Sudden unexpected death in epilepsy and ictal asystole in patients with autoimmune encephalitis: a systematic review.

OBJECTIVE: As autoimmune encephalitis (AE) often involves the mesial temporal structures which are known to be involved in both sudden unexpected death in epilepsy (SUDEP) and ictal asystole (IA), it may represent a good model to study the physiopathology of these phenomena. Herein, we systematically reviewed the occurrence of SUDEP and IA in AE. METHODS: We searched 4 databases (MEDLINE, Scopus, Embase, and Web of Science) for studies published between database inception and December 20, 2022, according to the PRISMA guidelines. We selected articles reporting cases of definite/probable/possible/near-SUDEP or IA in patients with possible/definite AE, or with histopathological signs of AE. RESULTS: Of 230 records assessed, we included 11 cases: 7 SUDEP/near-SUDEP and 4 IA. All patients with IA were female. The median age at AE onset was 30 years (range: 15-65), and the median delay between AE onset and SUDEP was 11 months; 0.9 months for IA. All the patients presented new-onset seizures, and 10/11 also manifested psychiatric, cognitive, or amnesic disorders. In patients with SUDEP, 2/7 were antibody-positive (1 anti-LGI1, 1 anti-GABABR); all IA cases were antibody-positive (3 anti-NMDAR, 1 anti-GAD65). Six patients received steroid bolus, 3 intravenous immunoglobulin, and 3 plasmapheresis. A pacemaker was implanted in 3 patients with IA. The 6 survivors improved after treatment. DISCUSSION: SUDEP and IA can be linked to AE, suggesting a role of the limbic system in their pathogenesis. IA tends to manifest in female patients with temporal lobe seizures early in AE, highlighting the importance of early diagnosis and treatment.

Anticonvulsive treatment in autoimmune encephalitis: a systematic literature review.

BACKGROUND: Epileptic seizures are a common manifestation of autoimmune encephalitis (AIE). Immunosuppression (IT) is an efficient therapeutic approach, particularly in AIE associated with antibodies against extracellular structures. The role of antiseizure medication (ASM) is less clear. However, it may be beneficial in disease refractory to IT or in chronic post-AIE epilepsy. METHODS: We conducted a systematic review assessing the PubMed and Cochrane databases to identify all reports on patients with epileptic seizures due to AIE in whom ASM was used and report it according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. We included case series (minimum 3 eligible patients), retrospective and prospective observational studies, and randomized controlled trials. The main outcome assessed was therapeutic efficacy of ASM. Secondary outcomes comprise number, type, and adverse effects of ASM. Descriptive statistics were used. The level of evidence was assessed according to the Centre for Evidence-Based Medicine. RESULTS: We screened a total of 3371 studies and included 30 (7 prospective, 23 retrospective). The reports cover a total of 708 patients, the majority (72.5%) suffering from AIE with antibodies against extracellular structures. Type of AIE, seizure frequency, and number and type of ASM used were heterogenous. While most patients profited from IT and/or ASM, the effect of ASM could rarely be isolated. Nine studies report on patients who received ASM monotherapy or were on ASM for a relevant length of time before IT initiation or after IT failure. One study reports a significant association between seizure freedom and use of sodium channel inhibitors. However, levels of evidence were generally low. CONCLUSION: Few robust data exist on the particular efficacy of ASM in autoimmune epileptic seizures. While these patients generally seem to respond less well to ASM or surgical interventions, sodium channel blockers may have an additional benefit compared to other substances. However, levels of evidence are low and early IT remains the mainstay of AIE therapy. Future trials should address optimal ASM selection and dosing in AIE.

Management of autoimmune temporal lobe epilepsy with GAD65 antibody: four case reports.

