our study is expected to elucidate the mechanism underlying the paclitaxel-induced neuropathic pain and its modulation by the CB2 receptor.

Methods: Rats received 1.0 mg/kg i.p. of paclitaxel (or vehicle) daily for 4 consecutive days. MDA7 (15 mg/kg) or vehicle was injected (i.p.) 15 min before the administration of paclitaxel for 4 days and continued for another 10 days. AM630 (5 mg/kg i.p.), a selective CB2 receptor antagonist, was used in subsets of experiments. Mechanical sensitivity was assessed by using a series of Von Frey filaments. Immunostaining and immunoblotting were performed to examine the activation state of microglia and the expression of BDNF and other proteins in dorsal horn (L4-5).

Results: Paclitaxel significantly increased microglia activity and CB2 expression in dorsal horn, which was attenuated by MDA7. Paclitaxel induced microglia polarization as shown by increase of IL-6 (M1 marker) expression and decrease of IL-10 (M2 marker) in dorsal horn, which was attenuated by MDA7. MDA7 also prevented the upregulation of microglial P2X4 in paclitaxel-treated rats. Paclitaxel also significantly increased the expression of CaMKIIa, phosphorylated CREB, DFosB and BDNF in the dorsal horn (L4-L5) tissue in rats treated with paclitaxel, which was reversed by MDA7. Furthermore, paclitaxel significantly increased the expression of glutamate receptor subunits NR2B and GluR1, and decreased expression of anion transporter KCC2 in the dorsal horn, which was reversed by MDA7. MDA7 also attenuated the mechanical allodynia induced by paclitaxel in the rats.

Conclusion: Paclitaxel induced significant microglial polarization, BDNF upregulation, and central sensitization in dorsal horn and mechanical allodynia in the rats, which was prevented by MDA7. This presented a novel pathogenesis mechanism, and proposed an innovative therapeutic approach with a novel CB2 agonist MDA7 for paclitaxelinduced neuropathic pain.

Vignesh Ravi, Megan Simmons, Derrick Huang, Christopher Lee, John S. Sergent, Lan Zhou and Jun Li. Nashville, TN and New York, NY Mutations in genes encoding for voltage-gated sodium channels (Nav1.7 and Nav1.8) are typically associated with painful sensory neuropathies. In contrast, Nav1.9 (or SCN11A) is primarily expressed in nociceptive neurons of ganglia. A missense mutation (Arg225Cys) in the Nav1.9 has been described in two Chinese families with episodic pain syndrome (Zhang et al., AJHG, 2013) . However, it is still unclear whether the mutations in Nav1.9 cause nociceptive or neuropathic pain with sensory neuropathy. We have identified the Arg225Cys mutation in a Caucasian family. The proband (29-year-old woman) was initially diagnosed as having"fibromyalgia" due to her chronic aching in joints and muscles. However, her family history prompted genetic testing that demonstrated the Arg225Cys mutation in Nav1.9. Thus, we studied 5 additional family members with the "fibromyalgia" phenotype and one non-affected member. The Arg225Cys mutation was found in all 5 affected members, except the non-affected one by Sanger sequencing of their DNA. To determine the nature of the pain, we have developed a pain differential scale consisting of 15 questions. This scale was first validated in patients with Amyotrophic Lateral Sclerosis (primarily nociceptive pain) and patients with Diabetic Polyneuropathy (primarily neuropathic pain). The scale showed significantly more nociceptive pain for patients with ALS (p50.02) and more neuropathic pain for patients with DP (p50.01). This scale was then applied to the family and demonstrated almost exclusively nociceptive pain (9.0 6 7.2 nociceptive and 0.3 6 0.82 neuropathic; p50.015). Furthermore, nerve conduction studies in three affected family members showed no large fiber neuropathy. Skin biopsies from all 7 family members were used to quantify the epidermal nerve fiber density, which were all within the normative range. Thus, no patient had peripheral neuropathy. Our findings are significant in several aspects: 1. Patients with the Arg225Cys mutation and prominent nociceptive pain are in line with the known localization of Nav1.9 in nociceptive neurons, thereby supporting a human molecular target specific to the nociceptive pain; 2. Patients with chronic aching in joints, muscles or carrying a diagnosis of "fibromyalgia" might become potential candidates for identifying additional mutations in the SCN11A gene. Supported by grants from NINDS (R01NS066927) and the NCATS (UL1TR000445). Background: Three million people in the United States carry an active diagnosis of a seizure disorder with approximately one-third being refractory. Headache disorder with migraine features is also highly prevalent affecting thirty eight million individuals, women more than men. Both disorders often co-exist and are associated with significant personal, social, and economic implications. Despite evidence, headache is often under-recognized and under-treated. This study examined the prevalence and classification of postictal headache in respect to its comorbidity.

Methods: The study took place in an eight bed Adult Epilepsy Monitoring unit at Mayo Clinic over a period of eight months. The participants were voluntary recruited via consent forms. Two questionnaires were administered: one query interictal headache and second one assessing characteristics and intensity of postictal headache within the three hours of a seizure onset. Headaches were classified in accordance with ICHD III-beta criteria. Patients with behavioral spells and those without confirmed epilepsy diagnosis were excluded from the study.

Results: Preliminary data includes 91 subjects who met inclusion criteria and completed the initial questionnaire and postictal survey. Interictal headaches were reported in 79 of 91 (84%) subjects. Interictal headaches met ICHD III-beta criteria for definite migraine in 18 (20%) subjects and for probable migraine in another 18 (20%) subjects. Criteria for definite and probable tension type headache were met in 13 (14%) and 11 (12%) subjects, respectively. Postictal headaches were reported by 57 of 91 (63%) subjects. Seven of 20 (35%) males and 22 of 37 (59%) females reported postictal headaches which met criteria for probable or definite migraine. Further 29 of 57 (51%) subjects met ICHD III-beta criteria for migraine: 30% definite and 21% probable migraine. Another 9 of 57 (16%) subjects met criteria for definite or probable tension type headache and 19 subjects of 57 (33%) were unclassified.

Conclusion: This study confirms that the prevalence of postictal headache is common in patients with epilepsy. Headache with migraine features appears to be dominant headache type. Neurology providers are in a position to intervene and offer additional treatment modalities for headache management to decrease comorbid disability and disease burden. Purpose: This study aimed to characterize the nature of visual field deficits in patients with visual symptoms presenting to the neuro-ophthalmology clinic that was eventually attributed to a headache disorder.

Methods: We performed a single-center prospective evaluation of visual complaints in the setting of a headache disorder at the Kentucky Eye Clinic between January 2012 and May 2014. Subjective visual complaints included blurry vision, visual distortions, double vision, transient visual loss and visual field losses. All underwent a detailed, standardized neuro-ophthalmology exam including visual acuity, color vision, contrast sensitivity, visual fields (Humphrey field analyzer 24-2 SITA Standard), examination of the pupil, anterior segment and dilated posterior segment exam and intraocular pressure.

Results: There were 159 individuals in this study, 75% female with a median age of 37 (range: 8-88) Visual complaints prompting consultation included visual distortions (n587) blurry vision (n542), transient visual loss (n527), diplopia (n518), visual field loss (n517), eye pain (n57) and tunnel vision (n54). These were attributed to a headache disorder after a thorough neuro-ophthalmology exam that was normal with no afferent pupillary defect. Per ICHD-II criteria, their pre-existing headache disorder included: Migraine with aura (n556), migraine without aura (n545), chronic migraines (n528) and typical aura without headache (n52). Some of the patients had no preexisting headache disorder prior to initial consult (n528). Clinical diagnoses for presenting symptoms based on neuroophthalmologic evaluation included typical aura without headache (n562), migraine with aura (n556), chronic migraine (n510), migraine without aura (n57) and retinal migraine (n51). Visual fields were normal in 84 patients (51.9%), unreliable in 11 (6.9%), had clover leaf pattern in 6 (3.8%-bilaterally), and had nerve fiber bundle pattern defects in 58 (36.5%).

Conclusions: In our prospective cohort of patients with visual symptoms attributable to a headache disorder, visual field abnormalities were not uncommon (seen in 36.5%), and most often monocular (68%). The pathophysiologic significance of these findings is uncertain. Purpose: A challenge confronting the U.S. is delivery of quality specialty health care to citizens living in rural areas. New Mexico's (NM) Albuquerque VA developed a teleneurology system to cover an extensive geographical area. We analyzed our first 1100 teleneurology patients.

Methods: Veterans living in remote areas of NM were offered follow-up teleneurology care at 16 rural communitybased outpatient clinics (CBOCs) following an initial evaluation in Albuquerque. Outcome measures mailed to the Veteran focused on patient-reported quality and satisfaction of care. Problems encountered, staff analysis of differences between face to face clinics and teleneurology, and cost savings were also examined.

Findings: All 698 returned surveys (63%) were reviewed. These showed 90% perceived they received good care, 91% felt there was good communication, 89% liked the convenience, 87% reported they desired to continue teleneurology care, 89% were satisfied with their care and 96% reported saving time, money or both by being seen at their local CBOC instead of driving round trip to Albuquerque. Nearly US$154,000 was saved.

Emergency room visits for neurologic problems were similar for both teleneurology and face to face patients.

Conclusions: Neurology staff and our rural Veterans overwhelmingly found high quality patient care can be delivered by teleneurology to a wide variety of chronic neurologic problems, and similar to care delivered in our faceto-face clinics. Veterans wanted to continue to be seen by teleneurology. Introduction: Reduction of recurrent stroke risk requires interventions that address multiple stroke risk factors, but most community-based trials are insufficiently powered to assess "hard" CVD outcomes like time to recurrent stroke. Demand exists for innovative approaches to estimate the impact on overall recurrent stroke risk of interventions targeting a range of stroke risk factors.

Methods: We conducted a review of meta-analyses, randomized trials, and observational studies on individual stroke risk factors of blood pressuring lowering, cholesterol reduction, smoking cessation, and antiplatelet/antithrombotic use, and we extracted relative risks for each. Stroke risk reduction was modeled using bootstrapping and simulation methods, to develop a modified GO Score or the proportion of potential benefit (relative risk reduction) achieved if all of the individual risk factor interventions were implemented perfectly. Sensitivity analyses varied assumptions about the impact of observed blood pressure changes and medication use. We applied the algorithm to one-year follow-up data from SUSTAIN, a community trial that randomized 407 participants with a recent stroke or TIA to receive either usual care, or culturally-tailored, care manager-led multiple risk factor program. We used observed changes in systolic blood pressure and LDL cholesterol and medication adherence data from the trial, assuming a multiplicative relationship for the relative risks for treatment of each individual risk factor, as derived from the review.

Results: The literature review yielded parameters sufficient to model stroke risk reduction among 272 SUSTAIN trial participants (60% male; mean age 57 years; 62% Spanish speaking) with complete 12 month data. Changes in individual risk factors and medications were similar in intervention and control groups (p0.2); and the estimated combined reductions in the relative risks of CVA were 0.42 and 0.37, respectively, a non-significant risk difference of 5%. GO Score results suggest that trial participants in both arms likely averted 30-50% of vascular events that could possibly have been prevented through maximal implementation of treatments for individual risk factors.

Conclusions: We demonstrate the feasibility of estimating the impact on "hard" CVD outcomes in the setting of a modest-sized, community-based, multi-faceted trial to prevent recurrent CVD and stroke. We propose global risk reduction as a secondary endpoint for SUCCEED, an ongoing randomized controlled trial of a multiple risk-factor coordinated care intervention to prevent recurrent stroke. Background: A hospital's designation status and/or certifications entail that the hospital has met a set of unique standards that define the facility's roles and parameters to serve the community. We hypothesize, that after controlling for confounding variables, a hospital designation/certifications status will influence a patient's health outcomes (i.e. length of stay (LOS), mortality).

Methods: Stroke patients (n5324,928) who were admitted to NYS hospitals between 2009 and 2014 were extracted from New York's Statewide Planning and Research Cooperative System. Patients were stratified based on hospital designation status [Safety-Net-Hospital (SNH), Non-Safety-Net-Hospital (NSNH)] and stroke-related certifications [Accredited-Advance-Comprehensive Stroke Center (ACSC), Accredited-Advance-Primary Stroke Center (APSC), Non-Accredited Stroke Center (NASC), or Hospitals without a Stroke Center (HwSC)]. The differences were examined using T-Tests and ANOVA. The interaction effect between hospital designation status and stroke-related certifications were examined with a negative binomial regression to assess its association with LOS, while, the logistic regression assessed its association with inpatient mortality.

Results: Patients treated at a SNH with an ACSC (7.03 days) had a longer average LOS relative to NSNH with a ACSC (5.98 days). The negative binomial regression results illustrated SNH (b:0.23, q50.000) were associated with shorter LOS relative to a NSNH. Patients treated at an ACSC (b:0.37, q50.000), APSC (b:0.25, q50.000), NASC (b:0.33, q50.000) were associated with shorter LOS compared to HwSC. The interaction effect illustrated SNH with ASCS (b:0.30, q50.000), APSC (b:0.25, q50.000), NASC (b:0.32, q50.000) were associated with longer LOS compared SNH without a stroke center. The logistic regression results illustrated patients treated at an ACSC (OR:0.72 q50.000), APSC (OR:0.78, q50.000), or NASC (OR:0.72, p50.000) were associated with lower odds of mortality relative to a HwSC. Patients treated at a SNH with an ACSC (OR:0.65 q50.000), or APSC (OR:0.86, q50.012) were associated with lower odds, while SNH with a NASC (OR:1.21, q50.000) were associated with higher odds of morality compared to a SNH without a Stroke Center.

Conclusion: ACSC have longer LOS, as ACSC are more likely to treat complicated stroke patients relative to other hospitals. Patients treated at ACSC are more likely to receive advanced care, thereby, reducing their mortality rates. Further investigation is warranted to examine whether the Joint Commission Certification guidelines influenced the differences in LOS and mortality. Background: Previous literature illustrates that stroke patients admitted on weekends, in general, have longer LOS relative to patients admitted on weekdays. Studies have compared the impacts of weekday and weekend admissions, and concluded LOS to be associated with the type of stroke, health outcomes and patient satisfaction. Minimal studies have examined the association between LOS and day of the week on health outcomes. After controlling for patient and hospital characteristics, it is expected that admission day will also influence LOS for stroke patients in NYS.

Methods: A retrospective study was conducted on a sample of 324,928 stroke patients who were admitted in NYS hospitals between 2009 to 2014. The data was extracted from New York's Statewide Planning and Research Cooperative System. Patients were stratified into three admission groups: Monday-Wednesday, Thursday-Friday, or Saturday-Sunday. ANOVA examined the variation among the descriptive statistics between admission groups. Negative binomial regression models examined the association between length of stay and admission day while controlling for confounding variables. The day of admission was treated as a binary dependent variable.

Results: Patients admitted on Saturday-Sunday (6.22 days) had longer average LOS relative to patients admitted on Monday-Wednesday (5.61 days), and Thursday-Friday (5.98 days). The negative binomial regression results illustrated, patients admitted between Thursday-Friday were estimated to have a 3.0% (q50.000) shorter LOS, while patients admitted between Saturday-Sunday were estimated to have a 3.8% (q50.000) longer LOS, compared to patients admitted between Monday-Wednesday. Patients admitted on Fridays were estimated to have a 11.2% (q50.000) longer LOS relative to patients admitted on Mondays. Patients treated at a non-accredited stroke center hospital were estimated to have shorter LOS if admitted on Tuesday by 16.6% (q50.037) or Friday by 14.5% (q50.045) relative to patients admitted at a hospital without a stroke center.

Conclusion: Stroke patients admitted in NYS on weekdays have a shorter LOS relative to patients admitted on the weekend. This study support current literature and highlights the influence a weekend has on LOS for patients admitted later in the week. Further investigation is warranted to examine whether the differences in LOS is associated with variation in treatment protocols practiced in NYS hospitals. Objective: Brachial plexus injury (BPI) disproportionately affects young males causing lifelong disability and decreased quality of life (QOL). There is little familiarity among medical practitioners, including neurologists, about options that reconstructive neurosurgery offers. However, the field has an array of procedures that can effectively restore lost function. Restoration of elbow flexion remains a surgical priority and time is critical. Within the first six months to a year of injury, nerves can be transferred, as the weak muscle remains receptive to reinnervation. Beyond a year, options remain but are more limited. The most common procedure to re-innervate elbow flexion is the Oberlin procedure. This involves cutting redundant motor fascicles of the ulnar nerve as it passes the biceps and attaching this fascicle to the musculocutaneous branch just before entering the Biceps muscle, usually with excellent results. We present a cost-effectiveness analysis for performing this procedure. This model assesses QOL impact, surgical costs, and the possible income recovered through restoration of elbow flexion.

Methods: A Markov model was used to simulate Oberlin nerve transfer versus conservative measures in terms of elbow flexion recovery and subsequent improvements in QOL for patients with upper BPI. Transition probabilities were collected from prior studies assessing surgical efficacy of Oberlin nerve transfer, complication rates, and natural history of conservative treatment. Incremental cost-effectiveness ratios (ICER), defined as cost in dollars per QALY (quality-adjusted life year), were calculated. Incremental cost-effectiveness ratios less than $50,000/QALY were considered cost-effective.

Results:

The base-case analysis demonstrated Oberlin nerve transfer had an estimated cost of $5066.19 and improved effectiveness by 0.79 QALY over a lifetime compared with conservative management. Ignoring indirect cost due to loss of income associated with elbow function loss, nerve transfer had an ICER of $6,453.41/QALY gained, indicating cost-effectiveness. Factoring in loss of income, surgical treatment had an ICER of -$96,755.42/QALY gained, demonstrating an overall lifetime cost saving due to increased probability of returning to work.

Conclusion: If performed within the critical window, the Oberlin procedure is not only efficacious in restoring function but also highly cost-effective. Nerve transfer surgery should be considered in the acute phase of any management plan for peripheral nerve injury. It is hoped this study will increase awareness among neurologists, often gate-keepers to the reconstructive neurosurgeon, of the efficacy of this procedure and urgency for appropriate evaluation. Background: Reducing the Door-to-Reperfusion time (D2R) is an essential factor to promote a good clinical outcome in the endovascular treatment of large vessel occlusion of anterior circulation stroke. It is imperative to know the critical steps, in which we can reduce the D2R time in the acute stroke intervention.

Objectives: The object of this study is to identify the critical steps that cause the delay in D2R by utilizing the time metric system. This study further evaluates the implementation of Quality Improvement project (QI) to to develop an optimal workflow to improve D2R in acute stroke intervention.

Methods: Retrospective cohort analysis was performed over a four-year-period in anterior-circulation stroke with thrombectomy. D2R was collected and subdivided into various interval time, such as Door-to-CT (D2C), CT-to-AngioSuite (C2A), and Puncture-to-Recanalization (P2R). Time metric system was implemented to detect the delay of each interval. The impact of time metric system was evaluated by comparing each interval time of pre-vs. post-QI cohort. The Angiographic outcomes in Thrombolysis in Cerebral Infarction (TICI) perfusion scale, and clinical outcome of modified Rankin Scale (mRS) at 90 days were also compared between pre-vs. post-QI cohort.

Results: Data of a total 40 patients pre-QI, and 81 patients post-QI cohort were analyzed. In the Pre-QI, the greatest delay was observed in the C2A with median 94 minutes. QI significantly shortened C2A (pre-QI vs Post-QI: 94 vs 35 min), resulted in significant reduction in D2R (229 vs 145 min). There was no significant difference in the P2R or in the proportion of the good angiographic outcomes of TICI IIB and III between pre-vs. post-QI cohort. The proportions of good clinical outcome in mRS 0-2 were significantly higher in post-QI (50% vs 64%).

Conclusion: The QI project with time metric implementation substantially reduce in various interval time of D2R, especially in the C2A, which lead better clinical outcome. Object: The objective of this study is to examine the underlying spinal disorders that share similar MR findings with SDAVF/SAVM. We further review their respective causative pathophysiology.

Patients and Methods: In this retrospective study, we reviewed the clinical and imaging data of a cohort of patients with suspected SDAF or SAVM on MRI. Each patient's spinal angiogram, MRI, CT myelogram and pathological data were reviewed.

Results: Between March 2010 and February 2017, 59 patients (m/f: 38/21, age: 19-72) underwent spinal angiography. Of this cohort, four patients showed no SDAVF or SAVM on their spinal angiograms. From this negative SDAVF/SAVM population there was: one intradural paraganglioma, one vertebral aneurysmal bone cyst, one craniocervical junction meningioma, and one Chiari malformation with syrinx. These four patients underwent surgical tumor removal or posterior fossa decompression with full resolution of their perimedullary venous dilatation on repeat imaging and clinical improvement.

Conclusion: Feeding/draining vessels of spinal tumors and spinal vein/CSF obstruction with secondary venous dilatation can mimic the pathognomonic findings in SDAVF or SAVM. SDAVF and SAVM are rare, underdiagnosed and can prove difficult to diagnose. Along with detailed MR imaging interpretation, spinal angiography can help in clinical decisions and should be performed in order to differentiate between SDAVF/SAVM and other possible radiographic mimics.

M242. Endovascular Thrombectomy of Wake-Up MCA Stroke Shuichi Suzuki, Monica Lavian, Wengui Yu and Frank Hsu. Orange, CA Background: Wake-up strokes consist of approximately a fourth of acute ischemic stroke (AIS). Although recent randomized control trials (RCTs) have demonstrated efficacy and safety of endovascular therapy for AIS, patients with wake-up stroke are generally not treated with thrombolysis or endovascular therapy due to unclear time of symptom onset and lack of RCT data as of April of 2017.

Objective: We report three cases of wake-up stroke with large vessel occlusion (LVO) that was successfully treated utilizing stent clot retrievers following multimodal imaging CT angiogram (CTA) and CT perfusion (CTP) studies.

Patients and Methods: Case 1: A 44-year-old righthanded gentleman with mechanical aortic valve woke up with speech difficulty and right-sided weakness at 4am. The last known well time (LKWT) was 9pm the night before. He was transferred to us 11 hours after LKWT. Neurological examination demonstrated expressive aphasia and severe right hemiparesis with NIHSS 15.

Case 2: A 51-year-old right-handed woman with history of hypertension and patent foramen ovale woke up with right hemiparesis and aphasia. The LKWT was 12 hours prior to our hospital arrival. Initial NIHSS was 8.

Case 3: A 31-year-old firefighter woke up with right sided weakness and aphasia. The LKWT was 8 hours prior to arrival at the primary stroke center. Initial NIHSS was 18, and he was transferred to us for endovascular treatment.

Results: For all three patients, Non-contrast CT showed hyperdense middle cerebral artery (MCA) sign. CTA confirmed left M1 LVO. CTP demonstrated a small decreased area of cerebral blood volume in the left sylvian region whereas large low perfusion area in the left MCA territory in cerebral blood flow images. This multimodal neuroimaging suggested the existence of salvageable brain tissue i.e. penumbra. Therefore, all three patients underwent embolectomy. The left M1 was successfully recanalized with stent retriever leading to TICI III. Their hospital stay was short with marked neurological recovery. All three patients achieved modified Rankin Scale 1 with minimal language deficits at 3 moths follow up.

Conclusions: Our case report suggests there is an opportunity to rescue ischemic brain by endovascular therapy with multi-modal image guided decision for patients with wake-up stroke.

Hamidreza Saber, Parthasarathi Chamiraju and Sandra Narayanan, Detroit, MI Background: Idiopathic intracranial hypertension (IIH) is characterized by an elevated intracranial pressure without any identifiable causative factor such as an intracranial mass. Venous sinus stenosis has been increasingly known as a treatable cause of elevated intracranial pressure in patients with medically refractory IIH.

Objective:We aimed to perform a systematic review and analysis of outcomes and complications in all patients undergoing dural venous sinus stenting (DVSS) for the management of medically refractory IIH.

Methods: We searched PubMed and Google Scholar databases to identify prospective or retrospective cohorts or case-series of patients with IIH treated with DVSS between 2000 and 2017.

Results: A total of 418 patients were included in our analysis from 30 studies. Headache was present in 386 (92%) of patients and resolved or improved in 293 (76%) after DVSS. Tinnitus resolved in 95% (129/136) of patients after venous stenting. Papilledema and visual changes improved in 87% (284/327) and 85% (211/247) of patients following DVSS. Overall, 12.2% of patients required re-treatment with re-stenting or other surgical procedures. The rate of major neurological complications was less than 0.1%.

Conclusion: Our results add to the growing body of literature that proposes DVSS as a safe treatment option with high clinical success rate and low complications in patients with medically refractory IIH and evidence of venous stenosis.

