B. Fiedler

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes

Objective: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. Methods: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case–control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. Results: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). Conclusion: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes. GLOSSARY: BNFC = benign neonatal familial convulsions; bp = base pair; cRNA = complementary RNA; IAE = idiopathic absence epilepsy; IE = idiopathic epilepsy; IGE = idiopathic generalized epilepsy; JME = juvenile myoclonic epilepsy; OR = odds ratio; RE = rolandic epilepsy; SNP = single nucleotide polymorphism; WT = wild type.

Role of endogenous testosterone concentration in pediatric stroke

Previous studies have indicated a male predominance in pediatric stroke. To elucidate this gender disparity, total testosterone concentration was measured in children with arterial ischemic stroke (AIS; n = 72), children with cerebral sinovenous thrombosis (CSVT; n = 52), and 109 healthy controls. Testosterone levels above the 90th percentile for age and gender were documented in 10 children with AIS (13.9%) and 10 with CSVT (19.2%), totaling 16.7% of patients with cerebral thromboembolism overall, as compared with only 2 of 109 controls (1.8%; p = 0.002). In multivariate analysis with adjustment for total cholesterol level, hematocrit, and pubertal status, elevated testosterone was independently associated with increased disease risk (odds ratio [95% confidence interval]: overall = 3.98 [1.38–11.45]; AIS = 3.88 [1.13–13.35]; CSVT = 5.50 [1.65–18.32]). Further adjusted analyses revealed that, for each 1nmol/l increase in testosterone in boys, the odds of cerebral thromboembolism were increased 1.3‐fold. Ann Neurol 2009;66:754–758

Magnetic resonance 4D flow characteristics of cerebrospinal fluid at the craniocervical junction and the cervical spinal canal

ObjectivesTo evaluate the applicability of 4D phase contrast (4D PC) MR imaging in the assessment of cerebrospinal fluid dynamics in healthy volunteers and patients with lesions at the craniocervical junction or the cervical spinal canal.MethodsTen healthy volunteers and four patients with lesions including Chiari I malformation and cervical canal stenoses were examined by a cardiac-gated 4D PC imaging sequence on 1.5T MRI. Phase contrast images were postprocessed allowing for flow quantification and flow pathline visualisation. Velocity data were compared with conventional axial 2D phase contrast images.ResultsThe 4D PC sequence allowed for flow quantification and visualisation in all individuals. Bland-Altman analysis showed good agreement of 2D and 4D PC velocity data. In healthy volunteers, CSF flow was homogeneously distributed in the anterior and anterolateral subarachnoid space with the flow directed caudally during systole and cranially during diastole. Flow velocities were closely related to the width of the subarachnoid space. Patients showed grossly altered CSF flow patterns with formation of flow jets with increased flow velocities.Conclusions4D PC MR imaging allows for a detailed assessment of CSF flow dynamics helping to distinguish physiological from complex pathological flow patterns at the craniocervical junction and the cervical spine.

Effectiveness and Tolerability of Perampanel in Children and Adolescents with Refractory Epilepsies: First Experiences

OBJECTIVE This article aims to report the first clinical experiences concerning effectiveness and tolerability of perampanel (PER) in a pediatric population with refractory epilepsies. PATIENTS AND METHODS This nonsponsored, observational, retrospective survey was conducted through collaboration with multiple centers in Europe. The clinical course of the first pediatric patients treated in these centers with PER was documented with the help of a questionnaire completed by the treating physicians. Effectiveness and adverse effects were evaluated. The study population consisted of 58 patients (mean age, 10.5 years; range, 2-17 years), suffering from various refractory epilepsies, classified as focal epilepsy (n = 36), unclassified generalized epilepsy (n = 12), Lennox-Gastaut syndrome (n = 5), West syndrome (n = 3), and Dravet syndrome (n = 2). RESULTS The response rate (≥ 50% seizure reduction) after the first 3 months of therapy was 31% (18/58 patients) in total. Complete seizure control was achieved in five patients (9% overall). Aggravation of seizures occurred in five cases (9%). The most frequently occurring adverse effects were reduced vigilance or fatigue (n = 16) and behavioral changes (n = 14). DISCUSSION PER seems to be effective also in children and adolescents with pharmaco-refractory epilepsies. Tolerability was acceptable.

