key: cord-0759397-szxw21jy
authors: Esposito, Susanna; Di Pietro, Giada Maria; Madini, Barbara; Mastrolia, Maria Vincenza; Rigante, Donato
title: A spectrum of inflammation and demyelination in acute disseminated encephalomyelitis (ADEM) of children
date: 2015-06-14
journal: Autoimmun Rev
DOI: 10.1016/j.autrev.2015.06.002
sha: 0ddef469c22f088d210061c6fad5deb0078bfeb6
doc_id: 759397
cord_uid: szxw21jy

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that involves multifocal areas of the white matter, rarely the gray matter and spinal cord, mainly affecting children and mostly occurring 1–2 weeks after infections or more rarely after vaccinations. Though a specific etiologic agent is not constantly identified, to evaluate carefully patient's clinical history and obtain adequate samples for the search of a potential ADEM causal agent is crucial. In the case of a prompt diagnosis and adequate treatment, most children with ADEM have a favorable outcome with full recovery, but in the case of diagnostic delays or inappropriate treatment some patients might display neurological sequelae and persistent deficits or even show an evolution to multiple sclerosis. The suspicion of ADEM rises on a clinical basis and derives from systemic and neurologic signs combined with magnetic resonance imaging of the central nervous system. Other advanced imaging techniques may help an appropriate differential diagnosis and definition of exact disease extension. Although there is no standardized protocol or management for ADEM, corticosteroids, intravenous immunoglobulin, and plasmapheresis have been successfully used. There is no marker that permits to identify the subset of children with worse prognosis and future studies should try to detect any biological clue for prevision of neurologic damage as well as should optimize treatment strategies using an approach based on the effective risk of negative evolution.

with ADEM have a favorable outcome with full recovery, but in the case of diagnostic delays or in the case of inappropriate treatment some children might develop neurological sequelae or persistent deficits and even show a dramatic evolution to multiple sclerosis (MS) [5] [6] [7] . However, due to the absence of pertinent biological markers, diagnosis of ADEM could be unfocused and, because of uncertainties on etiopathogenesis, an appropriate therapy might be established with delay. This review summarizes the main evidences on etiology, pathogenesis, and clinical features of ADEM in children and suggests an algorithm for both diagnosis and treatment.

ADEM mainly affects children under 10 years, is more common in males [1, [8] [9] [10] , and mostly arises 2 to 40 days after an infection or more rarely after vaccines [1, 10, 11] . In most cases ADEM follows a trivial infection, usually localized in the upper respiratory tract, whereas only less than 5% of cases can be classified as post-vaccine forms [12, 13] . History of a precipitating event can be reported in 70-80% of children who are diagnosed with ADEM [2, 10] , but in almost 25% of patients no possible etiology can be identified [1, 13, 14] .

A seasonal variation of ADEM frequency (with peaks in winter and spring) supports its infectious etiology [10, 15] . The most frequent infections involved are viral and related to the upper respiratory tract, such as measles [14, 16] , mumps [2, [17] [18] [19] , rubella [2] , varicella [2, 14] , influenza [5, 20] , and infectious mononucleosis [21, 22] . Also enterovirus [23] , coronavirus [24] , human immunodeficiency virus [2] , herpes simplex virus [25] , cytomegalovirus [22] , and hepatitis A virus [26, 27] have been associated with ADEM. Other pathogens anecdotally involved in ADEM have been Toxoplasma gondii [3] , Plasmodium falciparum [28] , Cryptococcus neoformans [29] , Haemophilus influenzae type b [30] , Leptospira sp. [31] , Streptococcus pyogenes [32] , Borrelia burgdorferi [33] , atypical bacteria (i.e., Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila) [13] , Rickettsia sp. [13] , and Campylobacter jejuni [13] . However, a microbiologic diagnosis is rarely reached despite the majority of patients has a positive history of recent previous infections.

