Susan Duncan

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.

Sleep and epilepsy

The intimate relationship between sleep and epilepsy has long been recognized, yet our understanding of the relationship is incomplete. In this article we address four key issues in this area. First, we consider the reciprocal interaction between sleep and epilepsy. Sleep state clearly influences seizure onset, particularly in certain epilepsy syndromes. The converse is also true; epilepsy may disrupt sleep, either directly through seizures and epileptiform activity, or indirectly through medication-related effects. Unraveling the influences of sleep stage, epilepsy syndrome, and drug effects is challenging, and the current state of knowledge is reviewed. Secondly, accurate diagnosis of sleep-related epilepsy can be difficult, particularly the distinction of nocturnal frontal lobe epilepsy (NFLE) from arousal parasomnias. The challenges in this area, along with work from the authors, are discussed. Thirdly, we will explore the putative relationship between obstructive sleep apnea (OSA) and epilepsy, including the effect of OSA on quality of life; this will lead us to a brief exploration of the effects of OSA on neuroendocrine function. Finally, we will review the evidence surrounding the role of sleep in sudden unexpected death in epilepsy (SUDEP).

Neuropsychological profiles of patients with juvenile myoclonic epilepsy and their siblings: A preliminary controlled experimental video-EEG case series

OBJECTIVEnThe aim of this study was to examine expressive language, memory, and higher executive tasks in patients with juvenile myoclonic epilepsy (JME) as compared with their siblings and a normal control group under video-EEG conditions.nnnMETHODSnEight sibling pairs, one in each pair with JME, were compared with 16 controls matched for age, sex, ethnicity, and educational level. The participants were administered a standard comprehensive set of neuropsychological measures to assess emotional well-being, intelligence, memory, language, visuospatial skills, reaction time, attention, and higher executive function, during and without video-EEG recording.nnnRESULTSnThe JME group differed significantly from controls on measures of phonemic and semantic verbal fluency. They also scored significantly higher on the Dysexecutive Questionnaire, being much more likely to report traits associated with executive dysfunction. Qualitative inspection of the data suggested a trend for patients with JME and their siblings to perform worse than controls on some measures, notably those of expressive language and higher executive function, but on other measures the differences were not statistically significant. In contrast, the JME and sibling group performed as well as controls on the Rey Complex Figure and other tests of visuospatial skills.nnnCONCLUSIONnThe present controlled experimental case series provides support for a neuropsychological profile of patients with JME and their siblings. Significant impairments in verbal and executive functioning may have important ramifications for the social, occupational, and academic performance of people with JME. The apparent corresponding likeness in cognitive performance, exhibited independent of EEG activity, between patients with JME and their siblings warrants further exploration as similar cortical and subcortical structures may be implicated in these two groups.

Sexual function in men with epilepsy: how important is testosterone?

Objective: To ascertain the effects on sexual function of men with epilepsy (MWE) of testosterone levels and indices of anxiety and depression. Methods: Sixty MWE taking one antiepileptic drug only (AED), with no comedication, were compared with 60 control men. Total testosterone (TT), free testosterone (FT), bioactive testosterone (BAT), dehydroepiandrosterone sulfate (DHEAS), androstenedione, and sex hormone–binding globulin (SHBG) were measured. Each man also completed validated questionnaires exploring sexual desire (Sexual Desire Inventory [SDI]), sexual response (Sexual Response Inventory [SRI]), erectile function (Sexual Self-Efficacy Scale [SSES]), and anxiety and depression (Hospital Anxiety and Depression Scale). Results: MWE reported lower levels of sexual desire and lower erectile function compared with controls. They had significantly higher levels of anxiety, depression, and psychological distress. MWE had significantly higher SHBG levels and significantly lower DHEAS. There were no significant differences between the groups’ TT, FT, or BAT levels. BAT levels were significantly lower in men taking enzyme-inducing AEDs than in those taking non–enzyme-inducing AEDs. Visual inspection of TT and BAT levels showed that the majority of MWE and controls had TT and BAT levels above the “androgen threshold” levels of 12 nmol/L TT or 3.8 nmol/L BAT considered necessary for normal sexual function. There was a significant correlation (Spearman rank and simple linear regression) between sexual function and indices of anxiety and depression. There was no significant relationship between SDI and SSES and TT, FT, or BAT (Spearman rank correlation). Conclusions: Concentrating on hormone levels alone as an explanation of sexual dysfunction in epilepsy represents an overly simplistic approach to the problem. Future studies should include measures of quality of life, anxiety, and depression.

