Joost Nicolai

Cognitive and behavioral effects of nocturnal epileptiform discharges in children with benign childhood epilepsy with centrotemporal spikes

This review addresses the effects of subclinical localized epileptiform discharges during sleep in children with benign childhood epilepsy with centrotemporal spikes (BCECTS) on cognition and behavior. A diversity of educational deficits, behavioral impairments, language delay, and neuropsychological test results have been reported in children with BCECTS. The occurrence of atypical seizure characteristics seems to be related to language delay, and several atypical EEG characteristics are related to cognitive or behavioral problems. It remains to be shown whether treatment of nocturnal discharges in children with BCECTS is indicated to improve cognitive and behavioral problems.

EEG characteristics related to educational impairments in children with benign childhood epilepsy with centrotemporal spikes.

Purpose: Learning and behavioral difficulties often occur in benign childhood epilepsy with centrotemporal spikes (BCECTS). In recent years, several electroencephalogram (EEG) characteristics have been related to the occurrence of learning and behavioral problems.

De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy

Background Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. Methods The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype–phenotype correlations of these and other cases were related to the functional analyses. Results The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. Conclusions Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.

Late onset autism and anti-NMDA-receptor encephalitis

In December, 2009, a 9-year-old boy was admitted to our hospital with an acute onset of secondary generalised seizures. He had no medical or psychiatric history and functioned very well socially and academically. He presented with speech and swallowing diffi culties, which after 10 days developed into a severely agitated catatonic state with opisthotonic posturing, tonic posturing of limbs, insomnia, and dyskinesia. Initially the electroencephalogram showed a normal background pattern with epileptic discharges, and oligoclonal bands were present in cerebrospinal fl uid (CSF). Brain MRI and extensive blood tests were normal. The neurological diagnosis was atypical childhood epilepsy with centrotemporal spikes, for which oral corticosteroids and antiepileptic drugs were prescribed. His catatonia was treated with benzodiazepines. In January, 2010, our patient presented in a robotic state with complete mutism and negativism, and he did not respond to any form of contact. We provisionally diagnosed acute late onset autism with a diff erential diagnosis of childhood dis integrative disorder or early onset schizophrenia. Childhood disintegrative disorder, early onset schizophrenia, and late onset autism often share a fi nal common pathway: previous normal development, followed by sudden neuropsychiatric regression of social interaction and communication skills, and a decline in intelligence and daily activities. The disorders are sometimes misrecognised and collectively called as autistic disorder. Although judged to be functional psychiatric diagnoses, the marked deterioration and poor prognosis suggest an organic cause, especially in children with catatonia, a normal development up to at least 5 years of age, or both. In our patient, late onset autism was considered because: it is associated with neurological disorders; it is a known end stage of acquired brain injury; progression of symptoms was fast and severe, unlike in early onset schizophrenia; the absence of positive symptoms made schizophrenia less plausible; the age of onset and rare prevalence made chronic disintegrative disorder unlikely; and accompanying catatonic features were present. After extensive diagnostic assessments, our patient was fi nally diagnosed with anti-NMDA-receptor encephalitis on the basis of slightly raised anti-NMDA-receptor antibody titres in serum and highly raised titres in CSF. Clinical characteristics of this condition are acute major neuropsychiatric symptoms including anxiety, aggres sion, agitation, behavioural changes and catatonia, delusional thoughts, progressive speech deterioration, and hallucinations. Neurological symptoms such as dyskinesia, abnormal seizure-like movements, and diff use and profound autonomic instability have also been reported. Anti-NMDA-receptor encephalitis can occur in the context of malignant disease; however for our patient extensive oncological investigations were negative. Electroconvulsive therapy was given for the severe catatonic state, and monoclonal antibody treatment (rituximab) was started because of the unsatisfactory response to the initial treatment with benzodiazepines. The acquired autism gradually subsided, he spoke fl uently and was able to draw a happy picture (fi gure). In June, 2011, he only had some mild cognitive dysfunction. Childhood disintegrative disorder, early onset schizophrenia, late onset autism and all stages of anti-NMDAreceptor encephalitis share core symptoms, as in our patient. We suggest that anti-NMDA-receptor encephalitis might be a possible organic cause underlying these three disorders. Patients previously diagnosed with these diagnoses might need to be re-examined for anti-NMDAreceptor encephalitis. We suggest that forthcoming editions of DSM-5 and ICD-11 exclude and defi ne cases of regressive autism spectrum disorders due to anti-NMDAreceptor encephalitis.

The cognitive effects of interictal epileptiform EEG discharges and short nonconvulsive epileptic seizures

Purpose:  Educational difficulties or even severe cognitive deterioration is seen in many childhood epilepsy syndromes. Many of those cognitive deficits are related directly to the brain disorder underlying the epilepsy syndrome. However, in other types of epilepsy, the epileptic seizures and/or epileptiform activity can be the dominant factor. This is especially unknown for the more “subtle” short nonconvulsive seizure types. For this reason, we analyzed a new cohort of children.

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy

KIF1A is a neuron‐specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type‐2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

The pathophysiological mechanisms of cognitive and behavioral disturbances in children with Landau–Kleffner syndrome or epilepsy with continuous spike-and-waves during slow-wave sleep

Epilepsy with continuous spike- and -waves during slow-wave sleep and Landau-Kleffner syndrome are two rare childhood epilepsy syndromes. The underlying pathophysiology remains unknown. The current opinions about epidemiologic risk factors, genetic predisposition, EEG and MEG findings, influence of anti-epileptic drugs, neuroradiology, positron emission tomopgraphy, evoked potentials, auto-immunity and subpial transection are summarized.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Pediatric illness severity measures predict delirium in a pediatric intensive care unit.

Context:Delirium in children is a serious but understudied neuropsychiatric disorder. So there is little to guide the clinician in terms of identifying those at risk. Objective:To study, in a pediatric intensive care unit (PICU), the predictive power of widely used generic pediatric mortality scoring systems in relation to the occurrence of pediatric delirium (PD). Design and Methods:Four-year prospective observational study, 2002–2005. Predictors used were the Pediatric Index of Mortality (PIM) and Pediatric Risk of Mortality (PRISM II). Setting:A tertiary 8-bed PICU in the Netherlands. Patients:877 critically ill children who were acutely, nonelectively, and consecutively admitted. Main Outcome Measure:Pediatric delirium. Main Results:Out of 877 children with mean age 4.4 yrs, 40 were diagnosed with PD (Cumulative incidence: 4.5%), 85% of whom (versus 40% with nondelirium) were mechanically ventilated. The area under the curve was 0.74 for PRISM II and 0.71 for the PIM, with optimal cut-off points at the 60th centile (PRISM: sensitivity: 76%; specificity: 62%; PIM: sensitivity: 82%; specificity: 62%). A PRISM II or PIM score above the 60th centile was strongly associated with later PD in terms of relative risk (PRISM II: risk ratio = 4.9; 95% confidence interval: 2.3–10.1; PIM: RR = 6.7; 95% confidence interval: 3.0–15.0). Given the low incidence of PD, values for positive predictive value were lower (PRISM II: 8.3%; PIM: 8.9%, rising to, respectively, 10.1% and 10.6% in mechanically ventilated patients) and values for negative predictive value were higher (PRISM II: 98.3%; PIM: 98.7%). Limitations:Given the relatively low incidence of delirium, a low detection rate biased toward the most severe cases cannot be excluded. Conclusions:Given the fact that PIM and PRISM II are widely used mortality scoring instruments, prospective associations with PD suggest additional value for ruling in, or out, patients at risk of PD.