Publications

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    ABSTRACT: To identify early prognostic factors of relapse and disability in children presenting with an acute idiopathic transverse myelitis (TM). Ninety-five children with acute idiopathic TM from 2 national European cohorts (France and United Kingdom) of CNS demyelinating diseases in children were identified and studied for early factors that predict relapse and disability using logistic regression models. Sixteen (17%) relapsed, with a diagnosis of multiple sclerosis in 13 (14%) and neuromyelitis optica in 3 (3%). Logistic regression revealed 2 main criteria as risk factors for relapse: female sex (odds ratio [OR] 3.21, 95% confidence interval [CI] 0.88-11.78) and presence of associated brain lesions (OR 14.0, 95% CI 2.8-69.3). Twenty-eight (30%) children had a poor outcome defined by a Kurtzke Expanded Disability Status Scale score ≥4 or an American Spinal Injury Association impairment (ASIA) scale <D at last follow-up. Five factors were associated with poor outcome: female sex (OR 5.8, 95% CI 0.99-32.7), severe ASIA scale at onset (OR 33.5, 95% CI 1.8-618), gadolinium enhancement on spinal MRI (OR 24.1, 95% CI 3.78-153.88), absence of pleocytosis (OR 4.6, 95% CI 0.87-26.0), and absence of cervical or cervico-thoracic lesion on spinal MRI (OR 3.9, 95% CI 0.78-19.6). Early predictors of relapse and disability identified in this large childhood study of acute idiopathic TM have important utility for clinical management. Larger prospective collaborative studies are required to validate these findings, which may improve the design of clinical trials. © 2014 American Academy of Neurology.
    Neurology 12/2014; · 8.30 Impact Factor
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    ABSTRACT: Acute necrotising encephalopathy (ANE) is a rapidly progressive encephalopathy associated with acute viral illness. A missense mutation in nuclear pore gene RANBP2 has been identified as a major cause of familial and recurrent ANE, which is now termed as ANE1. First presentation of ANE can mimic an acute disseminated encephalomyelitis (ADEM), although ANE presents in a slightly younger age group. Identification of this disorder at radiological study is the most important determinant of the outcome. ANE1 is inherited as autosomal dominant, but shows incomplete penetrance. We report two female children who presented with atypical clinical presentation (afebrile) and atypical radiological presentation (lack of bilateral thalamic involvement), not fitting into the original diagnostic criteria for ANE1. Both received steroid therapy for a presumed diagnosis of ADEM and made good clinical recovery. We also reviewed the available literature on ANE1, including the clinical profile, MRI brain descriptions, CSF characteristics and common mutations. A total of 59 patients are reported in patients with ANE1 were identified, the incidence of ANE was higher in younger age group (<4 yrs) as compared to ADEM 5.3 yrs (3.6-7). Male and female were equally affected. High CSF protein (>0.45 g/l) was reported in 44/47 (94%) in absence CSF pleocytosis (Cells > 5 × 10(6)/L). Neuroimaging findings showed multifocal involvement across different studies, and bilateral thalamic involvement was seen in 77% of patients. Based on the literature review of ANE1 with RANBP2 mutation, we propose a threshold for RANBP2 mutation testing. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
    European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 12/2014; · 2.01 Impact Factor
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    ABSTRACT: Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke.
    Journal of Neurology Neurosurgery & Psychiatry 10/2014; · 5.58 Impact Factor
  • Michael Eyre, Michael Absoud, Evangeline Wassmer
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    ABSTRACT: CNS inflammatory demyelinating diseases (CIDD) are rare. At first presentation children are diagnosed with acute disseminated encephalomyelitis (ADEM) or a clinically isolated syndrome (CIS) such as transverse myelitis (TM) or optic neuritis (ON). Many of these disorders are monophasic, however a small number of children relapse and are diagnosed with multiple sclerosis (MS) or neuromyelitis optica (NMO). Paediatric onset Multiple Sclerosis (POMS) is a chronic inflammatory neurodegenerative demyelinating disease of the CNS that is usually relapsing-remitting at onset. There has been significant recent interest and progress in these disorders. Encephalopathy (behavioural change or altered consciousness) distinguishes ADEM from other demyelinating conditions. A high index of suspicion for CIDD is required in children presenting with neurological deficits, encephalopathy or status epilepticus. Several UK and international studies are underway to further our understanding of these diseases. There has been significant development of new treatments for MS and NMO. A national service for these rare disorders will enable better management of these well deserving patients. In this review we describe current understanding of the epidemiology, pathogenesis, clinical features, outcome and management of childhood CIDD.
