key: cord-0923332-sc8zht4z
authors: Lewis, Ariane; Frontera, Jennifer; Placantonakis, Dimitris G.; Lighter, Jennifer; Galetta, Steven; Balcer, Laura; Melmed, Kara
title: Cerebrospinal fluid in COVID-19: A systematic review of the literature
date: 2021-01-10
journal: J Neurol Sci
DOI: 10.1016/j.jns.2021.117316
sha: 07dbbbe4f52cbf8bbd17cf23305173332663815c
doc_id: 923332
cord_uid: sc8zht4z

OBJECTIVE: We sought to review the literature on cerebrospinal fluid (CSF) testing in patients with COVID-19 for evidence of viral neuroinvasion by SARS-CoV-2. METHODS: We performed a systematic review of Medline and Embase between December 1, 2019 and November 18, 2020 to identify case reports or series of patients who had COVID-19 diagnosed based on positive SARS-CoV-2 polymerase chain reaction (PCR) or serologic testing and had CSF testing due to a neurologic symptom. RESULTS: We identified 242 relevant documents which included 430 patients with COVID-19 who had acute neurological symptoms prompting CSF testing. Of those, 321 (75%) patients had symptoms that localized to the central nervous system (CNS). Of 303 patients whose CSF was tested for SARS-CoV-2 PCR, there were 16 (5%) whose test was positive, all of whom had symptoms that localized to the central nervous system (CNS). The majority (12/16, 75%) of these patients were admitted to the hospital because of neurological symptoms. Of 58 patients whose CSF was tested for SARS-CoV-2 antibody, 7 (12%) had positive antibodies with evidence of intrathecal synthesis, all of whom had symptoms that localized to the CNS. Of 132 patients who had oligoclonal bands evaluated, 3 (2%) had evidence of intrathecal antibody synthesis. Of 72 patients tested for autoimmune antibodies in the CSF, 4 (6%) had positive findings. CONCLUSION: Detection of SARS-CoV-2 in CSF via PCR or evaluation for intrathecal antibody synthesis appears to be rare. Most neurological complications associated with SARS- CoV-2 are unlikely to be related to direct viral neuroinvasion.

CoV-2 PCR, oligoclonal bands, aquaporin-4 antibodies and myelin oligodendrocyte glycoprotein were all negative. Lastly, Guilmot et al. reported a patient who had polyradiculitis involving the cranial nerves and cauda equina 10 days after onset of cough and fever and had a CSF WBC count of 101 cells/uL (CSF RBC count was not reported). 171 CSF SARS-CoV-2 PCR was negative, CSF protein was normal and oligoclonal bands were matched. Repeat lumbar puncture 12 days later showed improved pleocytosis (WBC count 28 cells/uL).

Of 13 other patients who had quantitative results for CSF WBC count reported on more than one lumbar puncture, it was unchanged for 2/13 (15%) patients (both ≤6 cells/uL), decreased for 8/13 (62%) patients and increased for 5/13 (38%) patients. 10, 45, 51, 74, 77, 78, 170, 180, 184, 188, 205, 218, 220, 233, 246 The patients whose CSF WBC count increased included 1) a patient with quadriplegia due to Guillain-Barré Syndrome 

The protein was included in the CSF results for 397/430 (92%) patients, 160/397 (40%) of whom were noted to have "increased protein" or protein >60 mg/dL ( Figure 4 ). [5] [6] [7] [8] [9] [10] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [38] [39] [40] [42] [43] [44] [45] [46] [47] [48] [133] [134] [135] [136] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] 158, [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] [210] [211] [213] [214] [215] [216] [218] [219] [220] [221] [222] 224, 225, [227] [228] [229] [230] [231] [232] [233] [234] [235] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] [246] Hyperproteinorrachia can be indicative of the presence of inflammation or axonal injury and may reflect the existence of intrathecal antibodies. 248 was retested calls the initial findings into question, though retesting of low viral load samples after freezing and thawing can yield inaccurate results. All 3 patients had elevated CSF β2 microglobulin and neopterin.

Lastly, McAbee et al. reported a case of "encephalitis associated with COVID-19" and noted that "nasopharyngeal swab was positive for COVID-19 as well as rhinovirus/enterovirus, but the latter was absent in the CSF PCR." 202 We attempted to clarify with the authors whether this patient had a positive CSF SARS-CoV-2 PCR, but were unsuccessful, so we did not include him amongst the patients who had a CSF SARS-CoV-2 PCR testing performed.