Post-vaccination ADEM has been associated with many vaccines, such as those against smallpox, measles, mumps, rubella, diphtheriatetanus-polio, pertussis, hepatitis B, influenza, human papillomavirus, rabies, and Japanese B encephalitis [13, [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] . In almost all the available manuscripts we find only case reports and no definitive conclusions can be drawn about the association between a specific vaccine and the real risk of ADEM. Therefore, the exact pathogenesis of ADEM remains still unclear. This encephalomyelitis can be considered a transient autoimmune disease, that predominantly involves children under 10 years following T cell-mediated cross-activation and response against myelin proteins, such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein (MOG), through a mechanism of molecular mimicry [1] . Another pathogenic possibility is a non-specific self-sensitization of reactive T cells against myelin proteins secondary to infections localized in the CNS [44, 45] . The autoimmune hypothesis is supported by the presence of anti-MOG antibodies in the cerebrospinal fluid (CSF) and their progressive decline along with disease resolution [46] . However, there is no clear relationship between anti-MOG antibody levels at onset and disease severity, and furthermore they are not predictive of ADEM persistence.

Together with demyelination, other hallmarks of ADEM include axonal injury, perivenous inflammation, and edema [46] . The axonal damage is demonstrated by the increased level of a phosphorylated microtubule-associated protein, primarily located in neuronal axons, known as Tau protein, in the CSF, reflecting the clinical severity of ADEM [47] . The detection of inflammatory cells in the CNS also suggests an alteration of blood-brain barrier permeability [45, 46] . Interestingly, T cell activation and cytokine oversecretion during the different ADEM phases have been described [48] . A serum elevation of different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and E-selectin, typically expressed on the membranes of endothelial cells and leukocytes, can be found during the hyperacute phase of ADEM [48] . An increased serum concentration of two enzymes produced by T cells, endothelial cells, and macrophages: the matrix metalloproteinase-9 (MMP-9) and the tissue inhibitor of metalloproteinases, known as tissue metallopeptidase inhibitor-1, which modulates MMP-9 activity, can also be observed in the active phase of the disease [48] . In addition, ADEM acute phase is dominated by the predominance of T helper-1 lymphocytes and their cytokines, such as tumor necrosis factor-α, interferon-γ (IFN-γ), interleukin (IL)-1, IL-6, and IL-8. The latter upregulates also ICAM-1 and E-selectin biosynthesis. Conversely, during the phase of clinical remission, there is a shift to T helper-2 cells with elevation of IL-4, IL-10, transforming growth factor-β, downregulation of ICAM and E-selectin, and enhanced expression of vascular cell adhesion molecule-1 [48] . Lastly, there is an increment of serum IL-12 levels, which stimulates IFN-γ-producing CD4+ memory T cells, still in the last phase of ADEM [48] .

Many clinical features can herald the onset of ADEM. They can be both neurologic and systemic, with fever, headache, weakness, and vomiting, mostly related to the location of the lesions in CNS and generally appearing 4 to 13 days after the triggering infectious episode or after vaccination [8, 10, 49] .

Among neurological signs, encephalopathy, defined as a change in behavior and/or in consciousness (from lethargy to coma), is ADEM prominent clinical feature, though its absence should not preclude a clinical diagnosis of ADEM [50] . Other signs described in various combinations could be multifocal or focal deficits, such as hemiparesis, ataxia, dystonia, choreiform movements, aphasia, diplopia, and dyslexia [51] . Multiple cranial nerve involvement has been reported, especially optic nerves associated with optic disk edema [52] . Finally, signs of spinal cord involvement might be present, such as flaccid paralysis, constipation, or urinary retention [10] .

