David E. Mandelbaum

Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD

The long-term effects of monotherapy with levodopa or the dopamine agonist pergolide on the motor/sensory, behavioral, and cognitive variables in seven children with restless legs syndrome/periodic limb movements in sleep (RLS/PLMS) and attention-deficit-hyperactivity disorder (ADHD) were investigated. Five of the seven children had previously been treated with stimulants that had either been determined to be ineffective or to have intolerable side effects. Dopaminergic therapy improved the symptoms of RLS and reduced the number of PLMS per hour of sleep (P = 0.018) and associated arousals (P = 0.042) for the entire group. After treatment, three children no longer met the criteria for ADHD, and three reverted to normal on the Test of Variable Attention. ADHD improved in all seven as measured by the Connors parent rating scale (P<0.04) and the Child Behavior Checklist (P<0.05). A significant improvement also occurred in the visual, but not verbal, memory scores on the Wide Range Assessment of Memory and Learning (P<0.001). Five of seven children continue on dopaminergic therapy 3 years after treatment initiation, with good response. We postulate that the improvement in ADHD may be the result of the amelioration of RLS/PLMS and its associated sleep disturbance. Alternatively, ADHD and RLS/PLMS may share a common dopaminergic deficit.

Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4)

Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.

Baseline cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy.

Aim  Epilepsy is associated with difficulties in cognition and behavior in children. These problems have been attributed to genetics, ongoing seizures, psychosocial issues, underlying abnormality of the brain, and/or antiepileptic drugs. In a previous study, we found baseline cognitive differences between children with partial versus generalized and convulsive versus non‐convulsive seizures. Measures in that study focused primarily on IQ scores. In the present study, we assessed baseline function with respect to new learning, attention, and memory, thus providing a more comprehensive profile than our previous study.

Sensorimotor performance in school‐age children with autism, developmental language disorder, or low IQ

The purpose of the study was to determine the prevalence of ‘soft’ motor deficits in school‐aged children with either developmental language disorder (DLD), autism (with high IQ [HiAD] or low IQ [LoAD]), or low IQ without autism (LoIQ), and to evaluate the utility of a refined neurological examination to discriminate between these groups. A total of 242 children (74% male), aged 7 or 9 years, were evaluated as part of a longitudinal, multi‐institutional study, with a standardized neurological examination that included Dencklas Physical and Neurological Examination for Soft Signs. Most of the scores separated children into two groups defined by nonverbal IQ, with the DLD and HiAD groups performing better than the LoAD and LoIQ groups. Exceptions included motor impersistence and stereotypies, which were more likely in the autistic groups. The neurologists ‘summary clinical impressions indicated better sensory’ motor skills, oromotor skills, and praxis in the HiAD than in the DLD children. Inability/unwillingness to perform tasks was much more frequent in LoAD than LoIQ children.

Impact of antiepileptic drugs on cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy

OBJECTIVE As treatment options for epilepsy have increased, there has been a commensurate increase in interest in the side effect profiles of these drugs. METHODS In this study, children between the ages of 6 and 17 with a diagnosis of new-onset, idiopathic epilepsy were evaluated at baseline (n=57) and 6 (n=45) and 12 (n=31) months after initiation of antiepileptic drug therapy. RESULTS There was improvement in the cognitive functioning of children after 12 months of treatment. A transient drop in performance of children with generalized seizures (10 of 11 of whom had absence seizures) at 6 months may have been due to persistent seizures, the drugs used to treat them (predominantly ethosuximide), or both. Worsening of reaction time and reaction time variability in the focal seizure group, the only scores showing persistent deterioration over 12 months, may be attributable to the medications used for this group, the most common of which was carbamazepine. CONCLUSIONS There were few adverse effects of antiepileptic drug treatment in the group followed over 12 months. Carbamazepine may have been responsible for persistent impairment of reaction time and reaction time variability.

Efficacy of levetiracetam at 12 months in children classified by seizure type, cognitive status, and previous anticonvulsant drug use.

In a retrospective study of 59 children (ages 9 months to 23 years; mean age 11 years) with intractable epilepsy, seizure frequency was determined before and after 12 months of levetiracetam therapy. Charts were reviewed for seizure type (focal, generalized, or mixed), cognitive function (no special education versus special education), concomitant anticonvulsant medications (range 0—5), and the number of previous anticonvulsant drugs (range 1—12). Good to excellent seizure control (50—100% reduction) was attained in 6 (40%) patients with focal seizures, 16 (55%) patients with generalized seizures, and 8 (61%) patients with mixed seizures; these efficacy rates were not significantly different. The efficacy of levetiracetam was independent of cognitive status. Adverse effects were not associated with higher mean doses. This could be attributable to different rates of metabolism or represent idiosyncratic responses to the medication. Our finding that those children taking the combination of levetiracetam and zonisamide had a significantly worse outcome than those on levetiracetam and a different drug warrants further study, both clinically and from the standpoint of the mechanisms of action of levetiracetam and zonisamide and/or their pharmacodynamic interactions. (J Child Neurol 2005;20:590—594).

Phenotypic features of familial febrile seizures: case-control study.

Objective: To identify phenotypic features of febrile seizures that can be used to reduce heterogeneity and thereby increase power in linkage analysis. Background: Despite exciting discoveries in several rare pedigrees, the genetic basis of common febrile seizures remains a mystery. The major drawback of studying common febrile seizure disorder is etiologic and genetic heterogeneity. A linkage sample must therefore be classified a priori on phenotypic criteria likely to reflect genetically homogeneous subgroups. Methods: Eighty-three cases (children with one or more febrile seizure plus first-degree family history of febrile seizures) and 101 controls (children with one or more febrile seizure but no first-degree family history of febrile seizures) were compared for association of phenotypic features in an unmatched case-control design. Odds ratios were calculated using univariate and multivariate methods. Results: Recurrent febrile seizures was the only phenotypic feature significantly associated with first-degree family history of febrile seizures (OR 2.1, 95% CI 1.15 to 3.88). First-degree family history and later occurrence of afebrile seizures (OR 3.47, 95% CI 0.94 to 12.78) were independently associated with recurrent febrile seizures. Complex features did not show familial aggregation. Conclusions: The authors suggest recurrent and afebrile seizures as criteria on which to subgroup a linkage sample. These subgroups will not be evident at the time of the initial febrile seizure. Meticulous and prospective collection of phenotypic and family data are recommended.

A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.

Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome‐wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4‐PAX6 locus in two independent US and Canadian case–control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array.

The Genetics of Reading Disability in an Often Excluded Sample: Novel Loci Suggested for Reading Disability in Rolandic Epilepsy

Background Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating “pure” dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE. Methods We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus. Results In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation. Discussion Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in “pure” dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.

Serial Neuro‐psychological Follow‐up of a Child Following CraniospinaI Irradiation

Serial neuropsychological examinations were made of an eight‐year‐old girl following diagnosis and treatment of a pineocytoma. The tumor was resected and she received intensive radiation therapy to the entire neuraxis, with a boost to the pineal region. A battery of neuropsychological tests was administered every six to eight weeks, beginning before and continuing for 48 weeks after radiation therapy. Parental questionnaires on the patients everyday behavior were obtained, as well as past and present school records. MRI studies were performed seven weeks, nine months and 14 months after treatment had ended. The only functional area showing deterioration over the follow‐up period was memory, both verbal and spatial. The MRIs showed no abnormalities related either to the tumor or to the radiation therapy.