Mahya Beheshti, Hooman Salimipour, Mohammadmostafa Jahansouz, Fatemeh Azizi and Sayena Jabbehdar. Tehran, Islamic Republic of Iran; Bushehr, Islamic Republic of Iran and Tonekabon, Islamic Republic of Iran Objective: Restless leg syndrome (RLS) is a neurological disorder which is prevalent in patients on hemodialysis. The aim of this study was to identify possible risk factors of RLS in hemodialysis patients.

Methods: 130 patients on hemodialysis were enrolled in this cross-sectional study. The RLS was diagnosed using international criteria. The potential risk factors including demographic data, renal failure duration, a frequency of hemodialysis, family and drug history, underlying disorders, levels of blood urea nitrogen (BUN) and ferritin were recorded for all patients.

Results: Among enrolled cases, 43 patients had restless leg syndrome (18 females (41.9%) and 25 males (58.1%)). There is a statistically significant relationship between positive family history and restless leg syndrome (p<0.016). The family history of RLS results in 3.39 times more risk of having this syndrome in comparison with other patients (confidence interval 1.25-9.21). No significant correlation was found for gender, age, ferritin level, a length of renal failure, and BUN.

Conclusion: RLS has a high prevalence in our sample of patients on hemodialysis. The positive family history for this disorder had significant relation with RLS. Roberto A. Ortega, Anat Mirelman, Claustre Pont-Sunyer, Dolores Vilas, Kathrin Brockmann, Bjorg Warø, Jan Aasly, Karen Marder, Daniela Berg, Tatiana Foroud, Eduardo Tolosa, Nir Giladi, Ilir Agalliu, Susan B. Bressman and Rachel Saunders-Pullman. New York, NY; Tel Aviv, Israel; Barcelona, Catalona, Spain; Tubingen, Germany; Trondheim, Norway; Indianapolis and Bronx, NY Background: Inflammatory bowel disease has been associated with an increased risk of Parkinson's disease. Further, the LRRK2 gene has specifically been linked to Crohn's disease (CD). In order to determine whether LRRK2 G2019S mutation carriers as well as non-mutation PD participants had an increased rate of CD, data from a health care questionnaire that queried self-report of cancer and other illnesses was evaluated.

Methods: This consisted of demographic, lifestyle factors, and self-reported personal medical history, querying, "Have you ever been told by a physician that you have Crohn's disease." The questionnaire was completed by 1,272 participants from six LRRK2 Michael J Fox Consortium sites from the US, Europe, Israel, including 282 LRRK2 mutation carriers (279 G2019S, 3 I2020T) with Parkinson disease (PD) (LRRK2PD), 735 PD without a LRRK2 mutation (IPD) and 255 non-PD, non-LRRK2 mutation carrying controls (control). The occurrence of CD between IPD, LRRK2PD and controls was compared using univariate analysis, as well as multivariate analysis adjusted for age and gender [IPD were more likely to be male (62.3%) compared to LRRK2PD (48.6%) (p<0.01), and both IPD and LRRK2PD were more likely to male than controls (31.8%) (both p<0.01). IPD (67.8 6 10.7 years) and LRRK2PD (68.2 6 10.4) were not different in age, but were older than controls (59.4 6 16.0) (both p<0.01)]

Results: In univariate analysis, LRRK2PD had higher occurrence of CD (3.55%) compared to controls (0.78%) (p50.039), and IPD (1.63%), although the latter difference did not reach significance (p50.09). In multivariate models LRRK2PD had higher odds of CD than IPD (OR52.13, p50.08) as well as controls (OR53.77, p50.09) although the comparisons were not significant. IPD were not more likely than controls to carry diagnosis of CD (OR51.75, p50.47) Conclusion: Self-report questionnaire data suggests that PD cases with LRRK2 G2019S mutations may be more likely to have CD than mutation negative PD and controls. The connection between LRRK2 mutations and CD further implicates an inflammatory pathway in LRRK2 PD, and particularly a role of Mitogen-activated protein kinase kinase (MAPK) as the mutation carriers harbored either G2019S or I2020T mutations. It is of interest that our study did not show an overall association between non-LRRK2 PD and controls, as would be expected based on other studies. Larger studies evaluating the connection between CD and PD, especially LRRK2 PD, are warranted. The transition from pre-manifest Huntington's disease (HD) to the observable movement disorder in symptomatic HD can be a gradual process spanning several years. Few studies have examined motor behaviors that predate the onset of frank chorea in HD. The presence of a biomarker early in the transition period may help efforts to pharmacologically manage or delay onset of this debilitating movement disorder. In the present study, we examined whether handwriting movement abnormalities are present prior to the manifestation of clinically overt chorea. Prior research has demonstrated that measures of handwriting kinematics are sensitive to mild pre-clinical motor abnormalities stemming from other basal ganglia disorders. Fifteen individuals testing positive for the HD genetic mutation on the huntingtin gene (mean CAG, 41.2) currently in a pre-manifest stage of the disease, 15 gene negative individuals (mean CAG, 20.5), and 16 clinically symptomatic HD patients (mean CAG, 42.7) participated in this study. Participants completed handwriting tasks consisting of writing simple and complex loops, rapid circles, spirals and a sentence, each repeated multiple times on a digitizing tablet using a non-inking pen. Multiple measures of pen stroke kinematics and pressure were extracted from these trials. The clinical status of each participant was characterized using the UHDRS. Statistical comparisons revealed significant differences between symptomatic HD and and pre-manifest subjects on several handwriting stroke features, particularly stroke duration and fluency. Discriminant function analyses were conducted to identify a multivariate model that distinguished pre-manifest from gene negative subjects. An 8-factor model consisting of stroke amplitude, velocity, fluency, and pressure (means and between stroke variability) for complex loops distinguished pre-manifest from gene negative subjects with 90% accuracy (F(8,21) 5 4.22; p<0.01) . A discriminant function model based solely on the UHDRS score achieved only 63% accuracy for separating pre-manifest from gene negative subjects. We observed statistically significant positive correlations between CAG repeat number and several handwriting variables among pre-manifest and symptomatic HD subjects including stroke duration and fluency for sentence writing and rapid circles. These findings support the clinical utility of dynamic measures of handwriting kinematics as a potential behavioral biomarker of disease progress in early HD. The Computerized Test of Information Processing (CTiP), is a relatively simple and useful tool for evaluating the extent to which neurological conditions affect cognitive processing speed. Administered on a laptop, it consists of three computerized reaction time (RT) subtests that progressively increase in task complexity-Simple RT (SRT); Choice RT (CRT), with an added decisional component; and Semantic Search RT (SSRT) with an added conceptual component. The objective of the current study was to examine central processing speed as an early marker of Huntington's disease (HD) onset using the CTiP. Gene carriers (n581) were categorized using the UHDRS Total Functional Capacity and Penny Burden of Pathology score as early premanifest, transitional (i.e. individuals close to disease onset or with very mild HD), or moderate HD. Subjects were administered the CTiP in addition to traditional cognitive assessments commonly used in HD. Central processing speed was measured using motor-corrected CRT and SSRT values. A one-way ANCOVA adjusting for age was used to compare group performance on the RT subtests. Moderate HD subjects showed significantly slower reaction times in all conditions (p<0.001), as compared to NC. Importantly, even transitional subjects showed significantly slower reaction times on the CRT (p<0.01) and SSRT (p<0.01), and in central cognitive processing, compared to NC. Our results suggest that the CTiP may be a useful and early marker of deficits in central cognitive processing in individuals with, and transitioning to, HD. Behavioral changes, including apathy, depression, irritability, anxiety, and difficulty prioritizing and initiating activities, are characteristic features of HD and may serve as an early marker of disease onset. The UCSD HD-BQ consists of 30 items with a 3-point rating scale (0-3), and takes about 5 minutes to complete. The maximum score is 90 with higher scores indicating greater severity. The objective of the current study was to utilize the UCSD Huntington's Disease Behavioral Questionnaire (HD-BQ) to assess behavioral changes that distinguish HD gene carriers transitioning to manifest HD. Gene positive subjects (n5118) were stratified using the UHDRS Total Functional Capacity and Penny Burden of Pathology score as early pre-manifest (EPM); transitional (i.e. individuals close to disease onset or with very mild HD); or mild-moderate manifest HD. The UCSD HD-BQ was administered to 22 normal control (NC); 29 EPM; 27 transitional, and 62 HD subjects. We used one-way ANOVA/Tukey Posthoc to compare groups on dependent variables and effect sizes to quantify the mean difference between each group. Mean MMSE, TFC, and TMS scores were 28.9, 12.8, and 1.7 respectively for NC; 28.2, 13.0, and 1.6 respectively for EPM; 27.3, 12.4, and 7.6 respectively for transitional; and 24.1, 8.2, and 35.6 respectively for manifest HD subjects. Although statistically significant differences were not seen between transitional or EPM subjects and NC with regard to these cognitive, functional and motoric measures, statistically significant differences were seen with regard to the HD-BQ between transitional (mean HD-BQ532.3; p50.000) and, more surprisingly, EPM (mean HD-BQ522.8, p50.011) subjects and NC (mean HD-BQ55.7). HD showed the largest effect size (0.620) compared to transitional (0.611) and EPM (0.481) subjects. Highest scoring symptoms among transitional and EPM subjects comprised anxiety, difficulty concentrating, and memory. We concluded that the HD-BQ is a brief, reliable instrument for screening behavioral changes in individuals at risk for, and transitioning to, HD. Behavioral disturbances are important in HD and may serve as an early marker of disease onset.

Tritia R. Yamasaki, Andrew S. Welleford and Greg A. Gerhardt. Lexington, KY Objective: Determine whether biochemical differences exist in alpha-synuclein found in Parkinson's disease (PD) and multiple system atrophy (MSA).

Background: In synucleinopathies such as PD and MSA there is growing support for the idea that different conformations of alpha-synuclein exist. In prior studies we found alpha-synuclein seeding ability present in both PD and MSA brain extracts using a cell-based FRET assay (Holmes and Furman, PNAS 2013). Here we test biochemical properties and antibody-binding of alpha-synuclein in these two diseases.

Methods: Brain tissue was serially extracted from patients with PD (n53) and MSA (n53) to yield detergent-insoluble fractions. We used commercial and novel antibodies generated to alpha-synuclein fibril and monomer to test MSA and PD fractions for binding of alpha-synuclein by immunoprecipitation. The forms of alpha-synuclein bound to the antibodies were assessed by fluorescence microscopy for ability to induce alpha-synuclein aggregation in the cellbased FRET assay.

Results: There were distinct differences in the ability of various antibodies to bind to alpha-synuclein from PD vs MSA. Both commercial and novel antibodies were able to bind a form of alpha-synuclein which was capable of seeding synuclein aggregation in the cell-based assay from MSA samples, but only minimally from PD samples. Investigation of species bound by Western blot is in progress.

Conclusion: Biochemical differences in pathologic alphasynuclein in PD and MSA support the idea of conformational differences in the aggregated state and may underlie the diverse clinical and pathologic characteristics seen in these two synucleinopathies.

Disorders: Update and Literature Review Robert Fekete. Valhalla, NY Background: Convergence spasm (CS) consists of episodes of convergence of the eyes, miosis, and accommodation occurring inappropriately. It was prospectively evaluated by Fekete et al. (2011) in movement disorders patients, finding marked CS in 9/13 (69%) of psychogenic movement disorder cases.

Introduction: The aim is to evaluate further case reports and series of CS.

Methods: PubMed was searched with keywords convergence spasm for articles published 1/1/2012 or later. English language case reports and case series of CS in patients age 18 or older with were included. In addition, two case series of psychogenic ophthalmologic and facial movement disorders evaluated in tertiary movement disorders clinic were included.

Results: 9 articles were included. 3 case reports of psychogenic or functional CS were retrieved. There was a case series of 3 patients where CS symptoms approximated attacks of benign vertigo. Additional retrospective case series by Kaski et al. lists 8 patients with CS classified as psychogenic from 817 neuro-otology clinic patients. There was 1 case report in multiple sclerosis and 1 case report of CS in ocular neuromyotonia. Retrospective chart review by Fasano et al. of 87 patients with psychogenic facial movement disorders did not identify any patients with CS. Retrospective chart and video review by Baizabal-Carvallo of patients with psychogenic ocular movement disorders also did not identify patients with CS.

Summary: In this search, 13 patients with CS without active neurological disease and 2 with organic neurological disease were reported. CS continues to be reported primarily as a functional disorder. Absence of CS on retrospective movement disorders clinic reviews may indicate that CS needs to be elicited by specific examination maneuver.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? No specific conflict regarding material presented. Dr. Fekete served on the Advisory Board of Teva Neuroscience, Inc., US WorldMeds, Neurocrine Biosciences, Inc, Lundbeck, LLC. Dr. Fekete served as a consultant for Teva Neuroscience, Lundbeck, LLC., Acadia Pharmaceutical, Inc., and Impax Laboratories, Inc. Background: There is heterogeneity in motor and nonmotor response to Deep Brain Stimulation (DBS). The underlying genetic etiology may help parse this heterogeneity. Mutations in the Glucocerebrosidase (GBA) gene are the most common genetic risk factors for PD and GBA-PD overall may have more cognitive decline, and faster progression. While cases with GBA-PD have been reported in DBS registries, cognitive decline is a possible relative contraindication for DBS in this group. Methods: We report a series of four patients (two women: (Patient 1(P1) and P2), two men: P3, P4) who underwent DBS surgery and harbored the GBA-N370S mutation. They underwent DBS for improvement of motor fluctuations (all) or dyskinesias (P2,P3). P1, P3 and P4 received bilateral subthalamic nucleus (STN) stimulation while P2 received bilateral globus pallidus interna (GPi) stimulation. Results: Average age at diagnosis was 55.3 and average age at DBS was 62.5. Unified Parkinson's Disease Rating Scale (UPDRS) scores preoperative were compared with one year post-DBS scores. Part II (Activities of Daily Living) improved by an average of 5.3 (11.2 ! 5.9). UPDRS-III (Motor exam) improved by an average of 6.1 points (19.1 ! 13.0). This improvement was driven primarily by P2/P4 wile P1/P3 saw a slight worsening of motor symptoms. UPDRS-IV (Complications of Therapy) showed a significant reduction of 4.4 (5.1 ! 0.7) (two-year data used for P3). The dyskinesias reported by P1,P2,P3 were markedly reduced or absent at one year post-DBS. UPDRS Mentation Score (1-4) showed an average increase in 0.4 (0.9 ! 1.3). More comprehensive cognitive testing was performed on some patients, showing mildmoderate (P2), and mild (P4) frontal-subcortical dysfunction pre-DBS. Repeat testing post-DBS found progression of those deficits in both. However, there was an improvement of 0.6 points (3.7 ! 3.1) in Section I overall (Mentation, Behavior, and Mood). Reduction in DOPA-mg dose averaged 483.8 and ranged from 0 to 1400. Conclusions: Our cases also suggest a diversity of response, and that DBS may be well tolerated, at least short term, in GBA-PD with the mild N370S mutation. As a group, there was overall improvement in motor function and overall Part I "mentation/behavior/mood" scores despite decline in cognition. The relative improvement in Part I scores may be attributable to lower dose of medication afforded by the surgery. Comparison with GBA cases who did not receive DBS is underway.

Michael Strupp, Anna Kichler and Olympia Kremmyda.

The video head impulse test (vHIT) has become an important clinical tool for the quantification of the gain of the vestibulo-ocular reflex (VOR) in patients with vertigo/dizziness and also to discriminate acute peripheral from central vertigo. Based on observed differences between VOR gains to the right and the left in single patients and between the different systems, we directly compared two different commercial vHIT systems: ICS Impulse V R : GN Otometrics (OT) and EyeSeeCamHIT V R : Interacoustics (IA). It is important to note that in the OT system the camera is permanently fixed on the right side, whereas the IA system allows recordings from either the right or the left eye.

Horizontal HIT was performed in 100 healthy individuals (mean age6SD: 46.8 6 18.3 years, range: 22-95 years) with both systems in a randomized way. We used the automatic system gain calculation of each system: area under curve (AUC) gain by the OT system and the gain at 60 ms (eye angular velocity/head angular velocity) by the IA system. We recorded all subjects with the camera on the right eye and 33 of them were additionally recorded from the left eye with the IA system.

In both systems, when the camera was placed on the right side, rightward VOR gains (head turned to the right) were about 0.05 higher than leftward gains (ANOVA Repeated Measures: AUC: R: 0.94 6 0.1 vs. L: 0.89 6 0.01, p<0.001, gain for 60 ms: R: 0.96 60.1, L: 0.91 6 0.11, p50.002). In the 33 subjects, rightward gain at 60ms was higher than leftward gain when the right eye was recorded (1.02 6 0.1 vs 0.93 6 0.1, p<0.001), whereas leftward gain at 60 ms was higher than rightward gain when the left eye was recorded (0.99 6 0.1 vs 0.93 6 0.1).

This study shows that there is a significant and clinically relevant systematic 5% direction bias for the side where the camera is placed for both systems: for the OT system this is always for the right side, whereas for the IA system it depends on where the camera is placed. This might be explained by the longer latency and therefore larger movement of the adducting ipsilateral eye. This bias should be taken into account when calculating internal normal values, depending on which system and which eye is used for recordings. Background: Genetic studies of PD have identified multiple genetic risk loci associated with "sporadic" PD as well as mutations causing familial forms of PD. These studies have mainly focused on Caucasian populations. Some studies suggest PD may be less prevalent in African than European Americans, which could be due to ascertainment bias. Familial PD does occur in African-Americans. Genetic studies in African Americans may detect novel PD causing variants, which may be limited to this population. In this study, we aimed to identify mutations that cause PD in African American patients using whole exome sequencing.

Methods: Exome sequence data was generated for 28 African American PD patients (10 f; mean age: 75 610 years; mean age at onset: 64 610 years) with positive family history. We compared variant frequency with exome data of 108 African American controls and the ExAC database.

Results: We observed a total of 32 missense variants within the established PD genes (SNCA, LRRK2, VPS35, PARK2, PINK1 and DJ-1) in our African American patients. Almost 50% of these variants were reported as absent in the non-Finnish European series on the ExAC browser. It was also noted that 10 common variants (MAF >1%) are extremely rare within Caucasian populations. Thus, ethnic-specific variation within the established PD genes may play an important role in PD susceptibility in African American populations.

Conclusion: This is one of the first reports on exome sequencing in an African American population with PD. The African American population is widely underrepresented in genetic PD studies, both in pedigree-based gene mapping and in genome wide association studies. A number of potentially pathogenic mutations were identified in PD genes. Studying genetic variation across different ethnicities can provide important insights into pathogenic variation and disease mechanisms. Background: PD is a heterogeneous disorder which can be classified into specific clinical subtypes. In a recent largescale meta-analysis of genome-wide association studies (GWAS), 28 genetic loci associated with increased PD risk were identified [1] . So far, only few studies examined association of variants in mostly single genes (e.g., SNCA, LRRK2, GBA, MAPT) with clinical subtypes [2] [3] [4] [5] .

Methods: We reviewed medical records of patients with PD (Mayo Clinic, Florida, 1998 -2016 . We identified 1003 patients who fulfilled diagnostic PD criteria, and had detailed clinical information (motor and non-motor symptoms, disease progression) and DNA available. Based on the prevailing symptoms, patients were classified into one of four subtypes: tremor, akinetic rigid, gait, and mixed. Additionally, 28 PD risk loci as identified by [1] were investigated for the 1003 patients. Comparisons of clinical features across subtypes were performed using multivariable linear, logistic, and Cox proportional hazards regression models adjusted for potential confounding variables.

Results: Median age at PD onset was 64 years (range: 22 -94 years), 637 patients (64%) were male (n51003). Tremor was the most frequent PD subtype (44%), followed by akinetic rigid (29%), mixed (18%), and gait (9%). Rapid progression was observed more frequently for both gait (P<0.001) and mixed (P<0.001) subtypes versus the tremor subtype, more common for gait versus akinetic rigid (P<0.001), and less common in mixed versus gait subtype (P50.006). Hallucinations at the final visit were more likely for the akinetic rigid (P50.005) and mixed (P<0.001) compared to tremor subtype. Depression and hypotension were most commonly observed in the gait subtype, there was no significant difference among groups. There was no difference in age at disease onset and in survival (5 and 10 years after PD onset) among the four subtypes (P50.85). We present for the first time genetic association data of 28 GWAS risk loci on four PD subtypes.

Conclusions: Clinical differences exist in PD patients which allow classification of PD into 4 subtypes. Genetic associations may help to understand the clinical heterogeneity observed in PD.

References: [1] Nalls, et al., Nat Genet. 2014; 46:989-93. [2] Ma et al., J Neurol Sci. 2015; 351:41-5. [3] Di Baptista et al., J Neural Transm. 2014; 121:353-6. [3] Cooper et al., Ann Clin Transl Neurol. 2016; 4:15-25. [4] Pascale et al., Front Cell Neurosci. 2016; 10:96. [5] von Coelln & Shulman, Curr Opin Neurol. 2016; 29; 727-734 (review) .

M256. Effects of the Huntingtin Gene (HTT) on Brain Development Peggy Nopoulos, Jordan Schultz, Eric Epping, David Moser and Amy Conrad. Iowa City, IA Background: The Huntingtin gene (HTT) has a unique feature of trinucleotide repeats ranging from 10-35 in healthy people, and when expanded beyond 40, causes disease. HTT is well known to have a vital role in brain development. However this has never been studied in humans. We have previously shown that below disease threshold, greater number of CAG repeats are beneficial with higher repeats being associated with higher IQ. However mHTT could potentially interfere with brain development and therefore repeats above 40 may potentially be deleterious to brain development.

Aim: To evaluate functional measures of overall intellectual function (IQ) and specific cognitive domains. in relationship to CAG repeats across the entire range from normal through disease causing. This is done in two large data sets: 1) Kids-HD study and 2) ENROLL-HD data base.

Methods: The Iowa Kids-HD program enrolls subjects 8-25 years of age who are 1) healthy developing children with no family history of HD and 2) those who have a parent with HD. Subjects are followed up for repeat testing with a total of 501 data points for analysis. The ENROLL-HD data base was used to obtain subjects who were: 1) presymptomatic HD (motor score 5 or less), 2) gene negative and 3) community controls. To minimize aging effects, the sample was limited to those ages 55 and under. A global cognitive score was obtained by summing 5 key variables. A total of 4,570 data points were used, including repeat visits. Mixed models accounting for repeat visits evaluate the effects of CAG repeat length on cognitive measures.

Results: In the Kids-HD sample, Intelligence Quotient (IQ) showed significant non-linear relationship with CAG length in which greater repeats lengths were associated with higher IQ until a peak at roughly 41 repeats. Above the peak, increasing repeat lengths were associated with lower IQ. The same pattern was revealed in the ENROLL data as the global cognitive measure increased below disease threshold peaking at the intermediate range (36) (37) (38) (39) , then declining with increasingly long repeats.

Conclusion: HTT may confer an advantage or a disadvantage depending upon the repeat length. Below disease threshold increasing CAG repeats confer increasingly superior cognitive function. Above disease threshold increasing CAG repeats manifest in increasingly inferior cognitive function.

Huntington's Disease (JHD) Alexander Tereshchenko, Katherine Mathews, Patricia Espie-Pfeiferr, Vincent Magnotta and Peggy Nopoulos. Iowa City, IA Background: The cerebellum is integrated structurally and functionally with the striatum with the anterior lobe having input into the indirect pathway of the striatum -the pathway responsible for movement inhibition, and the pathway affected most by HD. In JHD, hyper-connectivity of the cerebellum could lead to the hypokinetic state seen in JHD.

Aim: To evaluate brain structure in a sample of JHD subjects

Methods: The University of Iowa Kids-JHD program enrolls children 8-18 years of age who have already received the clinical diagnosis. Each child undergoes an MRI scan. A total of 18 children with JHD, ages 6-17 were studied (mean CAG577). JHD subjects were compared to a large data base (>200 subjects) of control children. Structural brain measures and DTI measures were evaluated between groups.

Results: Subjects with JHD had substantially reduced Intracranial Volumes (ICV). After controlling for the overall small size of the brain, JHD, the striatum and globus pallidus were specifically affected with volumes that were far below normal. Thalamus and hippocampus were of normal size. The cerebellum was enlarged in the JHD sample. DTI measures indicated a hyper-connectivity between the cerebellum and the striatum. Finally, the size of the cerebellum and the strength of the associated white matter tracts were directly related to abnormalities in motor function (large volume and high FA associated with worse motor scores). This suggests that the enlargement and hyper-connected cerebellum is driving the hypokinetic state in the JHD subjects.

Conclusion: HTT is vital for normal brain development. In its mutant form, mHTT may alter the development of the striatum which in turn spurs the development of the cerebellum to have greater input to the indirect pathway. In Adult Onset HD (AOHD) this is likely compensatory. However in JHD, the striatal development is so severe that the cerebellar compensation is driven too far and instead of facilitating function, it actually inhibits motor function, manifesting in the hypokinetic state of JHD.