AIM OF STUDY: Glutamate decarboxylase (GAD) enzyme can be a target intracellular antigen in autoimmune focal epilepsy. GAD65 antibody is in found patients diagnosed with drug-refractory temporal lobe epilepsy (TLE). We explore the clinical features of the disease and therapeutic options. MATERIAL AND METHODS: We present the cases of four TLE patients, two of them with type 1 diabetes. All of them were drug-resistant and therefore underwent presurgical evaluation, which revealed GAD65 antibody positivity. We discuss the four GAD65 antibody positive temporal lobe epilepsy patients' electroclinical data, the treatments, and their effectiveness. RESULTS: One of them became seizure-free after right anterior temporal lobe resection, two of them did not show significant improvement with immunmodulatory agents, and the fourth patient with the shortest duration of disease had significant improvement in seizure status and normalisation of cognitive status with IVIg therapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our cases show that the earlier a GAD65 antibody is detected, the greater the chance of achieving seizure freedom or improvements in both seizure and cognitive status with immunomodulatory agents. However, in some cases, surgery may also bring seizure freedom, but with a risk of cognitive deterioration.

GAD65 Antibody-Associated Epilepsy.

Autoimmune processes are an increasingly recognized cause of seizures. Antibodies against neuronal surface antigens are implicated in the development of acute symptomatic seizures secondary to autoimmune encephalitis, whereas antibodies against intracellular antigens (anti-glutamic acid decarboxylase (GAD) and onconeural antibodies) are found in cases of autoimmune-associated epilepsy (AAE). AAE is described as isolated drug-resistant epilepsy without any specific magnetic resonance imaging (MRI) or cerebrospinal fluid changes and with a very limited response to immunotherapy. We present a clinical case and a literature review on autoimmune-associated epilepsy to increase awareness of this disease and illustrate its complexity. This is a clinical case of a female with a history of refractory focal epilepsy. The patient had been given several trials of multiple antiepileptic drugs and their combinations without any clear effect. Multiple evaluations including brain MRI, PET, and interictal and ictal electroencephalograms were performed. An APE2 score was calculated with a result of 4 and, in the presence of anti-GAD65 antibodies in the serum, the diagnosis of AAE was confirmed. There was no effect after five sessions of plasma exchange; however, after a course of intravenous immunoglobulin, a positive but temporary clinical effect was noticed: anti-GAD65 levels initially decreased but rebounded to previous levels 6 months later.

Acute symptomatic seizures secondary to myelin oligodendrocyte glycoprotein antibody-associated disease.

OBJECTIVE: To report the clinical presentations and outcomes of patients with seizure and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: We retrospectively reviewed the electronic medical records for clinical and paraclinical features among patients with seizures and MOG-IgG (immunoglobulin G) seropositivity. RESULTS: We identified 213 patients with MOG-IgG seropositivity who fulfilled criteria for MOGAD. Seizures attributed to central nervous system (CNS) autoimmunity were observed in 10% of patients (n = 23: 19 children, 4 adults). The majority (n = 19, 83%) had pediatric disease onset. Focal motor seizures were the most common seizure semiology (16/23; 70%). Focal to bilateral tonic-clonic seizures were present in 12 patients (53%), and 3 patients (13%) developed status epilepticus. All patients had features of encephalitis at onset of seizures. Cerebral cortical encephalitis (CCE) was the most common radiological finding (10 unilateral and 5 bilateral cases). Eight of 23 patients (35%) had only CCE, six of 23 patients (26%) had only acute disseminated encephalomyelitis (ADEM), and seven of 23 patients (30%) had features of both. Fifteen patients (65%) had leptomeningeal enhancement. Three patients (13%) had coexistence of N-methyl-d-aspartate receptor (NMDAR) IgG. Only 3 of 23 patients (13%) developed drug- resistant epilepsy. Although the majority had MOGAD relapses (14/23, 60%) had only 5 of 23 patients had recurrence of episodes of encephalitis with associated seizures. Twenty-one of 23 patients (91%) had seizure freedom at last follow-up. SIGNIFICANCE: MOG-IgG evaluation should be considered in patients who present with encephalitis and focal motor and/or focal to bilateral tonic-clonic seizures, especially pediatric patients with magnetic resonance imaging (MRI) brain findings consistent with CCE, ADEM, or other MOGAD presentations. The majority of these seizures are self-limited and do not require maintenance/chronic antiseizure medications. Although seizure recurrence is uncommon, many patients have MOGAD relapses in the form of encephalitis and optic neuritis.