CSF antibodies to SARS-CoV-2 were tested in 58/414 (14%) patients who did not have a positive CSF SARS-CoV-2 PCR (49/58 (84%) of whom had symptoms that localized to the CNS and 9/58 (16%) of whom had symptoms that localized to the PNS). 6, 13, 25, 31, 43, 46, 98, 101, 113, 119, 127, 141, 182, 193, 197, 209, 220, 224, 231, 233, 237, 246 Of these, 42/58 (72%) tested positive for SARS-CoV-2 antibodies in the CSF. 6, 25, 31, 43, 46, 98, 119, 127, 193, 197, 209, 224, 231, 237 Keller et al. noted that the 5 patients they reported did not have intrathecal synthesis of SARS-CoV-2 IgG, but did not comment on whether any SARS-CoV-2 antibodies were present in the CSF. 182 Additional testing was performed on the CSF from 32/42 (76%) patients with positive CSF SARS-CoV-2 antibodies in an attempt to distinguish intrathecal antibody synthesis from antibody transmission to the CSF due to breakdown of the blood-brain barrier. 25, 43, 119, 127, 193, 231 For 7/32 (22%) of these patients, all of whom had symptoms that localized to the CNS, the additional testing was consistent with intrathecal antibody synthesis. 25, 231 Using a SARS-CoV-2 epitope Luminex panel, Song et al. evaluated CSF and serum SARS-CoV-2 antibodies in 6 patients and found there were antibodies specific to different regions of the spike protein in both compartments. 231 The 552-589 region of the spike protein was an elevated target specific to the CSF, while the 818-855 region J o u r n a l P r e -p r o o f was an elevated target in the serum. Alexopoulos et al. identified 1 patient with encephalopathy who had SARS-CoV-2 antibodies in the CSF and an IgG index of 1.85, indicative of some intrathecal protein synthesis (the authors noted the threshold to identify intrathecal synthesis was an IgG index>1). 25 Song et al. did not provide outcome data, but the patient described by Alexopoulos et al. patient died. 25, 231 The remaining 25/32 (78%) patients with positive SARS-CoV-2 antibodies in the CSF who had additional testing to evaluate if the antibodies were synthesized intrathecally did not have evidence of intrathecal antibody synthesis. Bellon et al. identified 14 patients with SARS-CoV-2 antibodies in the CSF (12 with encephalopathy, 1 with a "meningeal syndrome" and 1 with a neuromuscular disorder). 127 They evaluated the CSF:serum SARS-CoV-2 IgG index and found that every patient had a ratio <2 (they considered a ratio >2 to be consistent with intrathecal production); 3 patients had a ratio between 1 and 1.22, but none had a ratio >1.22. Oligoclonal bands were tested in 13/14 patients and they all had absent or matched oligoclonal bands. The albumin quotient was tested in 13/14 patients; it was elevated for 8 (62%) patients, indicating breakdown of the blood-brain barrier. Thus, they concluded none of these patients had intrathecal SARS-CoV-2 antibody synthesis. Alexopoulos et al. identified 7 patients with encephalopathy/coma who had SARS-CoV-2 antibodies in the CSF, but a normal IgG index (reported normal <0.77). Of these 7 patients, 2 did not have SARS-CoV-2 antibodies in the CSF initially but had them on a second lumbar puncture one week later when the CSF was diluted 1:10, but not when it was diluted 1: 100. 25 To determine if the SARS-CoV-2 CSF antibodies for 2 patients originated due to intrathecal synthesis or transudation, Andriuta et al. calculated the Tibbling-Link, Delpech and transudation indices. For both patients, the indices reflected antibody entry to the CSF via transudation. 43 Senel et al. concluded that though their patient, who had Miller-Fisher Syndrome, had positive SARS-CoV-2 antibodies, these did not develop in the CSF because 1) the SARS-CoV-2 IgG and IgA CSF to blood antibody index was <1; 2) evaluation of all CSF immunoglobulins with the Reiber diagram showed no evidence of intrathecal synthesis; and 3) oligoclonal bands were negative. 119 Lastly, although J o u r n a l P r e -p r o o f Journal Pre-proof Lin et al. detected increased levels of IgM (1:64) for SARS-CoV-2 S1 and E proteins in the CSF, the IgG index was normal and oligoclonal bands were negative, suggesting there was no intrathecal synthesis. 193 

CSF oligoclonal bands were tested in 114 patients who did not have a positive CSF SARS-CoV-2 PCR or positive CSF antibodies to SARS-CoV-2 (103 (90%) who had symptoms that localized to the CNS and 11 (10%) who had symptoms that localized to the PNS). 9, 10, 19, 20, 35, 36, 42, 44, 45, 58, 69, 74, 79, 81, 101, 112, 113, 116, 117, 126, 127, 130, 135, 136, 147, 149, 152, 154, 160, [168] [169] [170] [171] 177, 181, 182, [185] [186] [187] [188] 191, 194, 203, 205, 207, 209, 212, 213, 215, 216, 218, 233, 242, 245 Of these, 35 (31%) had matched CSF and serum bands. 9, 35, 79, 112, 113, 127, 147, 170, 171, 177, 182, 185, 187, 203, 205, 207, 213, 215 There were 2/114 (2%) patients who did not have a positive CSF SARS-CoV-2 PCR or positive CSF antibodies to SARS-CoV-2 who had oligoclonal bands that were unique to the CSF, reflecting intrathecal antibody synthesis. 101, 171 First, a 21-year-old woman who developed ptosis and diplopia a week after she had mild respiratory symptoms was found to have SARS-CoV-2 IgG and IgA antibodies in her serum (but not in her CSF) and positive oligoclonal bands type 2 (not matched in serum) in her CSF. 101 Second, an 80-year-old patient who presented with hallucinations, memory problems and a seizure was found to have a positive nasopharyngeal SARS-CoV-2 PCR, CSF-specific oligoclonal bands and anti-contactinassociated protein 2 (Caspr2) IgG antibodies in serum and CSF. 171 Both patients recovered. 101, 171 There were two additional patients who did not have a positive CSF SARS-CoV-2 PCR or positive CSF antibodies to SARS-CoV-2 and may have had oligoclonal bands that were unique to the CSF. 154 29-year-old woman with no prior neurologic symptoms who presented with optic neuritis two weeks J o u r n a l P r e -p r o o f after acute onset of anosmia and myalgia and was found to have positive SARS-CoV-2 serum antibodies and oligoclonal bands in the CSF. 212 Imaging revealed enhancement of the optic nerve and periventricular demyelinating lesions, only one of which was enhancing. This prompted diagnosis of multiple sclerosis. Though the authors assumed her pathogenic process began prior to infection with COVID-19, we cannot conclusively explain the correlation between her imaging findings and clinical presentation. As serum oligoclonal bands were not reported, it is unclear if her bands were matched, but if they were not, it is possible that this reflects intrathecal synthesis of antibodies to SARS-CoV-2.

