Shlomo Shinnar

Classification of Childhood Epilepsy Syndromes in Newly Diagnosed Epilepsy : Interrater Agreement and Reasons for Disagreement

Summary: Purpose: The International League Against Epilepsy (ILAE) classification of the epilepsies is in increasingly widespread use. The following analysis was done to assess the interrater agreement in classifying epilepsy syndromes in children with newly diagnosed epilepsy.

Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy

Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.

The genetics of idiopathic generalized epilepsies of adolescent onset: Differences between juvenile myoclonic epilepsy and epilepsy with random grand mal and with awakening grand mal

Article abstract—Both linkage and association studies provide strong evidence that a gene locus on chromosome 6 is involved in the expression of juvenile myoclonic epilepsy (JME), an adolescent-onset form of primary idiopathic generalized epilepsy (IGE). This epilepsy-related gene locus, designated EJM-1, may also influence the expression of other forms of IGE. We report here evidence that at least one form of epilepsy that is similar to JME—pure, adolescent-onset grand mal epilepsy in which the seizures occur at any time during waking—is not linked to the EJM-1 locus. However, we also have evidence that another form of pure, adolescent-onset grand mal that occurs on awakening is linked to the EJM-1 locus and may be genetically the same as JME. This work suggests that clinically similar epileptic syndromes may have different genetic bases and underscores the critical importance of careful clinical observations in studying the genetics of the epilepsies.

Abnormalities of joint mobility and gait in children with autism spectrum disorders.

AIMS Abnormalities of gross motor function in children with autism are well known to clinicians but have not received much empirical documentation and, with the exception of stereotypies, are not among its diagnostic criteria. We recorded the characteristics of gait and prevalence of toe walking, the range of passive joint mobility, and age at walking in children with DSM IV autism spectrum disorders (ASDs) and in age- and gender-matched typically developing peers (mean age 4years 6months, range 22months-10years 9months). METHODS We evaluated maximum range of mobility at the elbow, wrist, metacarpo-phalangeal, and ankle joints and videoed children walking and running. Two neurologists blind to diagnosis independently scored features of gait clinically. RESULTS Children with ASDs had significantly greater joint mobility (p<.002), more gait abnormalities (p<.0001), and on average walked 1.6months later than their non-autistic peers. INTERPRETATION This study indicates that attention should be directed to motor abnormalities as well as sociability, communication, and restricted and repetitive behaviors in individuals with ASDs. Motor deficits add to childrens other handicaps. They indicate that ASDs affect a broader range of central nervous system circuitry than often appreciated.

Behavior and social competency in idiopathic and cryptogenic childhood epilepsy

Behaviroal and related disorders are frequently reported in association with childhood epilepsy but the reasons for this are unclear. In a long‐term prospective, community‐based study of newly‐diagnosed childhood epilepsy, behavioral assessments (Child Behavior Checklist) were performed in children 8 to 9 years after the initial diagnosis of epilepsy to determine the impact of remission and medication status on behavioral problems. Children with epilepsy were also compared with sibling controls. A total of 226 children (108 females, 118 males; mean age 13y 1mo [SD 2y 8mo], range 8‐17y) with idiopathic or cryptogenic epilepsy were included in the analyses. One hundred and twenty‐eight matched pairs were included in analyses of case‐sibling differences. Lack of remission and current medication use were associated with worse behavioral problem and competency scores. Lack of remission generally had a greater effect than medication use, except for attention problems; medication status had the more deleterious effect (p<0.001). Children with epilepsy had significantly worse behavioral problems and competency scores relative to sibling controls. Even in paris in which the patient was seizure‐free and off medication, significant case‐sibling differences persisted for most scales (p=0.05 to p=0.001). Lack of remission and continued use of antiepileptic drugs have a negative influence on behavioral problems in children with epilepsy but do not fully explain the worse scores relative to siblings. This suggests an independent effect associated with the epilepsy itself.

Seizing control of epileptic activity can improve outcome

In epileptic encephalopathy, the seizures and interictal epileptiform activity create additional neurocognitive dysfunction beyond that due to the underlying etiology. Treatment leading to a reduction in seizures or interictal abnormalities may help improve neurocognitive function in these situations. The focus of our discussion is reviewing data that support the concept that treatment can impact outcome independent of the etiology in some cases.

Fluent Aphasia in Children: Definition and Natural History

We compared the course of a preschool child we followed for 4 years with published reports of 24 children with fluent aphasia. Our patient spoke fluently within 3 weeks of the injury. She was severely anomic and made many semantic paraphasic errors. Unlike other children with fluent aphasia, her prosody of speech was impaired initially, and her spontaneous language was dominated by stock phrases. Residual deficits include chronic impairment of auditory comprehension, repetition, and word retrieval. She has more disfluencies in spontaneous speech 4 years after her head injury than acutely. School achievement in reading and mathematics remains below age level. Attention to the timing of recovery of fluent speech and to the characteristics of receptive and expressive language over time will permit more accurate description of fluent aphasia in childhood. ( J Child Neurol 1992;7:50-59).

1290 EXTERNAL HYDROCEPHALUS IN WEAVER SYNDROME

The Weaver syndrome is a rare disorder of overgrowth, characterized by accelerated somatic growth and osseous maturation, increased head size and unusual facies. Excessive macrocephaly is a striking finding that differentiates Weaver from other overgrowth syndromes. We report a male infant who had the characteristic features of Weaver syndrome including rapid growth. His facial features included round face, frontal bossing, wide bifrontal diameter, hypertelorism, down-slanted palpebral fissures, epicanthi, flat nasal bridge, long prominent philtrum, retromicrognathia and large ears. At birth his length (Lt) was 63.5cm and weight (Wt) 5.8kg. At age 2 months Lt was 72.5cm and wt 8.3kg. Carpal bone age was advanced to 6-9 months. At age 3 months his head circumferance (HC) was 50.4cm. A CT scan showed large bilateral extracerebral fluid collections. A repeat CT at 4 1/2 months showed a decrease in this collection and a picture more consistent with external hydrocephalus. A subdural tap confirmed that the fluid was normal CSF under no increasure pressure. No intervention was done. We have seen a similar CT abnormality in at least one patient with Soto syndrome and in several patients with benign familial macrocephaly. Based on the observation in patients with benign familial macrocephaly, we suggest that the CT appearance may be a relatively benign finding, common to syndromes with rapid head growth in early life.