Seizures in anti-Hu-associated extra-limbic encephalitis: Characterization of a unique disease manifestation.

Anti-Hu-associated neurologic autoimmunity most often occurs in the context of small cell lung cancer and typically presents with peripheral neuropathy, cerebellar ataxia, and/or limbic encephalitis. Extra-limbic encephalitis causing seizures is a rare disease manifestation, with only sparse reports in the literature. Herein we present a patient with seizures in anti-Hu-associated extra-limbic encephalitis, and review the literature for other cases to more fully characterize this entity. Among 27 patients we identified, the median age was 46 years (range: 2-69 years) and 18 of 27 (67%) were female. Focal motor seizures were most common, followed by ictal expressive speech difficulty. Seizure semiologies along with neuroimaging findings most frequently suggested the involvement of the peri-Rolandic cortex, more anterior frontal operculum, and insula, although other cortical regions were rarely affected as well. In contrast to other classical paraneoplastic neurologic syndromes, good response to treatment with attainment of seizure-free survival was often reported, although over one-third still died. A propensity for chronic seizures among children indicated the potential to develop autoimmune-associated epilepsy. The predilection for certain extra-limbic regions, as well as the possibility of good response to treatment, may reflect unique disease mechanisms that would benefit from further study.

"Obvious" indications for Neural antibody testing in Epilepsy or Seizures: The ONES checklist.

OBJECTIVE: Numerous predictive scores have been developed to help determine which patients with epilepsy or seizures of unknown etiology should undergo neural antibody testing. However, their diagnostic advantage compared to only performing testing in patients with "obvious" indications (e.g., broader features of autoimmune encephalitis, characteristic seizure semiologies) requires further study. We aimed to develop a checklist that identifies patients who have "obvious" indications for neural antibody testing and to compare its diagnostic performance to predictive scores. METHODS: We developed the "Obvious" indications for Neural antibody testing in Epilepsy or Seizures (ONES) checklist through literature review. We then retrospectively reviewed patients who underwent neural antibody testing for epilepsy or seizures at our center between March 2019 and January 2021, to determine and compare the sensitivity and specificity of the ONES checklist to the recently proposed Antibody Prevalence in Epilepsy and Encephalopathy (APE2)/Antibodies Contributing to Focal Epilepsy Signs and Symptoms (ACES) reflex score. RESULTS: One-hundred seventy patients who underwent neural antibody testing for epilepsy or seizures were identified. Seventy-four of 170 (43.5%) with a known etiology were excluded from sensitivity/specificity analyses; none had a true-positive neural antibody. Of the 96 patients with an unknown etiology, 14 (15%) had a true-positive neural antibody. The proportion of false-positives was significantly higher among patients with a known etiology (3/3, 100%) compared to an unknown etiology (2/16, 13%; p = .01). There was no significant difference of the APE2/ACES reflex score compared to the ONES checklist with regard to sensitivity (93% for both, p > .99) or specificity (71% vs. 78%, p = .18) for true-positive neural antibodies. SIGNIFICANCE: Compared to only performing neural antibody testing in patients with epilepsy or seizures of unknown etiology who have "obvious" indications, predictive scores confer no clear diagnostic advantage. Prespecified definitions of what constitutes a true-positive neural antibody is required in future studies to avoid false-positives that can confound results.

Infodemiology of autoimmune encephalitis, autoimmune seizures, and autoimmune epilepsy: An analysis of online search behavior using Google Trends.

