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 GABA A receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABA A 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 GABA A 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 GABA A receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABA A receptor). Interpretation High titres of serum and CSF GABA A 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 GABA A 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, Fundacio la Marato de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.

/pdf/encephalitis-with-refractory-seizures-status-epilepticus-and-ytu30kdevp.pdf

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

The term 'neuromyelitis optica' ('Devic's syndrome', NMO) refers to a syndrome characterized by optic neuritis and myelitis. In recent years, the condition has raised enormous interest among scientists and clinical neurologists, fuelled by the detection of a specific serum immunoglobulin (Ig)G reactivity (NMO-IgG) in up to 80% of patients with NMO. These autoantibodies were later shown to target aquaporin-4 (AQP4), the most abundant water channel in the central nervous system (CNS). Here we give an up-to-date overview of the clinical and paraclinical features, immunopathogenesis and treatment of NMO. We discuss the widening clinical spectrum of AQP4-related autoimmunity, the role of magnetic resonance imaging (MRI) and new diagnostic means such as optical coherence tomography in the diagnosis of NMO, the role of NMO-IgG, T cells and granulocytes in the pathophysiology of NMO, and outline prospects for new and emerging therapies for this rare, but often devastating condition.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cei.12271

Neuromyelitis optica: clinical features, immunopathogenesis and treatment

In parallel to the detection of new neuronal autoantibodies, the diagnosis of non-infectious limbic encephalitis has risen. Given that cerebral imaging studies show highly variable results, the present retrospective study investigates imaging findings in association with autoantibody type. An institutional database search identified 18 patients with non-infectious limbic encephalitis who had undergone [18F] fluorodeoxyglucose positron emission tomography (FDG-PET). Sixteen of these patients also underwent magnetic resonance imaging (MRI). MRI and FDG-PET images were categorized as follows: normal (0); mesiotemporal abnormality (1); normal mesiotemporal finding but otherwise abnormal (2). Neuronal autoantibodies were determined in serum and/or CSF. Autoantibodies were grouped according to the cellular localization of their target antigen: antibodies against surface antibodies (i.e., VGKC, NMDAR): 9; antibodies against intracellular antigens (i.e., Hu, Ri, GAD): 4; no autoantibodies: 5. The fraction of abnormal scans was lower for MRI (10/16) than for FDG-PET (14/18). There was a significant association between PET findings and autoantibody type: All patients with autoantibodies against intracellular antigens showed mesiotemporal findings on FDG-PET. In turn, only 2/9 patients with autoantibodies against surface antigens displayed mesiotemporal hypermetabolism. In the remaining seven patients, four scans were rated as normal and three only showed findings outside the mesiotemporal region. A similar association was found using MRI, although this did not reach statistical significance. Autoantibody type was found to be associated with FDG-PET and, to a lesser extent, with MRI imaging results. Our observations may explain the heterogeneity of imaging data in LE and based on in vivo findings support the assumption of different patho mechanisms underlying LE due to antibodies against surface and intracellular antigens, respectively.

Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types

Antibodies to glutamic acid decarboxylase (GAD) have been associated with several neurological syndromes, including stiff-person syndrome, cerebellar ataxia and epilepsy. These antibodies were first described in 1988, but several controversies about GAD autoimmunity still remain. No criteria exist to establish when a neurological syndrome is pathogenically linked to GAD antibodies, often leading to the assumption that any syndrome in which these antibodies are present is immune mediated, sometimes resulting in misdiagnosis and unnecessary treatment. In this Review, we provide recommendations for assessing the association between a neurological syndrome and the presence of GAD antibodies, and we critically review the evidence on the pathogenicity of GAD antibodies. Given that stiff-person syndrome is usually autoimmune, the presence of GAD antibodies in the cerebrospinal fluid is sufficient to confirm a pathogenic link with GAD autoimmunity. However, for cerebellar ataxia, epilepsy and other syndromes with different aetiologies, we propose that confirmation of a pathogenic link with GAD autoimmunity requires demonstration of intrathecal GAD antibody synthesis. Nevertheless, the evidence that GAD antibodies are directly pathogenic is not yet convincing. Studies in animal models are needed to demonstrate whether neurological syndromes are directly caused by specific disruption of GAD function by GAD antibodies. Antibodies to glutamic acid decarboxylase (GAD) are associated with several neurological syndromes but their importance and role are controversial. In this Review, Graus et al. propose criteria for assessing the association between GAD antibodies and neurological syndromes and discuss the pathogenicity of GAD antibodies.

