Carlos de Sousa

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.

Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.

Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene

Background Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Fibroblasts from these patients displayed a defect in the import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants. Objective To report on six patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the PEX16 gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leucodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes. Results Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical variables in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known PEX genes revealed five novel apparent homozygous mutations in the PEX16 gene. Conclusions An unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts, was identified. Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with enlarged import-competent peroxisomes in fibroblasts. This is important for future diagnostics of patients with a peroxisomal disorder.

Outcome and Prognostic Features in Opsoclonus-Myoclonus Syndrome From Infancy to Adult Life

OBJECTIVE: Opsoclonus-myoclonus syndrome (OMS) is a serious and often chronically disabling neurologic illness with onset in early childhood. Our aim was to identify long-term neurologic sequelae of OMS and predictors for disease outcome. METHODS: We retrospectively assessed the case records of 101 patients diagnosed with OMS over a 53-year period. Clinical data were obtained from medical record review; we documented age at onset, severity of symptoms, response to treatment, and neurocognitive sequelae. RESULTS: Overall, 21% of the patients had a neuroblastoma detected; however, in those born after 1990, this figure rose to 40%. Sixty-one percent of the patients had a chronic-relapsing course, 32% experienced several acute exacerbations, and 7% had a monophasic course. At the most recent review, 60% had residual motor problems, 66% speech abnormalities, 51% learning disability, and 46% behavior problems. One-third of the patients had normal intellectual outcome and cessation of symptoms. A severe initial presentation predicted a chronic disease course (odds ratio [OR]: 2.77 [95% confidence interval (CI): 1.47–5.23]; P = .002) and later learning disability (OR: 2.03 [95% CI: 1.08–3.79]; P = .026). Those with cognitive impairment were younger at disease onset (15.0 vs 19.5 months; P = .029). A chronic-relapsing disease course was associated with motor (P < .001), speech (P = .001), cognitive (P < .001), and behavior (P = .006) problems. CONCLUSIONS: OMS is a chronic and debilitating illness; those with severe initial symptoms and those who are very young at disease onset are at increased risk of developing long-term sequelae. It is important for affected children to be identified early, because they might benefit from targeted immunomodulating therapy in specialist centers.

A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom

The incidence, mode of presentation and management of Dancing Eye Syndrome/Opsoclonus-Myoclonus Syndrome (DES/OMS) was prospectively evaluated in 20 United Kingdom (UK) paediatric neurology centres by questionnaire over a 24-month period between 2003 and 2005. Nineteen children were notified, giving an incidence of 0.18 cases per million total population per year. Mean age at presentation was 18 months (range 3-42 months). Fifteen families consented to participate in the study. Atypical features were present in 6/15 cases including very delayed presentation of opsoclonus, dysphagia, and rapid spontaneous improvement without treatment. Only 4/15 cases were associated with neuroblastoma (NB) but current practice in excluding this is diverse and a standardised approach is suggested.

Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2

Pontocerebellar hypoplasia type 6 (PCH6) (MIM #611523) is a recently described disorder caused by mutations in RARS2 (MIM *611524), the gene encoding mitochondrial arginyl-transfer RNA (tRNA) synthetase, a protein essential for translation of all mitochondrially synthesised proteins. This case confirms that progressive cerebellar and cerebral atrophy with microcephaly and complex epilepsy are characteristic features of PCH6. Additional features of PCH subtypes 2 and 4, including severe dystonia, optic atrophy and thinning of the corpus callosum, are demonstrated. Congenital lactic acidosis can be present, but respiratory chain dysfunction may be mild or absent, suggesting that disordered mitochondrial messenger RNA (mRNA) translation may not be the only mechanism of impairment or that a secondary mechanism exists to allow some translation. We report two novel mutations and expand the phenotypic spectrum of this likely underdiagnosed PCH variant, where recognition of the characteristic neuroradiological phenotype could potentially expedite genetic diagnosis and limit invasive investigations.