M258. Improved Atypical Tremor Control After DBS Directly Targeting the Dentato-Rubro-Thalamic Tract Shivika Chandra, Mya C. Schiess and Albert Fenoy. Houston, TX Background: Atypical tremors secondary to a subcortical insult and characterized by cerebellar and rubral features are generally poorly controlled by medication. In contrast to the rhythmical oscillations of essential tremor, atypical tremors are ataxic and characterized as irregular, coarse, slow, high amplitude movements affecting proximal and distal parts of a limb that can be present at rest, posture and with intention. Direct targeting of the dentato-rubro-thalamic tract (DRTt) has been suggested to be efficacious in deep brain stimulation (DBS) for tremor suppression (Fenoy et al. Neuromodulation, 2017) ; we analyzed outcomes after such use in atypical tremor patients.

Methods: 6 consecutively enrolled atypical tremor patients obtained pre-operative MRI with diffusion tensor (dTi) sequences. The DRTt was drawn for each individual on StealthViz software (Medtronic) using the dentate nucleus as the seed region and the ipsilateral pre-central gyrus as the end region and then directly targeted during surgery.

Intraoperative testing confirmed improved tremor control. Post-operative analysis of electrode position relative to the DRTt was performed, as was assessment of tremor improvement. Mean baseline tremor amplitude based on The Essential Tremor Rating Assessment Scale (TETRAS) was recorded. TETRAS rating scale; Upper Limb tremor: 05no tremor, 15 barely visible, 1. 55<1 cm, 251-<3cm, 2.553-<5cm, 355-<10cm, 3.5 510-<20cm, 45>20cm . Upper limb tremor amplitude was assessed during performance of forward extension, proximal lateral wing posture, and finger-nose-finger.

Results: Patient demographics included 3 men and 3 women ages 23-53 years old; 2 bilateral DBS and 4 unilateral; 3 action)postural tremor and all arm/hand tremors had distal and proximal components. One patient had a monopolar configuration and the other five multipolar contacts; voltage range 2.2 to 6.0 v with a mean of 3.5v; rate range 90-180 Hz and pulse width 60 to 120 msecs. Mean distance from the center of the active electrode contact to the DRTt was 0.5 mm. Improvement in arm tremor amplitude from baseline after DBS was significant with the difference pre and post DBS p<0.005.

Conclusion: Direct targeting of the DRTt in DBS is an effective strategy for tremor improvement in patients with atypical tremor.

Dystonia-Parkinsonism Yeva M. Fernandez and Steven J. Frucht. New York, NY Objective: We describe and demonstrate by video a young man with rapid onset dystonia parkinsonism who has a robust response to levodopa.

Background:Rapid onset dystonia parkinsonism was first described by Dobyns et al. in 1993. Since that first report there have been multiple studies to elucidate the underlying mechanism of the disease. This disease is notoriously resistant to treatment with anticholinergics, benzodiazepines, muscle relaxants and GPi DBS. Treatment with these agents have shown limited to no benefit. Treatment with levodopa has not been helpful in improving dystonia or parkinsonism in patients with rapid onset dystonia parkinsonism.

Design/Methods: Case Report Results:A 16-year-old boy awoke with a sudden onset of dysarthria and global motoric slowing. He had cranial masking with a risor grin. He was unable to open and close the finger of the right hand and had slowing of left hand movements. Extension of his arms activated dystonia in his arms and hands. His 3rd, 4th and 5th fingers of the right hand were clenched and he has dystonic ulnar deviation of the right wrist. Tone was asymmetrically increased in the right arm and leg. He had a slow gait with small stride and right leg scuffing. His arm swing was depressed on the left. He was unable to run. MRI of the Brain and EMG were normal. Genetic testing revealed a mutation in the ATP1A3 gene, c2122G>A (p.Gly708 Ser).

Following a slow titration on carbidopa/levodopa, the patient had a noticeable improvement in his dysarthria. His cranial masking and risor improved. His voice was louder and articulation was clearer. While he continued to have dystonic ulnar deviation and right handed finger clenching, his rapid movements of his hands improved. He also hand improvement in the tone of his arm. His gait was quicker and his right arm swing was more prominent.

Conclusions: We report an unusual case of levodopa responsive rapid onset dystonia-parkinsonism. The patient had a robust response to levodopa which resulted in an improvement in his cranial masking, speech and gait. This medication responsiveness is encouraging and suggests that patients with newly diagnosed rapid onset dystonia parkinsonism warrant a trial of treatment with levodopa. Background: FOG, often a treatment-refractory symptom, leads to injuries, falls, and social embarrassment. External cues have been suggested to improve FOG. Metronomes, mostly auditory, have been studied as external cueing devices with mixed results. Given the unobtrusiveness of tactile stimuli, we sought to investigate the effect of a vibrating metronome on FOG.

Design/Methods: The study is a randomized, cross-over design. Subjects with idiopathic PD were recruited by their treating providers at one academic Movement Disorders Center. Inclusion criteria is FOG refractory to medication per subject report, and Montreal Cognitive assessment greater than 21. Subjects first train to walk a standardized course with common FOG triggers, and then practice walking to the beat of the metronome off the course to determine their preferred beat frequency. Next, they are randomized to complete the course twice more, once with the metronome on, and once with it off. Two investigators blinded to metronome status (on or off ) evaluate subjects' recorded videos for number of FOG episodes and total duration of FOG. Secondary outcomes include clinician and subject global impression of change.

Results: Enrollment is ongoing; eighteen subjects have been enrolled thus far. Mean age is 66, PD duration is 12.1 years, and FOG duration is 5.2 years with 61% reporting >5 FOG episodes per day. No significant difference has been detected for number of FOG episodes or duration of FOG. The mean (median, p) difference in number of FOG episodes was 20.44 (0, p50.08), while the mean (median, p) difference in duration of FOG was 20.36 (0, p50.7). 66% of subjects report a global improvement in FOG symptom with metronome use. No subjects reported worsening FOG with metronome use.

Conclusions: External cueing with a vibrating metronome may be a beneficial intervention for medication refractory FOG based on subjective reports of FOG. Background: In Parkinson disease (PD), the protein a-synuclein (a-syn) misfolds and aggregates to form toxic amyloid fibril structures that contribute to neuronal dysfunction and death. This process begins long before PD becomes clinically manifest, and recent evidence suggests that the conformation adopted by a-syn fibrils might change over the course of the disease. For these reasons, misfolded a-syn conformations are an ideal biomarker target.

Objective: We recently characterized two conformationselective monoclonal antibodies to a-syn, which demonstrate distinct patterns of a-syn neuropathology in PD brain. Here, we hypothesized that the presence of misfolded a-syn fibril conformations in PD biological fluids from living patients could be detected using these antibodies.

Methods: We leveraged these novel antibodies in an enzyme linked immunosorbent assay (ELISA) to detect conformations of a-syn fibrils in biological fluid samples. We expressed and purified wild-type a-syn in BL21(DE3)-RIL cells using PRK172 expression vectors. We prepared preformed fibrils (PFFs) of a-syn in alternate conformations using serial seeded fibrilization reactions. We iteratively optimized blocking reagents, incubation time, and other experimental variables to maximize signal-to-noise for detection of a-syn fibril conformations.

Results: We found that each antibody preferred a-syn PFFs over a-syn monomer in indirect ELISA. Conformation-selectivity for our antibodies were largely maintained in competitive indirect ELISA. However, in sandwich ELISA, each antibody also detected a-syn monomer in addition to a-syn PFFs. Using a convenience sample of 40 serum samples from our center, each antibody was successful in detecting a-syn in sandwich ELISA using two simultaneous a-syn detector antibodies.

Conclusions: Conformation-selective a-syn antibodies hold promise in detecting misfolded a-syn fibrils in an ELISA format. Further assay optimization is required to ensure that detection of natively folded a-syn does not occur with these antibodies when both a-syn monomer and a-syn fibrils are present in mixed, biologically relevant concentrations.

Brandon R. Barton. Chicago, IL Background: Three genes are associated with the rare occurrence of autosomal dominant primary familial basal ganglia calcification (PFBC): SLC20A2, PDGFRB, and PDGFB. Nearly half of families with PFBC have been identified to have a mutation in the SLC20A2 gene, and it is unclear how many families might have mutations in the other two genes. For families who clearly do have PFBC, there is a 95% penetrance for presence of calcifications on brain imaging and a 70% penetrance for clinical symptoms by the age of 50.

Methods: Case report and literature review Results: A 59 year old woman presented with abnormal scalp and limb sensations, headaches, fatigue, anxiety, cognitive complaints, and clumsiness of 9 month duration. Exam showed slight weakness on the right, mild rigidity and bradykinesia, more on the left, subtle chorea of the hand and foot intermittently when trying to perform other motor tasks, mild action/postural tremor, mild gait ataxia, decreased sensation on the left. Workup for secondary causes was negative. MRI and CT scans confirmed symmetric calcifications in the globus pallidus, putamen, caudate nucleus, and thalami bilaterally. Subsequently obtained brain CT scan of mother (asymptomatic) showed a similar pattern of calcifications, prompting genetic workup. A variant was found in the SLC20A2 gene, c.935-2 A>G that has not been seen at the testing lab nor documented previously; it occurs in a splice site preceding an exon, and is therefore highly suspicious to be pathogenic. Further testing of other family members revealed similar calcifications in brain, carotid vessels, and testicles (first son, asymptomatic); calcifications in carotids, heart, femoral arteries (second son, history of MI age 35), workup pending in other sibling. Further testing on the patient revealed diffuse atheroclerotic calcifications of the vasculature. Further testing of other family members revealed calcifications in brain, carotid vessels, and testicles (first son, asymptomatic); calcifications in carotids, heart, femoral arteries (second son, history of MI age 35), with workup pending in other siblings.

Conclusions: PFBC is likely under-reported; only through follow-through investigation of other family members can the genetic diagnosis be suspected and discovered.

Makito Hirano, Yusaku Nakamura, Kazumasa Saigoh, Makoto Samukawa and Susumu Kusunoki. Osakasayama, Osaka, Japan and Sakai, Osaka, Japan

Mutations or variations in the COQ2 gene encoding a protein for coenzyme Q10 (COQ10) synthesis have been found in patients with multiple system atrophy (MSA). However, the pathomechanisms, clinical characteristics, treatments of this disease remain to be fully investigated. We sequenced the COQ2 gene in 47 Japanese patients with MSA and in 41 with other types of ataxia (1 with SCA1, 7 with SCA3, 25 with SCA6, 3 with SCA8, 3 with SCA31, 1 with DRPLA, and 1 with unclassified ataxia). We found two novel mutations/variations in one patient with atypical MSA and in one patient with an atypical phenotype of spinocerebellar ataxia type 6 (SCA6). The former patient had clinically definite MSA parkinsonism type (MSA-P) without a typical MRI abnormality and also had an intermediate repeat expansion in the SCA2 gene, a finding associated with amyotrophic lateral sclerosis. The latter with SCA6 had major incontinence. A previously found variation linked to susceptibility to MSA, p.Val393Ala, was also detected in this study with a significantly higher frequency in MSA (6/47, 12.8%) than in controls (7/200, 3.5%). This variation was additionally found in a patient with unclassified ataxia with juvenile-onset myoclonus and mental impairment, one with atypical SCA8, and one with typical SCA31. Cultured fibroblasts from patients with COQ2-variation-positive/negative MSA were susceptible to oxidative stress and were partially protected by COQ10. Our findings suggest that COQ2 variations are found in some patients with atypical phenotypes of neurodegenerative diseases, and that they were possibly associated with oxidative stress.

Disorder Caused by Mutation in PROSC Resembles AADC Deficiency Autumn S. Ivy. Palo Alto, CA PROSC (proline synthetase co-transcribed bacterial homolog) encodes a binding protein involved in successful function of the cofactor pyridoxal-5-phosphate (PLP), the active form of vitamin B6. Here we describe a 2 month old male presenting with a new-onset movement disorder, characterized by dystonias, opisthotonus and oculogyric crises. Continuous video electroencephalogram was performed and revealed multiple epileptiform discharges; however his abnormal movements did not correlate with electrographic seizures. The patients clinical phenotype, taken together with his biochemical profile of elevated urine vanillactic acid and increased 3-methoxytyrosine in cerebrospinal fluid, closely resembled the known entity AADC (aromatic-L-amino acid decarboxylase) deficiency. He was initially treated with levodopa-carbidopa, B6 and PLP, and clinical symptoms resolved. Plasma AADC enzymatic function was tested and found to be reduced, but not absent. This result suggested at least partial functioning of the AADC enzyme, atypical of previously described AADC deficiency cases. Whole exome sequencing identified a homozygous mutation in the PROSC gene, which has recently been found in a small number of patients with B6 and/or PLP-responsive epilepsy (Darin et al., 2016) . Levodopa-carbidopa and antiepileptic medications were discontinued in our patient, and he continued receiving B6 and PLP therapies without reemergence of symptoms. Electroencephalogram was repeated and found to be normal; most notably, previously seen epileptiform activity was absent. The enzymatic pathways involved in mammalian B6/PLP synthesis and homeostasis are reviewed, and we discuss a novel, potential role of the PROSC protein in PLP function. Alpha-synucleinopathies are neurodegenerative diseases that are characterized by alpha-synuclein inclusions in neurons and glia. The role of glia in these diseases is poorly understood.

The Feany lab has previously expressed human alpha-synuclein in Drosophila neurons using the pan-neuronal driver Syb-QF. These flies have widespread neurodegeneration, recapitulating human pathology. We have now expanded this model to express human alpha-synuclein and other genetic modifiers in glia using a glial specific driver. These systems are independent, allowing us to co-express alphasynuclein or other modifiers in both neurons and glia and assess the degree of neurodegeneration pathologically and behaviorally.

Using this system we demonstrate that expression of alpha synuclein in glia alone induces neuronal death, and co-expression of alpha synuclein in both neurons and glia worsens synuclein aggregation compared to expression of synuclein in neurons only. We also characterize differential effects of alpha synuclein expression in neurons and glia in motor functioning. Finally, we identify additional glialspecific genes that modify the degree of neurodegeneration.

These results suggest that expression of alpha synuclein and other genetic modifiers in glia contributes to the burden of pathology the alpha synucleinopathies, and they identify potential novel glial-specific therapeutic targets. This study enrolled 37 CD patients with Toronto Western Spasmodic Torticollis Scale (TWSTRS)-Total scores of at least 20 and TWSTRS-Severity scores of at least 15, who were treatment naive or had not received BoNT within the last 6 months. Baseline characteristics were similar between subjects who received RT002 100-240 Units (U)(n521) and 300-450U (n516). TWSTRS-Total score decreased by mean of 37% (44.4 to 27.8) and from baseline to Week 4 for the 100-240U group, and by 39% (44.1 to 26.9) for the 300-450U group. Median duration of maintaining at least 20% of treatment effect was greater than 24 weeks for both groups. All adverse events (AEs) were mild or moderate, except for a case of severe neck pain (onset Day 10; duration 2 days). No serious AEs were reported. Dysphagia (all mild in severity) occurred in 14% of subjects.

In the study, RT002 appeared to be generally safe and well tolerated, and produced a long-lasting reduction in CD symptoms and signs.

Nucleus of the Thalamus Terence Sanger, Mark Liker, Aaron Robison, Enrique Arguelles and Arash Maskooki. Los Angeles, CA

The central origin of contralateral overflow movements in dystonia is not understood. We record extracellular spike events and local field potentials simultaneously from 160 electrodes in the basal ganglia and thalamus of awake unrestrained children continuously for 5 days as part of the planning process for deep-brain stimulation surgery. We present data from 6 children attempting unilateral hand or arm movement, in whom involuntary overflow to contralateral muscles is evident both clinically and on surface EMG. Single-unit recordings revealed widespread and nonspecific bilateral internal globus pallidus activity and widespread significant increase in ipsilateral Vim thalamus activity associated with overflow. In some cases, overflow was reduced or eliminated by high frequency stimulation in Vim. These results suggest that cerebellum participates in contralateral overflow, and they provide a potential target for treatment. Background: Preclinical data suggest that nilotinib, FDA approved forleukemias, may positively affect the a-synuclein pathology in Parkinson's disease (PD).

Objective: To assess the safety and tolerability of the daily oral administration of nilotinib in PD subjects.

Methods: We plan to conduct a randomized doubleblind placebo-controlled Phase 2a parallel group two cohort study. The study will enroll 75 subjects with moderate to advanced PD in Cohort 1 (150mg: 300mg: placebo) for 6 months and 60 de novo PD subjects in cohort 2 (2:1 nilotinib: placebo, the highest tolerated/safe dose from cohort 1) for 12 months. The primary outcome for both cohorts is safety and tolerability. Secondary and exploratory outcomes include assessment of symptomatic effect of nilotinib, impact on progression of PD disability, cognitive function, PK profile and a battery of serum and spinal fluid biomarkers.

Results: The study will be conducted at 25 US PSG sites. The first subject to be recruited in the fall 2017.

Conclusion: This study will expand the data on safety/ tolerability of a potential novel therapy to slow progression of PD.

Abnormalities in Cerebellar Ataxias from iPhone Video Anoopum S. Gupta, Zhuoqing Chang, Owen Smith, Jeremy D. Schmahmann and Guillermo Sapiro. Boston, MA and Durham, NC Advances in gene and biologic therapies will revolutionize the management of neurodegenerative disorders, including genetic ataxias such as ataxia-telangiectasia, Friedreich ataxia, and the spinocerebellar ataxias (Scoles, Nature, 2017). Clinical trials require sensitive, specific, and objective behavioral biomarkers to prove efficacy and to support early diagnosis and enrollment of patients (prior to neurodegeneration). Oculomotor abnormalities are prominent and early features of the genetic ataxias (Stephen, Neurology, 2017) . Here we demonstrate the ability to detect abnormalities from automated analysis of eye motion video captured with the Apple iPhone high-speed camera. Using computer vision (Xiong, IEEE, 2013) and signal processing algorithms applied to video data, we were able to detect abnormalities in smooth pursuit, saccades, and fixation in patients with cerebellar ataxias when compared with controls. This work demonstrates the feasibility of capturing important eye movement information using an inexpensive and widely accessible technology, while only requiring four minutes of testing time. Further development of this technology may provide a useful tool for screening for ataxias in resource-limited areas, without access to an expert, and for objectively and quantitatively measuring response to novel therapies over time without necessarily requiring a clinic visit. Methods: We investigated neurofilament light protein (NfL) in blood as a potential biomarker in HD in the 3-year, 366-participant international TRACK-HD cohort. In a separate 37-participant cohort, we quantified NfL in CSF and plasma.

Results: Baseline plasma NfL was 2.6-fold higher in mutation carriers than controls (p<0.0001), increasing with advancing disease. Cross-sectionally, plasma NfL was associated with age, CAG repeat count, and cognitive, motor and MRI brain volume measures. Baseline NfL predicted subsequent decline in cognition (symbol-digit p<0.0001; Stroop word p50.0033), total functional capacity (p50.0264), and global and regional brain atrophy (caudate p50.0087; whole-brain, grey matter, white matter & ventricles all p<0.0001). All but change in Stroop word reading and TFC remained significant after adjustment for age and CAG repeat length. Baseline plasma NfL predicted subsequent clinical onset in premanifest HD (p50.0036), even after adjustment for age, CAG, and brain volume measures. CSF and plasma NfL were correlated in mutation carriers (p<0.0001).

Conclusion: NfL shows promise as a prognostic blood biomarker of disease onset and progression in Huntington's disease.

Daniel K. Leventhal, Amy Hurst, Chris Cyr and Alexandra Bova. Ann Arbor, MI Striatal dopamine depletion causes key motor features of Parkinson Disease (PD), but the functional role(s) of dopamine in motor control remain unclear. Reduced movement velocity in PD patients suggests that striatal dopamine regulates movement vigor, while other evidence suggests that dopamine influences implicit learning by encoding prediction errors. To explore which mechanism is relevant for parkinsonian bradykinesia, we tested whether suppressing dopamine neurotransmission during a repetitive reaching task progressively degrades skilled performance, as expected for a learning mechanism, or simply slows movement, as expected for a vigor mechanism. We accomplished this by employing real-time high-speed video analysis to trigger optogenetic suppression of dopamine neurons selectively during reach-to-grasp movements in highly trained rats. We find that acutely inhibiting dopamine neurons disrupts reaching movements by impairing digit closure around a reward pellet and slowing or preventing pellet withdrawal. This deficit was not progressive and performance returned to baseline immediately upon stopping dopamine neuron suppression. These results suggest that dopamine primarily modulates action vigor in a dexterous task homologous to human reach-to-grasp movements. Ongoing work is directed towards dissecting how the timing of dopamine neuron suppression within individual trials affects reach-to-grasp movements. Background: Spasticity results in negative consequences and quality of life but is often left untreated; one impediment to care is under-recognition. There is no definitive method or independent biomarker to diagnose spasticity.

Objective: To test the inter-rater reliability of a novel flowchart-style algorithm designed to standardize the diagnosis of spasticity.

Design/Methods: An algorithm for the diagnosis of spasticity was developed through detailed review of the literature and expert consensus. This tool guides a neurological examination focused on the presence of spastic postures and indicators associated with spasticity (increased tone, velocity-dependent hypertonicity, hyperreflexia, clonus, and reflex spread) in order to reach a final determination. With IRB approval (IRB #090361, ClinicalTrials.gov #NCT01644123), two neurologists with movement disorders expertise independently utilized this bedside instrument on residents of a long-term care facility for veterans and their spouses. The inter-rater reliability was analyzed for spasticity diagnosis and separately for examination findings using Cohen's kappa and interpreted with the Koch-Landis scale for agreeability.

Participants: A total of 129 residents were approached for participation in the study. Of 72 residents deemed capable of providing consent, 64 elected to participate. For the 57 residents without decision-making capacity, letters were sent to their legal decision-maker. Consent was provided by 8 decision makers for a total of 72 enrolled subjects. Twenty-five subjects were excluded from the analysis (17 no longer resided at the home by the evaluation and eight were non-compliant with evaluation) and four withdrew consent.

Results: Of the 43 subjects who completed the study, agreement was reached for 38 (88% agreement) with spasticity present in seven (16% prevalence) and not in 31 (72%). Inter-rater reliability was high (Cohen's kappa 5 0.662, kappa max 0.80). Diagnostic disagreement in the remaining 12% of cases was associated with assessment of increased velocity-dependent tone. Disagreement for individual exam findings was more frequent for increased tone or increased velocity-dependent tone (81% discrepancies) and lower limb findings (79%; 60/76), particularly knee flexors (67%, 20/30).

Conclusions: Given the social and economic impact of untreated spasticity, it is imperative that the issue of underdiagnosis is addressed. Development of a standardized, brief, easy-to-use diagnostic flowchart for use by primary care providers will facilitate accurate identification of patients likely to have spasticity who would benefit from referral for evaluation and treatment. Use of this diagnostic algorithm to guide a focused neurologic examination resulted in substantial agreement between examiners.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests Acute hemorrhagic leukoencephalitis was first described by Weston Hurst in 1941. Its characterized by an acute onset and rapidly progressive inflammation with usually symmetric multifocal brain lesions with edematous necrosis and hemorrhage. It usually affect the children, mean age of 5. most cases are fatal within one week from onset. We present a 49-year-old man with a past medical history significant for hypertension, hyperlipidemia and coronary artery disease, brought to the emergency room after he was found down at home unresponsive and nonverbal. He was last seen normal 3 days prior to that. At the scene patient was oriented to name and birthdate briefly but subsequently declined. His blood pressure was 200/161 and was intubated for airway protection. Head CT showed 4.0 x 2.3 x 1.4 cm left parieto-occipital parasagittal hemorrhage. He was started on nicardipine drip, propofol drip and loaded with 1 gram of leveteracetam. His blood work shows elevated sodium, creatinine, elevated hemoglobin at 21.8, white cell count elevated at 19. EEG showed PLEDs frequently rhythmic coming from C3. MRI showed left parieto-occipital parasagittal hemorrhage measuring 3.3 x 3.1 cm consist of acute and subacute hemorrhage. There is also extensive diffuse confluent white matter hyperintensity of the cerebral hemispheres, extending into the posterior fossa including brainstem and bilateral cerebellar hemispheres and centrum semi ovale have mild restricted diffusion. Normal MRV of the brain normal spine MRI. CSF studies revealed 1 white cell count. CSF protein was normal at 41, glucose of 110. Patient was started on solumedrol 1 gram daily and immunoglobulin 0.4 gram per kg for 5 days. Patient neurological examination remained to be comatosed but opened eyes to painful stimuli. He did not withdraw any extremities on deep painful stimuli. His pupils were 3 mm sluggishly reacting to light. mental status improved only slightly to minimal conscious state and was discharged to hospice with tracheostomy and percutaneous gastrostomy tube. A favourable outcome even following very aggressive treatment, is rare in this condition. With our patient, early recognition of of the unsual distribution of the bleed pushed the team to obtain an MRI which eventually revealed the diagnosis led to early steroid administration and immunoglobulin.