GAD antibodies in neurological disorders — insights and challenges

Neuromyelitis optica (NMO) is an idiopathic inflammatory syndrome of the central nervous system that is characterized by severe attacks of optic neuritis (ON) and myelitis. Until recently, NMO was considered a disease without brain involvement. However, since the discovery of NMO-IgG/antiaqaporin-4 antibody, the concept of NMO was broadened to NMO spectrum disorder (NMOSD), and brain lesions are commonly recognized. Furthermore, some patients present with brain symptoms as their first manifestation and develop recurrent brain symptoms without ON or myelitis. Brain lesions with characteristic locations and configurations can be helpful in the diagnosis of NMOSD. Due to the growing recognition of brain abnormalities in NMOSD, these have been included in the NMO and NMOSD diagnostic criteria or guidelines. Recent technical developments such as diffusion tensor imaging, MR spectroscopy, and voxel-based morphometry reveal new findings related to brain abnormalities in NMOSD that were not identified using conventional MRI. This paper focuses on the incidence and characteristics of the brain lesions found in NMOSD and the symptoms that they cause. Recent studies using advanced imaging techniques are also introduced.

/pdf/brain-abnormalities-in-neuromyelitis-optica-spectrum-2ie1rnf9r7.pdf

Brain Abnormalities in Neuromyelitis Optica Spectrum Disorder

Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality?

Background. Primary Sjogren's syndrome (PSS) is a frequent systemic autoimmune disease. In this study, we aimed to explore the cognitive impairment and the correlations with brain MRI. Methods. Twenty-five patients (mean age 55 ± 11.8 years, 21 females) with PSS were prospectively selected and tested with a French translation of the Brief Repeatable Battery for Neuropsychological Examination. The results were compared with the scores for 25 matched patients with multiple sclerosis (MS) and 25 controls. Brain lesions were assessed by brain MRI using the Wahlund classification. Results. Fifteen of the 25 PSS patients (60%) presented with cognitive disorders versus 19/25 MS patients (76%). Five patients had dementia in the PSS group. Speed of information processing, attention, immediate and long-term memory, and executive functions were frequently impaired. The mean duration of cognitive complaints was 5.6 ± 6.1 years, and the mean duration of PSS was 15.8 ± 14.0 years. A trend towards a correlation was found between the severity of cognitive impairment and the degree of white matter lesions (WML) (P = 0.03, rho = 0.43). Conclusion. Cognitive impairment—mild or dementia—exists in patients with PSS. Further MRI studies are needed to better understand the precise neural basis of cognitive impairment in PSS patients.

/pdf/cognitive-dysfunction-and-dementia-in-primary-sjogren-s-4ojvhkpw77.pdf

Cognitive Dysfunction and Dementia in Primary Sjögren’s Syndrome

Neuromyélite optique de Devic, troubles cognitifs et imagerie cérébrale par résonance magnétique

Neuromyelitis optica (NMO) is an inflammatory disease of central nervous system characterized by optic neuritis and longitudinally extensive acute transverse myelitis. NMO patients have cognitive dysfunctions but other clinical symptoms of brain origin are rare. In the present study, we aimed to investigate cognitive functions and brain volume in NMO. The study population consisted of 28 patients with NMO and 28 healthy control subjects matched for age, sex and educational level. We applied a French translation of the Brief Repeatable Battery (BRB-N) to the NMO patients. Using SIENAx for global brain volume (Grey Matter, GM; White Matter, WM; and whole brain) and VBM for focal brain volume (GM and WM), NMO patients and controls were compared. Voxel-level correlations between diminished brain concentration and cognitive performance for each tests were performed. Focal and global brain volume of NMO patients with and without cognitive impairment were also compared. Fifteen NMO patients (54%) had cognitive impairment with memory, executive function, attention and speed of information processing deficits. Global and focal brain atrophy of WM but not Grey Matter (GM) was found in the NMO patients group. The focal WM atrophy included the optic chiasm, pons, cerebellum, the corpus callosum and parts of the frontal, temporal and parietal lobes, including superior longitudinal fascicle. Visual memory, verbal memory, speed of information processing, short-term memory and executive functions were correlated to focal WM volumes. The comparison of patients with, to patients without cognitive impairment showed a clear decrease of global and focal WM, including brainstem, corticospinal tracts, corpus callosum but also superior and inferior longitudinal fascicles. Cognitive impairment in NMO patients is correlated to the decreased of global and focal WM volume of the brain. Further studies are needed to better understand the precise origin of cognitive impairment in NMO patients, particularly in the WM.

/pdf/white-matter-atrophy-and-cognitive-dysfunctions-in-28iobk4ztv.pdf

White matter atrophy and cognitive dysfunctions in neuromyelitis optica.

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Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality?

Cognitive Dysfunction and Dementia in Primary Sjögren’s Syndrome

Neuromyélite optique de Devic, troubles cognitifs et imagerie cérébrale par résonance magnétique

White matter atrophy and cognitive dysfunctions in neuromyelitis optica.