ADEM clinical course is often monophasic, but also recurrent or multiphasic forms have been reported. Monophasic ADEM, that is the most frequent form occurring in 70-80% of cases, is defined as a first demyelinating or inflammatory clinical event in a previously healthy child, with acute onset affecting multiple areas of the CNS and resolving in a 3-month period [4, 13] . Recurrent ADEM describes the appearance of a new episode of ADEM occurring 3 or more months after the first ADEM event or 1 month after completing corticosteroid therapy, within 2 years after the first episode: this form is characterized by the same symptoms of the first episode and by the absence of new lesions on brain magnetic resonance imaging (MRI) [4, 13] . Multiphasic ADEM refers to a new ADEM-related clinical event that involves new CNS areas, and occurs 3 months after the first event or 1 month after completing corticosteroid therapy: clinical signs and symptoms may be different from those of the first event, and lesions associated with the onset of the disease may be partially or also completely resolved [4, 13] .

Diagnosis of ADEM is puzzling due to the lack of specific markers of the disease. The peculiar clinical scenery combining systemic and neurologic signs may raise the suspicion of ADEM, and then a lumbar puncture is usually performed to exclude an active meningoencephalitis. CSF can be normal or show lymphocytic pleiocytosis and/or increased level of proteins [53, 54] . The most important CSF finding is the absence of olygoclonal bands, which are typical of MS. Cell culture and molecular biology techniques for bacteria and viruses in CSF are commonly used, but their diagnostic value is uncertain because they are often negative and not contributive to the diagnosis [55, 56] .

MRI is the most useful technique to ascertain diagnosis of ADEM: lesions are more often identified in T2-weighted and fluid-attenuated inversion recovery images as multifocal, irregular, poorly marginated areas with diameters between 5 mm and 5 cm [8, 10] . They usually involve the subcortical and central white matter of the entire CNS, particularly frontal and temporal lobes, including also spinal cord and brainstem. Even gray matter of thalamus and basal ganglia can be involved, but lesions are mainly in the cortical gray-white junction [8, 10] .

Five patterns have been proposed to describe CNS lesions: ADEM with small lesions (b 5 mm), ADEM with large confluent white matter asymmetric lesions, ADEM with symmetric bithalamic involvement, ADEM with a leukodystrophic pattern with diffuse bilateral and usually non-enhanced white matter-sited lesions, and ADEM with acute hemorrhagic encephalomyelitis [55] . However, these patterns seem unrelated to the overall clinical course [55] .

Acute lesions can be enhanced after administration of gadolinium, and this could be helpful to identify regional distribution of CNS involvement [54] . Other advanced neuroimaging techniques such as diffusionweighted imaging and magnetic resonance spectroscopy appear useful to exclude other diseases, like strokes and neoplasms, to discriminate between acute and chronic lesions, and to add information about extension of the affected areas [56] .

Many different immune-mediated encephalitides, basically characterized by inflammation of brain parenchyma, have been described and should be differentiated from ADEM . Table 1 summarizes the main epidemiologic and clinical features, diagnostic findings and response to treatment of the most relevant types among immunemediated encephalitides of childhood, different from ADEM, as Hashimoto encephalitis (with high serum levels of anti-thyroid peroxidase antibodies), anti-NMDA receptor encephalitis (with antibodies directed against the NR1 subunit of the N-methyl-D-aspartate receptor), limbic encephalitis (exceptionally rare in pediatrics), and Rasmussen encephalitis (with cortical, subcortical, and caudate head atrophy). Other primary neurologic disorders defined by epilepsy or movement disorders are rare and have an uncertain autoimmunity-based pathogenesis. Since encephalitides are considered a neurologic emergency, because of substantially high rates of morbidity and mortality, a correct diagnosis and a well-timed treatment are essential conditions to reverse CNS clinical signs and reduce the risk of long-term sequelae.

