Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Seizures and Antiepileptic Drugs: From Pathophysiology to Clinical Practice

Recurrent, spontaneous seizure activity caused by abnormal neuronal firing in the brain is a hallmark of epilepsy, a common chronic neurological disorder. Recent research that has expanded the knowledge of the cellular and molecular mechanisms that modulate neuronal excitability and network activity in the brain provides the development and discovery of antiepileptic drugs (AEDs). AED therapy starts with the selection of the most appropriate drug for individual patient according to a strategic decision based on the risk-benefit ratio. Beyond three generations of AEDs developed over the last 40 years, more effective, better tolerated, disease-modifying pharmacological therapies are still needed to improve seizure outcome and reduce the safety burden. In this review, we aim to provide a special focus on epilepsy with an overview of underlying pathophysiological mechanisms that may contribute to seizure generation and propagation. Besides, knowledge of principle pharmacological properties of current AEDs which are essential for rational drug therapy is considered. Limited safety data are available especially for recent AEDs, we also discussed their safety profiles concerning major adverse effects, teratogenicity and their use in pregnancy and lactation. Epilepsy is a chronic disorder which needs special knowledge and experience during AED treatment with meticulous follow-up of patients to avoid short and long-term adverse effects with the best possible seizure controlled outcome and high quality of life

Reflex epilepsy: triggers and management strategies

Reflex epilepsies (REs) are identified as epileptic seizures that are consistently induced by identifiable and objective-specific triggers, which may be an afferent stimulus or by the patient's own activity. RE may have different subtypes depending on the stimulus characteristic. There are significant clinical and electrophysiologic differences between different RE types. Visual stimuli-sensitive or photosensitive epilepsies constitute a large proportion of the RE and are mainly related to genetic causes. Reflex epilepsies may present with focal or generalized seizures due to specific triggers, and sometimes seizures may occur spontaneously. The stimuli can be external (light flashes, hot water), internal (emotion, thinking), or both and should be distinguished from triggering precipitants, which most epileptic patients could report such as emotional stress, sleep deprivation, alcohol, and menstrual cycle. Different genetic and acquired factors may play a role in etiology of RE. This review will provide a current overview of the triggering factors and management of reflex seizures

Catamenial Epilepsy

When seizures occur in clusters during certain stages of the menstrual cycle (perimenstrual and periovulatory stages), it is defined as catamenial epilepsy. The prevalence varies between 10% and 70%. There are 3 patterns of catamenial epilepsy: perimenstrual (most common), periovulatory, and seizures in the insufficient luteal phase. In the pathophysiology of this occurrence, the neuroactive properties of the reproduction-associated steroid hormones (direct membrane-associated short-term effect and intracellular receptor/genomic-related long-term effect) and their cyclic changes in serum levels play a role in the susceptibility of the epileptogenic area to neuroactive steroids. Among steroid hormones, while progesterone and neurosteroids are known as anticonvulsants, estrogen, the best known proconvulsant, has been found in recent studies to also have anticonvulsant effects related to Neuropeptide Y. Hormonal (medroxyprogesterone acetate, clomiphene, triptorelin, leuprolide, progesterone, goserelin), non-hormonal (acetazolamide, clobazam, lamotrigine, levetiracetam), and neurosteroid-based therapies (ganaxolone) are used in the treatment of catamenial epilepsy. Seizure control and menstrual cycle maintenance, measurement of the blood level of antiepileptic drugs before and after menstruation and adjustment of the drug dosage as required, intermittent benzodiazepine administration, acetazolamide, or hormonal treatments such as oral contraceptives during menstruation are among the treatment strategies for catamenial epilepsy

Convulsive syncope: a condition to be differentiated from epilepsy

The clinical presentation of epilepsy and syncope can be confusingly similar. We present a patient with reflex syncopal episodes that mimic seizures using video-EEG recordings. During the episodes, head/eye deviations, automatisms and dystonic movements, suggesting an epileptic seizure, were observed. The EEG revealed diffuse slow waves when the patient lost consciousness and complete cessation of the cerebral activity occurred when the dystonic movements started. On ECG recordings, bradycardia, followed by complete asystolia lasting for 40 seconds, was observed. We conclude that the differential diagnosis of epilepsy and syncope can be quite misleading and clinical features may not always be reliable. In cases where diagnosis is uncertain, circulatory and cardiac causes should always be kept in mind and video-EEG with simultaneous cardiac recordings are mandatory for accuracy of diagnosis. [ Published with video sequences

Convulsive syncope: a condition to be differentiated from epilepsy

The clinical presentation of epilepsy and syncope can be confusingly similar. We present a patient with reflex syncopal episodes that mimic seizures using video-EEG recordings. During the episodes, head/eye deviations, automatisms and dystonic movements, suggesting an epileptic seizure, were observed. The EEG revealed diffuse slow waves when the patient lost consciousness and complete cessation of the cerebral activity occurred when the dystonic movements started. On ECG recordings, bradycardia, followed by complete asystolia lasting for 40 seconds, was observed. We conclude that the differential diagnosis of epilepsy and syncope can be quite misleading and clinical features may not always be reliable. In cases where diagnosis is uncertain, circulatory and cardiac causes should always be kept in mind and video-EEG with simultaneous cardiac recordings are mandatory for accuracy of diagnosis. [ Published with video sequences

Ongoing Photosensitivity in An Elderly Patient With Jeavons Sydrome

Introduction:Photosensitivity, which is a main feature of Jeavons syndrome, can be seen in other types of idiopathic or genetic epilepsies with focal or generalized seizures and tends to disappear spontaneously usually in the second decade. Although it responds well to antiepileptic treatment, especially to valproic acid, it may continue into adulthood in rare cases.Case Report:We describe a 63-year-old male patient with eyelid myoclonia with absences, generalized tonic-clonic seizures, and severe photosensitivity accompanied by eyelid myoclonia. Seizures were treated with antiepileptic treatment, whereas photosensitivity still continued on electroencephalogram without clinical findings.Conclusion:Our elderly patient with Jeavons syndrome with ongoing remarkable photosensitivity demonstrated that it may continue to older ages, although it is uncommon

Remembering the first seizure and the diagnosis of epilepsy: How much impact do they have in our lives

The aim of the study described here was to investigate what people with epilepsy (PWE) remember about their first seizures and the diagnoses they received, as well as what healthy control participants (HCP) remember about the first seizure they witnessed. Forty PWE were asked to recall in detail their first seizures and their diagnoses, and 40 HCP were asked to recall the first seizure they witnessed. All participants also rated aspects of their subjective reactions to these experiences. Although the first seizure was more surprising and received more covert rehearsal than the diagnosis, PWE recalled equal numbers of details about the two events. Free recall protocols showed that the memory narratives were longer for the first seizure than for the diagnosis. HCP also showed almost perfect recall for the personal circumstances of the first seizure they witnessed. These findings, combined with strong emotional reactions to these experiences, suggest that they lead to detailed and lasting memories. (c) 2009 Elsevier Inc. All rights reserved