    Paediatrics and Child Health 10/2014; · 1.55 Impact Factor
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    ABSTRACT: Neuromyelitis Optica (NMO) is a severe and rare inflammatory condition, where relapses are predictive of disability.
    Journal of Neurology Neurosurgery & Psychiatry 08/2014; · 5.58 Impact Factor
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    ABSTRACT: Abstract Objective: To assess the utility and safety of rituximab in paediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicentre retrospective study. Results: 144 children and adolescents (median age 8 years, range 0.7-17; 103 females) with NMDAR encephalitis (n=39), opsoclonus myoclonus ataxia syndrome (n=32), neuromyelitis optica spectrum disorders (n=20), neuropsychiatric systemic lupus erythematosus (n=18), and other neuro-inflammatory disorders (n=35) were studied at onset of neurological disease. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%) including Grade 4 (anaphylaxis) in three. 11 patients (7.6%) had an infectious adverse event (AE), including two with Grade 5 (death) and two with Grade 4 (disabling) infectious AE (median follow-up of 1.65 years (range 0.1-8.5). No patients developed progressive multifocal leukoencephalopathy. A definite, probable or possible benefit was reported in 125 of 144 (87%) patients. 17.4% of patients had a modified Rankin scale (mRS) of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data supports an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of Evidence: This study provides Class IV evidence that in paediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.
    Neurology 07/2014; · 8.30 Impact Factor
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    ABSTRACT: To report the clinical and radiologic findings of children with NMDA receptor (NMDAR) antibodies and white matter disorders.
    06/2014; 1(1):e2.
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    ABSTRACT: Introduction: Mitochondrial neurological disorders are known for their variable clinical presentation and diagnostic complexity. Despite an extensive battery of tests, the diagnosis may still remain unclear. We report our experience in the use of biochemical and molecular genetic testing, in the diagnostic algorithm of mitochondrial neurological disease in children. Aim: To evaluate the clinical, radiological, biochemical and molecular genetic features of cohort of children at a single centre with suspected mitochondrial neurological diseaseMethodology: We retrospectively reviewed the data of children with suspected mitochondrial neurological disorder over a 6 years period from April 2007 to 2013. Information on clinical, neuroimaging, biochemical parameters and molecular genetic diagnosis was recorded. Results: In our cohort of 105 children with suspected mitochondrial neurological disease 54 (51%) had multi organ involvement. Elevatedplasma lactate (>2.5 mmol/L) was found in 47(44%) and elevated CSF lactate in 21/41(51%). Neuroimaging revealed abnormalities of the white matter in 34/103 (32%), white matter and basal ganglia in 13 (12%). Isolated Basal ganglia abnormalities were noted in 11(10%) and atrophy in 14 (13%). Biochemical and molecular genetic confirmation was obtained in 44/105 (42%). 71 children had muscle and skin biopsy. Abnormal histopathology was noted in 13/71 (18%), enzyme abnormalities (respiratory chain complexes and pyruvate dehydrogenase) in 29/71 (40%). Fifteen of these 29 did not have a genetic diagnosis. In the whole cohort 29 children had a genetic diagnosis (23 nuclear ,6 mitochondrial DNA mutation) with predominantly white matter abnormalities in this subgroup (17/29). Conclusion- Grey Matter abnormalities have been traditionally considered to be features of mitochondrial disorders. It is interesting to note predominantly white matter abnormalities in our cohort (44%).The low diagnostic yield of biochemical and histological testing in our cohort may justify the use of exome sequencing as an early step to unravel the diagnostic maze of mitochondrial disorders.