Of the patients who did not have a positive CSF SARS-CoV-2 PCR, CSF SARS-CoV-2 antibodies or CSF-specific oligoclonal bands, 45 had CSF immunoglobulins measured. 9, 10, 42, 45, 49, 57, 58, 62, 69, 74, 81, 113, 117, 148, 181, 182, 187, 194, 205, 215, 220, 242, 246 Of these, 29 (64%) patients had normal immunoassays. 42, 45, 49, 57, 58, 62, 69, 74, 81, 113, 181, 182, 187, 194, 215, 242, 246 There were 2/45 (4%) patients who did not have a positive CSF SARS-CoV-2 PCR, CSF SARS-CoV-2 antibodies or CSF-specific oligoclonal bands who had immunoglobulin results consistent with intrathecal antibody synthesis. 117, 205 Rajdev et al. presented a patient with Guillain-Barré Syndrome who had an elevated IgG index (14.67; reported normal <0.86) and markedly elevated IgG synthesis (293.5 mg/day; reported normal 9.2 mg/day), with normal albumin levels and absence of oligoclonal bands. 117 The authors commented that these findings suggest intrathecal IgG synthesis, as there was no clear evidence of blood-brain barrier breakdown, but concluded that his polyneuropathy was postinfectious. had elevated CSF IgG levels from 3.8-16.9 mg/dL. 187 They did not stipulate the normal value or provide serum IgG or CSF albumin, so it is not feasible to interpret whether these findings reflect intrathecal IgG synthesis. However, two of these patients had matched oligoclonal bands in CSF and serum, suggesting these patients did not have unique intrathecal antibodies. The authors felt their findings were likely immune-mediated. Dogan et al. described a patient with encephalopathy who had an IgG index of 0.78 (upper limit of normal reported by the authors was 0.6), but the patient also had a CSF IgG of 3.23 mg/dL (upper limit of normal reported by the authors of 3.4 mg/dL) and negative oligoclonal bands. 42, 117 The authors concluded that these findings were likely the result of autoimmune/antibody-mediated inflammation. Similarly, Ghosh et al. described a patient who presented with coma and seizures and was found to have a frontoparietal hyperintense lesion with surrounding edema and foci of hemorrhage who had an elevated IgG index. 168 The value of the index was not provided. Additionally, oligoclonal bands were absent in the CSF. The authors did not conclude these findings were consistent with intrathecal antibody synthesis.

There were two patients with NMDA receptor antibodies in the CSF. 30, 205 Both patients presented with fever and psychosis and were found to have COVID-19 then developed dyskinesias.

Imaging was normal. They improved after treatment with intravenous immunoglobulins (IVIG) and steroids.

Guilmot et al. reported the aforementioned patient who presented with hallucinations, memory problems and a seizure and had anti-contactin-associated protein 2 (Caspr2) IgG antibodies in serum and CSF. 171 Neuroimaging was normal and an electroencephalogram showed slowing. Steroids were administered and plasmapheresis was performed after which there were no seizures.

Lastly, a 72-year-old man who presented with cerebellar symptoms 17 days after fever and odynophagia and, in addition to having a positive nasopharyngeal SARS-CoV-2 PCR and serum IgG and IgM to SARS-CoV-2, he had autoantibodies directed against the nuclei of Purkinje cells, striatal and hippocampal neurons in the CSF (1:96) and serum (1:25,000). 169 The intensity and reactivity in the serum and CSF observed at the same IgG concentration ruled out intrathecal autoantibody synthesis, as did the absence of CSF specific oligoclonal bands. MRI was normal. He was treated with IVIG and steroids and his symptoms improved.

Other CSF biomarkers were tested in the CSF of 58/430 (13%) patients (Table 3) , 46 (79%) of whom were reported to have elevation of at least one CSF biomarker. 10, 24, 25, 30, 31, 98, 111, 119, 128, 135, 136, 149, 157, 165, 182, 191, 205, 215, 217, 227, 231, 236 Notably, there is not consensus on the reference values for biomarkers and reported norms vary between labs.

There were 28 patients who had CSF IL-6 measured, 21 (75%) of whom had an increased concentration based on the author's reported normal; 11/21 patients with increased CSF IL-6 concentration had serum IL-6 concentration measured, and this was elevated for all 11 J o u r n a l P r e -p r o o f patients. 10, 30, 31, 98, 111, 128, 135, 149, 165, 182, 191, 205, 215, 217, 236 Keller et al. measured IL-6 in the CSF and serum of 5 patients (2 with hemiparesis, 1 who was comatose, 1 who was encephalopathic and 1 who had seizures) and found it was elevated in 4/5 patients, but was lower than it was in serum. 182 CSF IL-6 was mildly elevated in two patients with encephalopathy reported by Delorme et al. (13 pg/mL and 16 pg/mL; reported normal <6.5 pg/mL; serum levels not reported). 149 Le Guennec et al. measured IL-6 in the CSF and serum of a patient with status epilepticus and found it was elevated in both CSF and serum (16 pg/mL in CSF with reported normal <2.5 pg/mL and 28.8 pg/mL in serum with reported normal <6.5 pg/mL). 191 The two patients presented by Bodro et al. who had CSF protein >1,000 mg/dL in the setting of transient encephalopathy had increased CSF IL-6 (190 pg/mL and 25 pg/mL; reported normal <7 pg/mL); serum values were not reported. 128 Perrin et al. found that 3/5 patients with encephalopathy had an elevated CSF IL-6. 215 Only 2 of these patients had IL-6 measured in the serum, but both had an elevated concentration. Cani et al. measured IL-6 in the CSF and serum of a patient who initially had akinetic mutism after being weaned off sedation for acute respiratory failure, then improved and had only mild dysexecutive syndrome and finally recovered after 43 days. 135 CSF WBC count was normal, CSF SARS-CoV-2 PCR and oligoclonal bands were negative and CSF protein was mildly increased. CSF IL-6 was elevated on initial lumbar puncture 21 days after symptoms onset (55.1 pg/mL; reported normal <5.9 pg/mL) at which time serum IL-6 was slightly above normal (9.1 pg/mL; same limits as CSF), but repeat lumbar puncture 14 days later revealed normal IL-6 in both CSF and serum. Farhadian et al. compared biomarker concentration in the CSF and serum of a patient who had encephalopathy and seizures to the CSF and serum from two healthy controls and found that IL-6 was elevated in both CSF and serum in the patient with COVID-19 as compared to the control patients. 165 Lastly, both of the patients with NMDA receptor antibodies had elevated CSF IL-6: one had a concentration of 39 pg/mL (normal reported <7 pg/mL) and did not have serum levels reported; 30 the second had an elevated CSF IL-6 compared to 12 subjects with functional neurologic disorders (4.58 pg/mL one week after presentation and 5.75 pg/mL J o u r n a l P r e -p r o o f one month later) and elevated serum IL-6 compared to the established norm of <10 pg/mL (52 pg/mL and 206 pg/mL, respectively). 205 He also had elevated CSF interleukin-8 (IL-8) compared to the control patients.

