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• W2890180037 abstract "Myelin oligodendrocyte glycoprotein (MOG) antibodies have a strong association with acute disseminated encephalomyelitis (ADEM) in children, and bilateral and recurrent optic neuritis in children and adults. Recent reports suggest that seizures and encephalopathy may occur in children and adults with MOG antibody-associated disease. We describe the clinical, laboratory, and radiological course of four MOG antibody-positive children who first presented with isolated seizures without fulfilling clinical or radiological criteria for ADEM or other central nervous system demyelination syndromes, who months to years later developed more typical demyelination. This case series highlights a novel observation that isolated seizures in the absence of ADEM may be the index presentation for MOG antibody-associated disease, which should therefore be considered a form of autoimmune epilepsy. It would be reasonable to test for MOG antibodies in children with seizures accompanied by subtle inflammatory changes on magnetic resonance imaging or cerebrospinal fluid analyses, particularly if followed by demyelination, given the clinical and therapeutic implications of an expedited diagnosis in minimizing long-term disability. Los anticuerpos contra la Glicoproteina de los Oligodendrocitos de la Mielina (MOG) están fuertemente asociados con la Encefalomielitis Aguda Diseminada (EMAD) en niños, y con la Neuritis Óptica bilateral recurrente en niños y adultos. Recientes reportes sugieren que convulsiones y encefalopatía pueden presentarse con enfermedad asociada a anticuerpos MOG. Describimos la evolución clínica, serologica y radiológica de cuatro niños con anticuerpos positivos para MOG cuya primera presentación fueron convulsiones aisladas sin cumplir todos los criterios cínicos ni radiológicos para EMAD u otro síndrome desmielinizante del sistema nervioso central; y, que luego de meses a años, desarrollaron una desmielinización típica. Esta serie de casos resalta una nueva observación, en la cual, convulsiones aisladas en ausencia de EMAD puede ser la presentación de enfermedad asociada a anticuerpos para MOG; y, por lo tanto, debe ser considerada una forma de epilepsia autoinmune. Sería razonable buscar anticuerpos para MOG en aquellos niños con convulsiones que se acompañan de cambios inflamatorios sutiles en la resonancia magnética y análisis de líquido cefalorraquídeo, en particular, en aquellos que posteriormente desarrollan desmielinización teniendo en cuenta las implicancias clínicas y terapéuticas de realizar un diagnóstico rápido con el fin de minimizar la discapacidad a largo plazo. Anticorpos de glicoproteína de oligodendrócito da mielina (GOM) têm forte associação com encefalomielite aguda disseminada (EMAD) em crianças, e com neurite óptica bilateral e recorrente em crianças e adultos. Relatos recentes sugerem que convulsões e encefalopatia podem ocorrer em adultos e crianças com doença associada aos anticorpos GOM. Descrevemos o curso clínico, laboratorial, e radiológico de crianças com anticorpos GOM positivos que apresentaram convulsões isoladas pela primeira vez, sem preencher os critérios clínicos e radiológicos para EMAD ou para outras síndromes desmielinizantes do sistema nervoso central, que nos meses ou anos seguintes desenvolveram desmielinização mais típica. Esta série de casos realça uma nova observação de que convulsões isoladas na ausência de EMAD podem ser sinal de doença relacionada ao anticorpo GOM, e deve portanto ser considerada uma forma de epilepsia auto-imune. Seria razoável testar anticorpos GOM em crianças com convulsões acompanhada de doenças inflamatórias sutis à ressonância magnética ou na análise do fluido cérebro-espinhal, particularmente se seguida por desmielinização, dadas as implicações clínicas e terapêuticas do diagnóstico rápido em minimizar incapacidades no longo prazo. This article is commented on by O'Toole on pages 512–513 of this issue. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations. Myelin oligodendrocyte glycoprotein (MOG) antibodies have a strong association with acute disseminated encephalomyelitis (ADEM) in children, and bilateral and recurrent optic neuritis in children and adults.1-8 Recent reports in adults suggest that seizures and encephalopathy may be an emerging clinical phenotype with MOG antibodies, either concurrent with or remote from demyelination.9, 10 In some cases, these patients had unilateral cortical fluid-attenuated inversion recovery hyperintensities on magnetic resonance imaging (MRI) with resolution of these lesions after clinical remission.9 Seizures have been found to be more common in adults with MOG antibody-associated demyelination compared to those with aquaporin-4 antibody-associated demyelination.10 We describe four MOG antibody-positive children who first presented with isolated seizures without fulfilling clinical or radiological criteria for ADEM or other central nervous system (CNS) demyelination syndromes, who months to years later developed more typical demyelination. Using a highly specific live cell-based assay analysed by flow cytometry,4 we identified four MOG antibody-positive children with isolated seizures as their initial presentation. The first three patients presented with an acute onset of a cluster of focal seizures, which progressed to become secondarily generalized. These patients are detailed in Table SI, online supporting information. Ethics and research protocol approval (NEAF 12/SCHN/395) has been granted for this study. All patients or their carers have given informed consent to the research and to publication of the results. A previously typically developing 3-year-old female presented with ten focal seizures within 8 hours, which manifested as right facial twitching, eyes deviated to the right, and right hand jerking, with the longest seizure lasting 90 seconds. She had preserved consciousness during these episodes. She went on to have one secondarily generalized seizure lasting 60 seconds. There were no other neurological symptoms or signs. Ictal electroencephalograms (EEGs) 2 days and 5 days after seizure onset showed left centrotemporal slowing and focal polyspike epileptic discharges in the left posterior region which corresponded to right hemifacial jerking clinically. MRI within 24 hours of seizure onset revealed a single white matter lesion in the right posterior frontal subcortical white matter (Fig. 1a) which did not correspond to the identified epileptic foci on EEG, and which improved on repeat imaging 9 days later. Cerebrospinal fluid (CSF) analysis was normal at this stage. Acute management of seizures included phenytoin loading and midazolam. She was commenced on 15mg/kg/day carbamazepine and 5mg twice daily of clobazam. She was weaned off the clobazam after 6 months, but continued on carbamazepine for a total of 24 months. She had multiple focal seizures manifested by right facial jerking with preserved consciousness for the first 6 days of her admission, after which they ceased. She has had no further seizures. Follow-up EEGs 3 weeks after seizure onset showed mild generalized slowing but no focal discharges. Further EEGs performed 3 months, 15 months, and 19 months after seizure onset were normal. Eight months after this initial presentation, she represented with encephalopathy, gait disturbance, and an MRI consistent with ADEM. She responded to intravenous methylprednisolone (IVMP) followed by a 2-month prednisone taper, but presented with recurrent ADEM 2 months after steroid cessation. She responded to mycophenolate mofetil (30mg/kg/day) and a 6-month prednisone taper, but had a further ADEM relapse 6 weeks after steroid cessation. Ongoing mycophenolate and reintroduction of 30mg of prednisone twice weekly over a 2-year period, with more recent weaning of prednisone by 5mg per dose every 6 months, has maintained clinical and radiological remission. She was positive for MOG antibody testing during the first seizure event, acutely during all relapses, and twice while in remission. A 7-year-old female presented with a focal motor seizure, with clonic jerking of her eyes and face, and eye deviation, followed by an 8-minute generalized tonic–clonic seizure. She had experienced headaches, vomiting, and worsening school performance in the preceding 2 months, but no encephalopathy. She was treated acutely with midazolam but did not require ongoing anticonvulsants. An EEG performed 2 months after the seizure did not demonstrate any epileptiform discharges. Her headaches persisted and a brain MRI performed 5 months after the seizure was unremarkable. The symptoms resolved and she remained seizure free for 30 months, when she represented with a single complex partial seizure which was not treated, and a month later with a cluster of focal motor seizures which were followed by generalized status epilepticus. She was treated acutely with midazolam, phenobarbitone, and phenytoin loading for management of status. Sodium valproate was commenced at 30mg/kg/day (600mg twice daily). An interictal EEG at this time demonstrated a mild excess of paroxysmal slow transients over the left temporal area during drowsiness and sleep, but no epileptiform discharges. CSF analysis revealed a mononuclear lymphocytic pleocytosis with 20 lymphocytes. She experienced headaches, lethargy, and intermittent breakthrough seizures over 7 months, despite carbamazepine. A follow-up EEG at this stage was unremarkable, and she was changed from sodium valproate to carbamazepine 20mg/kg/day (400mg twice daily). Thirteen months after the episode of status, she presented with left optic neuritis with MRI demonstrating optic nerve inflammation but no brain lesions. Her symptoms improved with IVMP followed by a 2-month prednisone taper. One month after steroid cessation, she developed right optic neuritis once again unaccompanied by MRI brain lesions, which improved with IVMP and a 2-month prednisone taper. Six months after