M274. Effects of Natalizumab on JC Virus Antibody Titers Over Time Jakob Dobrowolski and Eric Williamson. Philadelphia, PA Background: John Cunningham virus (JCV) seropositivity is common and infection is mostly asymptomatic. However, the opportunistic resurgence of JCV infection in the brain of immunocompromised patients can cause a debilitating disease called Progressive Multifocal Leukoencephalopathy (PML). PML is a risk considered in the treatment of Multiple Sclerosis (MS) with natalizumab as well as other disease modifying therapies. A positive JCV antibody titer is the most commonly used biological marker for evaluating the risk of developing PML, with higher antibody index values signifying greater risk. Therefore, it is important to understand the fluctuations of JCV antibody indices over time for MS patients in order to interpret PML risk and make appropriate medical decisions.

Different groups have suggested that treatment with natalizumab may increase rates of patient JCV antibody seroconversion, but there is limited data examining JCV antibody indices of MS patients treated with natalizumab and matched controls of MS patients who pursued other treatments. In this retrospective study of MS patients from Penn Medicine's Multiple Sclerosis Center, we compared fluctuations of JCV antibody indices in patients treated with natalizumab to those who were never exposed to natalizumab in order to explore the impacts of natalizumab on this PML risk marker and probe whether JCV antibody titers of natalizumab patients fluctuate more over time compared to naive MS patients.

Methods: Over 150 MS patients treated with natalizumab were compared to just as many MS patients who are na€ ıve to natalizumab. All patients included in the study had multiple JCV antibody titers. The mean time period for which JCV antibody titers were available was two years. The demographics of both groups are comparable.

Results: MS Patients who were treated with natalizumab had a significantly higher seroconversion rate compared to MS patients who are na€ ıve to natalizumab treatment (P<0.01, 95% CI). When compared to the average of sequential JCV index values of patients without natalizumab treatment, the exposure to natalizumab was also associated with rising mean JCV index values for consecutive assays.

Conclusion: Treatment of MS with natalizumab is associated with significantly higher JCV antibody seroconversion when compared to MS patients never treated with natalizumab. Additionally, MS patients treated with natalizumab had more variation between successive JCV tests compared to control patients. Overall, immunosuppressive therapy with natalizumab in MS patients influences the JCV antibody biomarker used to determine the PML risk of this treatment. Results: Of the 55 patients with adequate follow-up, 34 had no further breakthrough disease for 14 months or more (range 14-192 months). 5 patients did not tolerate BIW dosing. Beta IFN neutralizing antibody testing was performed on 21 patients while on BIW dosing. Only one patient, who failed BIW dosing had consistently elevated neutralizing antibody titers (4.8%). More detailed characteristics of patients succeeding and failing on BIW dosing will be presented.

Conclusions: For MS patients having breakthrough disease on QD IM beta IFN-1a, switching to more frequently administered beta IFN may be an option. Advantages for using an IM beta IFN preparation for this include no skin reactions and lower incidence of beta IFN neutralizing antibodies. A prospective, blinded, randomized trial comparing IM QW and BIW beta IFN-1a may be indicated. Introduction: Subventricular zone (SVZ) is a germinal zone not only for neural progenitors (NPCs), but also for oligodendrocyte progenitors (OPCs), which subsequently migrate towards the corpus callosum (CC) and cortex. Recent studies showed that SVZ-derived progenitors contribute to myelin repair in various pathologic conditions. Cuprizoneinduced demyelination is characterized by increased production but delayed maturation of OPCs. Since OPCs are partially derived from neurogenic niche, we hypothesize that neurogenesis and oligodendrogenesis are inversely related and correlated with the extent of myelin loss.

Purpose: Identify associations between neurogenesis, oligodendrogenesis, and myelination in the cuprizone model.

Methods: Three groups of CD1 mice were used: controls (n54), demyelination (n54), and demyelination followed by remyelination (n55). Demyelination group received 0.5% cuprizone with standard chow during 10 weeks. Demyelination-remyelination group retuned to the normal diet after 5 weeks of cuprizone treatment. To quantify myelination, a recently proposed macromolecular proton fraction (MPF) mapping method was implemented using 11.7T MRI. Brain sections were stained with doublecortin for NPCs and NG2 for OPCs. Neurogenesis was evaluated in SVZ and hippocampal dentate gyrus (DG). Myelination and oligodendrogenesis were evaluated in adjacent to neurogenic niches CC and caudoputamen (CPu). The groups were compared using independent t-test. Associations between parameters were examined using Pearson's correlations.

Results: Cuprizone-treated mice showed significant demyelination both in CC and CPu (p < 0.05) according to MPF. NPCs quantities in DG and SVZ were significantly decreased (p < 0.01) in the demyelination group. Quantities of OPCs were significantly increased in all studied structures (p < 0.05). Cuprizone abolition restored all parameters to the control levels. Significant negative correlations were found between OPC and NPC number in both SVZ (CC: r5-0.70, CPu: r5-0.67, p<0.05) and DG (CC: r5-0.73, CPu: r5-0.70, p<0.05). Correlation between MPF and OPCs also was negative (r5-0.50; p<0.05), whereas correlation of MPF with NPCs was positive (SVZ: r50.61; DG: r50.69; p<0.05).

Conclusions: Inverse relationship between NPCs in neurogenic zones and OPCs in non-neurogenic demyelinated areas suggests that cuprizone-induced overproduction of OPCs may originate from the shift of stem cell differentiation in both SVZ and DG towards oligodendrocyte lineage followed by OPCs migration to demyelinated areas. Correlation of MPF with neurogenesis and oligodendrogenesis reveals the feasibility of using MPF as a surrogate marker of reparative processes in demyelinating diseases.

Grant support: Russian Science Foundation (project @ 14-45-00040).

Specimens of Tumefactive MS Subramaniam Sriram and Asa L. Rose. Nashville

An autoimmune and innate immune processes are thought to play a role in the evolution of acute inflammatory injury in multiple sclerosis. Alarmins are a group of proteins which are activated in the presence of danger and constitute one of the elements of the innate immune pathway. Alarmins are unique in having both intracellular and extracellular functions and are known to exert either beneficial cell housekeeping functions leading to tissue repair or provoke deleterious uncontrolled inflammation. This group of proteins includes IL-33, high-mobility group box 1 protein (HMGB1), interleukin (IL)-1a, and the Ca21-binding S100 proteins.

To determine the expression of alarmins and the participation of innate immunity in MS, we examined the tissue expression of IL-33 and HMGB1 in biopsy specimens of 7 MS patients using immunohistochemistry and quantitation was done using ImageJ software. The biopsies was performed due to the suspicion of an underlying neoplastic process. In four patients the tumefactive lesions were the initial presentation of MS. In three patients, these lesions evolved after the diagnosis was established. Six of seven patients are currently being followed for relapsing remitting MS.

There was widespread expression of IL-33 in the MS lesions and primarily located in the nucleus. IL-33 co-localized with GFAF1, (astrocytes), CC-11 (oligodendrocytes) and CD681 (macrophages/microglia). There was no statistical difference in the expression of IL-33between different populations of glial cells. The mean expression of IL-33 in CC-1 cells was 8.11 6 3.4; 6.39 6 4.2 in CD681 cells and 6.1 6 3.6 in GFAP1 cells. IL-33 expression was higher in adjoining areas of normal appearing white matter when compared to the central periventricular regions. The total IL-33 expression in demyelinated area was 6.42 6 0.0.8, and in the NAWM 7.8 6 1.1 (P,0.02). Although CD31 cells were present, primarily around blood vessels, they did not express IL-33. We also examined the expression of HMGB1 protein in the biopsy samples. The HMGB-1 protein was seen exclusively in the CD681 macrophages. Only rare co-localization of HMGB1 was seen in either astrocytes or macrophages.

Our study shows, for the first time, widespread expression of alarmins IL-33 and HMGB1 proteins in acute MS. The higher expression of IL-33 in areas of normal appearing white matter, when compared to demyelinating regions, would suggest the recognition of an as yet undetermined danger signal in regions "under threat". The factors driving the expression of IL-33 and HMGB1 are not known.

Sam Horng, Alexandra Gordon, Anthony Therattil, Gareth John and Candice Chapouly. New York, NY Objective: To interrogate the role of two dynamically expressed astrocytic tight junction proteins, Claudin-4 (CLDN-4) and Junctional Adhesion Molecule-A (JAM-A) in controlling the severity of CNS inflammatory lesions and clinical disability in a model of multiple sclerosis (MS). Background: Astrocytes upregulate tight junction (TJ) molecules, Claudin-1, Claudin-4 and JAM-A, at the glia limitans under conditions of inflammation in vitro and in vivo. We found that astrocytic CLDN-4 (a structural TJ protein) and JAM-A (a combined TJ and cell adhesion protein) exert distinct and opposing effects on cell trafficking into the CNS parenchyma and on clinical disability.

Design/Methods: To selectively delete CLDN-4 and JAM-A from reactive astrocytes, conditional knock-out (CKO) mouse lines were created by crossing mGFAP:Cre mice with Cldn-4fl/fl and JAM-Afl/fl mice. Two models of CNS inflammatory disease were induced in single CKOs, double CKOs and controls: 1) cortical injections of adenovirally mediated IL-1 and 2) experimental autoimmune encephalomyelitis (EAE). Lesion size, leukocyte and soluble factor entry, neuronal death and demyelination were measured in both models, as well as clinical disability in EAE. Results: Cldn-4 CKO mice showed increased CNS parenchymal infiltration of leukocytes in these two models of inflammatory disease, whereas JAM-A CKO mice showed accumulation of leukocytes within the perivascular spaces. In EAE, Cldn-4 CKOs showed exacerbated disability while JAM-A CKOs showed a milder disease course than controls. Conclusions: Reactive astrocytes upregulate TJ proteins, CLDN-4 and JAM-A, which have unique effects on leukocyte trafficking into the inflamed CNS, as well as opposing effects on clinical disability in a model of MS. Therefore, reactive astrocytes expresses cell surface proteins that bidirectionally modulate CNS inflammation. Background: People with multiple sclerosis (MS) often ask if diet could influence their MS. Intermittent fasting or calorie restriction may provide additional anti-inflammatory and neuroprotective advantages beyond the positive benefits obtained from weight loss alone. In the mouse forms of MS, fasting delays the onset of the disease, reduces pro-inflammatory cytokines and promotes oligodendrocyte precursor cell regeneration. However, data in humans are lacking.

Methods: We conducted a controlled feeding study of different calorie restriction diets in 36 people with MS for a period of 8 weeks. Energy expenditure was determined using indirect calorimetry, and patients were randomized to receive 1 of 3 diets: a continuous calorie restriction diet (22% daily reduction in energy needs), an intermittent calorie restriction diet (75% reduction in calorie needs 2 days/week; 100% of daily needs 5 days/week), and a weight-stable diet (100% of daily calorie needs). Participants provided blood samples for metabolomics at baseline and during weeks 4 and 8. To estimate the short term effects of aggressive reduction in calorie intake on the metabolome, all subjects had 2 visits during weeks 4 and 8. Those in the intermittent calorie restriction arm had one of those visits following a 25% intake day. Untargeted metabolomics was performed at each time point (5 total) and identified over 500 metabolites.

Results: Of the 36 patients enrolled, 31 (86%) completed the trial. Participants randomized to calorie restriction diets lost an average of 7.3 (SD: 4.6) lbs over 8 weeks; changes in weight (P50.12) did not differ by type of calorie restriction diet. Over time (and associated with weight loss), we observed increases in acyl-carnitine metabolites (involved in fatty acid metabolism), sphingolipids (fatty acid derivatives largely in cell membranes of brain/nervous tissue) and decreases in plasmalogens and phosphatidyl choline metabolites (both involved in glycerolipid metabolism). Interestingly, similar changes in these metabolites were also observed in the short-term after aggressive calorie reduction (e.g. between a 25% vs. 100% calorie day).

Conclusions: In people with MS, calorie restriction diets were associated with weight loss and with significant changes to the circulating metabolome. In particular, we observed notable changes in lipid metabolites (with relevance to neurologic and immunologic function) occurring over time as well as following a short-term aggressive reduction in calorie intake. Subsequent studies will integrate changes in the metabolome with changes in changes in the gut microbiota. Background: Lipid-laden CD141 monocytes/macrophages are a defining feature of multiple sclerosis lesion pathology. Monocytes are among a specialized subgroup of cells capable of converting vitamin D to its active form. Recent literature suggests intracellular metabolic pathways can play a deterministic role in immune cell fate. We sought to identify vitamin D-modified metabolic pathways in human monocytes in vivo.

Methods: We used flow cytometry and RNA arrays to isolate and analyze the transcriptomes of CD141 monocytes from blood drawn from adult multiple sclerosis patients (n516) before and after exposure to high dose oral vitamin D as part of a 6-month clinical trial (NCT01024777). We used gene set enrichment software to identify relevant metabolic and immune pathways. We validated relevant pathways via functional studies utilizing in vitro CD141 culture.

Results: Transcriptome data identified 15 immunologic pathways with normalized enrichment score >1.5 and nominal p-values <0.05. Among these, leading edge analysis distinguished 68 highly modulated genes. Twelve metabolic pathways yielded normalized enrichment scores >1.2 and nominal p-values <0.2; leading edge analysis highlighted 51 highly modulated genes. Functional immunologic and metabolic assays are underway.

Conclusions: We offer in vivo and in vitro evidence that human monocytes undergo a vitamin D-mediated shift away from lipid metabolism toward glycolytic pathways with an accompanying decrease in inflammatory signaling. This analysis offers new pathophysiologic insights and therapeutic targets for multiple sclerosis.

Jenny J. Feng, Kunio Nakamura, Bhaskar Thoomukuntla and Daniel D. Ontaneda. Cleveland, OH Background: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease characterized by sclerotic plaques in the central nervous system (CNS). Lesion segmentation is crucial in MS trials because lesional data can indicate disease activity, predict disease course, and correlate with clinical disease measures. Manual segmentation for T2 lesions can be time-consuming and is subject to human error. Several existing semiautomated and automated methods can be prone to misclassification errors. A novel fully-automated machine-learning method using random forest (RF) was proposed in this study, and comparative analysis with manual segmentation was conducted for validation.

Method: MRI scans were abstracted from an existing retrospective observational cohort study of patients with RRMS. First, a training dataset of 300 images extracted from all 5 MRI modalities was selected to train a RF with manual validation and correction of segmentation data. Second, a validation dataset comprised of 12 MRI scans from unique subjects in the cohort were segmented manually by three raters. Consensus delineation was constructed from the manual segmentations by using simultaneously truth and performance level estimation (STAPLE) algorithm. Various symmetric metrics (Dice coefficient, Jaccard Index, Pearson's r, volume difference and absolute difference) were used to compare the manual segmentations, consensus delineation, and RF method.

Results and Discussion: For inter-rater comparison, mean Dice overlap ranged from 0.621 to 0.685, mean Jaccard ranged from 0.484 to 0.534, and r ranged from 0.962 to 0.984. These metrics were similar to previous published metrics for raters in similar MS lesion studies. There was a greater range in Dice and Jaccard metrics between raters for scans with low T2 lesion volume; for scans with moderate to high T2 lesion volume, there is a more unified consensus. Metrics for RF method compared to consensus delineation -r of 0.979, mean Dice of 0.624 and mean Jaccard of 0.481, were similar to that of inter-rater comparisons. Further more, volumes between RF method and consensus delineation were not statistically significant at p 0.01. Results suggest that our novel automated RF method can achieve similar results as manual segmentation for T2 lesions in MS, and with higher efficiency.

Jakob Dobrowolski, Christopher Perrone and Eric Williamson. Philadelphia, PA Background: A decrease in lymphocyte counts over time is a known side effect of treatment with dimethyl fumarate (DMF), a commonly used therapy in MS patients. More dramatic declines have been observed in some patients, and in some T-cell lines, than others. Lymphopenia with the use of dimethyl fumarate is a risk factor for developing complications such as Progressive Multifocal Leukoencephalopathy (PML). PML is caused by JC virus in the brain, presumed to be a reactivation of a latent infection. Testing exists to understand a host's prior exposure or mounted immune response against JCV. JCV antibody testing is used to help assess the risk of PML with the use of other drugs. This retrospective review of medical records from patients at the Multiple Sclerosis Center at the University of Pennsylvania aimed to better assess the effects of DMF treatment on counts of specific T-lymphocyte populations and to concurrently catalogue JCV antibody testing results over time in these patients. We examined if there was a correlation between DMF use and the duration or characterization of lymphopenia and if lymphopenic patients were more prone to changes in JC virus antibody status.

Methods: We assessed CD3, CD4, and CD8 counts as well as CD4/CD8 ratios for over 50 patients treated with DMF for at least two years. Additionally, JC antibody seroconversions were catalogued in these patients and JCV indices were compared among patients with varying effects on T-cell populations. Statistical analysis was done using unpaired two-sided students t-test with a50.05.

Results: This study revealed that in a subset of patients, the treatment with DMF caused a disproportionate decline in CD81 T-cell populations compared to the decline of other T-lymphocyte populations. After at least two years of treatment with DMF, CD8 counts dropped the most, followed by a reduction in the number of CD3 cells and CD4 cell counts (all p<0.0001). The treatment of DMF also increased the CD4/CD8 ratios significantly (p<0.0001). JC virus seroconversion rates and titers were assessed where available and we saw higher indices in some of the patients with lymphopenia.

Conclusion: Treatment with DMF has an uneven effect on T-lymphocyte populations with CD81 cell populations being the most affected. We showed some correlation between the lymphopenia that results from drug use and rising JCV indices but further investigation is needed to better explore the link between DMF induced lymphopenia and JCV testing results. Introduction: Advanced neuroimaging assists in early diagnosis, classification, prognostication, and monitoring in multiple sclerosis(MS). It is not adequately researched in Balo Concentric Sclerosis(BCS), which is potentially fatal. This is the first paper to concurrently describe MRI, MRS, DTI and ASL in BCS.

Objective: Literature review and pilot study to evaluate feasibility and usefulness of advanced neuroimaging in BCS and establish neuroimaging protocol.

Methods: Literature review indicated that MRI, MRS, DTI and ASL perfusion are useful in MS. These techniques were performed on patient with left facial weakness progressing to involve left hand. Tractography evaluated extent of corticospinal/corticobulbar tract involvement. Imaging evaluated at 4 time-points.

Results: MRI showed multilayered concentric ring lesion, reduced rim diffusion, hypoperfusion with central hyperperfusion. MRS showed increased choline, decreased NAA, lactate doublet peak. Tractography showed anisotropy loss along inferolateral corticobulbar/corticospinal fibers. BCS was diagnosed based on neuroimaging. Intravenous steroids were administered without delay. Symptoms completely resolved for 1 year. Diffusion changes and contrast enhancement resolved with time.

Discussion: Neuroimaging may differentiate BCS from other diseases and avoid brain biopsy. This neuroimaging protocol is feasible and can be applied to future cases to advance understanding, facilitate early treatment, monitor progression and establish classification criteria for BCS. Background: Connexin47 (Cx47), encoded by the GJC2 gene, forms homotypic gap junction communication channels between oligodendrocytes (OLs) and heterotypic channels with Cx43 expressed in astrocytes. Mutations in GJC2 cause a severe disorder, Pelizaeus-Merzbacher-like disease 1 (PMLD1), or a much milder phenotype, hereditary spastic paraplegia type 44 (SPG44) phenotype. Here, we study for the first time the effect of these mutations expressed in primary OLs.

Methods: Primary OLs from neonatal Cx47 knockout mice were isolated using immunomagnetic beads and lentivirally transduced with Cx47WT and mutants. Immunofluorescence staining for Cx47, Grp94 (an ER resident chaperone), CHOP (a marker of the UPR mediated apoptosis pathway), and activated caspase-3 was performed.

Results: In primary OLs, PMLD1 mutations exhibited a diffuse cytoplasmic staining and colocalized with the ER marker Grp94. Cx47WT and the SPG44 mutant I33M showed punctate staining. Also, OLs expressing PMLD1 mutation showed increased CHOP activation, apoptosis and abnormal cell morphology compared to Cx47WT and Cx47I33M.

Conclusions: PMLD1 mutations may cause a toxic gainof-function in primary OLs compared to the milder mutations, which may explain the clinical manifestations of the disease.

M285. Methadone Leukoencephalopathy: A Case Report of Unique MRI Findings Allison Snyder, Prashant Raghavan and Neil C. Porter. Baltimore, MD Methadone is a common maintenance medication for opioid addiction. There are case reports of delayed leukoencephalopathy due to methadone toxicity. There are two forms of leukoencephalopathy described: spongiform and delayed. The underlying pathophysiology is unknown, but may be related to hypoxia. Previously reported imaging describe FLAIR white matter and basal ganglia hyperintensities, with or without corresponding DWI/ADC abnormalities. Imaging findings are often delayed and long-term can result in spongiform degeneration. We call attention to the rare entity of delayed leukoencephalopathy following methadone toxicity, present novel neuroimaging of a case, and review prior reports.

A 59 year old woman on methadone with hepatitis C cirrhosis and chronic kidney disease was admitted for altered mental status. After a recent admission for decompensated liver failure while at rehabilitation facility, she had headaches and a single generalized seizure. She had transient obscuration followed by total loss of vision in both eyes and was admitted to the hospital. On examination, she was intubated but not sedated. She opened eyes to noxious stimulation, but did not maintain wakefulness, blink to threat or follow commands. To noxious stimulation she had slow flexion of bilateral upper and triple flexion in bilateral lower extremities. Pupils were miotic but reactive; gaze was midline; brain stem reflexes were intact including oculocephalic. She was rigid with hyperreflexia. Laboratory studies notable for BUN 28 mg/dL, creatinine 1.84 mg/dL, and ammonia <9 mcmol/L. Urine toxicology was positive for methadone. CSF: 2 WBC, 86% lymphocytes, 2 RBC, glucose 83, protein 45; negative gram stain, culture and viral studies. On initial brain MRI, there was restricted diffusion with corresponding ADC hypointensity in the white matter of the bilateral parieto-occipital lobes and splenium without corresponding FLAIR signal abnormalities. There were periventricular hyperintensities consistent with chronic microangiopathy and bilateral basal ganglia hyperintensity consistent with liver disease. On repeat imaging, the parieto-occipital signal abnormality on DWI and ADC sequences nearly resolved and FLAIR remained negative. She was weaned off of methadone. Mental status gradually improved and spasticity resolved.

This case highlights important neurologic complications of methadone. First, methadone is metabolized by the liver and in the setting of liver failure can result in toxicity causing coma and spasticity. Second, toxicity can result in a leukoencephalopathy. The pattern of abnormal imaging findings is unique with prominent DWI and ADC signal involving the splenium without FLAIR abnormality, not described previously.

Yasir Al-Khalili, John Grothusen and Shadi Malaeb. Philadelphia, PA Background: Brain hypoxia, ischemia and reperfusion (HIR) injury remains a major cause of brain damage in patients who sustained catastrophic events such as drowning or cardiac arrest. Hypoxia activates a series of biological chain reactions that result in neuronal and non-neuronal cellular dysfunction in the brain. However, hypoxia also induces adaptive responses that confer resilience and restore homeostasis. Astrocytes are critical to maintain glutamine supply to neurons for subsequent reformation of glutamate. Unlike neurons, astrocytes can survive and adapt to anaerobic conditions by increasing affinity for glucose. This astrocyte response helps neurons survive transient periods of HI. We investigated the adaptive response by astrocytes in the piglet brain and tested the hypothesis that glutamine synthesis is enhanced following HIR.

Methods: Ventilated piglets (3-5 days old) were exposed to low oxygen (6-8%) for 1 hour then returned to normal oxygen levels for 4 hours. Physiologic parameters and arterial blood gases were recorded during normoxia, hypoxia and reoxygentation. Brains were harvested and flash frozen in liquid nitrogen. ATP levels per gram of tissue were determined spectrophotometrically. The amounts of glutamine and glutamate (mMol/g of wet tissue weight) in cytosolic extracts of cerebral cortical tissue were determined using HPLC.