There is no standardized therapy for ADEM [1] . Currently, the most widely used treatment is immunosuppression because of the presumed autoimmune etiopathogenesis of this encephalomyelitis. Pohl & Tenembaum have suggested the administration of intravenous highdose methylprednisolone (20-30 mg/kg/day, maximally 1 g) for 3-5 days, followed by prednisolone (1-2 mg/kg/day given orally for 1-2 weeks), tapering off within 2-6 weeks as the optimal treatment [6] . However, the second line therapy is a total dose of 2 g/kg of intravenous immunoglobulin G (IVIG) given over 2-5 days in corticosteroidresistant or refractory patients, with the aim of binding ADEM autoantibodies, neutralizing them, and finally inhibiting cytokine release [6, 87] . In patients with failure of treatment after corticosteroids and/or IVIG or in children with a severe fulminant disease another working option is plasmapheresis, a procedure that separates patient's plasma from other components, such as antibodies and cytokines, in order to remove autoantibodies and downregulate the immune system activation: the standard procedure suggests 5-7 exchanges, but complications as anemia, hypotension, and hypocalcemia are rather frequent [6] .

Cases of fulminant ADEM, such as acute hemorrhagic leukoencephalitis or forms complicated by severe brain edema, could be treated with mild hypothermia therapy, in which body's temperature is reduced to 34°C and intracranial pressure and cerebral perfusion pressure levels maintained low using mannitol and dopamine [24, 28] . In selected cases with persistently high intracranial pressure a decompressive craniectomy could be performed [88] .

There is new considerable interest in autoimmune forms of encephalitides, which are variably associated with specific antibodies directed against different neuronal antigens . A T cell-driven pathophysiology has been reported in all these cases, and clinical presentation of these encephalitides are remarkably similar in childhood, usually consisting of a combination of neuropsychological impairment and seizures. Different observations have also led to a shift from a merely clinic approach to an antibody-focused viewpoint for ADEM, suggesting a more rational choice in the immunomodulatory treatment of these disorders .

ADEM usually occurs after recent infections or rarely after vaccinations [1] [2] [3] . Also for systemic lupus erythematosus, the prototype of autoimmune disorders, the underlying trigger has remained elusive, and multiple interacting environmental and genetic factors probably contribute to the onset and perpetuation of the disease: among environmental influences, infectious agents have been suggested to play a pivotal role in driving an autoimmune pathogenesis via structural or functional molecular mimicry, the expression of proteins that induce cross-reactive responses against self-antigens, and the aberrant activation or apoptosis of different immune system cells in the context of a peculiar genetic background [89] . Moreover, the pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (also known as PANDAS), basically characterized by obsessive-compulsive symptoms and tics triggered by group-A betahemolytic Streptococcus infections, are another proof of the potential relationship existing between complex neurologic phenotypes and infections [90] .

Though a specific etiologic agent is not constantly recognized in children with ADEM, it is of paramount importance to evaluate carefully patient's clinical history and to obtain adequate samples for the search of a potential etiology. ADEM suspicion is clinical on the basis of systemic and neurologic signs, while MRI represents the main investigation tool for diagnosis confirmation [8, 10, 55] . Other advanced imaging techniques may be helpful for differential diagnosis and for the exact evaluation of disease extension [54, 56] . Although there is no standardized treatment approved for ADEM, actual therapeutic strategies include immunomodulatory therapies (particularly corticosteroids and IVIG), although no clinical trials have been performed to define the most efficacious agent; also plasmapheresis has been successfully used [1, 6, 87] . Although the majority of children with ADEM show a favorable outcome, some might develop neurological sequelae or persistent deficits, while others might show relapses and some a dramatic evolution to MS. There is no marker that permits to identify children with a negative outcome and in view of the treatment differences between ADEM and viral encephalitides, being familiar with ADEM is essential for pediatricians managing acute neurological disorders. Future studies are needed to define patients' characteristics or biohumoral parameters that permit to identify the subset of patients with a worse prognosis.