steroid taper and discontinuation of carbamazepine, she presented with a generalized tonic–clonic seizure lasting 2 minutes. This was followed by further clusters of focal seizures and generalized tonic–clonic seizures over the next 10 days, severe headaches and personality change, and clinical and radiological features consistent with ADEM and left optic neuritis. MOG antibody testing was seropositive at this stage. No regular anticonvulsants were started. Mycophenolate mofetil was trialled but not tolerated because of gastrointestinal adverse effects. Monthly intravenous immunoglobulin (2g/kg/mo) resulted in remission for 12 months. Intravenous immunoglobulin was withdrawn and replaced with 10mg of prednisone on alternate days. She relapsed 3 months later with headaches and generalized tonic–clonic seizures. She was treated with phenytoin loading, and recommenced on carbamazepine, and has remained seizure free at a dose of 200mg twice daily since then. MRI confirmed a single left temporal white matter lesion. She has remained relapse free for a further 12 months after recommencement of monthly intravenous immunoglobulin (1g/kg/mo), and remains MOG antibody positive. She has mild residual cognitive deficits, and retinal nerve fibre layer atrophy on optical coherence tomography. A 10-year-old Samoan female with a previous history of rheumatic fever presented with a cluster of focal right clonic seizures (right leg jerking) with one episode progressing to a 5-minute secondarily generalized seizure. EEG performed 1 month after acute presentation and MRI performed 2 months after onset were unremarkable, the seizures remitted, and no ongoing treatment was required. Twenty-nine months later, she presented with left optic neuritis without brain changes on MRI, prompting treatment with IVMP and a 3-week prednisone taper. Twenty-two months later she had a further right optic neuritis episode with inflammatory optic nerve changes but no brain lesions on MRI, and was treated with IVMP only. MOG antibody testing was seropositive at this stage. Five months later she suffered 2 days of intermittent focal seizures progressing to 24 hours of epilepsia partialis continua with right hand and face clonic jerking followed by a brief secondarily generalized tonic–clonic seizure. An interictal EEG done within 24 hours showed left temporal slowing, and a brain MRI performed 2 days after presentation showed left temporal cortical swelling but no white matter lesions. She was treated and remains on carbamazepine. She has some residual mild cognitive delay and an intermittent right-hand tremor, with no further relapses for 3 years. A recent MRI showed resolution of the temporal lesion, and a nonspecific single left parieto-occipital white matter lesion. A 5-year-old male presented with a 1-week history of intermittent left-sided headaches and vomiting followed by seizures. Seizure onset was unclear as he was found 15 minutes after last being seen, with eyes fixed and deviated to the right. This was followed by focal clonic status epilepticus with eye deviation, occurring in repetitive clusters over 90 minutes. He was given four doses of intranasal and intravenous midazolam over 1 hour, and a single dose of dexamethasone. He was commenced on intravenous levetiracetam acutely, and this was continued orally at 150mg twice daily but was ceased after 1 week. An EEG performed 3 days after seizure onset revealed mild slowing in the left occipital region but no epileptiform discharges. CSF analysis revealed 19 mononuclear cells, negative oligoclonal bands, and negative viral testing. MRI 1 week after onset showed a non-specific single white matter lesion in the left cerebellar hemisphere (Fig. 1b). MOG antibodies tested 4 days after seizure onset were positive. He has remained seizure free for 13 months. During the first episode, none of the children had encephalopathy or focal neurological signs, and their presentation was not consistent with any currently accepted syndrome of CNS demyelination in children, including ADEM.11 The initial MRI was normal in two patients, and showed a single non-specific white matter lesion in two patients. CSF analysis revealed lymphocytic pleocytosis in two patients. All patients were negative for N-methyl-D-aspartate receptor antibodies, and other neuronal surface antibodies were tested and negative in the serum of the first three patients (gamma-aminobutyric acid-b, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glycine receptor, Leucine-rich glioma inactivated 1, contactin-associated protein-like 2, and IgLON5). The initial seizure presentation resolved with treatment with antiepileptics in three patients, and spontaneously in one patient. The first three patients had an asymptomatic interval between 8 months and 48 months before subsequent clinical episodes. These patients had a total of 11 relapses of which nine were demyelinating (ADEM n=5, optic neuritis n=4) and two were isolated seizures (status epilepticus n=1, epilepsia partialis