Purpose: The EFHC1 gene, encoding a protein with a Ca2+‐sensing EF‐hand motif, is localized at 6p12 and was recently reported as mutated in six Mexican juvenile myoclonic epilepsy (JME) families ...linked to this region. We had previously confirmed linkage between JME and 6p11‐12 in 18 Dutch families, and shown exclusionary lod scores at 6p21.3. We therefore evaluated the relevance of EFHC1 in our set of 6p11‐12–linked families.
Methods: We screened all coding and regulatory regions of EFHC1 by direct sequencing, and the detected variants were tested in a case–control association study.
Results: We found none of the five mutations previously reported in the Mexican families, but identified nine variants, three of which are novel: 5′ upstream region (c.‐146_147delGC), nonsynonymous (R159W, R182H, M448T, I619L), intronic (IVS3 + 10A>G, IVS8 + 175_176delTT, IVS10 + 59C>T), and 3′ UTR (c.+121C>A). These variants did not cosegregate with JME and did not account for the observed linkage at the 6p11‐12 locus. Furthermore, no significant association was detected between JME and these variants in 112 unrelated patients and 180 controls. Finally, none of the mutations reported in Mexican families was found in 100 unrelated patients.
Conclusions: We found no evidence that EFHC1 is a major genetic risk factor for JME susceptibility in Dutch patients. The EFHC1 variants reported in Mexican families may be mendelian variants specific for those families, suggesting that for Dutch patients and possibly many other populations, the main disease variant at the 6p11‐12 is yet to be identified.
Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a ...very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2.17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3.50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
Abstract Purpose: To demonstrate the clinical importance of using a high quality photic stimulator for recording EEGs to diagnose photosensitivity. Methods: We performed EEG examinations on 2 adult ...and 2 paediatric patients with a history of visually induced seizures; routinely we used a Grass PS 40 photic stimulator (rectangular Xenon lamp giving flashes of 10 μs duration, 0.7 J, 1–30 Hz, width 7 cm, length 12 cm). We repeated the IPS with a Grass PS 33 plus stimulator (round Xenon lamp giving flashes of 10 μs duration, 1 J, 1–60 Hz, diameter 14 cm). Results: Patients were affected by both benign and catastrophic epilepsies. They complained about episodes of dizziness (case 1), dizziness accompanied by a sensation in the arms and fear (case 2), absences (case 3), and myoclonic jerks (case 4). These symptoms occurred when working with neon lights, computers or ironing striped clothes (case 1), while driving (case 2), whenever there was sunlight (case 3 and 4). Only IPS performed with the Grass PS 33 plus stimulator evoked PPRs accompanied by their typical complaints. In all cases, the revised diagnosis led to changes in their treatment and the disappearance or diminishment of their complaints and PPR range. Conclusion: A PPR can occur in various types of epilepsy, can have a different meaning, and requires a different therapeutic intervention. Only an appropriate photic stimulator with diffuse white light and a flash intensity level of 1 J/flash, can reliably demonstrate whether a patient is photosensitive, or equally important exclude it.
Summary
Purpose
To assess the effects of ICA‐105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so‐called ...photoparoxysmal responses (PPRs) in patients with epilepsy.
Methods
Male and female patients aged 18–60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single‐blind, single‐dose, multiple‐cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA‐105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA‐105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points.
Key Findings
Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA‐105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules.
Significance
ICA‐105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA‐105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.
Behavioral aspects of epilepsy Schachter, Steven C; Holmes, Gregory L; Kasteleijn-Nolst Trenite, Dorothée G. A
2008., 2007, 20071015, 2007-10-15
eBook
Covers the mechanisms underlying epilepsy and behavior, neurophysiologic function, neuropsychiatric and behavioral disorders in patients with epilepsy, the effects of treatments and surgery on ...behavior, pediatric and adolescent epilepsy, disorders associated with epilepsy that impact behavior, and more.
Purpose: To report a new form of reflex epilepsy in which the seizures are repeatedly and exclusively triggered by answering the telephone.
Methods: Three patients with a history of telephone‐induced ...seizures were studied in detail by means of clinical, EEG, and neuroradiologic investigations. Intensive video‐EEG monitoring to record the reflex seizures also was performed in all cases.
Results: The patients (two men, one woman, aged 21 to 30 years) had the onset during early adulthood of complex partial and secondarily generalized seizures exclusively triggered by answering the telephone. The seizures were stereotyped, with subjective auditory or vertiginous auras and inability to speak or understand the spoken voices. In one patient, a telephone‐induced seizure arising from the dominant temporal lobe was recorded by means of video‐EEG technique. In the interictal EEGs, temporal abnormalities were detected in all cases. The patients had a normal neurologic examination and normal magnetic resonance imaging or computed tomography scans.
Conclusions: We suggest that telephone epilepsy is a previously unrecognized form of reflex epilepsy induced by a complex auditory stimulus involving the lateral temporal areas.
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