Epileptic phenotypes, electroclinical features and clinical characteristics in 17 children with anti-NMDAR encephalitis.

BACKGROUND: Anti-N-methyl d-aspartate receptor (NMDAR) encephalitis is a rare disorder characterized by seizures, neuropsychiatric symptoms, dyskinesia and autonomic instability. OBJECTIVE: Aim of the present study was to evaluate the seizure phenotypes and electroencephalogram (EEG) features in children with anti-NMDAR encephalitis. METHODS: Seizure types, electroclinical features and clinical characteristics of 17 children with anti-NMDAR encephalitis were analysed in a retrospective case series from nine centres in Europe. RESULTS: Nearly half (8/17) of the children presented with psychiatric symptoms, whereas in 4/17 patients seizures were the first symptom and in 5/17 both symptoms occurred at the same time. During the following course seizures were reported in 16/17 children. The first EEG detected generalized slowing in 11/17 patients, focal slowing in 3/17 and normal background activity in only 3/17 children. The extreme delta brush (EDB) pattern was detected in 9/17 (53%) patients. CONCLUSION: In addition to psychiatric symptoms, children with anti-NMDAR encephalitis often show generalized slowing in EEG with or without seizures at initial presentation. EDB is present in half of all children and is potentially a helpful tool for early detection of this immune-mediated disease.

Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibodies have been recently described in children with acute disseminating encephalomyelitis (ADEM), but the clinical and neuroradiological characterisation of this subgroup is lacking. OBJECTIVE: To compare the clinical and neuroradiological features of paediatric ADEM with and without MOG antibodies. METHODS: Clinical course, cerebrospinal fluid (CSF)-, MRI studies, outcome and MOG status of 33 paediatric ADEM prospectively studied were reviewed. RESULTS: MOG antibodies (median 1:2560; range 1:160-1:20 480) were detected in 19 children with ADEM. The majority of children showed a decline of serum MOG-IgG titres over time. Children with MOG antibodies did not differ in their age at presentation, sex ratio, the presence of oligoclonal bands, clinical symptoms or initial severity, apart from a higher CSF cell count (p=0.038), compared with children without MOG antibodies. In addition, further relapsing demyelinating episodes associated with MOG antibodies were observed only in children with MOG antibodies. All 19 children with MOG antibodies had a uniform MRI pattern, characterised by large, hazy and bilateral lesions and the absence of atypical MRI features (eg, mainly small lesions, well-defined lesions), which was significantly different compared to that of children without MOG antibodies (p=0.003; and p=0.032, respectively). In addition, children with MOG antibodies had involvement of more anatomical areas (p=0.035) including the myelon characterised by a longitudinally extensive transverse myelitis (p=0.003), more often a complete resolution of lesions (p=0.036) and a better outcome (p=0.038). CONCLUSIONS: Patients with ADEM with MOG antibodies in our cohort had a uniform MRI characterised by large, bilateral and widespread lesions with an increased frequency of longitudinal extensive transverse myelitis and a favourable clinical outcome in contrast to children lacking MOG antibodies.

The burden of pneumococcal meningitis in Austrian children between 2001 and 2008.

UNLABELLED: The present study was conducted to evaluate the burden of pneumococcal meningitis in Austrian children between 2001 and 2008. Clinical outcome was retrospectively analyzed both on discharge and on follow-up investigations. This study was based on a prospective multicentre surveillance study on hospitalized invasive pneumococcal infections in Austrian children with a total annual "study population" of about 399,000 children aged below 5 years per year. Between 2001 and 2008, 74 cases of pneumococcal meningitis were identified in children aged below 5 years. The mean annual incidence rate for pneumococcal meningitis was 2.3 per 100,000 children in this age group. In 57/74 children (mean age on admission 14.5 ± 13.3 months), outcome data on hospital discharge were available: 5 deaths (8.8%), 20 children (35.1%) with sequelae and 32 children (56.1%) without sequelae were observed. Sequelae on discharge included motor impairment in 8 children (14.0%), hearing impairment in 9 children (15.8%) and/or other complications in 14 children (24.6%). In 7/8 children with motor deficits, matching cerebral lesions were identified by neuroimaging: cerebral infarction in five children, cerebral vasculitis and cerebral abscess in one child each. In 40/57 children, long-term outcome (18.9 ± 20.2 months after discharge) could be assessed: 1 child (2.5%) died 9 months after hospital discharge, 11 children (27.5%) had one or two long-term sequelae and 28 children (70.0%) had no sequelae. Long-term sequelae included motor impairment in three children (7.5%), hearing impairment in nine children (22.5%) and other deficits in two children (5.0%). CONCLUSION: Our study confirms that pneumococcal meningitis causes high mortality and severe long-term sequelae. On long-term follow-up, we observed improvements of motor impairment, but not of hearing impairment.

Novel mutations of the PRKAR1A gene in patients with acrodysostosis.