continua n=1), and their treatment is detailed in Table SI. Two patients who relapsed on steroid cessation have received ongoing immunotherapy. The most recent follow-up MRIs during remission were normal or demonstrated resolution of previous lesions in two, and a single non-specific white matter lesion in one. Two patients have residual deficits. The fourth case has not had a relapse, although the follow-up is short and he is being monitored closely. Serial samples in Case 1 and Case 2 demonstrated persistent MOG antibody seropositivity during relapses as well as clinical remission (Fig. 1c). In addition, Case 1 and Case 4 were seropositive during the original seizure episode even in the absence of demyelination. Recent publications evaluating children with relapsing MOG antibody-associated demyelination identified that seizures may be a component of the clinical presentation of ADEM.12, 13 Another study described patients who presented with isolated optic neuritis later developing seizures, either in the context of ADEM or during steroid taper.14 Pillai et al. 15 examined the risk of postencephalitic epilepsy at follow-up, and identified that the risk of drug-resistant epilepsy after ADEM is relatively low. In contrast, this case series highlights a novel observation that isolated seizures in the absence of acute ADEM or other demyelinating relapses may be the index presentation of MOG antibody-associated disease, for children who subsequently develop the more typical relapsing demyelinating episodes associated with MOG antibodies months to years later. The four patients we describe all had seizures which were typically focal with secondary generalization, sometimes status epilepticus, and sometimes associated headache and vomiting, but no clear encephalopathy or focal neurological signs, and not consistent with any currently accepted syndrome of CNS demyelination in children including ADEM.11 The index seizures were associated with abnormal CSF and subtle MRI changes in two patients, suggesting they were inflammatory in aetiology. In this series, there was a significant time lag between the seizure episode and subsequent demyelinating event (8–48mo), suggesting this was a discrete episode rather than part of an ADEM event. It is interesting to speculate that the initial seizure episode may represent a CNS infection such as viral encephalitis, triggering an autoimmune process. However, Case 1 and Case 4 were tested for MOG antibodies in the initial seizure presentation and were positive before the development of demyelination, suggesting that isolated seizures may be part of the expanding clinical spectrum of MOG antibodies. Additionally, three patients had either epilepsia partialis continua or status epilepticus, which in some were difficult to control with anticonvulsants alone, further suggesting a potential underlying immunological pathogenesis. Myelin oligodendrocyte glycoprotein is formed by oligodendrocyte plasma membranes that are wrapped around neuronal axons in the CNS. MOG is a protein expressed by oligodendrocytes and localized to the outermost lamellae of myelin.16 Although most notable in the subcortical white matter, myelinated oligodendrocytes are also present in the cortical grey matter, where they are essential for axonal conduction. This renders cortical presentations such as we describe plausible in the context of a MOG antibody-mediated process. We report that isolated seizures in children in the absence of ADEM11 may herald the subsequent development of relapsing demyelination associated with MOG antibodies, and MOG antibodies may be associated with autoimmune epilepsy. In addition to MRI and CSF analysis when evaluating children with this presentation, we would recommend testing for MOG antibodies acutely in the first episode in children with seizures, particularly if there are subtle features of inflammation, or if the clinical course progresses to involve demyelination. This is important given the clinical and therapeutic implications of an expedited diagnosis in minimizing long-term disability. Furthermore, ongoing seizures concurrent with or remote from demyelinating episodes may be managed with immunotherapy rather than anticonvulsant therapy in isolation. This work was supported by the National Health and Medical Research Council (Australia), the Petre Foundation (Australia), Multiple Sclerosis Research Australia, the Brain Foundation, and the Sydney Research Excellence Initiative 2020 Neuroimmunology Group (University of Sydney, Australia). The authors have stated that they had no interests which might be perceived as posing a conflict or bias. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2890180037 date "2018-09-17" @default.
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• W2890180037 title "Isolated seizures during the first episode of relapsing myelin oligodendrocyte glycoprotein antibody‐associated demyelination in children" @default.
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