Prevalence of <i>SCN1A</i>-Related Dravet Syndrome among Children Reported with Seizures following Vaccination: A Population-Based Ten-Year Cohort Study

<div><p>Objectives</p><p>To determine the prevalence of Dravet syndrome, an epileptic encephalopathy caused by <i>SCN1A-</i>mutations, often with seizure onset after vaccination, among infants reported with seizures following vaccination. To determine differences in characteristics of reported seizures after vaccination in children with and without <i>SCN1A</i>-related Dravet syndrome.</p><p>Methods</p><p>Data were reviewed of 1,269 children with seizures following immunization in the first two years of life, reported to the safety surveillance system of the Dutch national immunization program between 1 January 1997 and 31 December 2006. Selective, prospective follow-up was performed of children with clinical characteristics compatible with a diagnosis of Dravet syndrome.</p><p>Results</p><p>In 21.9% (n = 279) of children, a diagnosis of Dravet syndrome could not be excluded based on available clinical data (median age at follow-up 16 months). Additional follow-up data were obtained in 83.9% (n = 234) of these children (median age 8.5 years).</p><p>15 (1.2% of 1,269; 95%CI:0.6 to 1.8%) children were diagnosed with <i>SCN1A</i>-related Dravet syndrome. Of all reported seizures following vaccinations in the first year of life, 2.5% (95%CI:1.3 to 3.6%) were due to <i>SCN1A</i>-related Dravet syndrome, as were 5.9% of reported seizures (95%CI:3.1 to 8.7%) after 2^nd or 3^rd DTP-IPV-Hib vaccination.</p><p>Seizures in children with <i>SCN1A</i>-related Dravet syndrome occurred more often with a body temperature below 38.5°C (57.9% vs. 32.6%, p = 0.020) and reoccurred more often after following vaccinations (26.7% vs. 4.0%, p = 0.003), than in children without a diagnosis of <i>SCN1A</i>-related Dravet Syndrome.</p><p>Conclusions</p><p>Although Dravet syndrome is a rare genetic epilepsy syndrome, 2.5% of reported seizures following vaccinations in the first year of life in our cohort occurred in children with this disorder. Knowledge on the specific characteristics of vaccination-related seizures in this syndrome might promote early diagnosis and indirectly, public faith in vaccination safety.</p></div

Baseline characteristics of children with seizures following vaccinations, and with or without <i>SCN1A</i>-related Dravet syndrome.

<p>Median age at first seizure was missing in 10 children. These were seizures unrelated and prior to, the reported vaccination.</p>*<p>4 children with first seizure after age 2.0 years, and at least 0.5 years after last vaccination.</p

Description of seizures following vaccinations in children with <i>SCN1A</i>-related Dravet syndrome.

<p>Children 1–2 had been diagnosed at stage 1 and children 3–11 at stage 2 of the study by their treating physician. Children 12–15 were diagnosed at stage 2, by means of this study.</p><p>DTwP-IPV-Hib = Diphtheria, Tetanus, whole-cell Pertussis, inactivated Polio vaccine, Haemophilus influenzae type b; FS = febrile seizure; GTCS = Generalized tonic clonic seizure; ND = not determined; h = hours. NA = not available.</p>*<p>Use of valium rectiole or intravenous;</p>**<p>DNA diagnostics performed by DNA Diagnostic Unit of the Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp; unaffected parent mosaic for mutation.</p>***<p>Seizure was reported to the RIVM, but was not recognized as a seizure by either parents or co-workers of the RIVM.</p

Design of study.

<p>Design of study.</p

Characteristics of reported seizures following DTP-IPV(-)Hib vaccination in children with and without <i>SCN1A</i>-related Dravet syndrome.

*<p>P = 0.046 when the 69 missings were considered as temperature less than 38.5°C.</p

A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy.Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum.Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found.Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial.</p

Functional gene enrichment and network analysis.

<p>Significant gene-set enrichments on 329 genes deleted in GGE patients revealed an enrichment of GRIN2B interacting proteins, genes of the MGI abnormal emotion/affect behaviour annotation and of the GO cognition annotation. Segmental clusters of genes belonging to a gene family were removed. Positional clustering of genes physically linked on a microdeletion is indicated by a slash between the gene symbols.</p><p>Functional gene enrichment and network analysis.</p

Gene-disrupting microdeletions found only in patients with genetic generalised epilepsy.

<p>GGE, genetic generalised epilepsy; CTR: population control; Chr: chromosome, start/end: genomic start and end point of the deleted segment, hg19; ^<i>P</i>-value: type-1 error rate for a χ2-test with df = 1; OR, 95%-CI, odds ratio with 95% confidence interval. Disease phenotype: ASD: autism spectrum disorder, ADHD: attention deficit hyperactivity disorder, AN: anorexia nervosa, AUT: autism, BPD: bipolar disorder, EE: epileptic encephalopathy, EPI: epilepsy, ID: intellectual disability, MCP: microcephaly, SCZ: schizophrenia; GGE syndromes: CAE: childhood absence epilepsy, JAE: juvenile absence epilepsy, JME: juvenile myoclonic epilepsy, EGMA: epilepsy with generalised tonic-clonic seizures alone predominantly on awakening, EGTCS: epilepsy with generalised tonic-clonic seizures alone, gsw: generalised spike and wave discharges on the electroencephalogram, number/: age-at-onset of afebrile generalised seizures. # previously published in [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005226#pgen.1005226.ref026" target="_blank">26</a>] and * [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005226#pgen.1005226.ref027" target="_blank">27</a>]. Bold gene symbols indicate genes previously implicated in epileptogenesis.</p><p>Gene-disrupting microdeletions found only in patients with genetic generalised epilepsy.</p