Acrodysostosis is characterized by a peripheral dysostosis that is accompanied by short stature, midface hypoplasia, and developmental delay. Recently, it was shown that heterozygous point mutations in the PRKAR1A gene cause acrodysostosis with hormone resistance. By mutational analysis of the PRKAR1A gene we detected four different mutations (p.Arg368Stop, p.Ala213Thr, p.Tyr373Cys, and p.Arg335Cys) in four of seven affected patients with acrodysostosis. The combination of clinical results, endocrinological parameters and in silico mutation analysis gives evidence to suppose a pathogenic effect of each mutation. This assumption is supported by the de novo origin of these mutations. Apart from typical radiological abnormalities of the hand bones, elevated thyroid stimulating hormone and parathyroid hormone values as well as short stature are the most common findings. Less frequent features are characteristic facial dysmorphisms, sensorineural hearing loss and mild intellectual disability. These results lead to the conclusion that mutations of PKRAR1A are the major molecular cause for acrodysostosis with endocrinological abnormalities. In addition, in our cohort of 44 patients affected with brachydactyly type E (BDE) we detected only one sequence variant of PRKAR1A (p.Asp227Asn) with an unclear effect on protein function. Thus, we conclude that PRKAR1A mutations may play no major role in the pathogenesis of BDE.

Differences and similarities in the evolution of morphologic brain abnormalities between paediatric and adult-onset multiple sclerosis.

BACKGROUND: Paediatric-onset multiple sclerosis (pMS) is multiple sclerosis (MS) occurring before the age of 18 years and may present and develop differently from adult-onset MS (aMS). Whether there are also differences regarding the accrual of brain changes is largely unknown. METHODS: We compared the evolution of the T2- and T1-lesion load (LL), the black hole ratio (BHR), and annualised brain volume change (aBVC) between 21 pMS patients (age at onset: 14.4±2.3 years) and 21 aMS patients (age at onset: 29.4±6.5 years) matched for disease duration (pMS: 1.0±1.8 years; aMS: 1.6±1.7 years, p=0.27). Follow-up was for 4.2±3.7 years in pMS and 3.1±0.6 years in aMS. Clinical comparisons included the course of disability assessed with the Expanded Disability Status Scale (EDSS) score and annualised relapse rate (ARR). RESULTS: At baseline, pMS and aMS had similar EDSS, T1-LL, BHR, whereas T2-LL was higher in aMS (aMS: 9.2±11.6 ccm; pMS: 4.1±6.2 ccm, p=0.02). The change of T2-LL and T1-LL during the observation period was similar in both groups. At follow-up, disability was lower in pMS (EDSS score in pMS: 0.9±0.9; aMS: 1.7±1.3, p=0.04), despite a significantly higher accrual of destructive brain lesions (BHR in pMS: 23.7±23.7%; aMS: 5.9±4.0%, p=0.02) and a similar rate of brain volume loss. CONCLUSION: Our observation of a morphologically more aggressive disease evolution paralleled by less disability in pMS than in aMS (defined using EDSS) suggests a higher compensatory capacity in pMS. This fact may obscure the need for treatment of pMS patients with disease modifying treatments (DMTs) based solely on clinical observation.

Predictive diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing.

BACKGROUND: Li-Fraumeni syndrome greatly increases the risk of developing several types of cancer and is usually caused by TP53 germline mutations. Predictive testing of at-risk family members is only offered after a complex genetic counselling process. Recently the clinical implementation of array comparative genomic hybridisation (CGH) has revolutionised the diagnosis of patients with syndromic or non-syndromic mental retardation and has evolved to a routinely performed high resolution whole genome scan. METHODS AND RESULTS: When using array CGH to identify the cause for mental retardation in a 7-year-old child we found a submicroscopic de novo deletion of chromosome 17p13.1, which includes several genes likely to be causative for her phenotype, and also of TP53. CONCLUSION: Thus, array CGH resulted in an unintended predictive diagnosis of an increased tumour susceptibility as observed in Li-Fraumeni syndrome.

A splice site variant in the sodium channel gene SCN1A confers risk of febrile seizures.

OBJECTIVE: Our aim was to investigate whether the risk of febrile seizures is influenced by a common functional polymorphism in the sodium channel gene SCN1A. This single nucleotide polymorphism (IVS5N+5 G>A, rs3812718) was shown to modify the proportion of two alternative transcripts of the channel. METHODS: We performed an exploratory case-control association analysis in 90 adult epilepsy patients with childhood febrile seizures vs 486 epilepsy patients without a history of febrile seizures and also vs 701 population controls. In the replication step, we investigated children with febrile seizures without concomitant epilepsy at the time of their inclusion. We compared the genotypes of 55 of those children against population controls and performed a within-family association analysis in an additional 88 child-parent trios with febrile seizures. RESULTS: We observed a significant association of the splice-site interrupting A-allele with febrile seizures (p value in the exploratory step: 0.000017; joint p value of the replication: 0.00069). Our data suggest that the A-allele of this variant confers a threefold genotype relative risk in homozygotes and accounts for a population attributable fraction of up to 50% for the etiology of febrile seizures. CONCLUSIONS: The A-allele of the SCN1A single nucleotide polymorphism IVS5N+5 G>A (rs3812718) represents a common and relevant risk factor for febrile seizures. A limitation of the present study is that patients of the exploratory and replication steps differed in aspects of their phenotype (febrile seizures with and without additional epilepsy).