Epilepsia - Editor's Choice
SCN1A testing for epilepsy: Application in clinical practice.
Hirose S, Scheffer IE, Marini C, Jonghe P, Andermann E, Goldman AM, Kauffman M, Tan NCK, Lowenstein DH, Sisodiya SM, Ottman R, Berkovic SF for the Genetics Commission of the ILAE (2013)
This report is a useful reference guide for genetic testing of SCN1A in practice. Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilespy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. The authors make recommendations for testing and note cautions in interpreting test results.
Examining factors related to accelerated long-term forgetting in epilepsy using ambulatory EEG monitoring
Fitzgerald Z, Thayer Z, Mohamed A, Miller LA (2013)
Accelerated forgetting is an interesting phenomenon which may well explain the often-noted discrepancy between a patient's complaint of memory loss and the apparent normality of conventional memory testing when memory is tested at relatively short intervals (e.g., 30 min). Such patients may show substantial loss over longer delay periods (e.g., days or weeks) when compared to healthy control subjects. This pattern of accelerated "long-term forgetting" (ALF) impacts on the patients' everyday lives, yet goes undetected by standard neuropsychological memory tests. Its pathophysiological basis is poorly understood.
By testing memory over a period of concurrent ambulatory EEG, the current study aimed to investigate possible factors contributing to ALF. Thirty-nine patients diagnosed with epilepsy or probable epilepsy underwent 5 days of continuous ambulatory electroencephalography (EEG). Subjects were taught 13-item word and design lists to criterion, and recall was tested at 30 minutes, 24 hours and 4 days. Subjects also completed questionnaires pertaining to everyday memory and mood.
This group analyses (excluding patients who experienced seizures during monitoring) indicated that patients who experienced generalized discharges during the 24hr to 4 day delay intervals showed higher rates of forgetting for nonverbal information. Those with focal discharges showed ALF between 30 minutes and 4 days for verbal information, while those with normal EEGs over the 4 days recording had no evidence of ALF. Surprisingly, mood and epilepsy variables (such as duration of disease or number of anticonvulsant medications) showed no significant correlation with ALF. Self-report of everyday memory functioning was related to recall at longer delays, but not at 30 minutes.
The findings indicated that ALF in epilepsy is associated with subclinical discharges rather than AEDs, mood or sleep disturbance. Measures of longer-term recall can reveal correlations with subjective everyday memory complaints that are not evident when recall is only tested at a standard (30 minutes) delay interval. This study is a useful contribution to this fascinating topic.
A systematic review of meta-analysis of the role of ABCC2 variants on drug response in patients with epilepsy
Grover S, Kukreti R (2013)
There is a lot of nonsensical discussion about 'drug resistance' — as if this phenomenon is likely to be due to a single mechanism. In this study, the authors performed a meta-analysis of published studies on the commonly reported genetic variants of ABCC2 as associated with drug response in patients with epilepsy (PWE). In their search of electronic databases, the authors found a total of eight reports, which included 1294 good responders and 1529 poor responders.
Although the authors concluded that the results of their meta-analysis indirectly suggested a possible role of the ABCC2 transporter, the associations were not significant. The authors suggest that further studies are warranted in different ethnic groups to investigate the effects of the ABCC2 haplotypic variants, with stratified analysis on the basis of different phonotypic covariates. I wonder, however, if such analyses will really yield significant new insights.
April 2013 articles from Editor-in-Chief Philip A. Schwartzkroin
The April 2013 issue of Epilepsia contains a number of basic research papers using animal models. The following two papers reflect the power and opportunity for applying "bench work" to the real problems of clinical epileptology.
Altered sleep regulation in a mouse model of SCN1A-derived Genetic Epilepsy with Febrile Seizures Plus (GEFS+)
Ligia A. Papale, Christopher D. Makinson, J. Christopher Ehlen, Sergio Tufik, Michael J. Decker, Ketema N. Paul, Andrew Escayg
Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, a role for SCN1A in the regulation of sleep architecture has not been directly examined. Using a mouse model of GEFS+, the authors tested the hypothesis that SCN1A contributes to the regulation of sleep architecture - and therefore that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. They showed, immunohistochemically, expression of Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. In a detailed analysis of sleep and wake electroencephalographic (EEG) patterns (during 48 continuous hours) in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants), they found increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts. These results establish a direct role for SCN1A in the regulation of sleep. The use of this animal model to address this issue offers an excellent example of how animal models can be used to address clinically important questions.
Ethosuximide reduces epileptogenesis and behavioural comorbidity in the GAERS model of genetic generalised epilepsy
Gabi Dezsi, Ezgi Ozturk, Davor Stanic, Kim L. Powell, Hal Blumenfeld, Terence J. O'Brien, Nigel C. Jones
Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has previously been reported to have disease-modifying anti-epileptogenic activity in the WAG/Rij rat model of genetic generalized epilepsy with absence seizures. In the current study, the authors examined whether chronic treatment with ESX in a different model - the GAERS - also has anti-epileptogenic effects and results in mitigation of behavioral comorbidity. ESX treatment significantly reduced seizures in GAERS during treatment (3-22 weeks of age), and this effect was maintained during a 12 week post-treatment period. Further, the anxiety-like behaviors present in GAERS were reduced by this ESX treatment. These results confirm that early, chronic ESX treatment has disease-modifying effects in genetic models of generalized epilepsy, a result that may have important implications for clinical treatment. The study also suggests that the cellular mechanism for these effects involves epigenetic modifications.