In addition to that patient, there were 16 other patients who had CSF IL-8 measured, 16/17 (94%) of whom had elevated CSF IL-8; 6 patients with elevated CSF IL-8 had serum IL-8 measured, all of whom had elevated serum concentrations too. 10,31, 98, 111, 135, 149, 165, 205, 217 In comparison to historical controls with normal cognition and no viral illness, Benameur et al. found that 3 patients with CSF SARS-CoV-2 antibodies who were comatose or profoundly encephalopathic had increased levels of CSF IL-6, IL-8, interleukin-10 (IL-10), interferon gamma-induced protein-10 (IP-10) and TNF-α. 31 CSF cytokine levels for these patients were compared to those from patients with HIV-associated neurocognitive disorders and it was noted that elevated CSF IL-8 and IL-10 appeared to be unique to the patients with neurological complications of COVID-19. Inflammatory makers were not evaluated in blood. Gigli et al. performed cytokine testing in the CSF and serum of a 53-year-old man who presented to a hospital with paraparesis, paresthesias and ataxic gait 55 days after he had fever and diarrhea and was found to have a positive CSF SARS-CoV-2 IgG and IgM with specific reactivity against nucleocapsid and spike 2 glycoprotein. 98 IL-8 was markedly elevated (121 pg/mL; normal reported 32.6-88 pg/mL) in CSF and mildly elevated in serum (26 pg/mL; normal reported 6.7-16.2 pg/mL). Manganotti et al. measured in the CSF and serum of 3 patients who had Guillain-Barré Syndrome. 111 IL-8 was elevated in CSF for all three patients, and was higher than it was in serum (42.6 pg/mL in CSF and 17.8 pg/mL in serum; 96 pg/mL in CSF and 55 pg/mL in serum; and 22.7 pg/mL in CSF and 20 pg/mL in serum). Pilotto et al. evaluated CSF cytokines in a 60-year-old man who presented with five days of encephalopathy, fever and cough, who was found to have lymphocytic pleocytosis (WBC count of 18 cells/uL) and hyperproteinorrachia (127.2 mg/dL). 10,217 He had a negative CSF SARS-CoV-2 PCR and no evidence of intrathecal antibody synthesis, oligoclonal bands or autoimmune antibodies. MRI of the brain was J o u r n a l P r e -p r o o f normal. CSF IL-8 was markedly increased (>1,100 pg/mL; normal reported elsewhere <72 pg/mL) and was over ten times higher than the serum concentration (98.3 pg/mL) prompting the authors to equate their findings to immune effector cell-associated neurotoxicity syndrome (ICANS, also known as CAR Tcell neurotoxicity). 251 After treatment with five days of steroids, lopinavir/ritonavir, hydroxychloroquine, acyclovir and ampicillin, he returned to normal, and repeat CSF testing showed IL-8 decreased substantially to 97 pg/mL. Lastly, Song et al. compared CSF and serum concentration of IL-8, IL-1β, interleukin-12 (IL-12) and fibroblast growth factor-2 (FGF-2) for six patients with positive SARS-CoV-2 antibodies (3 with encephalopathy, 2 with headache and 1 with seizure) to CSF from controls. 231 Data was presented cumulatively, but they noted that all of these cytokines were elevated in the CSF of patients with COVID-19 compared with controls, but were not elevated in the plasma. Because these findings were not associated with viral detection, pleocytosis or disruption of the bloodbrain barrier (based on the albumin index), the authors concluded they were reflective of an indirect effect of systemic infection.

To evaluate for axonal injury, the CSF was tested for 1) 14-3-3 in 9 patients with encephalopathy, 2) neurofilament light chain in 8 patients with encephalopathy and 3) phosphorylated neurofilament heavy chain in 1 patient with ophthalmoplegia. 10,24,25,119,157,217 There were 4/9 (44%) patients who were positive for 14-3-3 in the CSF, 1 of whom was negative on an initial lumbar puncture then positive when a second CSF sample was obtained. 24,25 All of the patients with 14-3-3 detected in the CSF also had SARS-CoV-2 antibodies in the CSF at a 1:10 dilution and 3/4 had SARS-CoV-2 antibodies J o u r n a l P r e -p r o o f detected in the CSF at 1:100 dilution, though they all had a CSF:serum SARS-CoV-2 IgG index <1, and 2/4 had an elevated albumin index. 25 Eden et al. found that neurofilament light chain was elevated in the CSF of 2/6 patients with encephalopathy (including one whose initial CSF SARS-CoV-2 PCR resulted as indeterminate), which the authors felt may have been attributed to hypoxia. 157 Virhammar et al. found that CSF neurofilament light chain was markedly increased in a patient who was comatose on admission and was found to have a positive CSF SARS-CoV-2 PCR on the third lumbar puncture performed; serum concentration was not reported. 236 Senel et al. found elevated phosphorylated neurofilament heavy chain in the CSF (2,131 pg/mL; reported normal <30 pg/mL) of a patient with Miller-Fisher Syndrome who had positive CSF SARS-CoV-2 IgG and IgA, but no evidence of intrathecal antibody production. 119 After treatment with IVIG for five days, his symptoms resolved. The authors checked neurofilament light chain in blood 2 days later, and 16 days after that, and found that it was elevated (61 and 58 pg/mL, respectively; no reference range provided).

There were two patients who had the concentration of GFAP, a biomarker for gliosis, measured in the CSF. 10, 217, 236 The patient presented by Virhammar et al. who had a positive CSF SARS-CoV-2 PCR on the third lumbar puncture had markedly elevated GFAP on day 12 (~4,000 pg/mL) which then decreased to normal by day 30 (~500 pg/mL). 236 Serum levels were not reported.

Amyloid-β-42 and tau, biomarkers for Alzheimer-type pathologic changes in the CNS, were both tested in the CSF of 4 patients. 10,119,149,217,227,236 Delorme et al. described a patient who had markedly elevated CSF tau (2,000 pg/mL; reported normal 150-450 pg/mL). 149 Virhammar et al. presented a patient who was comatose on admission and was found to have a positive CSF SARS-CoV-2 PCR on the third lumbar puncture performed. 236 The patient had elevated CSF tau which continued to increase over the course of 30 days from ~2,000 pg/mL to ~7,000 pg/mL. The patient gradually improved and was discharged to rehab after 35 days.