Results: Exposure to hypoxia resulted in significant hypoxemia (PaO2 24.5 1/-4.9 mmHg) and 59 1/-3% reduction in systolic BP (P<0.05) in the piglets. Cerebral ATP levels were reduced by 70% following HI indicating energy failure (p<0.01 vs control). Glutamine and glutamate levels were 7.53 1/-1.40 and 7.25 1/-2.89 (N52) respectively in hypoxic animals and 4.71 1/-1.12 and 10.15 1/-2.67 in normal (N52). The data show over a 2-fold increase in glutamine relative to glutamate in the hypoxic piglet brain after reoxygenation, indicating that glutamine synthesis was significantly enhanced after HIR.

Conclusion: We conclude that glutamine synthesis is enhanced in the hypoxic brain after reoxygentation. Normal cerebral function depends upon interactions between neurons and supporting cells in the parenchyma. Astrocyte provide metabolic substrates to neurons, interchange glutamate and glutamine for synaptic transmission and buffer the extracellular space. Neurons easily succumb to ischemia, astrocytes rely more on glycolytic metabolism and less susceptible to lack of oxygen. Understanding the intricate relation between neurons and astrocytes provide insight into metabolic strategies for neuroprotection that can utilize the adaptive responses by astrocytes to support neurons survive a critical insult. Background: Hospitalized patients with neurologic diseases are especially prone to pneumonia, in which bed-ridden state, dysphagia, altered mental state, or mechanical ventilation due to respiratory muscle weakness can all increase its risk. Early empiric coverage for possible pathogens is crucial to improve survival, which requires knowledge of recent prevalence of antibiotic-resistant pathogens. We investigated the trends in microbial etiology of pneumonia in hospitalized patients with neurologic diseases, along with the changes of antibiotic s-resistance of common pathogens.

Materials and Methods: Data were retrospectively reviewed via electronic medical record system for patients admitted to the neurology ward, Seoul National University Hospital, Seoul, South Korea between January 2006 and December 2016. Gram stain results, culture, and antibiotic sensitivity results for respiratory specimen via expectoration or transtracheal aspiration and history for antibiotics administration were obtained. Specimen with over 10 squamous epithelial cells per low-power field were considered as inadequate samples and were excluded from analysis. Serial respiratory culture results in a single patient were regarded as separate events if the period of antibiotics was over 6 days.

Results: A total of 1056 patients were enrolled. The median age was 67 years (range, 14-110 years) and 412 (39%) were female. The number of events was 2156, of which a single microorganism was isolated in 1485 events while 671 events showed multiple microorganisms. Overall, Staphylococcus aureus was the most common pathogen (33.7%), followed by Acinetobacter baumannii (15.5%), Klebsiella pneumoniae (13.9%), Pseudomonas aeruginosa (10.6%), Enterobacter aerogenes (3.2%), and Streptococcus pneumoniae (3.2%). A. baumannii isolates dramatically increased in number (from 15.7 isolates/year in 2006-2008 to 69.3 isolates/year in 2014-2016) and in imipenem-resistance (from 25.5% in 2006-2008 to 89.5% in 2014-2016) . K. pneumoniae also increased in number (from 14.0 isolates/year to 52.3 isolates/year) with the first imipenemresistance detected in 2013 and remained at a low proportion (2.5%). S. aureus maintained a steadily high occurrence (93.3 isolates/year) with relatively high oxacillin-resistance (76.7%). P. aeruginosa showed little change over time in isolate numbers (29.3 isolates/year) and drug resistance.

Conclusion: Treatment choices targeting pneumonia in neurologic patients should change over time with close investigation of the local distribution of possible pathogens and its resistance to antibiotics. Given the high carbapenemresistance of A. baumannii, early administration of colistinbased therapy may be needed prior to determination of antimicrobial susceptibilities in respiratory infections by gram-negative pathogens. Background and aims: There is no consensus regarding optimal BP targets immediately post-thrombectomy, with uncertainty balancing optimal cerebral perfusion pressure and minimizing reperfusion injury. We sought to investigate the relationship between post-thrombectomy BP targets and cerebral perfusion through non-invasive cerebral oxygen monitoring with Near-Infrared Spectroscopy(NIRS).

Methods: This prospective observational feasibility study was performed through patient enrollment in an IRB approved Neurocritical care registry of patients at the University of Miami. Patients undergoing thrombectomy for acute LVO were monitored for 48 hours post-procedure with NIRS through the INVOS system (Medtronic). Blood pressure parameters were determined at the discretion of the admitting Neurointerventional team. All post-thrombectomy standards of care were followed.

Results: A total of 5 patients have been observed in this ongoing investigation. sBP goals post-thrombectomy varied from <120 to <140 mmHg. One patient developed L MCA syndrome during monitoring, undergoing repeat angiography showing robust collaterals and L M1 cut-off, followed by thrombectomy. NIRS monitoring showed symmetrical data during the event and immediately post thrombectomy, but then few hours later was observed to have lower values on the affected side, with a poor outcome. The second patient suffered hemorrhagic conversion and NIRS showed higher signals on the affected side. Other patient with successful thrombectomies showed symmetrical data and good outcomes.

Conclusion: NIRS monitoring is a feasible method of evaluating patients undergoing thrombectomy for LVO ischemic strokes. This study is continuing to enroll patients to help determine whether NIRS monitoring may help determine better blood pressure targets following thrombectomy. Although metagenomic next-generation sequencing (mNGS) is a promising approach for broad-based detection of microorganisms, it has yet to be applied in the clinical setting for diagnosis and management of patients with unknown infectious syndromes. Here we present the implementation of a clinically validated mNGS assay for pathogen identification from cerebrospinal fluid (CSF) for use in the diagnosis of meningitis and encephalitis. In June of 2016, we launched the PDAID ("Precision Diagnosis of Acute Infectious Diseases") study, a nationwide, one-year prospective study at 8 academic hospitals across the U.S. to evaluate the clinical utility and comparative effectiveness of the mNGS assay relative to conventional microbiological testing. Over the first 9 months of the study, we enrolled 151 patients, adults and children, presenting with acute meningitis, acute encephalitis, or an acute exacerbation of a chronic meningitis. Inclusion criteria included (1) unknown diagnosis at time of enrollment, (2) CSF pleocytosis or abnormal neuroimaging suggestive of an infectious etiology, and (3) acute presentation with time of enrollment within 7 days of symptom onset. Samples were processed and analyzed within 1 week of receipt in the clinical microbiology laboratory, with a sample-to-answer assay turnaround time of $72 hours. Clinical microbial sequencing boards were convened by realtime teleconferencing once a week to discuss mNGS results with treating physicians in a clinical context. mNGS identified a neurologic infection in 35 of 151 patients (23.2%). More than one-third (n512, 34.2%) of the infections detected by mNGS would not have been detected by conventional testing. These infections include the first documented case of St. Louis encephalitis virus in CA since 1986, human coronavirus 229E which has not previously been described in neuroinvasive disease, the first reported case of hepatitis E virus transmitted by a lung transplant donor and previously missed cases of Enterobacter aerogenes, Candida tropicalis, and Neisseria meningitides meningitis. Excluding cases of infections diagnosed only by serology (West Nile virus (n53), neurosyphilis (n52), dengue (n51), and Baylisascaris procyonis (n51)), the mNGS assay had 88.5% sensitivity and 97.2% specificity relative to conventional testing. These data show that an unbiased metagenomic assay for infectious disease diagnosis is clinically useful in clarifying diagnosis in a significant proportion of patients with acute meningitis and encephalitis. The outcome of hospitalized patients with neurologic diseases varies from complications during the hospital course. Hospital-acquired infections account for large proportion of these complications, and urinary tract infection is the most common infection in hospitalized patients.

Data were retrospectively reviewed via electronic medical record system for patients admitted to the neurology ward, Seoul National University Hospital between January 2006 and December 2015. Gram stain results, culture, and antibiotic sensitivity results for urinary specimen and history for antibiotics administration were obtained.

A total of 3919 patients were enrolled and the number of events was 1061. Overall, Escherichia coli was the most common pathogen (24.2%), followed by Klebsiella pneumoniae (17.1%), and Enterococcus faecalis (14.2%). K. pneumoniae isolates dramatically increased in number (from 6.33/year in 2006-2008 to 27/year in 2014-2016) Sporadic inclusion body myositis (sIBM) is a debilitating chronic progressive myopathy characterized by a combination of autoimmune and degenerative characteristics that contribute to the disease pathogenesis. Pro-inflammatory CD28null T cells have been shown to be the dominant T cell subset in both the peripheral blood and in the inflamed muscles of patients with sIBM. These T cells display a strong pro-inflammatory and cytotoxic phenotype and are believed to play a role in the muscle fiber destruction. T cell activation depends upon a calcium-signaling cascade that is regulated by voltage-gated potassium channels, providing a specific potential drug target. Dalazatide is a potent, highly specific inhibitor of Kv1.3, a potassium channel required for activation of effector memory T (TEM) cells. A key differentiating feature of dalazatide is that it specifically targets chronically activated TEM cells which rely on Kv1.3 expression for their effector function, while leaving other T cell subsets which upregulate KCa3.1 upon activation intact, thus providing an immune sparing profile. Dalazatide has demonstrated potent inhibition of TEM cells in numerous in vitro, ex vivo, and in vivo models of autoimmune disorders, and has successfully completed three Phase 1 clinical studies demonstrating safety in both healthy volunteers and in patients with plaque psoriasis. In addition, relevant T cell engagement and proof of concept efficacy was observed. Here we show through immunohistochemistry analysis that muscle biopsy samples from patients with sIBM display CD31 T cells in the perivascular space and in the muscle fibers, which express the Kv1.3 channel. Ongoing studies are underway to characterize the T cell population in the blood of patients with sIBM and evaluate ex vivo inhibition with dalazatide. Dalazatide inhibition of Kv1.3 may be a safe and attractive strategy for treating sIBM, for which there are no currently approved therapeutics.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? I have served on the advisory board for Sarepta, MT-Pharma and Grifols and received honoraria for these activities.

M294. An Odyssey in Epidemiology -From Snow to Hill to ALS: Acquired Somatic Mutations Cause ALS Carmel Armon. Tel Aviv, Israel and Zerifin, Israel

Objective: To show how application of evidence-based methods and classical epidemiological principles, including Hill's "viewpoints" to inferring causation, has led to elucidating the likely mechanism by which ALS is triggered.

Methods: The following epidemiological principles were applied: Non-random patterns of disease occurrence are keys to understanding its cause; Cause must precede biological disease onset; Confidence in conclusions about causality increases if they are biologically plausible and supported by findings that are coherent (internally and externally consistent). Clinical features and epidemiological characteristics of sporadic, familial, and western Pacific ALS drove the analysis.

Results: ALS is a cortically-generated disease, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor network. Focal onset supports biological plausibility that disease is triggered by changes in one cell. The age-dependent increase in incidence of sporadic ALS supports accrual of changes in a multi-step process, affecting cell components that do not turn over rapidly (DNA rather than protein). Smoking, the only established risk factor for the disease, induces DNA changes, as in carcinogenesis. The best interpretation of age-dependent penetrance of familial ALS is that additional nucleic acid changes need to occur so that potential disease will become active disease. Western Pacific ALS, previously considered a "neurotoxic" disease, is now explained as a "genotoxic" disease, to account better for the long latency from exposure and inexorable progression.

Conclusions: Classical epidemiological methods, applied systematically, have dispelled the mystery of how and why ALS is initiated. Accrued somatic mutations (nucleic acid changes) trigger its onset.

Disclosure: Do you (or your spouse/partner) have any relevant financial relationships (currently or within the past 12 months) with any commercial interests? Associate Editor of Journal of Neurological Sciences (editorial fee); Royalties as UpToDate author; Honoraria for updating eMedicine chapter; Medicolegal consulting fees. Mutations in the gene coding for myelin protein zero (MPZ, P0) are associated with different forms of Charcot-Marie-Tooth (CMT) disease. We describe a family harboring a frameshift mutation (c.306delA/p.Asp104ThrfsTer14) in the P0 gene, predicted to result in a nonfunctional P0 truncated very early in the extracellular domain. This offered the rare opportunity to assess the consequences P0 deficiency in absence of the potential gain-of-function effects of the mutations itself. Conventional conduction studies and multiple measures of nerve excitability by "threshold tracking" were carried out in 2 heterozygote parents (aged 63 and 52) and their two homozygote sons (aged 31 and 39). In the homozygous patients, all distal limb CMAPs and SNAPs were absent. For neurophysiological assessment, the spinal accessory nerve was stimulated at the neck and CMAP was recorded over the upper trapezius muscle. Eight normal subjects, mean age 34, were used as control. The two sibs showed a severe phenotype with early onset, severe scoliosis, complete loss of distal movements and relevant proximal weakness, CMT Examination Score (CMTES) 23-25/28; both heterozygous parents had very mild adult-onset neuropathy with CMTES <4/28. Control subjects had a trapezius CMAP with a latency of 6.2 ms and an amplitude of 7.4 mV. Heterozygotes had a mild CMT type 1B phenotype, with a CMAP latency of 7.5 ms and an amplitude of 2.9 mV whereas the homozygotes had a severe neuropathy with a CMAP latency of 35.9 ms and an amplitude of 0.2 mV. Consistently, the homozygotes had a more severe impairment in excitability with a rheobase of 16.2 mA as compared to 4.7 mA in the heterozygote and 3.5 mA in controls. Deviations in excitability measures were similar to our previous reports in P01/-and P0-/-mice. Mathematical modeling, indicated both altered passive cable properties due to dysmyelination and depolarizing features with increased Na1 currents. Our data suggest that P0 deficiency is associated with impaired axonal Na1 channel function, arguing for the translational value of Na1 channel blocker treatments as found in P0 null mouse models. Objective: To revise the two cases described by Guillain, Barr e and Strohl.

Methods: Review of the original report from 1916 and other related historical articles.

Results: Case 1 was a 25-year-old man with progressive paresthesia and limb weakness. Examination revealed distal predominant weakness. Case 2 was a 35-year-old man with pain, progressive limb weakness and difficulty walking. Exam demonstrated weakness involving the face, legs and distal arms. Both had areflexia and no objective sensory loss. Case 2 also had hypertonia, myoclonus and a maculopapular erythematous rash. There was no anteceding illness in either patient. Ventilatory dysfunction and autonomic instability were not observed. Cerebrospinal fluid (CSF) analysis, performed twice in each case, showed elevated protein without pleocytosis. Case 1 was treated with bed rest, muscle frictions and several chemicals. Both patients improved over the following weeks. The authors highlighted the CSF findings and good prognosis of the disease. They suspected an infectious or toxic cause and postulated a simultaneous pathology of the spinal roots, peripheral nerves and muscles.

Conclusion: These cases illustrate the classic clinical presentation and CSF findings in GBS. The atypical features in case 2 may suggest a GBS variant or mimic. The authors correctly hypothesized the simultaneous involvement of spinal roots and peripheral nerves but they were mistaken to include the muscles. The syndrome was considered separate from Landry's ascending paralysis owing to its good prognosis. There is no uniform explanation as to why Strohl's name was omitted in the eponym.

Damage Quantification Using Microfluidic Chamber Techniques Soneela Ramesh, Ron Hrstka, Christopher J. Klein and Nathan P. Staff. Rochester, MN Peripheral neuropathy is a common debilitating clinical problem with many etiologies, yet the precise pathophysiology of peripheral nerve damage is poorly understood. We have adopted an approach of using human patient induced pluripotent stem cell (iPSC) samples differentiated into sensory neurons (iSN) to study "neuropathy-in-a-dish," focusing on chemotherapy-induced peripheral neuropathy (CIPN) and Charcot-Marie-Tooth (CMT) disease. Skin fibroblasts from Mayo Clinic patient volunteers have been collected and stored at the Mayo Clinic Center for Regenerative Medicine's BioTrust. In our growing library, there are now either fibroblast or induced pluripotent stem cell (iPSC) samples from >100 healthy controls and >70 patients with CMT, many of which have known genotypes. iPSCs were reprogrammed using Sendai virus and Yamanaka factors (oct4, sox2, klf4 and c-myc) and quality control was done to verify pluripotency of iPSCs (immunostaining and PCR for oct4, nanog, ssea3/4, tra-1-60; karyotyping; germ layer differentiation). Neural crest stem cells were derived from iPSCs based on a previously established small molecule protocol and were seeded into microfluidic chambers and subsequently differentiated into iSN. iSN differentiation was confirmed utilizing real time PCR for sensory neuron gene expression, immunostaining to verify protein levels, and patch clamp electrophysiology. iSN then were treated with paclitaxel (0, 10 and 100uM) for 24-48 hours and dosedependent axonal damage of labeled axons was observed and quantified using image J. By studying iSN within microfluidic chambers, we now are able to separate distal axonal neurotoxicity and neuropathology from that occurring in the somatic region. This unique patient-derived neuropathy-in-a-dish model will be used going forward for detailed mechanistic studies of pathogenesis and neuroprotection for CIPN and CMT. The pathogenesis of sporadic inclusion body myositis (sIBM) is unknown. One myopathologic feature in sIBM is a rimmed vacuole (RV). RVs contain aggregated proteins that accumulate within myofibers and in many cases are amyloidogenic. We hypothesize that the identification of proteins that accumulate within RVs will reveal pathomechanistic insight into sIBM. Using laser microdissected RVs from skeletal muscle of 18 sIBM patients and matched controls, we performed mass spectrometry using label-free spectral count-based relative protein quantification. With this approach, we identified 213 proteins that were enriched by > 1.5 fold in RVs compared to controls samples. These proteins included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Several categories of proteins were present; with the largest groups being those associated with protein folding and autophagy. In a second tiered approach, we performed whole exome sequencing on 62 patients with sIBM and identifed the burden of rare missense coding variants in RV associated proteins. This strategy identifed FYCO1, an autophagic adaptor protein not previously identified in or associated with sIBM. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p50.003). FYCO1 colocalized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced colocalization with MAP1LC3 when expressed in mouse muscle. This study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. Specifically, FYCO1 accumulates at RVs, and rare missense variants in FYCO1 are over-represented in sIBM patients. These FYCO1 variants may impair autophagic function, leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways, supporting the hypothesis that impaired endolysosomal degradation underlies the pathogenesis of sIBM. Background: While extraocular muscles are affected early in generalised Myasthenia Gravis (MG) with acetylcholine receptor (AChR)-antibodies, we have identified a subphenotype of treatment-resistant ophthalmoplegia (OP-MG). These patients most frequently have African-genetic ancestry and juvenile-onset MG. A candidate approach identified 2 African-specific gene traits linked to OP-MG, decay accelerating factor (DAF) and transforming growth factor beta-1 (TGFB1). We speculate that OP-MG may result from aberrant responses in muscle damage/repair pathways, although the pathogenesis is unknown. Performing extended whole exome sequencing (WES) in an extreme sample of OP-MG vs control MG individuals, we discovered four potentially pathogenic gene variants relevant in extraocular muscle pathways. Three were sequence validated in an independent sample.

Objective: To assess, in phenotype-specific muscle cell models, differences in expression levels of the newly discovered WES genes, previous candidates (DAF, TGFB1) and related genes in the relevant pathways.

Method: We developed differentiated 'muscle' models for each subject (OP-MG (n510) vs control MG (n56)) by forcing dermal fibroblasts to transdifferentiate into myocytes through transduction with an adenovirus expressing a MyoD transgene. To mimic patient-specific MG-induced muscle pathway responses, we stimulated the myocytes with homologous AChR-antibody positive MG sera. Gene expression was assessed by qPCR (absolute quantification) and in an array using the 'muscle'-and 'MG'-disease models. Target transcripts were normalised to several reference genes.

Results: There were no differences in the mean transcript levels of DDX17, IL6R, ST8SIA1 and SPTLC3 between control MG and OP-MG myocytes. However, by phenotype IL6R, SPTLC3 and ST8SIA1 showed differences in the transcriptional response of AdMyoD-myocytes in response to MG sera. Next we analysed the cross-correlations between gene pairs of absolute transcripts levels in order to detect differential genetic regulatory networks between OP-MG and control MG myocytes. Strong correlations in expression levels of several gene pairs in both models were observed; in the MG model, ST8SIA1/DAF, ST8SIA1/TGFB1 and ST8SIA1/DDX17 were strongly correlated in control MG myocytes (r!0.9; p<1x10-4) but not in OP-MG myocytes (r 0.2). The gene expression array comprising >60 genes under both modelling conditions, are underway.

Conclusion: These results strongly implicate the WES genes and previous OP-MG susceptibility variants as part of a gene co-expression network tightly co-regulated in the control MG muscle transcriptomes in response to MG sera. Preliminary results suggest that phenotype-specific gene variants may impact on myogenesis and ganglioside biosynthesis in extraocular muscle during MG leading to the synaptopathy in OP-MG.

The research was funded by the AFM Telethon (20049) and the MRC and NRF of South Africa.

Goran Rakocevic, Matthew Woodford, Katrina Pack, Anthony Allen and William Sexaur. Philadelphia, PA Introduction: Respiratory manifestations in Stiff-person Syndrome (SPS) patients have not been systematically investigated and adequately managed. Approximately 50% of SPS patients report dyspnea contributing to their functional impairment. This study investigates the frequency and severity of dyspnea and associated pulmonary function abnormalities in SPS.

Methods: SPS patients were recruited prospectively from neurology clinic in a single university center. Demographic information, co-morbidities, history of lung disease, and smoking history were recorded for each subject. Dyspnea was assessed on each subject via a vertical Visual Analogue Scale assessed on the day of study visit (VAS1day) and over the preceding two weeks (VAS2weeks), and by the University of San Diego Shortness Of Breath Questionnaire (UCSD-SOBQ). Dyspnea 'descriptors' were assessed for each subject. Standardized assessments of SPS severity-the Heightened Sensitivity Scale and the Distribution of Stiffness Scale were assessed by an experienced neurologist. Spirometry was performed on all patients on the same day as assessment of dyspnea.

Results: Fifteen of 16 consented patients had evaluable data. Mean age was 56.1 113.1 SD years. 15/16 were female. 14/15 complained of dyspnea: 10 both at rest and with exertion, 3 only with exertion, and 1 only at rest. The two most common dyspnea descriptors were 'My chest feels tight' and 'My chest is constricted'. Mean UCSD-SOBQ score was 61.2 1 37.95. Group mean FVC % predicted was 76.5 117.99; FEV1% predicted 81.6 119.72; FEV1/FVC 85.2 110.02. 5/15 patients showed a restrictive pattern on spirometry, 9 had normal spirometry, and 1 patient with concomitant bronchiectasis showed a combined restrictive/ obstructive pattern. There was a significant inverse correlation between VAS2weeks and FVC %predicted (r 5 20.61, p50.017) and FEV1%predicted (r 5 20.65, p50.008). There was no significant association between pulmonary function and any of the following: VAS1day, UCSD-SOBQ, Distribution of Stiffness, or Heightened Sensitivity. No correlation between any dyspnea score and any measure of SPS disease severity was found.

Conclusions: Dyspnea in SPS is common, and occurs both at rest and with exertion. Many patients show a restrictive spirometry pattern, and there is some association between simple measures of dyspnea and pulmonary function. We postulate that chest wall constriction and/or superimposed spasm of the muscles of the trunk may be the underlying mechanism leading to the sensation of dyspnea and objective respiratory compromise. Potential involvement of diaphragmatic muscles is unknown. We have previously demonstrated that positively-charged oligo-polyethylene glycol fumarate (OPF1) hydrogel scaffolds implanted after complete thoracic spinal cord transection in rats facilitate a permissive regenerative environment by reducing scarring, and that there is a close relationship between new blood vessel formation and the number of regenerating axons. In this study we used multichannel OPF1 hydrogel scaffolds to provide a platform to control the micro-environment of the regenerating spinal cord. Our objective was to assess the spatial relationships between blood vessel formation and axonal regeneration in the core area of scaffold channels eight weeks after implantation. Poly-lacticco-glycolic acid (PLGA) microspheres were embedded within Schwann cell (SC)-loaded OPF1 scaffolds for sustained release of the anti-fibrotic and immunosuppressant drug rapamycin. Animals were implanted with spinal cord scaffolds containing Matrigel alone (n55), SCs plus empty PLGA microspheres (n56), or SCs plus rapamycin-eluting microspheres (n56). Stereologic methods were applied to measure core channel area, blood vessel number, volume, diameter, intervessel distances, total vessel surface and cross-sectional areas, and radial diffusion distances in each group. Neurolucida software, immunohistochemistry and confocal imaging were used to perform a Sholl analysis to count a total of 2,494 myelinated and 4,173 unmyelinated axons at 10 micron circumferential intervals around 708 individual blood vessel profiles within scaffold channels. Patterns in the Gaussian distribution of axons with respect to their distance from and density around blood vessels were measured. Despite an equivalent number of new blood vessels in each group, axon number and surface density in the SC group exceeded that seen in the Matrigel and SC plus rapamycin animal groups. Higher axonal densities correlated with smaller vessel crosssectional areas (Spearman r 5 20.1431, p50.0257). Axons in each group were concentrated within a concentric distance of 200 microns from the blood vessel wall, but were excluded from a 25 micron zone immediately adjacent to the vessel. Finally we used a statistical spatial algorithm to generate cumulative distribution functions of vessels and axons within each scaffold channel type. Whereas axons around vessels were definitively clustered, blood vessels themselves were distributed randomly within scaffold channels. Our results further refine spinal cord tissue engineering strategies to optimize the regeneration of complete neurovascular bundles in their relevant spatial relationships.