P50 sensory gating deficit in children with centrotemporal spikes and sharp waves in the EEG

Sensory gating refers to the ability of the brain to inhibit irrelevant sensory input. In several studies, a pathogenic role of the CHRNA7 gene and the CHRNA7-like gene, respectively, is suggested. In linkage analysis concerning familial centrotemporal spikes and sharp waves (CTS) and benign rolandic epilepsy, evidence for linkage was found to a region on chromosome 15q14, close to the alpha-7 subunit gene of the neuronal nicotinic acetylcholine receptor (CHRNA7). According to these findings, P50 evoked potentials to paired click stimuli were studied in 13 children with CTS in the EEG to determine whether they had normal sensory gating. The control group consisted of 13 healthy probands matched for gender and age. Children with CTS showed a significant sensory gating deficit (p=0.001). These results (1) suggest an inhibitory deficit in early pre-attentive auditory sensory processing in children with CTS and (2) confirm the assumption of a cholinergic pathology in CTS.

Add-on treatment with pyridoxine and sulthiame in 12 infants with West syndrome: an open clinical study

To investigate the effect of sulthiame (STM) in West syndrome (WS) an open, uncontrolled add-on study was undertaken during initial pyridoxine (PDX) therapy in 12 infants, two with idiopathic and ten with symptomatic WS. All patients were initially treated with PDX (150-300 mg x kg (-1)body weight day(-1) ). In seven patients (58%) seizures and hypsarrhythmia stopped during the week after introduction of STM (10 mg x kg (-1)body weight day (-1)). In one the positive effect was temporary. Five of the responders (42%) remained seizure-free and without hypsarrhythmia under STM monotherapy, while one developed complex partial seizures after 25 months. STM was most effective in idiopathic WS (2 /2). During treatment with STM medication no patient suffered side effects attributable to the substance. Further controlled studies are necessary to evaluate the benefit of this potentially effective treatment.

A bumpy road to the diagnosis of a Kytococcus schroeteri shunt infection.

We report a ventriculoperitoneal shunt infection associated with Kytococcus schroeteri, a Gram-positive bacterium from the family Dermacoccaceae. While the biochemical identification systems do not reliably identify this potential pathogen, sequence-based identification is recommended to guide the antibiotic treatment of this intrinsically meticillin-resistant species, which is susceptible to vancomycin, gentamicin and/or rifampicin.

A new mutation in enhanced S‐cone syndrome

mental studies in primates, in which the selective loss of small ganglion cells projecting to the parvocellular layers of the lateral geniculate nucleus was observed after occipital lobe ablation (Weller et al. 1979; Cowey et al. 1989; Weller & Kaas 1989; Johnson & Cowey 2000). The similarity between animal experiments and human studies suggests that the retinal thinning of the OCT is—at least in part—due to trans-synaptic retrograde degeneration.

Predictive Value of CSF Flow Cytometry in Pediatric Multiple Sclerosis

Background: Optic neuritis (ON) is identified as one of the most frequent potential risk factor associated with future multiple sclerosis (MS). In children, conversion to MS after isolated ON is lower than in adults. Here, we aim to identify cerebrospinal fluid (CSF) and peripheral blood (PB) cell composition and cell activation status as potential biomarkers to distinguish children with isolated ON from children at high risk for MS. Methods: Thirty patients were identified with ON (9), clinically isolated syndrome (CIS, 5), or pediatric MS (16) and first compared with age-matched healthy controls (12) and second to adult patients with MS (33), CIS (10), or isolated ON (17). All patients received intravenous cortisone pulse therapy at least 5 days (1,000 mg/d). CSF was taken prior to cortisone therapy. All MS patients were treatment naive. Results: CSF analysis revealed positive oligoclonal bands (OCB) in 15 of 16 MS children; none of the CIS patients show OCBs, whereas 4 of 9 children with ON expose OCBs. FACS analysis demonstrated elevated plasma cells in CSF both in children and adult MS patients and revealed high proportion of CD4+-T-cells in pediatric MS patients compared with childhood isolated ON. In contrast, proportion of CD8+-T-cells in PB in ON patients was elevated compared with the MS cohort. CSF results of children with CIS conduct completely different from that of adults. Conclusion: FACS analysis and T cell activation could be assumed as predictive parameter, distinguishing isolated ON from CIS or pediatric MS. CIS is supposed to show a different clinical disease course in children compared with adults.

4D MR imaging of cerebrospinal fluid flow in Chiari I malformation with and without syringomyelia and flow changes after decompressive surgery

Background The aim of our study was to evaluate the feasibility of 4D phase contrast (PC) flow imaging for visualisation and analysis of cerebrospinal fluid (CSF) flow in Chiari I malformation. CSF flow was compared between healthy volunteers and patients with Chiari I malformation with and without syringomyelia. Moreover, the effect of a craniocervical decompression on CSF flow was studied in Chiari I patients with syringomyelia.