Because it is postulated that SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 (ACE2) receptor, Bodro et al. measured ACE levels in the CSF of the two aforementioned patients with transient encephalopathy who had CSF protein >1,000 mg/dL. 128 Both patients had elevated CSF ACE (15.5 U/L and 10.9 U/L; reported normal 0-2.5 U/L). The authors acknowledged that it is unclear how to interpret this abnormality, particularly given that these patients had negative CSF SARS-CoV-2 PCRs and recovered fully after a few days, making infection of the CNS unlikely, but suggested it could be relevant.

In this systematic review, we identified 430 patients with COVID-19 diagnosed based on PCR or serology who had CSF obtained due to a neurological symptom. 5-10,13-246 A paucity of patients in this cohort had a positive CSF SARS-CoV-2 PCR; of 303 patients who had SARS-CoV-2 PCR tested in the CSF, 16 (5%) patients, all of whom had symptoms that localized to the CNS, had a positive result and an additional 3 (1%) had an indeterminate result. 5 [184] [185] [186] [187] 190, 191, 193, [195] [196] [197] [198] [199] [200] [201] 203, [205] [206] [207] 209, [212] [213] [214] [215] [216] [218] [219] [220] [221] [224] [225] [226] [227] 230, [233] [234] [235] [236] [237] [238] [240] [241] [242] [243] [244] [245] [246] Furthermore, only 14/252 (6%) patients who had direct or indirect evaluation for CSF SARS-CoV-2 antibodies (oligoclonal bands or immunoglobulins), had evidence of intrathecal antibody synthesis. 6, 9, 10, 13, 19, 20, 25, 31, 35, 36, [42] [43] [44] [45] [46] 49, 57, 58, 62, 69, 74, 79, 81, 98, 101, 112, 113, 116, 117, 119, 126, 127, 130, 135, 136, 141, [147] [148] [149] 152, 154, 160, [168] [169] [170] [171] 177, 181, 182, [185] [186] [187] [188] 191, 193, 194, 197, 203, 205, 207, 209, 212, 213, 215, 216, 218, 220, 224, 231, 233, 237, 242, 245, 246 Inconsistencies in the evaluation of CSF and serum and challenges associated with interpretation of laboratory results preclude determination of a finite rate of viral neuroinvasion in this cohort. However, neuroinvasion by SARS-CoV-2 appears to be rare, and it is likely that neurological symptoms in patients with COVID-19 are usually the result of hypoxic-ischemic injury, toxic-metabolic changes, stroke, or a parainfectious or post-infectious J o u r n a l P r e -p r o o f inflammatory response due to cytokine release syndrome or molecular mimicry between COVID-19 antibodies and peripheral nerve glycolipids, neuronal or glial cells. [5] [6] [7] [8] [9] [10] As is evident by the fact that 303/430 (70%) patients we identified had CSF SARS-CoV-2 PCR testing performed, it is feasible to perform PCR testing for SARS-CoV-2 in CSF. [5] [6] [7] [8] [9] [10] 15, 17, 22, 24, [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [68] [69] [70] [71] 73, 74, [76] [77] [78] 81, 84, 88, 89, 95, 97, 98, 101, 103, 105, 108, 109, 111, 113, 116, 119, 122, 123, 125, [127] [128] [129] 131, [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [147] [148] [149] [150] 152, 154, 156, 157, 161, 164, 165, 169, 171, 177, 178, [180] [181] [182] [184] [185] [186] [187] 190, 191, 193, [195] [196] [197] [198] [199] [200] [201] 203, [205] [206] [207] 209, [212] [213] [214] [215] [216] [218] [219] [220] [221] [224] [225] [226] [227] 230, [233] [234] [235] [236] [237] [238] [240] [241] [242] [243] [244] [245] [246] In fact, PCR testing for the N2 gene target of SARS-CoV-2 was noted to have the highest sensitivity in CSF when compared with a nasopharyngeal swab, bronchoalveolar lavage, sputum, plasma or stool. 252 Despite this, many hospitals lacked the ability to perform SARS-CoV-2 PCR testing in CSF early in the pandemic. 63 Additionally, viral detection via PCR testing is not 100% sensitive due to genetic variability in the virus itself and technical factors. 253 It has also been suggested that isolation of SARS-CoV-2 in CSF may be challenging because of rapid CSF clearance, low titers or delayed sampling. 33,37,254 Further, CSF SARS-CoV-2 PCR testing is not 100% specific for intrathecal virus, in part because a sample can be contaminated from shed airborne virus or blood contamination. 255 The CSF RBC count was only available for 7/16 (44%) patients we identified who had a positive SARS-CoV-2 CSF PCR, one of whom had a CSF RBC count of 1,685 with a CSF WBC count of 11 cells/uL, which may indicate the CSF SARS-CoV-2 PCR was falsely positive due to a traumatic lumbar puncture. [26] [27] [28] [29] 153, 164, 180, 184, 195, 199, 224, 225, 227, 236, 238, 241 The SARS-CoV-2 PCR can also be falsely positive if there is a pre-analytical error. 256 The process by which CSF SARS-CoV-2 PCR was evaluated varied and this information was not always provided, so we did not delineate the testing technique for each patient who had CSF SARS-CoV-2 PCR testing performed in this review; however, it is important to note that the sensitivity and specificity varies between tests.