• ADEM is a multifocal inflammatory demyelinating disease of the central nervous system that involves multiple areas of the white matter, which mostly affects children under 10 years after recent viral or bacterial infections or more rarely after vaccinations. • T cell-mediated cross-activation and response against myelin proteins, such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein, are considered the predominating High serum levels of anti-thyroid peroxidase antibodies (higher than in children affected by thyroiditis): a level N60 UI/mL in the presence of an acute neurological sign is diagnostic [58] Brain lesions observed in 50% of subjects, heterogeneous with diffuse white matter abnormalities and meningeal enhancement; EEG shows generalized slowing without a characteristic pattern [59] Responsive to high dose intravenous corticosteroids; unfortunately, only 55% of patients have a complete recovery [60] ; frequent relapses cause cognitive impairment [61] ; plasma exchange and IVIG have been effective in some cases [62] Familial history of autoimmune diseases; patients typically have hypothyroidism, but more than 40% have a normal thyroid function; some patients may develop hyperthyroidism [63] Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis

The exact prevalence and incidence of the disease is unknown; patients are younger than 18 years in 40% of the cases; this is the leading cause of autoimmune encephalitis in children; female sex is prevalently involved [64] The disease progresses from a specific viral-like prodromal phase (reported in up to 86% of patients) followed within a few days or weeks by seizures, abnormal movements, focal neurological deficits, and behavior or personality changes; visual or auditory hallucinations are common; autonomic dysfunction occurs less frequently in children [65] The target antigen of patients' antibodies is the NR1 subunit of the NMDAR; a comparison of anti-NMDAR antibody levels in serum and CSF indicates the presence of intrathecal synthesis and correlates with outcome [66] ; the application of these antibodies into cultures of hippocampal neurons results in a significant decrease of postsynaptic NMDAR clusters, that is reversed after antibody removal [67] Brain MRI is often normal or shows cortical and subcortical T2-fluid-attenuated inversion recovery signal abnormalities, sometimes with transient cortical-meningeal enhancement; in children the frequency of MRI abnormalities is less than in adults; EEG shows infrequent epileptic activity, but frequent slow disorganized activity [68] Treatment is based on first-line immunotherapy (i.e., corticosteroids, IVIG and/or plasma exchange); second-line therapies (i.e., rituximab alone or combined with cyclophosphamide) are adopted in cases of unsatisfactory response to first-line drugs (from 30% to 40% of patients) [69] ; children with neoplasms have more frequent full recovery and less relapses than those without; minimal residual deficits might persist in 25% of patients; moderate or severe disability occurs in 10% of children; the mortality rate is 8-10% [65] Ovarian or testicular teratoma (70%); the disease also occurs in patients without neoplasms [64] Limbic encephalitis This form is often associated with neoplasms; in children this disease is exceptional and rarely diagnosed in subjects less than 18 years [70] The main initial signs in young patients are impaired consciousness and rapidly developing seizures; this onset is different from that in adulthood, which usually demonstrates a subacute loss of short-term memory or psychiatric signs; antecedent febrile illnesses are common in children, suggesting a considerable influence of infections in its pathogenesis [70] A sub-classification is possible by the presence of specific neuronal antibodies, including onconeural antibodies that target intracellular antigens (anti-Hu, anti-Yo, anti-Ri, anti-Ma1/2) and autoantibodies that are directed against cell surface antigens (anti-LGI1, anti-AMPA, anti-GABA) [ • ADEM general course is monophasic in 70-80% of cases, and defined as a first demyelinating or inflammatory clinical event in a previously healthy child with acute onset involving multiple areas of the central nervous system and resolving in a 3-month period. • Many different immune-mediated encephalitides characterized by diffuse inflammation of brain parenchyma have been also described and should be differentiated from ADEM. • The most currently used treatment in children with ADEM is immunosuppression because of its presumed autoimmune pathogenesis: intravenous high-dose methylprednisolone, intravenous immunoglobulin as a second line treatment in corticosteroid-resistant or refractory patients, and plasmapheresis have been used with successful results. • Future studies are needed to identify patients' biologic clues that characterize the subset of ADEM patients with worst outcome as well to optimize treatment strategies using an approach based on the effective risk of neurologic sequelae. The significance of antibody detection in CSF or serum of these patients appears unclear; CNS inflammation and blood-brain barrier disruption could be one of the mechanisms responsible for seizure recurrence [84] In some patients brain MRI reveals bilateral peri-insular hyperintensity; EEG shows background activity associated with focal or diffuse slow waves and epileptiform abnormalities; seizure onset occurs in most cases in the fronto-temporal and temporal areas [85] The beneficial effects of corticosteroids and IVIG suggest an immune-mediated pathogenesis; residual symptoms include cognitive impairment, temporal lobe epilepsy and mesial temporal sclerosis [85] Several associations between epilepsy and immunological diseases have been described, such as systemic lupus erythematosus (in 10-20% of cases) with the presence of anti-phospholipid and anti-cardiolipin antibodies [86] CNS, central nervous system; CSF cerebral spinal fluid; EEG, electroencephalography; IVIG, intravenous immunoglobulins; MRI, magnetic resonance imaging.