BACKGROUND: Patients and their caregivers, including clinicians and educators, use web-based search engines to access healthcare-related information from the internet. Online search behavior analysis has been used to obtain insights on health information demand. OBJECTIVES: We aimed to describe the online search behavior for autoimmune encephalitis, autoimmune seizures, and autoimmune encephalitis (AE) worldwide over time through the analysis of search volumes made on Google. METHODS: In this infodemiological study, we retrieved search volume indices for the keyword "autoimmune encephalitis (search term)", "autoimmune seizures (search term)", and "autoimmune encephalitis (search term)" based on worldwide search data from January 01, 2004 to October 31, 2021, using Google Trends. We performed a descriptive analysis of search volume patterns, including related topics and queries. RESULTS: There was a progressive increase in search volume numbers over time for the keyword "autoimmune encephalitis", "autoimmune seizures", and "autoimmune epilepsy" with no annual seasonal variation. Peak search volumes for these keywords were recorded in July 2018, February 2005, December 2012, respectively. The greatest search volume for "autoimmune encephalitis" was recorded in Singapore, followed by Australia, the United States of America, the Philippines, and New Zealand, whereas it was highest in the United States for "autoimmune seizures" and "autoimmune epilepsy". The most searched topics were related to definition, causes, symptoms, diagnosis, and treatment. All related topics and queries increased in volume by more than 5000-fold over time. CONCLUSIONS: This study showed an uptrend in the online search interest on autoimmune encephalitis, autoimmune seizures, and autoimmune epilepsy over time, which may reflect the increased awareness of the condition by the public and the medical community. Information on online health information-seeking behavior may be obtained from Google Trends data despite its limitations.

Do the neurologists recognize autoimmune epilepsy well enough? What is the effect of the pandemic on this matter?

INTRODUCTION: The concept of "autoimmune epilepsy" (AE) has been emphasized more frequently through the recent increase in recognition of various autoantibodies specific to neuronal proteins. AIMS: To evaluate the attitudes of neurologists in regard to AE, to review the differential diagnosis, treatment options, and to reveal the effect of COVID-19 on this matter. METHODS: A detailed questionnaire prepared for AE was sent to neurologists via social media and WhatsApp after the approval of the Ethics Committee. The responses of 245 respondents working in different settings were analyzed, and the group with 15 years or less experience in neurology was statistically compared to the group with more than 15 years of experience. RESULTS: Awareness and knowledge levels on AE seemed high in all groups, while 11% had never thought about AE during the differential diagnosis in real life. Before starting treatment, 20% thought that the autoantibody result should definitely support it, and 77.6% reported that they did not recognize AE well. Participants stated that satisfactory guidelines for diagnosis and treatment (88.2%) and widespread laboratory support (83.7%) were lacking. Neurologists with less experience and those working outside of training hospitals get more often consultation from an experienced clinician while diagnosing and conduct more detailed investigations at the diagnosis stage (p = 0.0025, p = 0.0001). CONCLUSION: This first survey study conducted in a large group of neurologists on the attitudes for the concept of AE suggested that postgraduate education, and diagnostic and treatment guidelines should be organized and antibody screening tests need to be better disseminated.

Antibody Prevalence in Epilepsy before Surgery (APES) in drug-resistant focal epilepsy.

OBJECTIVE: There is a growing recognition of immune-mediated causes in patients with focal drug-resistant epilepsy (DRE); however, they are not systematically assessed in the pre-surgical diagnostic workup. Early diagnosis and initiation of immunotherapy is associated with a favorable outcome in immune-mediated seizures. Patients with refractory focal epilepsy with neuronal antibodies (Abs) tend to have a worse surgical prognosis when compared to other etiologies. METHODS: We studied the prevalence of serum Abs in patients ≥18 years of age with DRE of unknown cause before surgery. We proposed and calculated a clinical APES (Antibody Prevalence in Epilepsy before Surgery) score for each subject, which was modified based on Dubey's previously published APE2 score. RESULTS`: A total of 335 patients were screened and 86 subjects were included in final analysis. The mean age at the time of recruitment was 44.84 ± 14.86 years, with age at seizure onset 30.89 ± 19.88 years. There were no significant differences among baseline clinical features between retrospective and prospective sub-cohorts. The prevalence of at least one positive Ab was 33.72%, and central nervous system (CNS)-specific Abs was 8.14%. APES score ≥4 showed slightly better overall prediction (area under the curve [AUC]: 0.84 vs 0.74) and higher sensitivity (100% vs 71.4%), with slightly lower but similar specificity (44.3% vs 49.4%), when compared to APE2 score ≥4. For subjects who had available positron emission tomography (PET) results and all components of APES score (n = 60), the sensitivity of APES score ≥4 yielded a similar prediction potential with an AUC of 0.80. SIGNIFICANCE: Our findings provide persuasive evidence that a subset of patients with focal DRE have potentially immune-mediated causes. We propose an APES score to help identify patients who may benefit from a workup for immune etiologies during the pre-surgical evaluation for focal refractory epilepsy with unknown cause.

