Sukhvir Wright

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction

Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor α2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology.

Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens

Objective To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens. Method Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007–2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase. Results Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect. Conclusions Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.

Autoantibodies to neuronal antigens in children with new-onset seizures classified according to the revised ILAE organization of seizures and epilepsies.

Potentially pathogenic autoantibodies are found increasingly in adults with seizure disorders, including focal seizures and those of unknown cause. In this study, we investigated a cohort of children with new‐onset seizures to see whether there were autoantibodies and the relationship to any specific seizure or epilepsy type.

Elevated VGKC-complex antibodies in a boy with fever-induced refractory epileptic encephalopathy in school-age children (FIRES)

Fever‐induced refractory epileptic encephalopathy in school‐age children (FIRES) is a clinically recognized epileptic encephalopathy of unknown aetiology. Presentation in previously healthy children is characterized by febrile status epilepticus. A pharmacoresistant epilepsy ensues, occurring in parallel with dramatic cognitive decline and behavioural difficulties. We describe a case of FIRES in a 4‐year‐old boy that was associated with elevated voltage‐gated potassium channel (VGKC) complex antibodies and a significant clinical and immunological response to immunomodulation. This case, therefore, potentially expands the clinical phenotype of VGKC antibody‐associated disease to include that of FIRES. Prior to immunomodulation, neuropsychology assessment highlighted significant attention, memory, and word‐finding difficulties. The UK version of the Wechsler Preschool and Primary Scale of Intelligence assessment indicated particular difficulties with verbal skills (9th centile). Immunomodulation was initially administered as intravenous methylprednisolone (followed by maintenance oral prednisolone) and later in the disease course as regular monthly intravenous immunoglobulin infusions and low‐dose azathioprine. Now aged 6 years, the seizure burden in this child is much reduced, although increased seizure frequency is observed in the few days before his monthly immunoglobulin infusions. Formal IQ assessment has not been repeated but there is no clinical suggestion of further cognitive regression. VGKC complex antibodies have been reported in a range of central and peripheral neurological disorders (predominantly presenting in adulthood), and the identification of elevated VGKC complex antibodies, combined with the response to immunotherapies in this child, supports an autoimmune pathogenesis in FIRES with potential diagnostic and therapeutic implications.

Progress in autoimmune epileptic encephalitis.

PURPOSE OF REVIEW Autoimmune epileptic encephalopathy is a potentially treatable neurological syndrome characterized by the coexistence of a neuronal antibody in serum and, often, cerebrospinal fluid. Patients present with combinations of seizures, neuropsychiatric features, movement disorder, and cognitive decline, but some patients have isolated seizures either at first presentation or during their illness. This review summarizes our current understanding of the roles of specific neuronal antibodies in epilepsy-related syndromes and aims to aid the clinician in diagnosis and treatment. RECENT FINDINGS Antigen discovery methods in three neuroimmunology centres independently identified antibodies to different subunits of the γ amino butyric acid-A receptor; high levels of these antibodies were found mainly in patients with severe refractory seizures. These and other antibodies were also found in a proportion (<10%) of children and adults with epilepsy. A clinical study comparing immunotherapy in patients with autoantibodies or without an identified target antigen found neuroinflammatory features were predictive of a therapeutic response. New in-vitro and in-vivo studies, and spontaneous animal models, have confirmed the pathogenicity and epileptogenicity of neuronal antibodies and their relevance to other mammals. SUMMARY Neuronal antibodies are an important cause of autoimmune epileptic encephalopathy, early recognition is important as there may be an underlying tumour, and early treatment is associated with a better outcome. In the absence of an antibody, the clinician should adopt a pragmatic approach and consider a trial of immunotherapy when other causes have been excluded.

A clinico-radiological phenotype of voltage-gated potassium channel complex antibody-mediated disorder presenting with seizures and basal ganglia changes.

In childhood, central nervous system (CNS) presentations associated with antibodies to voltage‐gated potassium channel (VGKC) complex include limbic encephalitis, status epilepticus, epileptic encephalopathy, and autistic regression. We report the cases of two individuals (a 6‐year‐old male and an 11‐year‐old female) who presented with an acute‐onset explosive seizure disorder with positive VGKC complex antibodies and bilateral basal ganglia changes on magnetic resonance imaging (MRI). Both patients made a complete clinical recovery, without immunotherapy, with resolution of the MRI changes and normalization of the antibody levels. Extended antibody testing, including testing for leucine‐rich glioma‐inactivated 1 (LGI1), contactin‐associated protein 2, and contactin‐2 was negative. This could suggest that the clinico‐radiological phenotype in our patients may in fact be associated with a novel autoreactive target(s) within the VGKC complex, as may be the case in other children with VGKC complex‐mediated CNS disorders.