International Pediatric MS Study Group. Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients

Acute disseminated encephalomyelitis associated with acute Toxoplasma gondii infection

Acute disseminated encephalomyelitis in children: differential diagnosis from multiple sclerosis on the basis of clinical course

Therapeutic hypothermia with the use of intracranial pressure monitoring for acute disseminated encephalomyelitis with brainstem lesion: a case report

Treatment of acute disseminated encephalomyelitis

Autoimmune encephalitis: a case series and comprehensive review of the literature

Acute disseminated encephalomyelitis in children

Severe acute disseminated encephalomyelitis with clinical findings of transverse myelitis after herpes simplex virus infection

Acute disseminated encephalomyelitis in children and adolescents: a single center experience

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis onset: evaluation based on vaccine adverse events reporting systems

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis: a report of six cases

Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children

Measles with acute disseminated encephalomyelitis (ADEM)

Brainstem encephalitis and acute disseminated encephalomyelitis following mumps

Fulminant form of acute disseminated encephalomyelitis in a child treated with mild hypothermia

Magnetic resonance imaging in a case of mumps postinfectious encephalitis with asymptomatic optic neuritis

Acute disseminated encephalomyelitis associated with influenza A H1N1 infection

Epstein-Barr virus acute encephalomyelitis in a 13-year-old boy

Recurrent acute disseminated encephalomyelitis associated with acute cytomegalovirus and Epstein-Barr virus infection

Positive PCR for enterovirus in the cerebrospinal fluid of a child with acute disseminated encephalomyelitis

Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis

Severe acute disseminated encephalomyelitis with clinical findings of transverse myelitis after herpes simplex virus infection

Evaluation of the cases with acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis following hepatitis A virus infection

Acute disseminated encephalomyelitis (ADEM) a rare complication of falciparum malaria

Acute demyelinating encephalomyelitis (ADEM), cryptococcal reactivation and disseminated herpes simplex in an HIV infected child following HAART

Probable acute disseminated encephalomyelitis due to Haemophilus influenzae meningitis

Acute disseminated encephalomyelitis after leptospirosis

Acute disseminated encephalomyelitis associated with acute rheumatic fever

Acute disseminated encephalomyelitis associated with Borrelia burgdorferi

Post-vaccination encephalomyelitis: literature review and illustrative case

Bithalamic compromise in acute disseminated encephalomyelitis following H1N1 influenza vaccine

Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccine

Adverse neurologic reactions after both doses of pandemic H1N1 influenza vaccine with optic neuritis and demyelination

An adverse event following 2009 H1N1 influenza vaccination: a case of acute disseminated encephalomyelitis

Post-H1N1 vaccine acute disseminated encephalomyelitis

Encephalitis related to a H1N1 vaccination: case report and review of the literature

Post vaccine acute disseminated encephalomyelitis as the first manifestation of chromosome 22q11.2 deletion syndrome in a 15-month-old baby: a case report

On the relationship between human papilloma virus vaccine and autoimmune diseases

