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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 in fluence 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.
\n \n\n \n \nNeuromyelitis optica and neuromyelitis optica spectrum disorders have been recently associated with the disease-specific autoantibody aquaporin-4, thought to be pathogenic. Identifying this antibody has allowed the clinical phenotype to be broadened. It is clear that some patients with similar clinical features do not have this antibody and may have a different condition with different outcomes and prognosis. Previous clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies have included such patients. We investigated clinical outcomes and prognostic characteristics of 106 aquaporin-4 antibody-seropositive patients from the UK and Japan. We looked at predictors of disability outcomes, namely visual disability (permanent bilateral visual loss with visual acuity of <6/36 in the best eye), motor disability (permanent inability to walk further than 100m unaided), wheelchair dependence and mortality. Data were collected largely retrospectively through review of case records. After median disease duration of 75 months, 18 had developed permanent bilateral visual disability, 34 permanent motor disability, 23 had become wheelchair dependent and 9 had died. Age at disease onset appeared to be an important predictor of disability type. Young-onset patients in the UK, but not the Japanese cohort, commonly presenting with optic neuritis, had a high risk of visual disability while older patients in both cohorts had a high risk of motor disability, regardless of their onset symptom. Genetic factors also appeared important. The UK cohort seemed to have more severe disease than the Japanese cohort, with more severe onset attacks, a higher relapse frequency and greater disability at follow-up, despite earlier immunosuppression. Moreover, within the UK cohort, there were important differences between ethnic groups, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and higher likelihood of visual disability than Caucasian patients. Thus, age at disease onset and genetic factors are both likely to be important in determining clinical outcomes in aquaporin-4 disease. This has important implications for interpreting clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies, since clinical features and outcomes appear not to be generic across populations and may need to be tailored to individual groups. These factors need to be explored further in future prospective neuromyelitis optica and neuromyelitis optica spectrum disorder studies. \u00a9 2012 The Author.
\n \n\n \n \nBackground: Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disorder associated with considerable relapse-related disability. Immunosuppression is the mainstay of treatment but many patients do not tolerate first-line immunosuppressive agents, or experience ongoing relapses. Objective: To evaluate the effectiveness and tolerability of methotrexate in aquaporin-4 antibody seropositive NMO spectrum disorders. Methods: Retrospective observational case series of 14 aquaporin-4 antibody positive NMO and NMO spectrum disorder patients treated with methotrexate at two specialist centres within the UK. Annualised relapse rates, Expanded Disability Status Scale scores and tolerability were evaluated. Results: Median duration of treatment with methotrexate was 21.5 months (range 6-28 months) and only three patients were prescribed it first line. Median annualised relapse rate signi ficantly decreased following treatment (0.18 during methotrexate therapy vs 1.39 premethotrexate; p<0.005). On treatment, 43% patients were relapse free, although this increased to 64% when relapses occurring within the first 3 months of treatment or on subtherapeutic doses were excluded. Disability stabilised or improved in 79%. No patients stopped methotrexate due to adverse effects. Conclusions: Methotrexate is a commonly prescribed drug in general practice and when used in NMO it reduces relapse frequency, stabilises disability and is well tolerated, even in patients who have failed one or more other treatments. We would therefore recommend methotrexate as a treatment option in NMO patients who do not tolerate first-line therapy, experience ongoing relapses or in situations where financial constraints limit the available treatment options.
\n \n\n \n \n\u00a9 2015, BMJ Publishing Group. All rights reserved. Background: Neuromyelitis Optica (NMO) is a severe and rare inflammatory condition, where relapses are predictive of disability. Methods We describe a national paediatric NMO cohort's clinical, MRI, outcome, and prognostic features in relation to Aquaporin-4 antibody (AQP4-Ab) status, and compared to a non NMO control cohort. Observations: Twenty NMO cases (females=90%; AQP4-Ab positive=60%; median age=10.5yrs) with median follow-up=6.1yrs were compared to a national cohort sample of known sequential AQP4-Ab negative first episode CNS acquired demyelination cases (n=29; females=55%; all AQP4-Ab negative; median age=13.6yrs). At presentation, 40% NMO cases had unilateral optic neuritis (ON); 20% bilateral ON; 15% transverse myelitis (TM); 15% simultaneous TM&ON; 10% Acute disseminated encephalomyelitis. At follow up, 55% had a clinical demyelinating episode involving the brain; 30% of cases had abnormal brain MRI at onset and 75% by follow up. NMO brain scan lesions compared to controls were large (>2 cm), acute lesions largely resolved on repeat imaging, and often showed T1 hypointense lesions. Mean time to relapse=0.76yrs (95% CI 0.43-1.1yrs) for AQP4-Ab positive vs 2.4yrs in AQP4-Ab negative cases (95% CI 1.1-3.6yrs). In AQP4-Ab positive cases, 10/12 had visual acuity<6/60 Snellen in \u22651 eye (0/8 AQP4-Ab negative), and 3 AQP4-Ab negative cases were wheelchair-dependent. Conclusions: In children, NMO is associated with early recurrence and visual impairment in AQP4-Ab positivity and physical disability in AP4-Ab negative relapsing cases. Distinct MRI changes appear more commonly and earlier compared to adult NMO. Early AQP4-Ab testing may allow prompt immunomodulatory treatment to minimise disability.
\n \n\n \n \nHerpes simplex virus encephalitis (HSVE) is a devastating condition that relapses, often with a chorea in children, despite adequate antiviral treatment. At relapse, evidence of viral replication is frequently absent, suggesting that the relapse may be immune-mediated. Seven children who had a neurological relapse following their initial encephalitis, identified from 20 cases of pediatric HSVE, were studied. Serum and/or cerebrospinal fluid (CSF) were tested for N-methyl-D-aspartate receptor (NMDAR) and other antibodies previously reported in central nervous system autoimmunity. Five of the 7 relapsing children had choreoathetosis; 2 of these were NMDAR antibody-positive, 2 were negative (1 with HSV-positive CSF), and 1 was not available for testing. An additional patient, who relapsed with cognitive regression but with no movement disorder, was also NMDAR antibody-positive. In 2 of the NMDAR antibody-positive patients who were treated at relapse and in 1 who was treated only after 10 years of having a relapsing encephalopathy, a beneficial response was observed. Neurological relapses after HSVE may frequently be immune-mediated, particularly in children with chorea. NMDAR antibodies are common, and immunotherapy may be beneficial. \u00a9 2013 Movement Disorder Society.
\n \n\n \n \nNeuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow-Robin spaces was described in patients with NMO [called NMO-IgG (NMO-immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO-IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO. \u00a9 2008 The Author(s).
\n \n\n \n \n\u00a9 2014 Elsevier B.V. Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anticholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission.
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