Data on the Ct was only available for 2/16 (13%) patients with a positive CSF SARS-CoV-2 PCR, and they both had a high Ct (37.12, 37.52 and 36.44 for one patient and 34.29 for the second (whose positive result was not reproducible)), which is indicative of a low viral load, though the author of J o u r n a l P r e -p r o o f another report on a patient with a positive CSF SARS-CoV-2 PCR noted that a cycle threshold of 35 was the cutoff for a positive SARS-CoV-2 PCR. [26] [27] [28] [29] 150, 164, 180, 184, 195, 199, 224, 225, 227, 236, 238, 241 While many labs use a cutoff of 40 to consider a test positive, some classify a Ct of 37-40 as indeterminate. 157, 257 Accordingly, when Eden et al. repeated CSF SARS-CoV-2 PCR testing for three patients who had a Ct of 37-40, they found no evidence of SARS-CoV-2 RNA in the CSF. 157 There was considerable variability in the CSF WBC count of patients we identified who had a positive CSF SARS-CoV-2 PCR. [26] [27] [28] [29] 150, 164, 180, 184, 195, 199, 224, 225, 227, 238, 241 There were 2 patients who had a CSF WBC count >1,500 cells/uL, 90% of which were neutrophils. 199, 241 Viral encephalitis is typically characterized by a CSF lymphocytic pleocytosis, while a neutrophilic pleocytosis is generally associated with a bacterial infection, but a retrospective review of 182 patients with confirmed viral infections in the CNS found that 25% had CSF neutrophilic pleocytosis. 258 However, it is worth noting that the patient reported by Mardani et al. had hypoglycorrhachia (CSF glucose of 10 mg/dL when blood glucose was 162 mg/dL) and a tracheal aspiration culture that grew Klebsiella pneumoniae in conjunction with her neutrophilic pleocytosis which raises the questions of whether 1) she, in fact, had culture negative meningitis and 2) her CSF SARS-CoV-2 PCR was a true positive. 199 On the other end of the spectrum, there were 5 patients with a positive CSF SARS-CoV-2 PCR who had a CSF WBC count of only 1-5 cells/uL, 2 with "no pleocytosis" and 2 with a CSF WBC count of 0 cells/uL. 150, 153, 180, 195, 224, 225, 236, 238 Absence of pleocytosis in general, and acellular CSF in particular, is atypical in the setting of viral encephalitis. 259, 260 However, there have been reports of patients without pleocytosis who had a positive CSF PCR for Enterovirus, Echovirus, Adenovirus and Herpes and CSF can be acellular in the early stages of herpes encephalitis. 259, 261 Nonetheless, it is also feasible that the patients with acellular CSF had a false-positive CSF SARS-CoV-2 PCR, particularly given that for one patient, this was the only means employed to diagnose COVID-19 since a rapid COVID-19 test was negative and no other PCR or serologic testing was performed. 262 However, 5 of the other 15 (33%) patients with a positive CSF SARS-CoV-2 PCR also had J o u r n a l P r e -p r o o f negative nasopharyngeal swabs, though one had positive serum SARS-CoV-2 antibodies. [26] [27] [28] [29] 153, 164, 180, 184, 195, 199, 225, 227, 236, 241 Chest imaging was consistent with viral pneumonia for 2/5 (40%) patients who were only diagnosed with COVID-19 based on a positive SARS-CoV-2 PCR in the CSF. 26, 150, 153, 184, 241 Domingues et al. postulated that SARS-CoV-2 may be more persistent in the CNS because it is an immunoprivileged site. 153 Serological testing for viruses may have a higher sensitivity and specificity than PCR testing, but like PCR testing, the sensitivity and specificity among serological tests vary. 263, 264 The mere presence of antibodies in CSF is not indicative of antibody synthesis in the CSF, as antibodies, or the cells that secrete them, can be transmitted to the CSF via a damaged blood-brain barrier or a traumatic tap. 31, 265, 266 The presence of CSF SARS-CoV-2 antibodies, oligoclonal bands or elevated CSF IgG is notable, but measuring IgG synthesis or comparing CSF and serum IgG or oligoclonal bands can help facilitate a distinction between intrathecal synthesis of antibodies and transudation of antibodies through a damaged bloodbrain barrier. 25,43, 119, 127, 193, 231 However, it is important to note that evidence of intrathecal antibody synthesis based on oligoclonal band or immunoglobulin analysis in this patient population does not elucidate the type of antibodies being synthesized, so it is feasible some patients had intrathecal synthesis of antibodies other than SARS-CoV-2 antibodies, such as antibodies to myelin or autoimmune antibodies. 169, 171, 205 Song et al.'s finding that anti-SARS-CoV-2 antibodies in the CSF of six patients had different epitope specificity compared with antibodies in the serum, suggesting that there are compartment-specific immune responses, is provocative and warrants further investigation in a larger cohort and consideration about how or if this finding can be used translationally. 231 Although CSF testing of biomarkers is not universally available, we identified 58 patients who had CSF biomarkers measured, 46 (79%) of whom had elevation of at least one CSF biomarker suggesting the presence of inflammation, axonal injury, gliosis and Alzheimer-type pathologic changes. 10,24,25,30,31, 98, 111, 119, 128, 135, 136, 149, 157, 165, 182, 191, 205, 215, 217, 227, 231, 236 Interestingly, some of these patients J o u r n a l P r e -p r o o f had elevation of biomarkers in the CSF, but not the serum, which is similar to ICANS, the neurotoxicity that occurs after treatment with chimeric antigen receptor T-cell therapy. 10,217,231 While further data is needed, these findings suggest that there are compartment-specific immune responses to SARS-CoV-2. 231 Further, Gigli et al. suggested that some patients may have a specific genetic predisposition to postinfectious inflammatory syndromes and associated intrathecal cytokine responses after COVID-19. 98 Of course, it is imperative to recognize that elevated CSF and serum biomarkers is not clearly indicative of neuroinvasion as this can result from other mechanisms such as hypoxic injury. 267, 268 Additional research into treatment implications and the diagnostic and prognostic value of CSF biomarkers in patients with COVID-19 who have neurological symptoms is needed.

Of course, this review of the neuroinvasiveness of COVID-19 and associated CSF changes is limited based on publication bias, in general, and our search methodology, in particular. There were two pre-print case reports of patients who had CSF testing by Xiang et al. and Cai et al. cited in reviews that we did not include in our discussion, as one was not accessible and one was not in English. However, both of these patients reportedly had a positive SARS-CoV-2 PCR in CSF. 269, 270 Additionally, we noted three letters-to-the-editor that mentioned patients in China who had positive CSF SARS-CoV-2 PCRs, but we did not include these cases as no details were provided; similarly Finsterer et al. mentioned an unpublished report of a patient in India with a positive SARS-CoV-2 PCR in CSF. [271] [272] [273] [274] On the other hand, we excluded 1) documents that described cases in which CSF was obtained from a patient with COVID-19 who did not have neurological symptoms, such as a report by Bajwa et al.

who described two patients with COVID-19 who had CSF collected during administration of spinal anesthesia; 275 and 2) those that provided cumulative CSF data for a series of patients, but did not include clinical details for individual patients.

