Aggressive Course in Encephalitis With Opsoclonus, Ataxia, Chorea, and Seizures

Kruer, Michael C.; Hoeftberger, Romana; Lim, Kit Yeng; Coryell, Jason; Svoboda, Melissa D.; Woltjer, Randall L.; Dalmau, Josep

doi:10.1001/jamaneurol.2013.4786

Cited by 62 publications

(19 citation statements)

References 8 publications

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“…Three of these patients had total or partial recovery and two died as a result of sepsis during status epilepticus. One death was a child (patient 4) with concomitant GABA B R antibodies indicated above (clinical and autopsy findings have been reported in detail elsewhere; 18 the GABA A R antibodies were identified in archived serum and CSF samples). The oldest of the six patients (age 63 years) also had GABA B R antibodies; the GABA A R antibodies were identified in samples that had been archived for 7 years.…”

Section: Resultsmentioning

confidence: 81%

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Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies

Petit‐Pedrol

Armangué

Peng

et al. 2014

The Lancet Neurology

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532

539

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Summary Background Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients’ antibodies on neuronal cultures. Methods In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy. Findings Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3–63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2–74 years, median 26·5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients’ antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor). Interpretation High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable. Funding The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Rese...

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Section: Resultsmentioning

confidence: 81%

“…9,18 Our final protocol was approved by the institutional review boards of the University of Pennsylvania and the Hospital Clinic, and written informed consent was obtained from all patients or representatives.…”

Section: Methodsmentioning

confidence: 99%

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies

Petit‐Pedrol

Armangué

Peng

et al. 2014

The Lancet Neurology

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532

539

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“…Although there are reports that an antibody against GABA B receptor mediates epilepsy opsoclonus-myoclonus syndrome and ataxia (Hoftberger et al, 2013;Kruer et al, 2014), there is no mutation identified in GABA B receptor subunit genes up to date. Thus, we will only focus on GABA A receptor mutations in this review article.…”

Section: Gabamentioning

confidence: 99%

Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

Kang

2017

Epilepsy Research

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Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ~15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long-established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post-synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies.

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“…The volume of these regions typically swells during the acute phase, but during the recovery phase, the volume becomes even smaller than normal [92]. Some lesions may involve other regions of the brain aside from the limbic structures [93][94][95]. However, in some patients, the MRI findings were normal, particularly in cases of early onset.…”

Section: Auxiliary Examinationsmentioning

confidence: 99%

Differences in epileptic symptoms depending on the type of autoimmune-mediated limbic encephalitis

Lin

Wang²

2015

Expert Review of Clinical Immunology

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Limbic encephalitis (LE) is an inflammatory disease of the central nervous system that is characterized by the selective involvement of limbic structures. The clinical manifestations of LE include the acute or sub-acute onset of recent memory disorders, mental disorders and seizures. Autoimmune-mediated LE is a major type of non-infectious LE; seizure is a hallmark of this type of LE. The treatment of epilepsy, which is a key factor that affects the prognosis of LE patients, warrants special attention. Understanding the characteristics of epilepsy caused by autoimmune-mediated LE and providing the appropriate treatment will help to improve patients' outcomes. In this article, we extensively review the literature related to autoimmune-mediated LE epidemiology, mechanisms, characteristics and seizure frequency and onset, and we discuss the possible diagnosis and treatment of this disease.

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Aggressive Course in Encephalitis With Opsoclonus, Ataxia, Chorea, and Seizures

Cited by 62 publications

References 8 publications

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies

Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

Differences in epileptic symptoms depending on the type of autoimmune-mediated limbic encephalitis

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