M303. Some Like It Hot: Temperature-Induced Increased Gustatory Response in Those with Chemosensory Dysfunction Ayesha Siddiqui and Alan R. Hirsch. Karachi, Sindh, Pakistan and Chicago, IL In those with chemosensory dysfunction, temperature dependent effects on flavor have not heretofore been described.

Methods: Case study: Case 1: A 57 year-old right-handed male, two years prior, developed an upper respiratory tract infection and a reduction in smell and taste. He can taste salt, tomatoes, and spices. He is better able to perceive flavor of hot foods: chicken when hot, has 60-75% of its normal flavor but when cold has a mere 30%. Pork when hot has 65-70% of its normal flavor whereas when cold, there is a total absence of flavor. Hot French fries have 75-80% of flavor, which dissipates to 50% when cold.

Results: Chemosensory examination: olfactory testing: Anosmia on: Brief Smell Identification Test: 4. Alcohol Sniff Test: 4. Pocket Smell Identification Test: 3 (normosmia). Retronasal Smell Index: 3 (abnormal). Gustatory testing: Propylthiouracil disc taste test: 1 (aguesia). Other: CT scan of sinuses: normal. MRI of Brain: normal. Fiberoptic endoscopy: normal.

Case 2: A 60 year-old right-handed female, one year prior, suffered head trauma with loss of consciousness, with impaired ability to taste. She complains of dysgeusia, cacoguesia, and salty phantogeusia. There is a temperature difference in her ability to taste food: she cannot taste brownies or tomato soup or marinara sauce normally, unless hot.

Results: Chemosensory testing: olfactory testing: Brief Smell Identification Test: 11 (normosmia). Alcohol Sniff Test: 1 (anosmia). Pocket Smell Identification Test: 3 (normosmia). Retronasal Smell Index: 9 (normal). Gustatory testing: Propylthiouracil disc taste test: 9 (normogeusia). Other: MRI of the brain with and without infusion: mild to moderate small vessel ischemic changes. Fungiform papillae count: right 18, left 22 (normal).

Discussion: The orthonasal component of olfaction is more sensitive to hot foods and odor. Plausibly at higher temperature, the greater volatility of odor, enhances the ambient aroma and thus, enhancing the perception of flavor (Davies and Taylor, 1959) .

In normogeusic individuals, temperature of food, to a point, increases perceived taste, which may similarly be enhancing the flavor perception in these patients. Alternatively, it may not be the temperature of the food but rather the temperature of the tongue, which is most relevant: increased tongue temperature increases taste (Green and George, 2004). Since elevated temperature improves chemosensory ability, heating consumables in those with chemosensory disorders may maximize chemosensory perceptions.

Sabri Jaber and Alan Heirsh. October 6th City, Cairo, Egypt and Chicago, IL Objective: Simultaneous upper respiratory tract infection induced phantogeusia in an espoused couple is described.

Method: Case Report: A 56 year old nasute male developed upper respiratory tract infection and 1018 fever, reduced smell and taste, dysosmia and flavorful eructations.

He also noted dysgeusia whereby Oreo cookies taste like flowers and green olives taste like garbage. This has been unresponsive to 3 courses of oral steroids.

Results: Proband chemosensory testing: olfactory: all tests demonstrate anosmia including; Brief Smell Identification Test: 6. Olfactometer Butanol Identification: left 9, right 9. Pocket Smell Test: 1. Alcohol Sniff Test: 0. Retronasal Smell: Retronasal Olfactory Testing: Retronasal Smell Index: 0 (abnormal). Gustatory: Propylthiouracil Disc Taste Test: 10 (normogeusia). MRA of the head, CT scan of the sinuses and ENT evaluation: normal. Spouse of proband: A 58year-old nasute female developed a respiratory infection 4 days after her husband. Two weeks after resolution of the cold, she noted the onset of distorted perception whereby soap would smell organic/perfumery/spice like. Once a day she experienced organic/spicy/perfumery/cilantro phantogeusia, 4/10 in severity. Immediately after the upper respiratory infection resolved she noted dysgeusia whereby cola tasted like Pine Sol. She was without chemosensory problem until the proband revealed to his spouse his chemosensory complaints, and within 4 days she developed the above.

Conclusion: While an olfactotropic virus has been demonstrated in siblings (Hirsch, 1994) , a similar effect in matrimonial partners has not been described. Further investigation in matrimonial chemosensory dysfunction is warranted.

After 3 weeks in the ICU, and one month of supportive treatment, the patient recovered.

Conclusion: To our knowledge this is the first reported case of botulism presenting as bilateral vocal cord paralysis. The gold standard diagnostic study takes several days to result. Electrophysiological testing can be helpful in establishing the diagnosis. The immediate clinical diagnosis of botulism and rapid treatment depends on understanding of the clinical presentation, neurological exam and epidemiological understanding of the association between IDU and wound botulism.

Eva L. Feldman, Ben Murdock, Tingting Zhou, Samy R. Kashlan, Roderick J. Little and Stephen A. Goutman. Ann Arbor, MI Amyotrophic lateral sclerosis (ALS) is a devastating illness which results in progressive degeneration of the motor neurons. There is currently no cure and treatment options are incredibly limited. Previous studies have demonstrated that the immune system plays a dual role in ALS pathogenesis: it can protect against or exacerbate neuronal damage. It is therefore critically important to determine the role of specific immune cell populations during the course of disease. However, despite strong evidence that the immune system plays a significant role in ALS pathogenesis, clinical studies have yet to identify a viable immune target in ALS patients. Our data indicate that numerous immune populations are increased in ALS patients compared to healthy controls. By tracking patients over multiple visits to the clinic and utilizing multivariate regression analysis, we are able to show that changes in several cell populations correlates with disease progression. In particular, increases in total numbers of neutrophils and decreases in CD4 T cell levels are closely tied with rapid disease progression. In addition, we find that the number of natural killer cells increases dramatically during the early stages of disease. Together, these data support the hypothesis that the immune system plays a central role in ALS pathogenesis and that peripheral immunity may be a viable therapeutic target. Peripheral neuropathy (PN) is a common complication of type 2 diabetes (T2D), and no effective treatments currently exist. We have evidence demonstrating that PN which manifests in high fat diet (HFD)-fed mice can be completely corrected through a paradigm of dietary reversal (DR). As HFD-fed mice more closely represent a model of impaired glucose tolerance/prediabetes rather than T2D, it is unclear whether DR can similarly benefit patients with frank T2D. Therefore, we investigated the effects of DR on PN in HFD-fed mice injected with streptozotocin (STZ), a model described by Yorek MS et al. (2014) which more accurately resembles a T2D phenotype.

From 12wk of age, male C57BL6/J mice were fed either a standard diet (10% kcal fat; CTRL) or a HFD (60% kcal fat; HF). At 20wk, a subset of HF mice were administered low dose STZ (1x75mg/kg, 1x50mg/kg; HF-STZ) to induce hyperglycemia. At 24wk, additional subsets of HF and HF-STZ mice were placed on a 10% kcal fat diet for 8wk (HF-DR and HF-STZ-DR, respectively) until the study conclusion at 32wk when terminal neuropathy phenotyping was performed.

By study conclusion, HF mice exhibit signs of impaired glucose tolerance and robust PN. As predicted, HF-DR mice displayed an improved metabolic profile which corresponded with improved peripheral nerve function when compared to HF mice. As a consequence of STZ administration, HF-STZ mice developed a robust hyperglycemia compared to HF mice. Despite this hyperglycemia, the presentation of PN was of a similar degree to that seen in HF mice. Similar to HF-DR mice, after 8wk of DR, HF-STZ-DR mice had a significantly improved metabolic profile and PN was corrected.

In conclusion, DR of HF-STZ mice can improve the metabolic profile and restore peripheral nerve function. This study supports the premise that dietary intervention is a feasible strategy to improve peripheral nerve health in patients with both pre-diabetes and T2D. Peripheral neuropathy (PN) is a common and debilitating complication of obesity and diabetes that triggers pain and loss of sensation. Substantial nerve damage occurs in many patients prior to noticeable symptoms and no treatments are currently available; therefore, there is a critical need to identify treatment strategies that impact the underlying disease pathogenesis. Our in vivo fluxomics data in the BKS-db/db mouse model of type 2 diabetes (T2DM) and PN suggest that 'metabolic reprogramming' occurs in the T2DM nerve to downregulate mitochondrial oxidative phosphorylation of substrates derived from glycolysis and fatty acid beta-oxidation. We therefore hypothesize that distinct systemic metabolic alterations occur in obesity and diabetes which induce tissue-specific metabolic reprogramming within the peripheral nerve, altering fuel utilization and ultimately leading to tissue dysfunction. We contend that identifying conserved bioenergetic profiles across mouse models of PN will provide insight into key PN mechanisms. The current study utilized two mouse models of PN: the 60% High Fat Diet (HFD) mouse model of obesity and prediabetes at 20 wk of age (16 wk HFD), and the leptin receptor-deficient BKSdb/db model of T2DM at 24 wk of age. Mitochondrial function was determined in primary dorsal root ganglia (DRG) neurons and sural nerve tissue from both models using the Seahorse XF24 Analyzer. Resting mitochondrial oxidative metabolism was upregulated in DRG neurons from mice with PN, with increased resting ATP production and maintained mitochondrial coupling. In contrast, resting ATP generation was decreased in sural nerve from mice with PN, with decreased coupling efficiency. Relative spare respiratory capacity was attenuated in both DRG neurons and sural nerve from mice with PN, indicating that mitochondria were less able to increase respiration in response to an energetic challenge. Moreover, mitochondrial copy number was unchanged in DRG neurons, but decreased in sural nerve tissue of mice with PN compared with respective controls. These data suggest a change in absolute number and function of sural nerve mitochondria, and a conserved cross-model proximal-distal bioenergetic profile in PN. We are currently exploring the relationship between these changes and PN pathogenesis. Background: RTS is an extremely rare autosomal dominant genetic disease characterized by growth deficiency, broad thumbs and great toes, intellectual disability and characteristic craniofacial appearance. Although patients frequently present with cardiorespiratory, musculoskeletal, genitourinary and endocrine abnormalities, neurological manifestations are not rare. The most common neurological manifestations of RTS include: seizures, primary brain tumors, cranio-spinal and posterior fossa anomalies.

Methods: We describe a 21 year-old male with past medical history of congenital heart disease, kypho-scoliosis, intellectual disability, and global developmental delay, who presented to the neuromuscular clinic with spasticity in all the extremities. Neurological examination revealed spasticity with atrophic changes in all the extremities.

Results: Brain MRI was unremarkable and spinal MRI revealed multi-level degenerative changes in cervical spine and cervical spinal stenosis. Patient underwent C4-C6 laminectomy with postero-lateral fusion for congenital cervical cord stenosis. A diagnosis of RTS was confirmed on genetic testing. Although patient underwent de-compressive surgery for cervical spinal stenosis, the spasticity persisted making RTS as the most likely etiology. Patient's spasticity was managed with baclofen and tizanidine.

Conclusion: RTS is an extremely rare condition for which although some clinical aspects have been clearly identified, a lot of multicenter studies are needed to expand our current knowledge on the clinical phenotype. We report an interesting case of RTS with spasticity in all the extremities. The ultimate goal of this case report is to extend our current knowledge on RTS and to define new international guidelines for diagnosis, care and treatment of patients with RTS. Early intervention, special education, vocational training to address developmental disabilities is critical in the management of this rare disorder. Objective: The fluoroquinolone antibiotic group is used for conditions such as pneumonia, sinusitis, bronchitis and urinary tract infections. High serum levels, good bioavailability and wide distribution are pharmacokinetics that make fluoroquinolones a favorable antibiotic. However, they've been described to have multiple multisystem and neurologic side effects. Hyposmia and hypogeusia have been reported but not heretofore objectified. Five cases with hyposmia and hypogeusia following use of levofloxacin are presented.

Methods: Case 1: 51 year old male immediately following levofloxacin use for a urinary tract infection experienced a multitude of side effects but noted residual diminished smell and taste.

Case 2: 69 year old female developed a sudden loss in her sense of smell and taste after treatment with levofloxacin for sinusitis. Sinusitis resolved but her chemosensory problems persisted.

Case 3: 61 year old female developed abrupt loss of smell and taste post-sinusitis treatment with levofloxacin.

Case 4: 53 year old male presented with sudden onset stale taste after increased dose of simvastatin and subsequent treatment with levofloxacin intensified this sensation. Complaints were primarily taste related.

Case 5: 38 year old male within seven days of treatment with levofloxacin for an influenza infection and sinusitis experienced sudden loss of smell and taste. Upon resolution of the infection the ability to smell was still diminished. Two weeks later, his taste dulled.

Results: Chemosensory testing of the cases revealed hyposmia and hypogeusia.

Discussion: Multiple pathophysiological mechanisms can be postulated. Bactericidal antibiotics induce oxidative damage in bacteria. Mitochondria are of bacterial origin. Levofloxacin induced mitochondrial damage may have occurred affecting the neurons for olfaction and gustation. Levofloxacin may have a similar effect to ciprofloxacin which causes cytotoxicity and genotoxicity on the chemosensory system. Fluoroquinolones have been described to have peripheral sensory disturbances. Levofloxacin can have a pathological effect on the somatosensory system; homologous effects on the chemosensory system may exist. Additionally, central or peripheral intracellular accumulation with passive transbilayer diffusion and active transport with poor efflux protein activity of levofloxacin may cause chemosensory damage. Moreover, hepatic metabolism and biliary excretion via glucoronidation are routes of elimination for fluoroquinolones, thus levofloxacin has limited clearance. Excess drug may precipitate toxicity based on the above mechanisms. In conclusion, fluoroquinolones should be used cautiously due to a multitude of side effects. The data warrants inquiry of levofloxacin induced hyposmia and hypogeusia. Hereditary ATTR (hATTR) amyloidosis is a rapidly progressive, life-threatening disease. Currently, the only medication approved for treatment of hATTR amyloidosis is tafamidis, but its approval is limited to select countries outside the US. Diflunisal, a NSAID shown to prevent dissociation of TTR tetramers, and doxycycline, a TTR fibril disrupter, are sometimes used off-label for hATTR amyloidosis. Patisiran, an investigational RNAi therapeutic targeting hepatic TTR production, is being studied in an ongoing Phase 3 study which has completed enrollment. The objective of this abstract is to highlight demographics of patients approved for the EAP who were receiving diflunisal and/or doxycycline prior to requesting access to patisiran and the reasons for the request.

The EAP is an open-label, multicenter study in the United States (NCT02939820) providing access to patisiran to adults with genotype-confirmed hATTR amyloidosis and symptomatic polyneuropathy who meet eligibility criteria. Patients who received active drug in an interventional hATTR amyloidosis trial in the past 24 months are excluded. The primary endpoint of the EAP is the incidence and severity of adverse events. After approval for patient access to the EAP, requesting physicians were asked to provide details on the rationale for access to patisiran despite treatment with diflunisal and/or doxycycline.

As of February 2017, 30 patients met preliminary eligibility criteria and were approved to receive access to patisiran through the EAP; 16 patients had a history or current use of diflunisal (n514), doxycycline (n51), or diflunisal/ doxycycline combination (n51). Patient demographics of this subgroup: mean age: 58 years (range 41-70); male: 88%, Val30Met TTR mutation: 13%; non-Val30Met mutations: 87%. Disease severity: mean NIS: 46 points (6-144); mean KPS: 75 (50-100); PND I: 44%; PND II: 25%; PND III: 31%; Heart failure (NYHA II): 25%. Physicianreported reasons for requesting EAP (available for 11/16 patients): disease progression and/or desire to use combination therapy (73%), intolerance of diflunisal and/or doxycycline (9%), or other (18%).

Majority of physicians requested access to patisiran for their patients within this subgroup on diflunisal and/or doxycycline due to disease progression and/or desire to use combination therapy, suggesting the need for new hATTR amyloidosis therapies. The EAP provides access to patisiran for requesting physicians of qualified hATTR amyloidosis patients with a significant unmet need. Challenges of the neurologic exam include the subjectivity and reproducibility of testing sensation due to the psychophysiological nature of the assessments. To quantify the reliability of a standard sensory examination, 127 patients (average age 53.3, SD 12.7, 41.7% female) were prospectively examined by neuromuscular neurology practitioners using a traditional 165 Hz tuning fork, a numerical Rydel-Seiffer (RS) tuning fork, or both. Vibratory loss was defined as a score less than 21.5 on the 4 point Mayo Clinic scale (05normal, 22550% loss, 245anesthesia) with a 165 Hz tuning fork, or less than 6 for an upper extremity or less than 4 on a lower extremity using a RS tuning fork. Subsequent testing included sensory nerve conduction studies (NCS), quantitative sensory testing (QST), or both to be used as gold-standard measurements of sensory dysfunction. For NCS, abnormality was defined as median or sural nerve sensory action potential amplitude less than 100% of agematched control normal values, and for QST abnormality was greater than or equal to the 95th percentile. Using sensory NCS as a gold standard, the sensitivity and specificity of the 165 Hz tuning fork for detecting vibratory loss were 28.9% and 98.7% respectively, whereas for the RS tuning fork values were 45.5% and 90%, respectively. Using QST as a gold standard, the sensitivity and specificity of the 165 Hz tuning fork for detecting vibratory loss was 18.3% and 97.4%, respectively, whereas for the RS tuning fork values were 32.6% and 85.0%, respectively. Compared to the 165 Hz tuning fork, the RS tuning fork showed a trend toward greater sensitivity, but this was not statistically significant (p 5 0.065 with NCS, p 5 0.289 with QST). With sensory NCS as a gold-standard, the accuracy of the 165 Hz tuning fork and the RS tuning forks were similar, 75.9% and 74.2%, respectively (p 5 1.0). Preliminary data suggests both tuning forks have low sensitivity for detecting vibratory sensory loss, but high specificity. Ongoing analysis will study these comparisons further, assess sensitivity and specificity values by examiner, and investigate the reliability of bedside testing for pain (pin prick) and temperature compared with sensory NCS and QST.

Gene Is Associated with an Axonal Polyneuropathy Michael Wang, Ryan Castoro, Megan Simmons, Bo Hu and Jun Li. Nashville, TN AIFM1 (apoptosis-inducing factor, mitochondrion-associated-1) has captured great attention from biomedical researchers due its critical role in the regulation of cell apoptosis. This flavoprotein is typically located in the mitochondrial intermembrane space where it is associated with respiratory chain complex-I. Upon a cell-death insult, AIFM1 is cleaved into a 57Kd protein that is released into the cytosol. The 57Kd peptide may enter the nucleus to trigger chromosome condensation and fragmentation, initiating a caspase-independent pathway of apoptosis. However, this nuclear translocation may be blocked by cytosolic Heat-Shock Protein-70 (HSP70) that binds with the FAD domain (aa 150 -228) of AIFM1. Mutations in AIFM1 gene have resulted in several clinical phenotypes, including a family with CMTX4 (Glu493Val). Clinical deficits in these patients usually involve multiple organs. In this study however, we identified a family with a novel missense mutation (Phe210Leu) in AIFM1 that developed a late-onset sensory motor axonal polyneuropathy by nerve conduction criteria. The proband and affected siblings exhibited distal muscle weakness and atrophy with normal cognitive and cranial nerve functions. There was no obvious phenotype from other organs. Interestingly, this Phe210Leu mutation affects a highly conserved amino acid at the center of the FAD domain. We hypothesize that this mutation impairs the binding between AIFM1 and HSP70, leading to an enhancement of cell-death signaling. This family therefore provides a unique opportunity to explore how altered apoptotic signaling affects the peripheral nerve system. Supported by grants from NINDS (R01NS066927) and the National Center for Advancing Translational Sciences (UL1TR000445). Introduction: Recently, a prospective trial looking at the use of ultrasound in the assessment of focal neuropathy detected improvement in several outcomes when ultrasound was performed, one being the SF-36 (Cartwright et al., 2015) . This study randomized 120 patients with focal neuropathies to either have their ultrasound reports sent or not sent to their management teams. Based on this published data, we calculated Quality-Adjusted-Life-Years (QALY) data by extracting the SF-6D scores, a preference-based health related quality of life (HR-QOL) index, from the original SF-36 scores. This information was used to statistically assess whether the originally reported improvement attributed to the use of diagnostic ultrasound extended to a preference-based HR-QOL score such as the SF-6D, as measured in QALYs.

Methods: Using the individual SF-36 values provided from the original prospective study, we extracted the SF-6D scores, a measurement of QALY, through applying a validated published algorithm. Differences in the mean change in QALY from baseline line to 6-month follow up in each group were assessed using paired-samples t-tests. Differences between the groups were evaluated using a linear regression model with backward elimination. Comparisons of the proportions of patients that had improvements in QALY between groups was also assessed using logistic regression.

Results: The "sent" group showed a 0.04 QALY improvement from baseline to 6-month follow up (p<0.012), as measured by SF-6D. The "not sent" group did not significantly change between baseline and 6 months (0.007 QALY, p<0.689). When comparing the groups directly, a strong trend was shown, with the "sent" group increasing QALY by an average of 0.036 above that of the "not sent" group (p<0.11). Sending the ultrasound report was associated with a 2.1 odds ratio of improved QALY between baseline and 6 months (p<0.092).

Conclusion: QALY, as measured by the preference-based HR-QOL index, SF-6D, was significantly improved between baseline and 6 month follow up when diagnostic ultrasound was used in evaluation of focal neuropathy. In addition to the positive outcomes found in the original study, this result further supports the efficacy of diagnostic ultrasound in focal neuropathy with a measure that can integrate both quality and quantity of life. Such a measure can be applied in future research into the cost effectiveness of diagnostic ultrasound in focal neuropathy. Purpose: Weakness of the arm caused by any non-progressive insult to the peripheral, or occasionally central, nervous system may be amenable to nerve transfer surgery to reverse that weakness. Nerve transfer involves cutting a redundant nerve, or fascicle from a neighboring healthy nerve, and transferring these functioning axons to the nerve branch supplying the paralyzed muscle. These transferred axons then regenerate into the new target, restoring function of that muscle. This field is little known among medical practitioners in general, but an impressive degree of functionality can often be restored. Too often, peripheral nerve injuries are referred after a long delay. When this delay is greater than a year the patient may miss the opportunity to benefit from these procedures and therefore fail to regain meaningful function. This pilot study aims to advance evaluation of patients considered for nerve transfer surgery and stimulate much needed further research and discussion regarding neurophysiologic evaluation to determine candidacy for nerve transfer surgery. We evaluated whether the degree of innervation in a donor nerve as assessed by quantitative electromyography predicted outcome of nerve transfer surgery as measured by hand-held manometry.

Methods: A chart review was performed to obtain the results of pre-operative quantitative neurophysiological studies on the donor nerve and post-operative force measurements of the recipient muscle after a minimum of one year follow up in patients who had undergone nerve transfer surgery. The quantitative electromyographic characteristic used was average motor unit count of a sample of maximal interference patterns, a continuous variable with a ceiling of >6 motor units. This was correlated with hand-held manometry force measurements, standardized as a percent of the contralateral unaffected arm, using linear regression.

Results: Twenty-eight nerve transfer cases were included. The correlation between motor unit count of the donor nerve and strength of its target muscle (the axon recipient) was strong (r 5 0.67, p<0.001). Importantly, Medical Research Council grading of the donor muscle did not predict recipient force outcome (p>0.54).

Conclusions: The quantitative electromyographic technique of motor unit count predicts recipient muscle force after nerve transfer surgery in the upper limb and should be considered in the evaluation of patients to aid in donor nerve selection. It is hoped that presentation of these results will improve awareness among neurologists of this important intervention as well as how to evaluate for nerve transfer surgery among neurophysiologists. Background: Small acute hematomas in anatomical spaces produce dramatic peripheral nerve dysfunction secondary to compression/traction injury. Animal studies demonstrate that acute nerve elongation greater than 6% affects nerve function and greater than 11% leads to irreversible vascular nerve changes. Hemophilic pseudo-tumors are very rare, with upper extremity involvement being rarer. Our patient presented with minimal neurological dysfunction despite giant chronic forearm hemophilic pseudo-tumors.