A number of cumulative analyses were published by authors in France. [276] [277] [278] [279] [280] We report these results here, but it is important to acknowledge that we believe it is very likely some of these patients J o u r n a l P r e -p r o o f were described in the case reports/case series included in our review. Further, as there are multiple cumulative analyses using data from one country in a brief time period, some of which have overlapping authors, we are unsure if any patients were included in more than one cumulative analysis. For example, our review includes 1) 15 patients that were described by Kremer to April 27, 2020 and identified: 21 patients with encephalitis (defined as altered mental status lasting ≥24 hours and either CSF WBC >5 cells/uL or compatible acute lesion on brain MRI) and found that 2 (10%) had a positive CSF SARS-CoV-2 PCR, 14 (67%) had a CSF WBC count >5 cells/uL and 12 (57%) had CSF protein>45 mg/dL; 36 patients with COVID-encephalopathy (defined as altered mental status lasting ≥24 hours that does not meet criteria for encephalitis and was not attributed to another toxic or J o u r n a l P r e -p r o o f metabolic etiology) who had CSF testing, none of whom had a positive SARS-CoV-2 PCR in CSF or a CSF WBC count >5 cells/uL, but 8 (22%) who had CSF protein>45 mg/dL; and 14 patients with Guillain-Barré Syndrome who had CSF testing, none of whom had a positive CSF SARS-CoV-2 PCR, 1 (7%) who had a CSF WBC count >5 cells/uL and 8 (57%) who had CSF protein>45 mg/dL. 277 concluded that it was difficult to parse out whether the findings were the result of viral neuroinvasion, hypoxia, multiorgan failure, cytokine storming, reduced immune response or strokes; they recommended the need for large-scale molecular and cellular investigations of brain tissue and CSF in conjunction with data on the neurological evaluation and neuroimaging for each patient. 284 Notably, Paniz-Mondolfi reported the presence of SARS-CoV-2 identified in brain tissue via ultrastructural analysis and molecular testing despite a negative SARS-CoV-2 PCR in CSF. 285 It is important to note that CSF results can change over the course of a patient's illness. This is evident in the results from some of the patients included in this review who had more than one lumbar J o u r n a l P r e -p r o o f puncture performed. 10, 14, 25, 45, 51, 53, 74, 135 Although we documented the number of days between onset of symptoms of COVID-19 and development of neurological symptoms in Supplementary Tables 1&2, we did not indicate the number of days after onset of neurological symptoms that CSF was obtained.

Further, the fact that CSF results were not obtained at a specific time point relative to development of neurological symptoms certainly impacts our results. It has previously been suggested that detection of viral neuroinvasion via a positive CSF PCR is highest when CSF is obtained 5 days after onset of neurological symptoms. 286 Additionally, CSF (particularly CSF protein) can be abnormal due to a number of etiologies other than COVID-19 which were not addressed herein. These include, but are not limited to, male sex, body mass index, diabetes mellitus, hypothyroidism, hypoparathyroidism, Cushing's disease, uremia, medications (such as phenytoin and phenothiazines). 287, 288 Elevated CSF protein has been observed in a wide range of neuropsychiatric disorders and we did not document past medical/neuropsychiatric history for patients included in this review. 288, 289 Further, though perspectives on the relationship between CSF protein and age vary, it has been suggested that CSF protein may increase with age throughout adulthood and we did not take age into consideration when we reviewed CSF protein. [287] [288] [289] [290] Finally, it has been postulated that viruses in the CSF of patients with neurological disorders can sometimes be bystanders, rather than causative agents of disease, so a positive SARS-CoV-2 PCR or evidence of intrathecal antibody production does not definitively indicate neuroinvasion is responsible for a given constellation of symptoms. 291 

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Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study. The Journal of infectious diseases

Reply to the Letter "COVID-19-Associated Encephalopathy and Cytokine-Mediated Neuroinflammation

CNS inflammatory vasculopathy with antimyelin oligodendrocyte glycoprotein antibodies in COVID-19

Three-tier stratification for CNS COVID-19 to help decide which patients should undergo lumbar puncture with CSF analysis: A case report and literature review. Romanian journal of internal medicine = Revue roumaine de medecine interne

Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus

A case series of Guillain-Barré Syndrome following Covid-19 infection in New York

Behavioral Changes Without Respiratory Symptoms as a Presenting Sign of COVID-19 Encephalitis

Pediatric inflammatory multisystem syndrome with central nervous system involvement and hypocomplementemia following SARS-COV-2 infection

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital

Brain microvascular occlusive disorder in COVID-19: a case report

Epileptiform activity and seizures in patients with COVID-19

Clinical, Radiological, and Molecular Findings of Acute Encephalitis in a COVID-19 Patient: A Rare Case Report

COVID-19)-Associated Encephalopathies and Cerebrovascular Disease: The New Orleans Experience

Clinical characteristics of 10 children with a pediatric inflammatory multisystem syndrome associated with COVID-19 in Iran

Isolated intracranial hypertension associated with COVID-19. Cephalalgia : an international journal of headache

Immunologically distinct responses occur in the CNS of COVID-19 patients. bioRxiv : the preprint server for biology

Pseudotumor Cerebri Caused by SARS-CoV-2 Infection in a Boy

Encephalopathy in COVID-19 patients; viral, parainfectious, or both? eNeurologicalSci

Interdisciplinary neurosurgery : Advanced techniques and case management

Cerebral nervous system vasculitis in a Covid-19 patient with pneumonia

Acute necrotizing encephalopathy with SARS-CoV-2 RNA confirmed in cerebrospinal fluid

