Elaine Wirrell

De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study

BACKGROUNDnVaccination, particularly for pertussis, has been implicated as a direct cause of an encephalopathy with refractory seizures and intellectual impairment. We postulated that cases of so-called vaccine encephalopathy could have mutations in the neuronal sodium channel alpha1 subunit gene (SCN1A) because of a clinical resemblance to severe myoclonic epilepsy of infancy (SMEI) for which such mutations have been identified.nnnMETHODSnWe retrospectively studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 h of vaccination. We reviewed the relation to vaccination from source records and assessed the specific epilepsy phenotype. Mutations in SCN1A were identified by PCR amplification and denaturing high performance liquid chromatography analysis, with subsequent sequencing. Parental DNA was examined to ascertain the origin of the mutation.nnnFINDINGSnSCN1A mutations were identified in 11 of 14 patients with alleged vaccine encephalopathy; a diagnosis of a specific epilepsy syndrome was made in all 14 cases. Five mutations predicted truncation of the protein and six were missense in conserved regions of the molecule. In all nine cases where parental DNA was available the mutations arose de novo. Clinical-molecular correlation showed mutations in eight of eight cases with phenotypes of SMEI, in three of four cases with borderline SMEI, but not in two cases with Lennox-Gastaut syndrome.nnnINTERPRETATIONnCases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. These findings have important clinical implications for diagnosis and management of encephalopathy and, if confirmed in other cohorts, major societal implications for the general acceptance of vaccination.

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population. An identity-by-descent mapping approach using eight patients from three interrelated Hutterite families localized the gene for this syndrome to chromosome region 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. To our knowledge, this syndrome represents the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect.

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.

Epilepsy-related injuries

Summary:u2002 Only one prospective, controlled study has compared the risk of accidental injury in persons with epilepsy to controls without seizures. A mildly increased risk in the epilepsy group was found, predominantly due to injuries that result directly from a seizure. With regard to injury type, this study found significantly higher rates of only head and soft tissue injury; however, most injuries were minor. Several retrospective, population‐based studies have suggested increased rates of more serious injury types. Submersion injury has a high mortality; the risk of submersion in children with epilepsy is 7.5–13.9 fold higher than in the general population. The risk of fracture is elevated approximately twofold, either resulting directly from seizure‐induced injury or predisposed by drug‐induced reduction in bone mineral density. Burns due to seizures account for between 1.6% and 3.7% of burn unit admissions. The risk of motor vehicle accidents in drivers with epilepsy also appears increased, albeit marginally.

Preventing hyperthermia decreases brain damage following neonatal hypoxic-ischemic seizures

Neonatal seizures are the most common manifestation of underlying cerebral dysfunction. Hypoxic-ischemic encephalopathy is the cause of seizures in 40-60% of newborns. Previous work from our laboratory demonstrates that seizures associated with a hypoxic-ischemic insult results in aggravation of neuronal cell death, specifically within the hippocampus. The latter occurs in the setting of spontaneously occurring hyperthermia of 1.5 degrees C. The purpose of this study was to determine whether preventing the onset of seizure induced hyperthermia would be neuroprotective. Three groups of 10-day old rat pups received unilateral hypoxic-ischemic insults for 30 min followed by KA-induced seizures. Hyperthermia was prevented by lowering the environmental temperature (relative hypothermia) to 29 degrees C such that the seizuring rat pups were normothermic. In one group, the prevention of hyperthermia occurred immediately following hypoxia-ischemia, whereas in the other group it occurred at the onset of seizures. The third group of rat pups (controls) remained at their nesting temperature and therefore became hyperthermic during seizures. Early (3 days) and late (20 days) neuropathology was assessed. Rat pups in whom hyperthermia was prevented during seizures displayed a significant reduction in brain damage compared to controls (p<0.05). Assessment of hippocampal brain damage also showed a significant improvement in neuronal necrosis at 20 days of recovery compared to 3 days of recovery (p<0.05). The results indicate that preventing spontaneous hyperthermia in this model of hypoxic-ischemic seizures in the newborn is neuroprotective.

Physical Activity in Children/Teens with Epilepsy Compared with That in Their Siblings without Epilepsy

Summary:u2002 Purpose: To determine (a) whether children and teens with epilepsy participate in less physical activity and have higher body mass index (BMI) percentiles for age than do their siblings without epilepsy; and (b) what epilepsy‐specific factors limit their participation.