Design/Methods: Case study Results: 29 year-old male with history of Hemophilia A presented with bilateral forearm masses since birth which have expanded enormously within the last 2 years, producing forearm circumference of 57cm. Exam demonstrated normal left upper extremity motor/sensory function, and mild weakness of right finger abduction and 5th digit hypoaesthesia. Electrodiagnostic testing under ultrasound guidance demonstrated right ulnar axonal neuropathy with active and chronic denervation changes in the ADM and FDI muscles. Forearm MRI and MR neurography showed extensive bilateral mildly enhancing masses (largest left 25x12x11cm, right 19x16x14cm) with osteolytic ulna and radius destruction and neurovascular displacement. Calculated median and ulnar nerve elongation was 13% and 16% respectively on the right, 8% and 10% respectively on the left. Biopsy showed hemorrhage from chronic hemophilic bleeding.

Conclusions: Peripheral nerve injury and subsequent remodeling process have distinct pathophysiologies in the acute and chronic settings. In our patient calculated nerve elongation due to displacement by giant masses was expected to produce significant neurological dysfunction. However, he presented with minimal neurological symptoms suggesting different mechanisms in chronic versus acute injury. Although both events cause nerve traction/compression, it is likely that adaptive and remodeling processes differentiate functional outcome in slow injury, where there is greater potential for neural plasticity and preservation of peripheral nerve function. This case represents the tremendous potential of neural plasticity and nerve adaptability of the peripheral nervous system. We present a very rare case that demonstrates the extremes at which peripheral nerves can adapt after injuries. This case demonstrates that duration of injury is crucial in determining the outcome of nerve function. A better understanding of differences in mechanisms in acute versus chronic injury at the basic science level can help in developing translation clinical approaches. The findings from this case have the potential to contribute in our understanding in the development of clinical neurological disciplines of neurorehabilitation and sports neurology. Objectives: Given evidence that accumulation of C9orf72 repeat-associated non-ATG (RAN) peptides are highest in the cerebellum, we aimed to investigate the frequency of C9orf72 in a cohort of patients with ataxic disorders.

Methods: We screened 384 DNA samples from patients with cerebellar ataxia (n5368) and ataxia without cerebellar features (n518). Among patients with cerebellar ataxia 169 had episodic ataxia, 195 with progressive ataxia, and 2 with congenital nonprogressive ataxia.

We used repeat-primed PCR to identify repeat expansions in C9orf72.

Result: In this cohort of patients with did not see an overrepresentation of C9orf72 repeat expansion. Only one patient with early onset of classic episodic ataxia with a confirmed mutation in the EA2 gene carried the repeat expansion.

Conclusion: Despite the neuropathological involvement of cerebellum in C9orf72 spectrum disorders, we did not observe an association between pathologic repeat expansion in C9orf72 and ataxic disorders. Objective: To identify the molecular defect underlying a predominantly proximal myopathy in two unrelated fourgeneration families and a sporadic case.

Background: Mutations in the calpain-3 (CAPN3) gene cause one of the most common autosomal recessive limb girdle muscular dystrophies (LGMD). Recently a CAPN3 inframe deletion (c.643_663del21) was linked to autosomal dominant LGMD (Vissing et al., Brain 2016) . A critique of this paper suggested the alternative possibility of digenic disease (Saenz and Lopez de Munain, Brain 2016).

Methods: Clinical history, physical examination, electromyography (EMG), muscle biopsy evaluation by histochemistry, immunohistochemistry, and western blots, targeted next generation (NGS) for 106 genes causative of myopathies, targeted Sanger sequencing, and whole exome sequencing (WES).

Results: All probands reported adult-onset weakness, varying from early 40s to late 60s, although all of them had myalgia, low back pain or hyperlordosis for the preceding 20-25 years. The weakness affects predominantly pelvic girdle muscles, but one proband developed asymmetric abdominal wall muscle weakness at onset. The degree of weakness varies from mild to severe. One family had Norwegian ancestry, one family had German and Scandinavian ancestry, and the sporadic case was of mixed Northern European descent. Creatine kinase (CK) values ranged from normal (patient with abdominal wall weakness) to 1,800 U/ L independently from the severity of weakness. Some individuals with elevated CK were reportedly asymptomatic or had only low back pain (not available for examination). Needle EMG study showed mild proximal and/or axial myopathic changes without fibrillation potentials in most patients but it was normal in two patients despite the objective muscle weakness. Low frequency repetitive nerve stimulations detected no decrement. One muscle biopsy was normal, while the others ranged in severity from mild, nonspecific myopathic changes to mild, necrotizing myopathy. Muscle western blots showed greatly reduced calpain-3 in three unrelated patients and normal dysferlin. Atrophy of the paraspinal muscles was noted in the MRI images of the lumbar spine and abdominal CT in three patients. Affected individuals were found to carry CAPN3 c.643_663del21 (p.Ser215_Gly221del). The patient who had abdominal wall weakness at onset underwent WES, which showed no additional variants in genes so far known to be causative of myopathies.

Conclusions: The study provides further evidence for a dominantly inherited calpainopathy due to the heterozygous inframe CAPN3 deletion c.643_663del21. Calpainopathy should be considered in patients with autosomal dominant proximal and axial myopathy. Introduction: Paraneoplastic syndromes are rarely reported in patients with gliomas. This is a case report of a patient with glioblastoma who died of a sigmoid volvulus secondary to paraneoplastic gastrointestinal dysmotility syndrome.

Case Description: A 49-year-old man was diagnosed with a right temporal glioblastoma after presenting with headaches, slurred speech, and left-sided clumsiness. He was treated with radiation concomitant with daily temozolomide followed by monthly temozolomide. When he developed local recurrence two years after diagnosis, his tumor was treated with radiosurgery, dose-dense temozolomide, and a combination of bevacizumab, irinotecan, TCCC (6-thioguanine, lomustine, capecitabine, celecoxib), doxycycline, and an intermittent ketogenic diet for the next six years. Dexamethasone was discontinued once bevacizumab was started.

Seven years after his initial presentation, he was diagnosed with dysautonomia in the setting of labile blood pressures. He then began to have episodes of back pain and both urinary and bowel incontinence. MRI spine did not reveal cord compression or leptomeningeal enhancement. Cerebrospinal fluid analysis showed pleocytosis with elevated protein, but cytology was negative for malignant cells. Latest T-cell counts showed 935 CD3, 523 CD4, and 405 CD8 cells. Brain MRI revealed disease progression in the right temporal and frontal lobes, which were treated with multiple radiosurgery sessions. He continued to decline and was hospitalized for worsening confusion thought to be caused by subclinical seizures. Hospital course was complicated by abdominal distension secondary to a sigmoid volvulus, which subsequently caused his death at the age of 57.

Autopsy showed recurrent glioblastoma in the right temporal and frontal lobes with lymphoplasmacytic infiltrates and no other organ involvement. There was near complete loss of the right cerebellar peduncle likely due to Wallerian degeneration. On microscopic examination, the dorsal root ganglion associated with the superior mesenteric nerve had focal lymphocytic cuffing. There was also focal dense lymphocytic infiltrates consisting mostly of T-lymphocytes (CD3 positive) with a mixture of CD4 and CD8 cells in the celiac nerve and sympathetic chain. These findings were suggestive of an autoimmune neuronopathy and neuropathy that likely led to his ileus and potential bowel strangulation.

Discussion: The observed paraneoplastic gastrointestinal dysmotility syndrome likely occurred under the condition of a robust T-cell effector function, early discontinuation of dexamethasone and use of bevacizumab, as well as yet unknown tumor-related genetic and host-related immunologic factors.

Endpoint for Future Single-Arm Clinical Trials in Glioblastoma Chirag B. Patel, Reena P. Thomas, Seema Nagpal and Lawrence D. Recht. Stanford, CA Introduction: While randomized controlled trials (RCTs) remain the "gold standard" for registration trials in glioblastoma (GBM), they are limited by their costs, the need for control groups, and the limited number of patients relative to the prospective treatments to be studied. An alternative to this approach would be, instead of going for an incremental change, that the target would be clinically-significant overall survival (OS) endpoints, i.e. well beyond what could reasonably be expected with the current armamentarium. We evaluated whether the conditional probability of survival could lead to the identification of such a clinically-significant endpoint using an intradivisional database.

Methods: We retrospectively analyzed our database of GBM cases to calculate the conditional probability of an additional survival (AS) of 6 months given an achieved OS time (P(AS56 months|OStime)). The OStime that resulted in the absolute maximum of the P(AS56 months|OStime) curve was denoted as OStime(ASmax).

Results: 376 patients (mean age 58.7 6 14.1 years) were diagnosed between June 2001 and October 2016. The median OS from the time of pathology-proven diagnosis was 14.0 months. The 12-, 24-, and 36-month OS rates were 66.9%, 35.4%, and 24.1%, respectively. 85% of patients who were alive at OStime530 months went on to survive to 36 months. Analyzing our data out to 36 months, the OStime(ASmax) was found to be 32 months, i.e. patients who were alive at OStime532 months had a 87% probability of surviving an additional 6 months to a total OS of 38 months. Using the recent tumor treating fields (TTFields) study [Stupp, JAMA 2015] as a comparison, we noted that in order to validate such a conditional probability-based endpoint approach, the P(AS|OS) has to be high (>70%) at OStime530 months and must remain high in a plateau-like fashion (65%) for the 6-month period preceding OStime530 months (i.e. OStime 5 24-30 months) Conclusion: It should be possible to perform a successful trial with a limited number of patients (approximately 30). For example, if the goal of a novel experimental therapy were set to achieve a 48% 36-month OS rate (double that of our series), this could be tested without a placebo/control group. The trial could be stopped at 30 months after the last patient is enrolled declaring the therapy successful if 56.5% of patients (i.e. 48% 4 85%) remain alive at the 30-month OStime.

M323. An Interesting Case of Nocardial Brain Abscess Mimicking Brain Tumor in an Immunocompetent Patient Aiga Rakhesh, Bakhtier Nurmukhamedov and Eufrosina Young. Syracuse, NY Background: Nocardia cerebral abscess is rare, constituting approximately 1-2% of all cerebral abscesses. It is a very severe infection that carries the highest mortality rate among all bacterial cerebral abscesses, with mortality rates as high as 55% and 20% in immune compromised and immunocompetent patients, respectively. Early diagnosis and appropriate antibiotic therapy are crucial for a good outcome.

Case description: We report a 53-year-old woman presenting with Nocardial brain abscess mimicking primary brain tumor. Two weeks prior to the hospitalization she had presented with three episodes of transient aphasia and magnetic resonance imaging (MRI) brain demonstrated a left frontal lobe lesion with surrounding vasogenic edema suspicious for metastatic brain tumor. A metastatic workup including computed tomography (CT) scans of the thorax, abdomen, and pelvis revealed no evidence of primary lesions. Neurosurgery service had been consulted and an elective brain biopsy was scheduled and then she presented with progressive aphasia for 10 days and right arm weakness and headache for 2 days. Her neurological examination was significant for Broca's aphasia and mild R upper extremity weakness. Initial lab work up was unremarkable and there was no evidence of immunological abnormalities. CT scan of the head revealed increase in size of the previous heterogeneous mass in the left frontal lobe with increased amount of surrounding vasogenic edema and brain compression on the adjacent sulci. Due to increased vasogenic edema, patient was started on high-dose dexamethasone. Patient underwent a left sided craniotomy with resection of left frontal lobe mass. During the procedure, purulent material was obtained from the lesion. Dexamethasone was discontinued postoperatively due to suspicion of intracranial abscess. Intraoperative Gram stain revealed 21 WBCs with no organisms seen. Bacterial culture revealed gram-positive branching filamentous bacteria, consisting of Nocardi abscessus. Patient was started on targeted antibiotic therapy with linezolid and imipenem. Four months later, patient recovered and MRI brain showed no residual abscess. Patient continues to follow with ID and neurosurgery services.

Conclusion: We report a case of nocardial brain abscess mimicking metastatic brain tumor. Nocardial brain abscesses are rare but very severe infection that carries a high mortality rate. Despite their low incidence, we need to consider nocardial infection in the differential diagnosis of a cerebral lesion, even in immunocompetent patients, in order to obtain an early diagnosis and to start treatment as soon as possible.

M324. Semi-Automated MRI Segmentation Workflow for Glioblastoma Treated by Tumor Treating Fields Joshua J. Timmons, San Pyay, Kevin Bui, Edwin Lok and Eric T. Wong. Boston, MA Background: Tumor Treating Fields (TTFields) therapy is an approved modality of treatment for glioblastoma. Patient anatomy-based finite element analysis (FEA) has the potential to reveal not only how these fields affect tumor control but also how they can be optimized to improve efficacy. Historically, models for FEA has been created with manual segmentation by an expert familiar with intracranial neuroanatomical structures. But this method is time-consuming, financially costly, and variable between experts. While the availability of tools for segmenting MRIs obviates some of these obstacles, creating FEA models requires manual adjustments including removal of disconnected voxels, incorporation of unsegmented structures that may alter the electric field, and addition of 36 electrodes matching those of the transducers on the scalp. Existing approaches are also not scalable to a large number of patient MRI scans. A semiautomated workflow was developed to address these concerns.

Methods: The workflow encompassed image pre-processing, segmentation, placement of gel and electrode models, automated post-processing, and mesh generation in ScanIP. Tissues, including the scalp, bone, CSF, GM, WM, and cerebellum, were segmented using the NewSegment algorithm from Statistical Paramedic Mapping 8 (SPM8). The tumor and GTV were manually segmented by an expert. Electrodes and gel masks were generated using inverse deformation fields. Automated post-processing in ScanIP, from Simpleware (Exeter, UK), cleaned up disconnected voxels, smoothed surfaces, and layered the masks to prevent erroneous boundary conditions. The electric properties of each tissue were applied to these masks in silico using COMSOL Multiphysics (Burlington, MA). The completeness of the automatic methods, relative to the final manually adjusted model, was determined using the Dice coefficient, and COMSOL generated electric field maps were compared for models with and without post-processing in ScanIP.

Results: The Dice coefficient increased-5.6% for scalp, 12.2% for bone, 31.2% for CSF, 21.7% for GM, 9.0% for WM, and 18.3% for cerebellum-in segmentations with automated post-processing versus those without. This indicated that the masks with automated post-processing converged on a manually corrected model. COMSOL generated electric field maps displayed similarity between models generated with manual corrections versus those without.

Conclusions: These software and workflow may be used to accelerate the investigation of TTFields in patients by facilitating the creation of FEA models, like electric field maps, derived from patient MRI.

Stem-Like Cells in Patient-Derived Tumor Organoids Jaime Imitola, Yeshavanth Banasavadi-Siddegowda, Balveen Kaur, Fumihiro Watanabe and Alfredo Quinonez-Hinojosa.

The mechanisms that maintain self-renewal capacity in glioblastoma stem-like cells (GSC) are still unknown. Here we show that Aryl hydrocarbon receptor (AhR) and AhR target genes are functionally expressed on GSCs. Activating AhR is sufficient to increase the self-renewal capacity of CSC, the canonical gene expression of CYP1A1 and other AhR targets on GSCs. In contrast, inhibition of AhR leads to a decrease of self-renewal capacity and AhR targets genes. We showed that putative AhR genes increase during GSC differentiation and can be targeted at both the GSCs and differentiated stages of tumor progression in vitro. Using a novel "reporter" organoid model of glioblastoma from GSCs carrying OLIG2-GFP-Luc dual transcriptional reporters, we demonstrated that AhR inhibition decreases proliferation, increased apoptosis, reduce the size of the organoids and the expression of OLIG2. Furthermore, increasing the apoptotic niches in the organoids. Using a complementary approach, we demonstrated that AhR knockdown in GSCs induced loss of self-renewal with increased in p53 phosphorylation. Implantation of AhR deficient human GSCs leads to a decrease in tumor size and survival advantage in mice. Furthermore, using microarray gene expression analysis of patient-derived organoids, we established the molecular programs affected by targeting AhR in these organoids, corresponded to genes related to stemness and inflammation that are independently associated with survival. Our findings established the functional expression of AhR in GSC as critical to maintaining tumor growth and self-renewal in vivo and in a patient-derived model of glioblastoma during two critical stages of tumorogenesis. Our results indicate that tumor derived-organoids can be used as a preclinical predictive model to study the molecular vulnerabilities of tumors to distinct candidate therapies in a given patient, toward personalized Neuro-Oncology.

Secondary to High-Grade Astrocytoma Neeraj Singh and Derrece K. Reid. Albany, NY R.R. is a 26-year-old man who developed lower back pain three months after Zika virus infection. Three months later, he developed left leg numbness and weakness with inability to urinate. Contrasted MRI thoracic spine showed T8-T9 cord signal abnormality with peripheral cord enhancement. Lumbar puncture revealed elevated protein (290) and oligoclonal bands (5), but no infection. Despite five plasmapheresis sessions for presumed transverse myelitis, repeat contrasted MRI thoracic spine revealed abnormal cord signal extending from C3 to L1, with leptomeningeal enhancement of the thoracolumbar cord and cauda equina. PET scan showed abnormal FDG uptake at the thoracic cord. R.R. was discharged to an inpatient rehabilitation center with no immediate follow-up. Two months later, he presented to another hospital with headache and emesis. Neurological exam revealed disorientation, global aphasia, and paraplegia. Repeat lumbar puncture showed xanthochromia, high white blood cells (127), and markedly high protein (1750). Thoracic leptomeningeal biopsy revealed high-grade astrocytoma. Intravenous dexamethasone was started; neuroaxis radiation therapy with temozolomide was planned. This case demonstrates the importance of including neoplasms in the differential diagnosis of spinal cord lesions, and of timely communication between hospitals to ensure prompt diagnosis and treatment. Introduction: Resting state functional connectivity is profoundly influenced by states of consciousness. However, the neural basis of these state-dependent changes is poorly understood. Towards this end, we have utilized transgenic mice genetically encoding calcium indicators in cortical neurons (GCaMP mice) to monitor neuronal activity in mice, during wakefulness, under anesthesia, and during natural sleep.

Methods: Transparent windows were affixed with translucent adhesive cement (C&B-Metabond) to the intact skull (scalp removed) of living Thy1-GCaMP6 transgenic mice, to permit serial imaging over weeks to months. EEG bone screws were implanted 1 and 5 mm posterior, lateral to bregma respectively. Optical intrinsic signal imaging (OIS) was utilized to detect calcium-induced fluorescence using blue light and a CCD camera. Mice were serially imaged during wakefulness, natural sleep, and under dexmedetomidine (0.5 lg/g, ip) and ketamine/xylazine (86.9 mg/kg ketamine, 13.4 mg/kg xylazine, ip) anesthesia with simultaneous EEG recording. Each imaging session recorded 60 min of resting state data; with an interval of at least three days between imaging sessions.

Results: GCAMP6 fluorescence results demonstrate with high temporal resolution (20Hz) cortical neuronal activity at a population level with a high spatial resolution of 78 lm2 while simultaneously imaging multiple areas in a bihemispheric distribution from olfactory bulb to superior colliculus. Under sleep and anesthesia compared to wakefulness, there is a significant increase in the spectral content of the GCAMP signal in the delta range over the motor, somatosensory, and visual cortices. There is a marked anterior to posterior contiguous propagation of GCAMP6 activity remarkably similar to the previously described propagation of sleep slow waves in humans. Functional connectivity (FC) analysis showed a transition from a correlative pattern that was binary along the anterior-posterior axis during sleep and anesthesia to a more complex, local connectivity pattern seen in wakefulness.

Conclusions: OIS imaging of GCaMP mice provides repeatable, non-invasive, high spatial and temporal resolution data enabling us to better understand the cortical slow oscillation. By combining this novel imaging approach in mice with powerful genetic and surgical manipulations, we will be able to study cellular and molecular mechanisms underlying state-dependent changes in functional connectivity. Introduction: Sleep disturbances are highly prevalent among US Veterans with traumatic brain injury (TBI). TBI is associated with nightmares, disruptive nocturnal behaviors, dream enactment, and REM sleep without atonia (RSWA). Cases may meet the clinical diagnostic criteria for Rapid Eye Movement (REM) sleep behavior disorder, a sleep disorder widely regarded as one of the earliest clinical symptoms of Parkinson's disease and other synucleinopathies. The prevalence and characteristic physiology of RBD among in Veterans with TBI is unknown.

Methods: A large cohort of Veterans (n5670) were enrolled during their clinical in-lab polysomnography. Selfreport data collected included validated questionnaires about sleep quality, dream enactment, TBI and PTSD history and severity, and mental health comorbidities. Polysomnography was staged for sleep, and EMG tone was classified as low (50% below median EMG tone), medium (50 to 80%) or high (EMG values 80% and above), and analyzed within each sleep stage. Of the 670 Veterans, 198 did not have sufficient PSG, REM, or EMG signals to analyze for this study, 19 were excluded due to taking zolpidem on the night of the study, 15 did not answer the dream enactment question, and 88 were excluded for PTSD. Group and individual differences of the remaining 350 subjects were analyzed using chi-square and one-way ANOVA.

Results: A surprisingly high number of Veterans reported a high rate of dream enactment and nightmares: 66% TBI versus 29% non-TBI controls for dream enactment (p<0.0001; X2534.7), and 56% TBI versus 17% non-TBI controls for nightmares (p<0.0001; X2573.5). Of those with TBI, 10.5% had high EMG tone and reported dream enactment, compared to only 3.4% of non-TBI subjects with high EMG tone and dream enactment (p50.009, X256.82). Average absolute EMG tone during REM sleep was significantly higher in those with TBI compared to non-TBI controls (24.9 1/-1.6 vs. 19.8 1/-0.6 mV, p50.003, t53.02). Veterans with TBI spent significantly more time in NREM stage N2 sleep (p50.032, t52.16) and N3 sleep (p50.0039, t52.93), and less time in N1 sleep (p50.047, t51.99) than controls. REM sleep staging did not significantly differ between groups.

Conclusion: Veterans with TBI have a high rate of dream enactment behavior, nightmares, and elevated EMG tone during REM sleep. Further analysis is underway to determine whether polysomnography data meets formal clinical criteria for RSWA and REM behavior disorder, and to determine long-term neurological outcomes indicative of neurodegeneration.

covariates in the ANCOVA. Two blinded researchers counted PVS in the midbrain, BG, and CS, and determined 4 categories (mild, moderate, frequent, and severe) based on an established PVS rating scale (Potter et al., 2015) .

Results: Of the forty-four patients, 8 had mild PVS burden (18%), 16 moderate (36%), 11 frequent (25%), and 9 severe (21%). Nineteen patients (43%) reported TBI (4 with mild PVS, 8 moderate, 3 frequent and 4 severe).

Patients with severe PVS burden in the BG and CS had shorter mean sleep time (246 minutes versus 375; P50.005), spent less time in NREM sleep (50% vs. 66%; P50.015), and had worse sleep efficiency (62% vs. 83%; P50.036) when compared to the mild PVS group in an ANCOVA controlling for age, TBI, and OSA status. Patients with severe PVS burden in the BG and CS had higher FOSQ scores (13.3 versus 14.7) than the group with mild PVS burden, but these differences were not statistically significant. Lower PVS in the in BG and CS correlated with longer sleep time (r 5 20.411; P50.0061).

Conclusions: Severe PVS burden was associated with shorter sleep time, less NREM sleep, poorer sleep efficiency, and worse quality of life due to sleep problems on FOSQ. In this small study, self-reported TBI was not significantly associated with increased PVS burden. Background: Sleep quality is closely linked with cognitive function. Monitoring sleep patterns may offer insight into the early prognosis of aging adults at risk for dementia. Disrupted sleep has been documented in studies of adults with mild cognitive impairment. Sleep patterns are strongly influenced by circadian rhythms on a daily scale and also vary seasonally depending on day length and environmental temperature, with longer sleep periods observed during the winter months. In a uniquely longitudinal cohort study using in-home passive monitoring, we evaluated whether normal seasonal (infradian) rhythms are disrupted in individuals with MCI.

Methods: Participants were 128 older adults; mean age, 85 years. Ninety-eight were cognitively intact and 30 had been diagnosed with MCI (22 non-amnestic MCI; 8 amnestic MCI) using standard psychometric and clinical criteria. All were enrolled in an ongoing longitudinal study using inhome passive monitoring technology. Infrared sensors were placed throughout each participant's home to monitor movement and presence in each room of the home. Algorithms were developed to estimate rest-activity patterns during the night.

Results: Activity data was collected from the sensors for more than five hundred days. Rest-activity patterns were found to vary seasonally for the cognitively intact group with longer sleep periods during the winter months. This seasonal variation was not observed for those with nonamnestic mild cognitive impairment. Total time asleep was associated with the seasonal length of the night for the cognitively intact group and more weakly for the group with amnestic MCI. The cognitively intact group was found to sleep an average of 18 minutes longer in winter, while the MCI group slept 9 minutes less in winter.