Investigating neuroblastoma in childhood opsoclonus-myoclonus syndrome

Objective Opsoclonus-myoclonus syndrome (OMS) is a serious, often disabling neurological illness of early childhood which is frequently associated with occult neuroblastoma. As investigation methods vary significantly, the authors assessed the usefulness of imaging and metabolic studies in tumour detection. Methods Retrospective case note review of 101 OMS patients from two paediatric neurology centres over 53 years. Results The prevalence of neuroblastoma in OMS was 8% in the 1970s, 16% in the 1980s, 38% in the 1990s and 43% in the 2000s, with tumours being mainly low grade. CT/MR imaging of the chest and abdomen was the most accurate test to detect occult neuroblastoma. Poorer sensitivities were noted for metaiodobenzylguanidine scintigraphy and urine catecholamines, reflecting the low metabolic activity of these tumours. Conclusion CT/MR imaging has the highest detection rate of neuroblastoma and this should be reflected in investigation protocols to achieve the best possible outcome for children with OMS.

Paradoxic Reaction to Lamotrigine in a Child with Benign Focal Epilepsy of Childhood with Centrotemporal Spikes

Summary: A girl aged 5 years developed nocturnal seizures (mouth twitching, salivation, anarthria, with right arm jerking and occasional secondary generalisation), with frequent focal sharp waves over the left centrotemporal region in her EEG, suggesting benign childhood epilepsy with centrotemporal spikes (BECTS). Seizures became diurnal and frequent, not modified by carbamazepine (CBZ) or valproate (VPA) but responding to VPA and lamotrigine (LTG) with recommended dosage schedules for this combination.

Childhood chorea-encephalopathy associated with human parvovirus B19 infection.

An 8-year-old female presented with a distinct clinical course characterized by an acute self-limiting chorea-encephalopathy with cerebrospinal fluid (CSF)-specific oligoclonal bands. During the clinical course, genomic human parvovirus B19 DNA was detected in her serum and CSF. It was concluded that this patient represents the first published case of childhood chorea-encephalopathy associated with, and probably caused by, human parvovirus B19 infection.

Clinical and neurophysiological characteristics of congenital myasthenic syndromes presenting in early infancy

The congenital myasthenic syndromes (CMS) constitute a group of genetic disorders, which affect neuromuscular transmission, presenting usually within the first years of life and with a clinical spectrum ranging from mild muscle weakness to severe disability with life-threatening episodes. We present clinical and neurophysiological data of 11 patients (four males, seven females) with CMS diagnosed during the last 5 years. Eight of the 11 patients presented immediately after birth and the remainder by 10 months of age; eight patients had contractures at birth and seven of them required assisted ventilation either immediately in the neonatal period, or at some point afterwards due to respiratory distress or recurrent apnoeas. Neurological signs at presentation were: in nine patients profound hypotonia, in five absent tendon reflexes, in seven ptosis and in eight bulbar signs. In six patients an edrophonium test was performed: only three of them had a positive response; however, eight out of 11 patients responded at least partially at some point in their illness to pyridostigmine. Diagnosis of CMS was confirmed either by demonstration of a decrement after repetitive nerve stimulation or by increased instability and jitter after stimulated single fibre EMG. In five patients, there was a positive family history with death of at least one previous sibling with an undiagnosed neuromuscular disorder. As regards final outcome, five patients died at ages ranging from 1 to 17 months, two patients are still ventilator-dependent at 3 and 5 months of life, respectively, and four patients still survive with either a mild or a moderate motor delay (follow-up range 8-38 months). None of the clinical or neurophysiological characteristics were correlated with outcome (Fishers exact test). We conclude that a significant number of CMS patients may present in the neonatal period with a variable clinical expression and usually with a poor prognosis. The recognition of specific clinical constellations combined with a search for aetiology at a molecular level will enable the further characterisation of subgroups of CMS.