Dual-Targeted Autoimmune Sword in Fatal Epilepsy: Patient's glutamate receptor AMPA GluR3B peptide autoimmune antibodies bind, induce Reactive Oxygen Species (ROS) in, and kill both human neural cells and T cells.

Nodding Syndrome (NS) is a fatal pediatric epilepsy of unknown etiology, accompanied by multiple neurological impairments, and associated with Onchocerca volvulus (Ov), malnutrition, war-induced trauma, and other insults. NS patients have neuroinflammation, and ~50% have cross-reactive Ov/Leiomodin-1 neurotoxic autoimmune antibodies. RESULTS: Studying 30 South Sudanese NS patients and a similar number of healthy subjects from the same geographical region, revealed autoimmune antibodies to 3 extracellular peptides of ionotropic glutamate receptors in NS patients: AMPA-GluR3B peptide antibodies (86%), NMDA-NR1 peptide antibodies (77%) and NMDA-NR2 peptide antibodies (87%) (in either 1:10, 1:100 or 1:1000 serum dilution). In contrast, NS patients did not have 26 other well-known autoantibodies that target the nervous system in several autoimmune-mediated neurological diseases. We demonstrated high expression of both AMPA-GluR3 and NMDA-NR1 in human neural cells, and also in normal human CD3+ T cells of both helper CD4+ and cytotoxic CD8+ types. Patient's GluR3B peptide antibodies were affinity-purified, and by themselves precipitated short 70 kDa neuronal GluR3. NS patient's affinity-purified GluR3B peptide antibodies also bound to, induced Reactive Oxygen Species (ROS) in, and killed both human neural cells and T cells within 1-2 hours only. NS patient's purified IgGs, or serum (1:10 or 1:30), induced similar effects. In vivo video EEG experiments in normal mice, revealed that when NS patient's purified IgGs were released continuously (24/7 for 1 week) in normal mouse brain, they induced all the following: 1.Seizures, 2. Cerebellar Purkinje cell loss, 3. Degeneration in the hippocampus and cerebral cortex, and 4. Elevation of CD3+ T cells, and of activated Mac-2+microglia and GFAP+astrocytes in both the gray and white matter of the cerebral cortex, hippocampus, corpus calossum and cerebellum of mice. NS patient's serum cytokines: IL-1ß, IL-2, IL-6, IL-8, TNFα, IFNγ, are reduced by 85-99% compared to healthy subjects, suggesting severe immunodeficiency in NS patients. This suspected immunodeficiency could be caused by combined effects of the: 1. Chronic Ov infection, 2. Malnutrition, 3. Killing of NS patient's T cells by patient's own GluR3B peptide autoimmune antibodies (alike the killing of normal human T cells by the NS patient's GluR3B peptide antibodies found herein in vitro). CONCLUSIONS: Regardless of NS etiology, NS patients suffer from 'Dual-targeted Autoimmune Sword': autoimmune AMPA GluR3B peptide antibodies that bind, induce ROS in, and kill both neural cells and T cells. These neurotoxic and immunotoxic GluR3B peptide autoimmune antibodies, and also NS patient's NMDA-NR1/NR2A and Ov/Leiomodin-1 autoimmune antibodies, must be silenced or removed. Moreover, the findings of this study are relevant not only to NS, but also to many more patients with other types of epilepsy, which have GluR3B peptide antibodies in serum and/or CSF. This claim is based on the following facts: 1. The GluR3 subunit is expressed in neural cells in crucial brains regions, in motor neurons in the spinal cord, and also in other cells in the body, among them T cells of the immune system, 2. The GluR3 subunit has diverse neurophysiological role, and its deletion or abnormal function can: disrupt oscillatory networks of both sleep and breathing, impair motor coordination and exploratory activity, and increase the susceptibility to generate seizures, 3. GluR3B peptide antibodies were found so far in ~27% of >300 epilepsy patients worldwide, which suffer from various other types of severe, intractable and enigmatic epilepsy, and which turned out to be 'Autoimmune Epilepsy'. Furthermore, the findings of this study could be relevant to different neurological diseases besides epilepsy, since other neurotransmitter-receptors autoantibodies are present in other neurological and psychiatric diseases, e.g. autoimmune antibodies against other GluRs, Dopamine receptors, GABA receptors, Acetylcholine receptors and others. These neurotransmitter-receptors autoimmune autoantibodies might also act as 'Dual-targeted Autoimmune Sword' and damage both neural cells and T cells (as the AMPA-GluR3B peptide antibodies induced in the present study), since T cells, alike neural cells, express most if not all these neurotransmitter receptors, and respond functionally to the respective neurotransmitters - a scientific and clinical topic we coined 'Nerve-Driven Immunity'.