The spectrum of post-vaccination inflammatory CNS demyelinating syndromes

Vasculitis and rheumatologic diseases may play role in the pathogenesis of acute disseminated encephalomyelitis (ADEM)

CSF cytokine and chemokine profiles in acute disseminated encephalomyelitis

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis

Tau protein concentrations in the cerebrospinal fluid of children with acute disseminated encephalomyelitis

Soluble adhesion molecules in acute disseminated encephalomyelitis

Consensus definition proposed for pediatric multiple sclerosis and related disorders

Multiple sclerosis and acute disseminated encephalomyelitis diagnosed in children after long-term follow-up: comparison of presenting features

Alexia without agraphia in a child with acute disseminated encephalomyelitis

Ophthalmologic manifestations in pediatric patient with acute disseminated encephalomyelitis

Acute disseminated enchephalomyelitis. An update

Inflammatory/post-infectious encephalomyelitis

Disseminated encephalomyelitis in children

Modern MRI tools for characterization of acute disseminating lesion: value of chemical shift and diffusionweighted imaging

Hashimoto's encephalopathy: epidemiologic data and pathogenetic considerations

Hashimoto's encephalopathy: identification and long-term outcome in children

Reversible MRI findings in a patient with Hashimoto's encephalopathy

Unexplained seizures, confusion or hallucinations: think Hashimoto encephalopathy

Paediatric Hashimoto encephalopathy, refractory epilepsy and immunoglobulin treatment -unusual case report and review of the literature

Hashimoto's encephalopathy in children and adolescents

Encephalopathy associated with autoimmune thyroid disease in patients with Graves' disease: clinical manifestations, follow-up, and outcomes

Anti-NMDAR encephalitis: a new, severe and challenging enduring entity

Pediatric anti-N-methyl-D-aspartate receptor encephalitis -clinical analysis and novel findings in a series of 20 patients

Prolonged follow-up and CSF antibody titers in a patient with anti-NMDA receptor encephalitis

AntiNMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain

Anti-N-methyl-Daspartate receptor (NMDAR) encephalitis in children and adolescents

Response of anti-NMDA receptor encephalitis without tumor to immunotherapy including rituximab

Limbic encephalitis in children and adolescents

Auto-antibody mediated disorders of the central nervous system

Limbic encephalitis and variants: classification, diagnosis and treatment

Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis

Acute nonparaneoplastic limbic encephalitis in childhood: a case series in Japan

Recognizing paraneoplastic limbic encephalitis

Limbic encephalitis associated with anti-GAD antibody and common variable immune deficiency

Rasmussen encephalitis: incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins

Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances

Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis

Temporal changes in brain MRI findings in Rasmussen syndrome

Immunomodulatory therapy versus surgery for Rasmussen syndrome in early childhood

Acute encephalitis with refractory, repetitive partial seizures

Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis

The blood-brain barrier and epilepsy

Epileptic encephalopathy in children possibly related to immune-mediated pathogenesis

Epilepsy and the immune system

Intravenous immunoglobulin in the treatment of acute disseminated encephalomyelitis

Life-saving decompressive craniectomy for acute disseminated encephalomyelitis in a child: a case report

The cryptic interplay between systemic lupus erythematosus and infections

Evaluation of autoimmune phenomena in patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

Using the UK Clinical Practice Research Datalink (CPRD), i.e. a longitudinal database of UK general practice records incepted in 1987 and deemed to be representative of the UK population

000 person/year in 2010 with an annual decline of 1.8% and a progressive increase of prevalence form 64.63/100,000 people in 1999 to 97.04/100,000 people in 2012. Prevalence and incidence were about six fold higher in women compared with men with a peak of incidence in the group of 50-59 years of age

Luca Iaccarino Incidence and prevalence of systemic lupus erythematosus stratified for year, age, gender and ethnicity: results from a nationwide database

This review was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009 GR-2009-1596786). The authors declare that they have no potential conflict of interest.