Sunny Philip

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.

N-methyl-D-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children

Objective N-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK. Design A prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians. Results Thirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fishers exact test). Seven patients relapsed, with four needing additional second-line immunotherapy. Conclusions Paediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.

The clinical utility of an SCN1A genetic diagnosis in infantile‐onset epilepsy

Aimu2002 Genetic testing in the epilepsies is becoming an increasingly accessible clinical tool. Mutations in the sodium channel alpha 1 subunit (SCN1A) gene are most notably associated with Dravet syndrome. This is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives.

Retention rate of Levetiracetam in children with intractable epilepsy at 1 year

UNLABELLEDnLevetiracetam (LEV) is a novel antiepileptic drug (AED) that has recently obtained marketing authorisation for use in children. The purpose of this study was to assess the efficacy, tolerability and retention rate of LEV in children with refractory epilepsies. It is a retrospective multicentre observational study reporting the use of LEV in 200 children, aged 0.3-19 years (median 9-years-old) over a 4-year period. All of the patients included in the study had refractory epilepsy with a median age of onset of epilepsy of 3 years (range 0-13 years). The 38% had failed and withdrawn 3 or more AEDs previously and 24% were taking at least 2 other AEDs in addition to LEV. The 47% had focal, and 58% had symptomatic epilepsies. The LEV dose ranged from 8 to 100 mg/kg/day (mean 39 mg/kg). The study comprised 215 person years of LEV exposure.nnnRESULTSnLEV was well tolerated with a retention rate of 49% at 1 year. No serious adverse events were reported with possibly related adverse events reported in only 24% of patients (mainly emotional or behavioural changes). At more than 2, 6 and 12 months, worthwhile improvement (>50% seizure reduction) was noted in 60, 40 and 32%, including seizure freedom in 14, 14 and 5%, respectively.nnnCONCLUSIONnOur results confirm the efficacy and tolerability of LEV in children with refractory epilepsies and demonstrate good response and retention rates at 12 months. It represents the largest cohort of paediatric patients published so far on LEV with a 1-year follow-up.

The ketogenic diet in childhood epilepsy: where are we now?

The ketogenic diet is a therapeutic dietary treatment for epilepsy in children which is resistant to medication. Until recently, evidence for use and resources available has been sparse. This review aims to provide a summary of the evidence supporting its use in children, some guidance towards its implementation and the services currently available in the UK.

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C>G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121–123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C>G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.

Magnetic Resonance Spectroscopy in the Diagnostic Evaluation of Brainstem Lesions in Alexander Disease

Alexander disease is a progressive neurodegenerative disease, which can present with brainstem lesions with imaging characteristics similar to multifocal low-grade glioma, thus presenting a diagnostic dilemma. The authors report a 6-year-old child presenting with multifocal brainstem lesions subsequently diagnosed to have Alexander disease. In vivo magnetic resonance spectroscopy generated a metabolite profile of the lesion allowing differentiation from low-grade glioma. Magnetic resonance spectroscopy is a powerful tool in the assessment of brainstem lesions and is a useful adjunct to conventional magnetic resonance imaging in the assessment and diagnosis of atypical brain lesions.

Misleading data in Shastin et al.’s paper

Dear Editor: We write to comment on a paper by Shastin and colleagues recently published online by your journal. It is entitled BMonitoring the changing pattern of delivery of paediatric epilepsy surgery in England—an audit of a regional service and examination of national trends^ [1]. The topic is currently of considerable interest, but unfortunately, we note a number of inaccuracies in the data relating to epilepsy surgery in children since the Children’s Epilepsy Surgery Service (CESS) for England was commissioned in November 2012. Shastin et al.’s paper reports on a national audit compiled by the British Paediatric Neurosurgical Group (BPNG), which records numbers and types of procedures performed on children up to the age of 16 years in centres in England, Scotland, Wales and Southern Ireland. The BPNG data suggest that there has been a drop in paediatric epilepsy surgery numbers in the four CESS centres: in 2012, the total number of operations in these centres reported by the BPNGwas 115, and in 2013, it was 104. The CESS is responsible for children in England and is gathering data prospectively through a national database with the aim of matching similar databases, such as that established in Sweden [2]. Since November 2012, the four centres making up the CESS have gathered and presented data both to NHS England and, latterly, to the British Paediatric Neurology Association (BPNA) in January of 2015. The abstract of the BPNA presentation has been published [3] and describes referrals to the CESS service and procedures performed for the first full financial year April 2013 toMarch 2014. During that time, there was a total of 445 referrals, resulting in 278 full evaluations and 138 surgical procedures (50 lobectomies, 24 lesionectomies, 28 hemidisconnections, 21 invasive EEGs, 9 disconnections and 6 corpus callosotomies). This compares with 112 paediatric surgery operations documented in a UK study in 2010–2011 [4], the last full year prior to initiation of the CESS process. In addition, the CESS data for the first 6 months of 2013 were presented, and when compared to the first 6 months of 2014, they demonstrate clear evidence of growth with 202 vs 271 referrals and 62 vs 93 surgeries (excluding operations related to vagal nerve stimulation). Shastin et al. [1] concluded from the BPNG data quoted in their paper that a trend of increasing numbers in the years prior to the CESS had been reversed since its inception. In contrast, the data prospectively collected by the CESS centres show that for the CESS, this conclusion is incorrect. The progressive increase in the years prior to the initiation of the CESS process can be mainly accounted for by the increase in surgeries at Great Ormond Street Hospital. The CESS process is designed to bring the expertise and experience of all four CESS centres up to the best international standards, increasing the numbers of surgeries to levels estimated using the results of a prospective epidemiological study [5]. Shastin et al. [1] state, Boutcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making^. However, they report their single-centre experience of 43 cases over an 8-year period, an average of just 5 cases per year. They have based their analyses on small numbers obtained via a retrospective note-based review. It is misleading for them to suggest that the comparison of their outcome data * Christopher Verity christopher.verity@addenbrookes.nhs.uk; cm.verity@btinternet.com

046 EAST syndrome: probable closure in many an adult case

Introduction It is frustrating for patients, families and clinicians when a unifying diagnosis for the constellations of neurological signs and symptoms remains elusive. Two recent reports, working independently, have hypothesised that KCNJ10 mutations on Chrosome 1q23.2 are responsible for Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy (EAST syndrome/ SeSAME syndrome). We present a series of six patients with ages ranging from 3-22u2005years from three families. Case series We describe three Asian siblings, two Caribbean siblings, and one Caucasian child who have epilepsy, ataxia, sensorineural hearing loss, and tubulopathy. Consanguinity was present only in the Asian family. Seizures were a presenting symptom in four with onset as early as 3–7u2005months of age. Development delay and learning difficulties were present in all of the cases. Ataxia was evident from early on. Sensorineural hearing loss was identified at different ages and in some cases was asymptomatic. In some cases, tubulopathy was an incidental finding. In the five children who have been extensively investigated, metabolic and mitochondrial investigations, magnetic resonance images, and electroencephalograms were normal. All six children had biochemical evidence of a tubulopathy with hypokalaemia, hypomagnesaemia, and alkalosis. KCNJ10 DNA mutations have since been identified in all of them. Conclusion This condition does not seem to be life limiting as is evident from the early reports and our own experience. Three patients from our series have moved on to the adult services. We hypothesise that there are adult patients with similar findings who are still waiting for a closure.