Early predictors of epilepsy and subsequent relapse in children with acute disseminated encephalomyelitis.

OBJECTIVE: To identify predictors of epilepsy and clinical relapses in children presenting with acute disseminated encephalomyelitis (ADEM). METHODS: Children presenting with ADEM between 2005 and 2017 and tested clinically for MOG-Ab were identified from three tertiary paediatric neurology centres in the United Kingdom. Patients were followed up for a median of 6 years (range, 1-16 years). RESULTS: A total of 74 children were studied (38 females; median age at first presentation: 4.5 years (range, 1.4-16 years)). MOG-Ab was positive in 50/74 (67.6%) of cases, and 27 (54%) of MOG-Ab positive children presented with a neurological relapse over time. MOG-Ab was more frequently positive in the relapsing group than in the monophasic group (27/31 vs 23/43; odds ratio 5.9 (95% CI: 1.8-19.7); p = 0.002). 16/74 (22%) children had seizures during the acute presentation with ADEM and 12/74 (16.2%) patients were diagnosed with post-ADEM epilepsy. The diagnosis of post-ADEM epilepsy was more frequently observed in children with relapsing disease than monophasic disease (10/31 vs 2/43; odds ratio 9.8 (95% confidence interval (CI): 2.0-48.7); p = 0.003), in children who had positive intrathecal oligoclonal bands than those with negative bands (4/7 vs 4/30; odds ratio 8.7 (95% CI: 1.4-54.0); p = 0.027) and in children who had positive MOG-Ab than negative MOG-Ab cases (11/12 vs 39/62; odds ratio 6.5 (95% CI:0.8-53.6); p = 0.051). CONCLUSION: A higher relapse rate and a greater risk of post-ADEM epilepsy in children with MOG-Ab-associated disease may indicate a chronic disease with immune-mediated seizures in these children.

Seizures in autoimmune encephalitis: Kindling the fire.

Epilepsy is a common neurological disorder that increases the risk of morbidity and mortality. Autoimmune epilepsy is a subset of epilepsy that occurs in the setting of autoimmunity, such as in autoimmune encephalitis (AIE). AIE is an autoimmune disorder characterized by immune-mediated neuroinflammation resulting in a variety of neurological symptoms, including psychiatric disturbance, cognitive dysfunction, and seizures. Seizures in AIE are thought to be a result of antibodies directed against neuronal cell-surface proteins involved in synaptic transmission. The role of blood-brain barrier dysfunction, myeloid cell infiltration, and the initiation of proinflammatory cascades in epileptogenesis has been shown to be important in animal models and human patients with epilepsy. Epileptogenesis in AIE is likely to arise from the synergistic effect of both innately driven neuroinflammation and antibody-induced hyperexcitability. Together, these processes produce persistent drug-resistant seizures that contribute to the morbidity seen in AIE. Understanding the proinflammatory pathways involved in this process may improve diagnostics and provide alternative treatment targets in AIE.