Sleep disturbances in children with epilepsy compared with their nearest‐aged siblings

The aim of the study was to compare sleep patterns in children with epilepsy with those of their non-epileptic siblings and to determine which epilepsy-specific factors predict greater sleep disturbance. We conducted a case-control study of 55 children with epilepsy (mean age 10y, range 4 to 16y; 27 males, 28 females) and their nearest-aged non-epileptic sibling (mean age 10y, range 4 to 18y; 26 males, 29 females). Epilepsy was idiopathic generalized in eight children (15%), symptomatic generalized in seven (13%), and focal in 40 (73%); the mean duration was 5 years 8 months. Parents or caregivers completed the Sleep Behavior Questionnaire (SBQ) and Child Behavior Checklist (CBCL) for patients and controls, and the Quality of Life in Childhood Epilepsy (QOLCE) for patients. Patients had a higher (more adverse) Total Sleep score (p<0.001) and scored worse than controls on nearly all subscales of the SBQ. In patients, higher Total Sleep scores were correlated with higher scores on the Withdrawn, Somatic complaints, Social problems, and Attention subscales of the CBCL, and significantly lower Total Quality of Life Scores. Refractory epilepsy, mental retardation, and remote symptomatic etiology predicted greater sleep problems in those with epilepsy. We conclude that children with epilepsy in this current study had significantly greater sleep problems than their non-epileptic siblings.

Prolonged Neonatal Seizures Exacerbate Hypoxic-Ischemic Brain Damage: Correlation with Cerebral Energy Metabolism and Excitatory Amino Acid Release

Background: Perinatal hypoxia-ischemia (HI) is the most common precipitant of seizures in the first 24–48 h of a newborn’s life. In a previous study, our laboratory developed a model of prolonged, continuous electrographic seizures in 10-day-old rat pups using kainic acid (KA) as a proconvulsant. Groups of animals included those receiving only KA, or HI for 15 or 30 min, followed by KA infusion. Our results showed that prolonged electrographic seizures following 30 min of HI resulted in a marked exacerbation of brain damage. We have undertaken studies to determine alterations in hippocampal high-energy phosphate reserves and the extracellular release of hippocampal amino acids in an attempt to ascertain the underlying mechanisms responsible for the damage promoted by the combination of HI and KA seizures. Methods: All studies were performed on 10-day-old rats. Five groups were identified: (1) group I – KA alone, (2) group II – 15 min of HI plus KA, (3) group III – 15 min of HI alone, (4) group IV – 30 min of HI plus KA, and (5) group VI – 30 min of HI alone. HI was induced by right common carotid artery ligation and exposure to 8% oxygen/balance nitrogen. Glycolytic intermediates and high-energy phosphates were measured. Prior to treatment, at the end of HI (both 15 and 30 min), prior to KA injection, and at 1 (onset of seizures), 3, 5 (end of seizures), 7, 24 and 48 h, blood samples were taken for glucose, lactate and β-hydroxybutyrate. At the same time points, animals were sacrificed by decapitation and brains were rapidly frozen for subsequent dissection of the hippocampus and measurement of glucose, lactate, β-hydroxybutyrate, adenosine triphosphate (ATP) and phosphocreatine (PCr). In separate groups of rats as defined above, microdialysis probes (CMA) were stereotactically implanted into the CA2–3 region of the ipsilateral hippocampus for measurement of extracellular amino acid release. Dialysate was collected prior to any treatment, at the end of HI (15 and 30 min), prior to KA injection, and at 1 (onset of seizures), 3, 5 (end of seizures), 7 and 9 h. Determination of glutamate, serine, glutamine, glycine, taurine, alanine, and GABA was accomplished using high-performance liquid chromatography with EC detection. Results: Blood and hippocampal glucose concentrations in all groups receiving KA were significantly lower than control during seizures (p < 0.05). β-Hydroxybutyrate values displayed the inverse, in that values were significantly higher (p < 0.01) in all KA groups compared with pretreatment controls during seizure activity. Values returned to control by 2 h following the cessation of seizures. Lactate concentrations in brain and blood mimicked those of β-hydroxybutyrate. ATP values declined to 0.36 mmol/l in both the 15 and 30 min hypoxia groups compared with 1.85 mmol/l for controls (p < 0.01). During seizures, ATP and PCr values declined significantly below their homologous controls. Following seizures, ATP values only for those animals receiving KA plus HI for 30 min remained below their homologous controls for at least 24 h. Determination of amino acid release revealed elevations of glutamate, glycine, taurine, alanine and GABA above pretreatment control during HI, with a return to normal prior to KA injections. During seizures and for the 4 h of recovery monitored, only glutamate in the combined HI and KA group rose significantly above both the 15 min of HI plus KA and the KA alone group (p < 0.05). Conclusion: Under circumstances in which there is a protracted depletion of high-energy phosphate reserves, as occurs with a combination of HI- and KA-induced seizures, excess amounts of glutamate become toxic to the brain. The latter may account for the exacerbation of damage to the newborn hippocampus, and serve as a target for future therapeutic intervention.

