Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Acquired visual agnosia as an uncommon presentation of epileptic encephalopathy in a 6-year-old boy with CSWS.

BACKGROUND: Acquired visual agnosia in the context of continuous spikes and waves during slow sleep (CSWS) is rarely described. We present a case of an almost 7-year-old boy who lost his ability to name pictures and recognize familiar faces. Initial encephalography (EEG) revealed sleep induced epileptiform activity with a spike-wave index (SWI) of 100%, predominanting in the left posterior head region. METHODS: Serial neuropsychological testing with concomitant EEG was done during the first 18 months of treatment with intravenous methylprednisolone. We administered intelligence scales, verbal tasks (memory, fluency), visual tasks (drawings, search, face recognition), and tasks requiring visual-verbal integration (picture naming, visual closure). ANALYSES: Neuropsychological recovery studied with reliable cognitive change cut-offs and 95% confidence intervals. RESULTS: With treatment, there was an improvement of the EEG pattern (SWI reduction to 45%), followed by a relapse (SWI 82%). Neuropsychological measures in part synchronized with improvement, stability, and fluctuating values. Significant increases were seen on Verbal Comprehension Index and semantic memory. Visual Spatial Index remained unchanged (67 to 73). Naming pictures showed only limited change. Interpreting degraded pictures remained extremely difficult. DISCUSSION: Acquired visual agnosia may be seen in children with CSWS. Early recognition, prompt accurate treatment and tailored neuropsychological assessment remain crucial.

Effect of vaccinations on seizure risk and disease course in Dravet syndrome.

OBJECTIVE: To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS). METHODS: We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as "vaccination-associated." Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared. RESULTS: Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p < 0.001) but not in age at first nonvaccination-associated seizure, age at first report of developmental delay, or cognitive outcome. The risk of subsequent vaccination-associated seizures was significantly lower for acellular pertussis (9%; odds ratio 0.18, 95% confidence interval [CI] 0.05-0.71) and nonpertussis (8%; odds ratio 0.11, 95% CI 0.02-0.59) than whole-cell pertussis (37%; reference) vaccines. Self-controlled case series analysis showed an increased incidence rate ratio of seizures of 2.3 (95% CI 1.5-3.4) within the risk period of 5 to 12 days following MMR vaccination. CONCLUSIONS: Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.

Duration of epilepsy and cognitive development in children: a longitudinal study.

OBJECTIVE: To study the pattern of cognitive development in relation to duration of epilepsy. METHODS: Participants were 113 children with epilepsy referred because of concerns about their cognitive development and tested at least twice at tertiary epilepsy settings. Verbal, Performance, and Full Scale IQ were measured with Wechsler Intelligence Scales. Various epilepsy and demographic variables were included. Change over time was modeled with multilevel analysis for longitudinal data with variable measurement occasion. RESULTS: The Verbal and Full Scales could be fitted best as a downward progressing function. Earlier in time, decline was likely to be largest; later in time, decline followed a continuous, dwindling course. A similar trend was seen for the Performance Scale. Initially, Verbal IQ was higher than Performance IQ but this discrepancy decreased over time. Later onset of epilepsy was associated with an attenuated decline of the Verbal Scale. None of the other epilepsy variables were related to the course of cognitive development. Higher parental education was associated with higher IQ, but was not protective against decline. CONCLUSIONS: Verbal IQ, though initially spared, drops. The Performance IQ, which may have shown its vulnerability earlier in the course of the epilepsy, shows overall smaller changes. It is suggested that seizures impact synergistically on an affected brain, which leads to progressive cognitive decline. Earlier onset of epilepsy is associated with relatively higher VIQ, larger VIQ > PIQ discrepancies and more decline.

Univerricht-Lundborg disease: underdiagnosed in the Netherlands.

PURPOSE: Univerricht-Lundborg disease (ULD), with its major symptom of action myoclonus, is supposed to be very rare in the Netherlands and western Europe. We hypothesized that the syndrome may be underdiagnosed in patients with myoclonus epilepsy. METHODS: Mutation analysis of the cystatin B gene was performed in 21 cases with uncontrolled myoclonus. RESULTS: Seven of the 21 evaluated cases carried mutations in the cystatin B gene. Diagnosis of ULD was made with a mean delay of 20 years from symptom onset. CONCLUSIONS: This study from a country without previous reports of ULD suggests that underdiagnosis of the syndrome is likely. These findings also indicate that persons with juvenile-onset myoclonus epilepsy with action myoclonus should be analyzed for ULD.