Acute symptomatic seizures secondary to autoimmune encephalitis and autoimmune-associated epilepsy: Conceptual definitions.

Seizures are a well-recognized and often prominent manifestation of autoimmune encephalitic syndromes. Progress in detection of pathogenic neural autoantibodies has led to increased awareness of autoimmune causes of seizures. Clinical studies of patients with these autoantibodies have improved our understanding of the seizure characteristics, treatments, and seizure prognosis in these disorders. The International League Against Epilepsy (ILAE) Autoimmunity and Inflammation Taskforce proposes conceptual definitions for two main diagnostic entities: (a) acute symptomatic seizures secondary to autoimmune encephalitis, and (b) autoimmune-associated epilepsy, the latter of which suggests an enduring predisposition to seizures. Such a distinction is relevant when discussing the pathophysiology, treatment, prognosis, and social consequences of these disorders. We discuss the role of biomarkers in the application of these conceptual definitions and illustrate their use in patients cared for by members of the task force.

Diagnostic algorithm for children presenting with epilepsia partialis continua.

OBJECTIVE: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. METHODS: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. RESULTS: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed. SIGNIFICANCE: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis.

Anti-GAD epileptic encephalopathy in a toddler with Parry-Romberg syndrome.

Parry-Romberg syndrome (PRS) is a progressive facial hemiatrophy often associated with severe epilepsy. Although an immune-mediated vasculitic pathogenesis is widely assumed, no CNS-specific autoantibody has been described so far. A 2-year-old boy was admitted for a status epilepticus preceded by fever, restlessness, insomnia, and left facial rash. Cerebrospinal fluid was positive for glutamic acid decarboxylase (GAD)-antibodies. Brain MRI revealed FLAIR hyperintensities on left mediotemporal areas. He was successfully treated with intravenous methylprednisolone. One month later, seizures and facial rash reappeared and steroids were satisfactorily repeated. However, left hemifacial rash reappeared 5 months later, slowly followed by sclerotic skin lesions on frontal scalp and hemifacial sub-atrophy, leading to a diagnosis of PRS. Three years later, and despite chronic immunosuppression, new MRI lesions on left white matter are seen and left hemifacial atrophy has progressed. For the first time, we describe GAD autoantibodies in a PRS patient with epileptic encephalopathy. Epileptic syndromes with GAD autoantibodies are frequently described though with a questionable pathogenic significance. Given the clinical and MRI similarities of PRS with both Morphea and Rasmussen's encephalitis, we suggest that, in our patient, the initial facial skin vasculitis spread into CNS vessels through perforating arteries, inducing neuronal MHC-class I presentation of GAD epitopes, ultimately causing CD8-mediated neuronal cytotoxicity and the epileptic encephalopathy. GAD autoantibodies might represent the missing pathophysiological link between PRS and neuropsychiatric manifestations.

Neurological Syndromes Associated with Anti-GAD Antibodies.

Glutamic acid decarboxylase (GAD) is an intracellular enzyme whose physiologic function is the decarboxylation of glutamate to gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter within the central nervous system. GAD antibodies (Ab) have been associated with multiple neurological syndromes, including stiff-person syndrome, cerebellar ataxia, and limbic encephalitis, which are all considered to result from reduced GABAergic transmission. The pathogenic role of GAD Ab is still debated, and some evidence suggests that GAD autoimmunity might primarily be cell-mediated. Diagnosis relies on the detection of high titers of GAD Ab in serum and/or in the detection of GAD Ab in the cerebrospinal fluid. Due to the relative rarity of these syndromes, treatment schemes and predictors of response are poorly defined, highlighting the unmet need for multicentric prospective trials in this population. Here, we reviewed the main clinical characteristics of neurological syndromes associated with GAD Ab, focusing on pathophysiologic mechanisms.

Follow-up of patients with epilepsy harboring antiglycine receptor antibodies.