Pediatric Autoimmune Epileptic Encephalopathies.

Pediatric autoimmune epileptic encephalopathies are predominantly characterized by the presence of autoantibodies to the surface of neuronal proteins, for example, N-methyl-d-aspartate (NMDA) receptor antibodies, but also include diseases with non–cell surface antibodies (eg, anti-Hu, glutamic-acid decarboxylase antibodies). In some cases with distinct clinical and para-clinical features, an autoimmune epileptic encephalopathy can be diagnosed without the presence of an antibody and will also respond favorably to immunotherapy. In this review, we summarize the common presentations of pediatric autoimmune epileptic encephalopathies, treatments, and outcomes, and report recent findings in the field of epilepsy, encephalopathy, and the immune system.

Autoimmune epilepsy: the search for a definition

Neuroinflammation observed in a range of neurological disorders may represent the primary pathology, such as in an autoimmune condition like multiple sclerosis; but can also represent a secondary response to biological processes such as seizures and neurodegeneration. The role of the immune system in epilepsy has been critically reviewed, particularly how neuroinflammation is integrally related to the pathogenesis in epilepsy, and in sustaining seizure activity. Pathogenic autoantibodies to a range of neuronal proteins essential to neurotransmission and/or synaptic function (e.g. the N-methyl-D-aspartate receptor [NMDAR] in NMDAR antibody encephalitis) have now been identified, where seizures often form a significant part of the presentation and disease. Following on from this, the concept of ‘autoimmune epilepsy’ has evolved to being considered a separate, but closely linked, clinical entity to autoimmune encephalitis. Suleiman and Dale provide a welcome and comprehensive overview of the recognition, investigation, and treatment of autoimmune epilepsy in children, as studies to date have largely focused on adult epilepsy cohorts. The authors describe how the potential pathological effect of the adaptive immune response, comprising either of B-cells and/or T-cells, is integral to developing autoimmune epilepsy. A frequent conundrum facing the clinician here is when to initiate immunotherapy. Most recommendations rely on an algorithm comprising clinical and paraclinical parameters purported to support an autoimmune or immune aetiology, although their specificity and sensitivity have not been systematically evaluated. Furthermore, imaging and biological surrogate markers of inflammation identified in serum and cerebrospinal fluid are not consistently observed in children, as highlighted by Suleiman and Dale in their review. The International League Against Epilepsy (ILAE) has recently included ‘immune’ as an aetiology in the ILAE Revised Terminology for Organisation of Seizures and Epilepsies 2011 to 2013 and recommends that targeted immunotherapies should be reserved for those patients who have recurrent seizures and/or epilepsy within the context of an autoantibody mediated encephalitis. Importantly, treatment decisions have to account for the monophasic course and the potential for spontaneous recovery without treatment that are observed in some children. Currently, the final clinical diagnosis of autoimmune epilepsy, as applied to adult cohorts, is reliant on either identification of neuronal autoantibodies and/or a positive response to immunotherapy. These are two criteria that pragmatically combine the specificity of identifying an antibody-mediated aetiology using robust, clinically available detection assays, and the sensitivity of an immunotherapy response in additionally identifying an autoimmune process in patients where the precise antigenic target has yet to be identified or may have a T-cell mediated autoimmunity. This may also include patients with broader involvement of the innate immune system. A response to immunotherapeutic agents such as steroids may also reflect a non-immune biological effect, such as in the treatment of infantile spasms or continuous spikes and waves during sleep, and should thus not be the sole indicator of an autoimmune aetiology as this may result in unnecessary escalation or prolonged use of immunotherapy. How, and if, autoimmune epilepsy differs from autoimmune encephalitis remains debatable. Acute seizures as part of an autoimmune encephalitic illness would be considered ‘provoked’ or ‘acute symptomatic’ and do not fulfill the recently revised ILAE criteria for the definition of epilepsy. Patients that develop seizures following autoimmune encephalitis may have an enduring risk for unprovoked seizures, and may then be considered as ‘epileptic’. Crucially, the epilepsy at this stage is likely to represent a sequelae of the autoimmune process rather than indicating an active immune process that require immunotherapy, as may be the case in paediatric and adult patients with focal epilepsy of unknown cause where neuronal autoantibodies are detected (reviewed in Suleiman and Dale). This review provides an important early effort towards discussing a potential definition of autoimmune epilepsy in children, one that is likely to evolve as we begin to unravel the pathobiology of these disorders; where nosological adjustments may be required to reflect the primary or prevailing immune or extra-immune pathology. Exploiting these mechanisms will provide exciting new therapeutic strategies.