    Developmental medicine and child neurology. Supplement 01/2014; 56(s1):4.
  • Developmental medicine and child neurology. Supplement 01/2014; 56(s1):7.
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    ABSTRACT: A reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis.
    Pediatric Rheumatology 01/2014; 12:44. · 1.62 Impact Factor
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    ABSTRACT: Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture-recapture analysis was used to estimate completeness of ascertainment. We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30-1·96). Capture-recapture analysis suggested that case ascertainment was 89% (95% CI 77-97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36-6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18-2·12] for boys and 1·61 per 100 000 per year [1·18-2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11-3·85; p=0·017) and black (2·28, 1·00-4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. The Stroke Association, UK.
    The Lancet Neurology 11/2013; · 21.82 Impact Factor
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    ABSTRACT: Autoantibodies to glial, myelin and neuronal antigens have been reported in a range of central demyelination syndromes and autoimmune encephalopathies in children, but there has not been a systematic evaluation across the range of central nervous system (CNS) autoantibodies in childhood-acquired demyelinating syndromes (ADS). Children under the age of 16 years with first-episode ADS were identified from a national prospective surveillance study; serum from 65 patients had been sent for a variety of diagnostic tests. Antibodies to astrocyte, myelin and neuronal antigens were tested or retested in all samples. Fifteen patients (23%) were positive for at least one antibody (Ab): AQ4-Ab was detected in three; two presenting with neuromyelitis optica (NMO) and one with isolated optic neuritis (ON). Myelin oligodendrocyte glycoprotein (MOG)-Ab was detected in seven; two with acute disseminated encephalomyelitis (ADEM), two with ON, one with transverse myelitis (TM) and two with clinically isolated syndrome (CIS). N-Methyl-D-Aspartate receptor (NMDAR)-Ab was found in two; one presenting with ADEM and one with ON. Voltage-gated potassium channel (VGKC)-complex antibodies were positive in three; one presenting with ADEM, one with ON and one with CIS. GlyR-Ab was detected in one patient with TM. All patients were negative for the VGKC-complex-associated proteins LGI1, CASPR2 and contactin-2. A range of CNS-directed autoantibodies were found in association with childhood ADS. Although these antibodies are clinically relevant when associated with the specific neurological syndromes that have been described, further studies are required to evaluate their roles and clinical relevance in demyelinating diseases.
    Journal of neurology, neurosurgery, and psychiatry 10/2013; · 4.87 Impact Factor
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    ABSTRACT: Background: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope.
    Multiple Sclerosis 09/2013; 19(10):1261-1267. · 4.86 Impact Factor
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    ABSTRACT: Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities. We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6-20y) with genetically proven EAST syndrome. All children presented with tonic-clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm. The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.
    Developmental Medicine & Child Neurology 09/2013; 55(9):846-56. · 2.68 Impact Factor
  • European Journal of Paediatric Neurology 09/2013; 17:S15-S16. · 1.93 Impact Factor
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    ABSTRACT: OBJECTIVE: Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research. METHODS: The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions. RESULTS: The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge. CONCLUSION: Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.
    Neurology 03/2013; 80(12):1161-1168. · 8.30 Impact Factor
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    ABSTRACT: 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.
    Journal of neurology, neurosurgery, and psychiatry 11/2012; · 4.87 Impact Factor
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    ABSTRACT: Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.
    Nature Genetics 09/2012; · 29.65 Impact Factor
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    ABSTRACT: Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency.
    Journal of Medical Genetics 09/2012; 49(9):569-77. · 5.64 Impact Factor
  • Archives of Disease in Childhood 05/2012; 97(Suppl 1):A135-A135. · 2.91 Impact Factor

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