Coronavirus disease 2019 associated with aggressive neurological and mental abnormalities confirmed based on cerebrospinal fluid antibodies: A case report

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

Lessons of the month 1: A case of rhombencephalitis as a rare complication of acute COVID-19 infection

Concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease 2019

Viral meningitis associated with COVID-19 in a 9-year-old child: a case report. The Pediatric infectious disease journal

A case of limbic encephalitis associated with asymptomatic COVID-19 infection

Encephalopathy in patients with COVID-19: 'Causality or coincidence

COVID-19-Associated Acute Multi-infarct Encephalopathy in an Asymptomatic CADASIL Patient

A case of possible atypical demyelinating event of the central nervous system following COVID-19. Multiple sclerosis and related disorders

Parainfectious encephalitis in COVID-19

Defining diagnostic approaches and outcomes in patients with inflammatory CSF: A retrospective cohort study

CHAPTER 32 -Approach to the Patient with Abnormal Cerebrospinal Fluid Protein Content

Personal Communication with Dr. Shole Yaqubi

Fahr's syndrome presenting with seizures in SARS-CoV-2 (COVID-19) pneumonia-a case report

Cerebrospinal Fluid Levels of Interleukin-8 in Delirium, Dementia, and Cognitively Healthy Patients

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology

Multiple assays in a real-time RT-PCR SARS-CoV-2 panel can mitigate the risk of loss of sensitivity by new genomic variants during the COVID-19 outbreak

Three-steps" infection model and CSF diagnostic implication

Neurological Implications of COVID-19 Infections

COVID-19 PCR Test, Cluster of False Positive and Importance of Quality Control

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

The clinical significance of neutrophilic pleocytosis in cerebrospinal fluid in patients with viral central nervous system infections

A systematic review of cases of meningitis in the absence of cerebrospinal fluid pleocytosis on lumbar puncture

CSF findings in 250 patients with serologically confirmed West Nile virus meningitis and encephalitis

Acellular cerebral spinal fluid in the early stages of herpes simplex encephalitis

Real-time RT-PCR in COVID-19 detection: issues affecting the results. Expert review of molecular diagnostics

Diagnostic performances and thresholds: The key to harmonization in serological SARS-CoV-2 assays? Clinica chimica acta

Cerebrospinal fluid challenges for the diagnosis of herpes simplex infection in the central nervous system. Arquivos de neuro-psiquiatria

Development, maintenance and disruption of the blood-brain barrier

Immunoglobulin abnormalities in cerebrospinal fluid and blood in children with febrile seizures

Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

Blood Biomarkers for Detection of Brain Injury in COVID-19 Patients

COVID-19 Pandemic: A Neurological Perspective

A systematic review of neurological manifestations of SARS-CoV-2 infection: the devil is hidden in the details

Novel coronavirus and the central nervous system

Sars-Cov-2: Underestimated damage to nervous system. Travel medicine and infectious disease

Update on the neurology of COVID-19

Neurological manifestations of the coronavirus (SARS-CoV-2) pandemic 2019-2020

Exploring the unknown territories in the new normal world of COVID

Systematic SARS-CoV-2 screening in cerebrospinal fluid during the COVID-19 pandemic

Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

Brain MRI Findings in Severe COVID-19: A Retrospective Observational Study

Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients

Neurologic aspects of covid-19: a concise review

Cerebrospinal fluid findings in neurological diseases associated with COVID-19 and insights into mechanisms of disease development. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms

Inflammatory leptomeningeal cytokines mediate delayed COVID-19 encephalopathy. medRxiv : the preprint server for health sciences

Invited Review: The spectrum of neuropathology in COVID-19. Neuropathology and applied neurobiology

Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)

Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections

Determinants of lumbar CSF protein concentration

Elevated CSF protein in male patients with depression

Causes of albuminocytological dissociation and the impact of age-adjusted cerebrospinal fluid protein reference intervals: a retrospective chart review of 2627 samples collected at tertiary care centre

Cerebrospinal fluid analysis. Handbook of clinical neurology

Human Polyomaviruses in the

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series

Correction: Guillain-Barré syndrome related to SARS-CoV-2 infection

AMS: altered mental status; CSF: cerebrospinal fluid; CXCL: chemokine ligand; GFAP: Glial fibrillary acidic protein; HEM: hemiparesis; I: indeterminate (virus present but with Ct above

IL: interleukin; INF: interferon; IP: interferon gammainduced protein; M: matched in serum and CSF; N: noted to be normal with no specific value/range provided by authors; NfL: neurofilament light chain; OPH: ophthalmoparesis

QUAD: quadriparesis; RBC: red blood cells; SZ: seizures; TNF: tumor necrosis factor; WBC: white blood cells; ~: value interpreted based on review of graph

*Values that are elevated are bolded (normal ranges specified by authors are noted here with alternate ranges included when there was discrepancy in normal limits between authors

pg/mL; β2 microglobulin serum <2.1 mg/L and CSF <1.8 mg/L; IL-1β serum <0.21 pg/mL (or <0.001 pg/mL) and CSF 0.1-0.5 pg/mL (or <2

IL-2R serum 440-1435 pg/mL and CSF range assumed equal to serum due to absence of standardized values; IL-/mL or <7 pg/mL)

IL-8 serum 6.7-16.2 pg/mL (or <70 pg/mL) and CSF 32.6-88 pg/mL (or <72 pg/mL or <70 pg/mL)

IL-10 serum 1.8-3.8 pg/mL (or <9 pg/mL) and CSF range assumed equal to serum due to absence of standardized values (or <2.5 pg/mL or <9 pg/mL)

IL-17A control data serum ~0 pg/mL and CSF ~10 pg/mL: INF-α serum <0.99 pg/mL and CSF range assumed equal to serum due to absence of standardized values; IP-10 serum 37.2-222 pg/mL and CSF range assumed equal to serum due to absence of standardized values

MCP-1 control data serum ~0 pg/mL and CSF ~140 pg/mL; Neopterin serum <8.8 nmol/L and CSF <5.8 nmol/L; NfL CSF <1850 pg/mL (or <1

pNfH CSF <560 pg/mL; Tau CSF <479 pg/mL (or 150-450 pg/mL)