Use of complementary and alternative medical therapies in a pediatric neurology clinic

BACKGROUNDnComplementary and alternative medicine (CAM) is increasingly used in adults and children. Studies on CAM in neurological disorders have focused on the adult population and its use among pediatric neurology patients has not been well characterized.nnnOBJECTIVESnThe purpose of this study was: 1) To characterize the prevalence of CAM in pediatric neurology patients; 2) To determine the perceived effectiveness of CAM in these children; 3) To compare the cost of CAM with conventional therapies; and 4) To describe caregiver or patient-related variables associated with the use of CAM.nnnMETHODSnThis was a cross-sectional survey of patients and families attending the Alberta Childrens Hospital neurology clinic between February and May 2004. Patients were considered eligible if they were between two and 18 years of age and had a known history of neurological disorders. Caregivers completed several self-administered questionnaires regarding their socio-demographic profile, their childs neurological illness, and their experience with CAM. Caregivers also rated their childs quality of life using the Pediatric Quality of Life Inventory.nnnRESULTSnOne hundred and five of 228 (46%) families completed the survey. The mean age of the neurology patients was 9.8 +/- 4.5 years. Forty-six (44%) out of 105 patients received one or more types of CAM, with the most common types being chiropractic manipulations (15%), dietary therapy (12%), herbal remedies (8%), homeopathy (8%), and prayer/faith healing (8%). Caregivers sociodemographic variables or pediatric health-related quality of life were not significantly associated with the use of CAM. Fifty-nine percent of CAM users reported benefits, and only one patient experienced side effects. There was no significant difference in the total median cost of CAM compared to conventional therapies (31.70 dollars vs. 50.00 dollars per month). Caregivers personal experience or success stories from friends and media were common reasons for trying CAM.nnnCONCLUSIONSnThe use of CAM was common among pediatric neurology patients. Over half of the families reported benefits with CAM, and side effects were perceived to be few. Physicians should initiate discussion on CAM during clinic visits so that the families and patients can make informed decisions about using CAM. Further studies should address the specific role of CAM in children with neurological disorders, and to determine the potential interactions between CAM and conventional therapies in these patients.

Valproic acid-associated weight gain in older children and teens with epilepsy.

This research was undertaken to determine the incidence and predictors of weight gain in older children and teens treated with valproate for epilepsy. Subjects who were 10 to 17 years of age, who began valproate treatment between January 1, 1996, and December 31, 2000, and who had documented weight and height measurements at medication initiation and at least one follow-up visit were retrospectively identified. Exclusion criteria were follow-up <2 months, discontinuation of valproate within 2 months, concurrent therapy with medication known to affect weight, or gastrostomy feeding. Body mass index was calculated at initiation and either discontinuation of valproate or last follow-up and stratified into four categories: underweight, (/=eighty-fifth to ninety-fifth percentile) and overweight (ninety-fifth percentile or higher). Potential predictors of change in body mass index were examined. Mild-to-moderate weight gain was observed in 58% of the 43 subjects treated with valproate (median increase, 2; twenty-fifth to seventy-fifth percentile, 1-6.4). Seventy-nine percent remained in the same body mass index category, and 14% moved up to a potentially overweight or overweight category. The only predictor of an overweight category at follow-up was a potentially overweight or overweight category at initiation (P <0.0002). Two factors tended to predict an increase in body mass index: normal neurocognitive status (P = 0.06) and primary generalized seizure type (P = 0.07).