Conclusions: MCI is associated with an attenuation of seasonal variation in sleep patterns during the night, particularly within the subjects with non-amnestic MCI. Detection of changes in infradian sleep patterns may be an early marker of cognitive decline. Which key determinants are driving these disturbed rhythms, home environmental factors or external environmental cues, remains an important question for ongoing and future studies.

Movement Periods (nSOREMPs) on Diagnosing Narcolepsy David R. Landzberg, James Andry and Kanika Bagai. Nashville, TN Background: The ICSD and DSM have both recently incorporated nSOREMPs in their diagnostic criteria for narcolepsy. We sought to examine the effects of these new diagnostic criteria.

Methods: We retrospectively analyzed 1200 patients evaluated for hypersomnolence who underwent both polysomnography and multiple sleep latency testing. The ICSD-2, ICSD-3, and DSM-V criteria for narcolepsy were used to classify patients. The prevalence of nSOREMPs was evaluated using ICSD-3 classification.

Results: 32 patients were diagnosed with narcolepsy type 1 (NT1) using both ICSD-2 and ICSD-3 criteria. Narcolepsy type 2 (NT2) was diagnosed in 126 patients using ICSD-2 criteria and 129 patients using ICSD-3 criteria. Narcolepsy (type 1 and 2) was diagnosed in 161 patients using ICSD-3 criteria and 172 patients using DSM-V criteria.

The prevalence of nSOREMPs was 18.75% in NT1, 7.75% in NT2 and 1.06% in patients without narcolepsy (p<.00001).

Conclusion: Use of nSOREMPs did not affect the ICSD-3 diagnosis of NT1, and minimally affected the ISCD-3 diagnosis of NT2 compared with ICSD-2 criteria. Use of nSOREMPs mildly increased the DSM-V diagnosis of narcolepsy compared with ICSD-3 criteria. nSOREMPs were more prevalent in NT1 than NT2 patients. Autism spectrum disorders are prevalent neurodevelopmental disorders with great societal cost; however, treatment options remain parsimonious due to limited understanding of the underlying molecular, cellular, and circuit mechanisms. We have recently demonstrated in a mouse model of Tuberous Sclerosis Complex, that cerebellar specific dysfunction is sufficient to generate autistic-like behaviors. To better understand the cerebellar topography governing the cerebellar regulation of these ASD-relevant behaviors, we identified abnormalities in a clinically-implicated region in our cerebellar ASD mouse model. In addition, we have demonstrated that inhibition of this cerebellar domain is sufficient to generate social deficits and repetitive behaviors. Moreover, we have demonstrated that stimulation of this domain is sufficient to rescue abnormal behaviors in our cerebellar ASD mouse model, even into adulthood, thereby demonstrating the potential for cerebellar neuromodulation-based therapies in the treatment of abnormal ASD behaviors. We further explore the cerebellar -cortical circuits regulated by this domains to better understand the circuit networks involved in ASD behaviors and to identify additional therapeutic targets for neural circuit-based therapeutic development.

develop PD, suggesting the presence of modifiers. To investigate how GBA1 influences PD pathogenesis, we created a Drosophila model of GBA1 deficiency (GBA1 del ) that has neurodegeneration and impaired autophagy. A screen using our GBA1 del model is being conducted to identify modifier loci that suppress or enhance GBA1 del mutant phenotypes. Targeted lipidomic analysis is used to evaluate alterations in lipid metabolism due to genetic perturbations of modifiers in GBA1 del mutants.

Glucosylceramide transferase (GlcT-1), which encodes an enzyme with the reverse enzymatic activity to GBA1, was identified as a modifying locus. Mutant GlcT-1 suppressed accelerated insoluble protein aggregation in GBA1 del homozygotes, while ectopic expression of GlcT-1 enhanced the climbing deficit, autophagy defects, and shortened lifespan of GBA1 del homozygotes.

Our initial results suggest that decreased levels of ceramide and/or increased levels of glucosylceramide drive pathogenesis in GBA1 del homozygotes. Characterizing additional modifiers will elucidate whether alterations in lipid metabolite levels are responsible for the pathogenic mechanisms causing parkinsonism, and may reveal new targets for disease-modifying therapies in PD.

Recapitulates Key Features of Essential Tremor Sheng-Han Kuo, Ming-Kai Pan, Shi-Bing Wang, Yong-Shi Li and Phyllis Faust. New York and Taipei, Taiwan Essential tremor (ET) is the most prevalent movement disorders, affecting 4% of individuals aged 40 years or older. The mechanism of ET remains unclear, mainly due to the lack of chronic tremor animal model. Previously, we discovered that climbing fiber (CF) synaptic pathology in the postmortem ET cerebellum (i.e. the invasion of CFs into the parallel fiber (PF) synaptic territory on the Purkinje cell dendrites). Here we reported that GluRdelta2-insufficient mice (hotfoot 17J) also had ET-like CF pathology and developed 20Hz tremor. Similar to ET, the characteristics of mouse tremor was kinetic-predominant, adult onset and worsening with aging. The ET-like tremor in mice responded to ET-medications, including primidone, propranolol and alcohol. Since GluRdelta2 is a Purkinje cellspecific molecule, our study demonstrated that ET-like tremor could be generated from the cerebellar cortex with hyper-innervated CFs. Therefore, we uncovered a major mechanism of ET and also provided a disease model to study cerebellar motor functions, with evidence that can be mutually referenced between mouse and human at the molecular (GluRdelta2), pathological (CF wirings) and behavioral (tremor) levels.

The collagen VI related muscular dystrophies (COL6-RD) are inherited disorders of collagen VI characterized by progressive muscle weakness and a combination of distal joint laxity and proximal joint contractures. Phenotypic heterogeneity is a hallmark of COL6-RD with a spectrum of severity in patients from the very severe Ullrich congenital muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). Factors controlling severity in COL6-RD patients are largely unknown, however, patients with identical mutations can have the full spectrum of phenotypes, suggesting the existence of genetic modifiers. In this study, we test the hypothesis that LTBP4, a regulator of TGF-b signaling which has been shown to influence severity Duchenne muscular dystrophy, can also modify severity in COL6-RD by testing for association of LTPB4 haplotype with major markers of clinical progression in COL6-RD including time to loss of ambulation in a large cohort of comprehensively phenotyped patients. These studies provide critical insights into the phenotypic heterogeneity seen in patients with COL6-RD, identify targets for the development of therapies, and provide an important model for future studies of the molecular pathogenesis. Painful diabetic neuropathy (PDN) is one of the most common and intractable symptoms of diabetes, affecting 25% of diabetic patients. The hallmarks of PDN are neuropathic pain and small-fiber degeneration, the loss of dorsal root ganglion (DRG) nociceptor axons. In states of neuropathic pain, DRG nociceptors become responsive to a variety of excitatory influences, including inflammatory cytokines. However, the molecular mechanisms leading to DRG nociceptors hyperexcitability and small-fiber degeneration in PDN are unknown.

Using electrophysiological, optical and molecular methods in transgenic mice, we have shown that selective chemokine receptor CXCR4 deletion from nociceptors reverses neuropathic pain and nerve terminal degeneration in the High Fat Diet (HFD) model of PDN. Furthermore, we have shown that dampening of nociceptors excitability with designer receptors exclusively activated by designer drugs (DREADD) prevents neuropathic pain, neuronal calcium overload, mitochondrial dysfunction and small-fiber degeneration in PDN.

This study reveals that neuronal chemokine signaling contributes to neuronal hyperexcitability, which causes neuronal calcium overload and mitochondrial dysfunction, ultimately leading to neuropathic pain and neuronal fiber degeneration in PDN. Hence, targeting chemokine-induced nociceptor hyperexcitability represents a novel disease-modifying approach to a currently intractable and widespread affliction. S123 Al-Janabi, Omar M. S170 Al-Khalili, Yasir S125, S145, S217, M213, M273, M287 Allen, Anthony M300 Allendorfer, Jane B. S135 Alquezar, Carolina M176 Alrajeh, Saad M. S123 Alsshikho, Mohamad CD372 Al-Subu, Rand CD369 AlTassan, Nada S123 D Deep Brain Stimulation S245, S255, S256, M125, M250, M258, M267 Delirium S118, M171, M173, M185 Dementia S123, S132, S169, S174, S185WIP, S188, S239, S244, S279, M120, M127, M164, M165, M172, M174, M176, M180, M227 Dementia with Lewy Bodies (DLB) S182, M169 Demyelination S119, S279, S281, S284, M101, M113, M141, M159, M219, M283, M284WIP, M295 Diabetic Neuropathy S223, S235, S307, S309, S315, M219, M305, M308, M309, M314 Drosophila M265 E Epilepsy S188, S193, S194, S195, S196, S197, S198, S199, S201, S202, S203, S204, S205, S206, S211, S213, S214, S215, S216, S217, S218, S219, S220, S222, M110, M116, M193, M194, M195, M196, M197, M199, M202, M204, M205, M206, M207, M208, M210, M211, M212, M213, M214, M217, M218, M223, M230, M233, M235, M264 Epilepsy Model S198, S210, S211, S215, M196, M202, M217 Epileptic Seizures S111, S118, S153, S189, S200, S201, S204, S207, S211, S215, S217, S219, S320, M110, M116, M195, M196, M197, M200, M201, M202, M205, M216, M217, M218, M230 Epileptogenesis M208, M230 Experimental Autoimmune Encephalomyelitis (EAE) S273, S281, M113 F FDG PET M119, M336WIP fMRI S122, S126, S127, S128, S130, S163, S217, S335, M123, M126 Friedreich's Ataxia M269WIP Frontotemporal Dementia (FTD) S167, S181, S264, S314, M176, M178, M319 G Gene Expression S134WIP, S183, M117, M159, M171, M280, M299

Gene Regulation S148, S179, S242, M299 Gene Therapy S167, S275, S301, M165 Genetic Mutations S120WIP, S123, S140, S142, S194 ,  S213, S247, S262, S264, S265, S269, S275, S293, S294,  S316, M177, M184, M202, M232, M244, M250, M254,  M255, M263, M264, M284WIP, M295, M297, M298,  M310, M312, M315, M319, M269WIP Magnetic Resonance Imaging (MRI) S137, S158, S170, S173, S177, S181, S184, S188, S249, S274, S305, M107, M108, N Neurodegenerative Diseases S163, S168, S177, S181, S185WIP , S225, S255, S256, S260, S261, S265, S297,  S310, S314, S316, M167, M174, M176, M177, M179,  M182, M248, M254, M255, M262, M269WIP,  M270WIP, M282, M293, M297, M319, M330,  M331, M300 Stroke S135, S137, S138, S139, S140, S142, S143, S144, S152, S153, S154, S162, S189, S220, S224, S228, S229, S230, S234, S238, S285, S289, S291, S320, M103, V Visual Cortex S126 Visual Function S102, S159

S232 Annals of Neurology Vol 82 (suppl 21) 2017

Olfactory Loss in a Brother and Sister Following Their Simultaneously Contracted Upper Respiratory Viral Infections: A Case Report

M305. Impairment of Mitochondrial Trafficking in Dorsal Root Ganglion Neurons Is Dependent on Hydrocarbon Chain Length of Saturated Fatty Acids

M312. Expanded Access Protocol (EAP) of Patisiran for Patients with Hereditary ATTR Amyloidosis: Demographics of Patients on Diflunisal and/or Doxycycline and Reasons for Requesting Access to Patisiran John L. Berk, Sa sa A. Z ivkovic´

Objective sleepiness was defined as mean sleep latency time (MSL) 8 minutes on MSLT. Results: 155 patients met criteria for mild OSA. The average ESS score was 13.98 6 5.08 with 81.8% (117/143) meeting criteria for subjective sleepiness

For mild OSA patients with objective sleepiness, the average sleep efficiency was 84%. Conclusion: Over one-third of patients with mild OSA have objective evidence of sleepiness despite adequate sleep efficiency and total sleep time. This subgroup may benefit from treatment of their mild OSA to improve objective sleepiness and to prevent consequences of decreased daytime vigilance

Traumatic Brain Injury M335. 18F-AV1451 Tau PET in Patients at Risk for Chronic Traumatic

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that can only be diagnosed post-mortem

Methods: We included nine patients with a prior history of repetitive mild TBI who presented to our clinic with neurologic complaints (all male

All patients underwent detailed neurological and cognitive assessments, PET with 18F-AV1451 (tau), 11C-PIB (amyloid-beta) and MRI (3T). PET images were co-registered to MRI to create Standardized Uptake Value Ratio images (PIB: 50-70 min postinjection, cerebellum gray-matter reference; AV1451: 80-100 min, inferior-cerebellum gray-matter). Eighteen cognitively normal, amyloid PET-negative, age-matched male controls were used for comparison

Results: Three patients were diagnosed with dementia, five with mild cognitive impairment and one was judged to have subjective complaints. Two patients were amyloid positive -one showed a diffusely positive PIB scan (mean cortical PIB SUVR51.68) while the other showed focal uptake in left frontal cortex and precuneus (mean cortical SUVR51.28). As expected, these patients showed highest AV1451 retention values, with uptake noted in bilateral frontal, parietal and temporal regions and spatial extent values of 77.59% and 20.24% respectively (mean spatial extent in controls 0.78%60.61%). Three other patients showed more modest, patchy, cortical AV1451 uptake on visual inspection in the frontal

Conclusions: We detected elevated AV1451 uptake in 5/9 patients at risk for CTE, including 3/7 that were amyloid PET negative. The pattern of retention prominently involved frontal and temporal lobes, mirroring the distribution of pathology in CTE pathologic stages III-IV. AV1451 may detect tau in later stages of CTE

M336WIP. Association Between Head Injury and Brain Amyloid Deposition Andrea Schneider

There were no differences in the prevalence of elevated SUVR in the anterior cingulate, posterior cingulate, precuneus, lateral temporal, parietal, or occipital lobes (all p>0.05). Conclusions: A history of prior head injury is associated with increased amyloid deposition globally and in the frontal cortex; further work is needed to determine if increased amyloid deposition contributes to dementia in this population

intron of STK17B (chr 2), inhibiting TGF-b signaling; rs7900948 (LBF5 5.039) in gene desert; rs11666532 (LBF59.245) in intron of NLRP11 (chr 19), involved in inflammasome activation; and rs7276690 (LBF56.213) in intron of RCAN1 (chr 21), regulating calcineurin 1 that attenuates inflammatory cascades and induced by cellular calcium overload and oxidative stress. Conclusion: GWAS in a transethnic population using MANTRA identified 4 novel genome-wide associations close to genes related to inflammation and apoptosis that are related to early neurologic changes following AIS. Dementia and Aging CD346. ALS-Linked Mutations Increase the Viscosity of Liquid-Like Axonal TDP-43 RNP Granules in

Whether neuronal RNP granules are liquidlike, and how their properties contribute to disease is unknown. Here we show that TDP-43 RNP granules in axons of primary cortical neurons display liquid-like properties, including fusion events with rapid relaxation to circular shape, shear stress-induced deformation, and rapid fluorescence recovery after photobleaching. Furthermore, wild type TDP-43 RNP granules show distinct biophysical properties depending on their location along the axon. ALS-linked mutant TDP-43 granules display slower bleach recovery and increased viscosity compared to wild type TDP-43, indicating that the mutations alter the biophysical properties of the granules in neurons. Together these data demonstrate diversity of neuronal RNP granules that may reflect different maturational states. Moreover

CD349. Targeting Microglial and Macrophage Kv1

Objective: Determine the diagnostic accuracy of high-frequency oscillation (HFO) rates for localizing epileptogenic regions in the temporal lobe. Methods: Intra-operative iEEG recordings from patients with temporal lobe epilepsy (TLE) obtained at the time of impantation or at the time of resection were analyzed using a custom HFO detector. The identified HFO events were classified and characterized as true or false ripple/fast ripple on spikes, or ripples/fast ripples on oscillations, and confirmed by visual inspection. Results: Preliminary analysis demonstrates that in a cohort of seven patients anesthetized using remifentanil with multiple subdural strips, and a hippocampal depth electrode

We previously described age-dependent differences in microglial responses to ischemia, and in the therapeutic effect of microglial inhibition after injury. The aim of the current study was to assess the genetic control of these age-dependent differences in microglial functioning. Methods: Immunostaining was performed in naive P2, P9, P30, and P60 mice. Microglia were isolated from P2, P9, P30 and P60 mice and quantitative rt-PCR was performed. Ischemia was induced in P9 and P30 mice by unilateral carotid artery ligation and exposure to 10% O2 for 50 minutes and immunostaining and rt-PCR were performed 2 days post-injury. Results: During brain development, microglia progress from ameboid to highly ramified morphology. Among a panel of genes involved in microglia function, expression of the TGFbeta and MerTK receptors significantly increased during development. Ischemia induced an increased TGFbeta receptor signaling in P9 mice

Role of S100A8/A9 in Sustained Neuroinflammation After

In a mouse model of sepsis survival, S100A8/A9 is persistently expressed in the brain for at least two weeks after sepsis. S100A9 deficiency decreases recruitment of neutrophils to the brain after sepsis. In sepsis survivor mice, microglia are primed to produce TNFa or reactive oxygen species. S100A9 deficiency abolishes priming of both ROS production and TNFa secretion in sepsis survivors. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial reactive oxygen species and cytokine production

Alpha Synuclein Toxicity S179, S260, M169, M248, M261

Alzheimer's Disease Mutants S173, S174, M177

M289 Brain Mapping S130, M126, M137, M193, M214, M258, M324 Brain Metabolism S216, M159, M264 Brain Radiation S321

Cognitive and Neurobehavioral Status Examination (CNS) S106, S114

Cytotoxic T Cells M293 Cytotoxicity

Background: During sleep, astrocytes mediate clearance of brain waste products including amyloid-beta through perivascular spaces (PVS). Sleep disturbances are strongly associated with early symptoms of Alzheimer's disease (AD) and traumatic brain injury (TBI). Sleep-related failure of "glymphatic" clearance may contribute to the pathophysiology of AD and chronic TBI.Enlarged PVS are visible in the midbrain, basal ganglia (BG), and centrum semiovale (CS) on MRI. Recent studies suggest the number of enlarged PVS may be predictors of neurological outcomes. Visible PVS on MRI could be a marker of abnormal glymphatic clearance in the brain.We hypothesized that patients with sleep disturbances would have increased burden of visible PVS on MRI.Methods: Patients with in-lab overnight polysomnography and available brain MRI's completed the Functional Outcomes of Sleep Questionnaire (FOSQ) as part of a larger IRB-approved study at a single site, the Portland VA (MIRB #3641, PI: Lim). Additional data were examined including age, self-reported TBI and apnea-hypopnea index (AHI -a metric of obstructive sleep apnea, or OSA) as

Diabetic neuropathy (DN) is the most common complication of diabetes affecting up to 60% of diabetic patients. The pathogenesis of DN in Type 2 diabetes is directly related to dyslipidemia associated with the western diet composed of elevated levels of long chain saturated fatty acids (SFAs) and low levels of medium chain SFAs. Long chain SFAs are associated with insulin resistance and dyslipidemia while medium chain SFAs have been associated with decreased lipid accumulation and improved mitochondrial function. Since DN is primarily a disorder of the sensory dorsal root ganglion (DRG) neurons, we sought to evaluate the impact of medium and long chain SFA hydrocarbon chain length on mitochondrial trafficking mechanisms that are critical for distributing ATP throughout the DRG axon to provide energy for neuronal function. We hypothesize that long chain SFAs will impair mitochondrial trafficking whereas medium length SFAs will not impact mitochondrial transport along the DRG axon. In this study, we examined the impact of SFA hydrocarbon chain length on mitochondrial trafficking, directionality and velocity in primary mouse DRG neurons. DRG neurons were treated with increasing concentrations of long chain SFAs, stearate and palmitate, or medium chain SFA, laurate, ranging from 31.25 to 250 micromolar for twenty-four hours. DRG neurons treated with long-chain SFAs, palmitate and stearate, showed a significant decrease in the percentage of motile mitochondria whereas medium chain SFA, laurate, does not alter mitochondrial motility. We next assessed whether motile mitochondria in DRG neurons treated with palmitate or stearate exhibited altered directionality or velocity of mitochondrial trafficking. Palmitate and stearate treatments resulted in a trending decrease in the number of mitochondria trafficking in both anterograde and retrograde directions. Furthermore, 62.5 to 250 micromolar palmitate and stearate induced a significant decrease in mitochondrial velocity. Laurate treatment, on the other hand, retained directionality and velocity of mitochondrial trafficking. These results suggest that hydrocarbon chain length of saturated fatty acids plays an important role in regulating mitochondrial trafficking mechanisms in dorsal root ganglion neurons. Impaired mitochondrial trafficking in DRG neurons exposed to elevated levels of long-chain SFAs may play a critical role in the progression of DN.

Rajarshi Mazumder, Jessica Rexach, Nasheed I. Jamal and Shri K. Mishra. Los Angeles, CA Objective: We report a case of wound botulism presenting as acute bilateral vocal cord paralysis and review the literature for approaches to emergent diagnosis of botulism.Background: Botulism present as flaccid paralysis due to enzymatic inhibition of acetylcholine release in the synapses by the botulinum toxin (BoNT). Seven serotypes of neurotoxin, labeled A to G, are produced by Clostridium botulinum species. Given that the clinical manifestation of botulism might often mimic other neuromuscular disease, an emergent diagnosis remains a challenge.Methods: Case report. Case presentation: A 31 year-old previously healthy man with a history of polysubstance abuse and IV drug use (IDU) presented with two days of worsening muffled voice and shortness of breath. He was first evaluated in the Emergency Department by an otolaryngologist who identified bilateral vocal cord paralysis on laryngoscopy. Subsequent neurological examination identified dysarthria, bilateral dilated pupils, bilateral ptosis, proximal muscle weakness and diffuse areflexia. General physical exam identified a large abscess in the left gluteal region. Within the first nine hours, the patient was intubated for respiratory failure. Botulism infection was suspected based on the combination of acute onset flaccid paralysis, history of drug use, the abscess, and a bedside syringe later confirmed to contain black tar heroin. Within twenty-four hours, the patient was treated with heptavalent equine antitoxin obtained from the CDC. Serum Botulinum toxin A was confirmed five days later. Repetitive nerve stimulation demonstrated an incremental response of compound muscle action potential after exercise.Adherence to migraine treatment recommendations can prevent migraine attacks and reduce the impact of each attack. Headache diaries are commonly used in migraine treatment. This study aimed to develop a clinical decision support tool (CDST) embedded in an electronic headache diary. Initial development of the electronic headache diary included creating a HIPAA-compliant, research-grade headache diary iOS application and eliciting feedback from people with migraine. Overall, people with migraine (n 5 10) reported the user experience was intuitive, but reported comprehension difficulty with certain item responses and perceived overlap between items.Initial development of the CDST diary incorporated clinical treatment guidelines and clinical provider interviews. Neurologists (n 5 5) and psychologists (n 5 4) provided a wide range of candidate CDST messages, including simple reminders about daily lifestyle changes, and complex reminders to support inthe-moment acute management decision-making.Continuing iterative development of the CDST diary includes (a) creating an educational module to accompany the CDST-embedded diary and (b) piloting the CDST dairy and educational module in people with migraine, who provided feedback on user experience, message content, message delivery and frequency, and overall satisfaction.

Thomas D. Arnold, Carlos O. Lizama, Ann C. Zovein and Dean Sheppard. San Francisco, CA Cerebral palsy (CP), a devastating neurodevelopmental disorder, is known to be associated with brain inflammation, but the core molecular pathways controlling this inflammation and the relationship to the downstream neuropathology in CP are poorly understood. Here we show that mice with CNS-specific conditional deletion of the integrin aVb8 ((Itgb8DCNS mice), develop neurologic symptoms (motor dysfunction and spasticity), typical of CP. Similar to humans, Itgb8DCNS mice have diffuse astro-and microgliosis, hypomyelination, and reduced numbers of interneurons. The principal role for aVb8 is to activate TGFb. We therefore asked which cells in the brain require TGFb to suppress this CP-like phenotype. We found that microglia in Itgb8DCNS mice have reduced phospho-SMAD3 and altered gene expression consistent with reduced TGFb signaling in these cells. Furthermore, mice with microglia-specific conditional deletion of the TGFb receptor phenocopy Itgb8DCNS mice, suggesting that loss ofb TGFb signaling in microglia is sufficient to cause the CP phenoty. Together, these data identify a novel role for aVb8/TGFb signaling in microgliogenesis, CNS inflammation and CP, and have profound implications for the development of new therapeutic strategies to treat this devastating disease.