OBJECTIVE: The long-term follow-up of patients with epilepsy harboring autoantibodies against the glycine receptor (also glycine receptor antibodies or GlyR-Ab) is not well-known. Our aim was to investigate the 5-year prognosis and treatment response of patients with epilepsy who were seropositive for GlyR-Ab. METHODS: Clinical features; electroencephalogram (EEG), neuroradiological, and neuropathological findings; and treatment responses of patients with epilepsy with GlyR-Ab seropositivity were investigated. RESULTS: Thirteen (5.46%) of 238 patients with epilepsy were GlyR-Ab positive: focal epilepsy of unknown cause (FEoUC) was diagnosed in four (7.27%) out of 55 patients, mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) in five (4.5%) out of 111 patients, epileptic encephalopathy (EE) in two (4%) out of 50 patients, and status epilepticus (SE) in two (9.09%) out of 22 patients. None of the patients developed any other neurological symptoms or cancer during the 5-year follow-up. Seven of them had seizures that were resistant to antiepileptic drug (AED). Immunotherapy was used in two patients (with FEoUC and EE) improving seizure control. Three patients with MTLE-HS benefited from epilepsy surgery, and another patient with EE showed spontaneous remission. CONCLUSION: Glycine receptor antibodies are detected in a wide spectrum of epileptic disorders with unclear pathogenic significance. Two GlyR-Ab seropositive patients with AED-resistant epilepsy treated with intravenous immunoglobulin (IVIg) showed clear benefit from immunotherapy. Future studies will be valuable in determining the role of screening patients with drug-resistant epilepsy for GlyR-Ab in order to identify patients who may benefit or respond to immunotherapy.

A systematic review of Gamma-aminobutyric Acid Receptor Type B autoimmunity.

OBJECTIVE: To review the available research to describe the clinical characteristics and neoplastic associations of patients with gamma-aminobutyric acid receptor type B (GABAB-R) autoantibodies. METHODS: Literature was reviewed on PubMed, Mendeley literature search, and the American Academy of Neurology database for articles published from June 2008 to October of 2018 using a variety of key words. These key words include: "gamma-aminobutyric acid seizures," "gamma-aminobutyric acid limbic encephalitis", "GABA(B) receptor antibodies," "autoimmune encephalitis," "autoimmune epilepsy," "GABA(B) encephalitis, " and "GABA paraneoplastic." With the results, the papers were reviewed in a systematic manner. RESULTS: A total of 10 studies were reviewed. A summary of the demographic, clinical, and serological findings of the cases detailed in the literature are provided. An additional illustrative case is described. In total, 94 patients were reviewed. CONCLUSIONS: GABAB-R autoimmune disease is characterized by refractory seizures or status epilepticus and frequent association with small cell lung cancer. Additionally, a substantial minority of patients have non-inflammatory CSF.

Antiglycine receptor antibody related disease: a case series and literature review.

BACKGROUND AND PURPOSE: Antibodies to glycine receptors (GlyR-Abs) were first defined in progressive encephalopathy with rigidity and myoclonus (PERM) but were subsequently identified in other clinical presentations. Our aim was to assess the clinical associations of all patients identified with GlyR-Abs in Queensland, Australia, between April 2014 and May 2017 and to compare these to cases reported in the literature. METHODS: A literature review identified the clinical features of all published GlyR-Ab-positive cases through online databases. A case series was undertaken via collection of clinical information from all patients diagnosed or known to immunology, pathology or neurological services in Queensland during the study period of 3 years. RESULTS: In all, 187 GlyR-Ab-positive cases were identified in the literature. The majority (47.6%) had PERM, 22.4% had epilepsy, but the remaining 30% included mixed phenotypes consisting of cerebellar ataxia, movement disorders, demyelination and encephalitis/cognitive dysfunction. By contrast, in our series of 14 cases, eight had clinical presentations consistent with seizures and epilepsy and only three cases had classical features of PERM. There was one case each of global fatiguable weakness with sustained clonus, laryngeal dystonia and movement disorder with hemiballismus and tics. The rate of response to immune therapy was similar in all groups. CONCLUSION: Antibodies to glycine receptors are linked to a spectrum of neurological disease. The results of the literature review and our case series suggest a greater relationship between GlyR-Abs and epilepsy than previously reported.