Neuroendocrinological aspects of epilepsy: Important issues and trends in future research☆

Neuroendocrine research in epilepsy focuses on the interface among neurology, endocrinology, gynecology/andrology and psychiatry as it pertains to epilepsy. There are clinically important reciprocal interactions between hormones and the brain such that neuroactive hormones can modulate neuronal excitability and seizure occurrence while epileptiform discharges can disrupt hormonal secretion and promote the development of reproductive disorders. An understanding of these interactions and their mechanisms is important to the comprehensive management of individuals with epilepsy. The interactions are relevant not only to the management of seizure disorder but also epilepsy comorbidities such as reproductive dysfunction, hyposexuality and emotional disorders. This review focuses on some of the established biological underpinnings of the relationship and their clinical relevance. It identifies gaps in our knowledge and areas of promising research. The research has led to ongoing clinical trials to develop hormonal therapies for the treatment of epilepsy. The review also focuses on complications of epilepsy treatment with antiepileptic drugs. Although antiepileptic drugs have been the mainstay of epilepsy treatment, they can also have some adverse effects on sexual and reproductive function as well as bone density. As longevity increases, the prevention, diagnosis and treatment of osteoporosis becomes an increasingly more important topic, especially for individuals with epilepsy. The differential effects of antiepileptic drugs on bone density and their various mechanisms of action are reviewed and some guidelines and future directions for prevention of osteoporosis and treatment are presented.

Erectile function, sexual desire, and psychological well-being in men with epilepsy

OBJECTIVEnThe aim of this study was to explore the effects of anxiety, depression, and self-reported quality of life (QOL) on sexual function of men with epilepsy (MWE).nnnMETHODSnSixty-nine MWE taking one antiepileptic drug and 50 controls were recruited. All completed sexual function questionnaires, the Hospital Anxiety and Depression Scale (HADS), and the World Health Organization Brief Quality of Life Questionnaire (WHOQOL-BREF). Blood was taken to analyze testosterone and dihydroepiandrosterone sulfate levels.nnnRESULTSnCompared with controls, MWE reported higher levels of anxiety, depression, and psychological distress; lower overall quality of life and health; and lower levels of sexual desire and erectile function. Seizure frequency did not affect any of these variables, and testosterone levels did not correlate with sexual desire or erectile function. Simple linear regression showed a significant negative correlation between sexual desire and indices of anxiety, depression, and psychological distress. Multiple linear regression using overall QOL as dependent variable showed that anxiety, depression, psychological distress, and the Psychological Well-Being subscale of the WHOQOL-BREF predicted 48% of its variability. Interestingly, sexual function and seizure status did not.nnnCONCLUSIONnMWE reported lower levels of sexual desire and were more likely to report erectile dysfunction than controls. But the most important determinant of QOL was psychological status, not seizure frequency or sexual function.

Sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) has an incidence ranging between 0.09 and 9 per 1000 patient-years depending on the patient population and the study methodology. It is the commonest cause of death directly attributable to epilepsy, and occurs at or around the time of a seizure. The principal risk factor for SUDEP is poorly controlled generalized tonic-clonic seizures. Other risk factors include polytherapy, male sex, early age at onset of epilepsy, symptomatic etiology, and, possibly, treatment with lamotrigine. The mechanisms underlying SUDEP are poorly understood, but autonomic dysfunction, central apnea, cerebral depression, and cardiac arrthymias have all been described in animal models of SUDEP and during human seizures. Prevention of this fatal event should be aimed at optimizing control of seizures, including prompt referral for consideration of epilepsy surgery. All patients should be told about the risks of SUDEP and informed that complete seizure control appears to be the one proven way of preventing the phenomenon.

Adult attachment style and childhood interpersonal trauma in non-epileptic attack disorder

Non-epileptic attack disorder (NEAD) poses a significant clinical problem but is poorly understood. Attachment theory provides a framework for understanding the development and maintenance of NEAD and the contribution of childhood abuse and neglect to these processes. A cross-sectional design was used to study attachment style and early traumatic experiences in individuals with NEAD (N=17) compared to those with epilepsy (N=26). A significant difference in predominant attachment style between the two groups was found, with fearful attachment occurring more frequently in the NEAD group. Abuse and neglect were also significantly more common in the NEAD patients. Both early traumatic experiences and fearful attachment added significantly to the predictive power of a logistic regression equation after controlling for anxiety and dysthymia. The findings suggest a link between disturbed attachment and NEAD and have clinical implications for therapeutic intervention with this group.

Retrospective study of sensitivity and specificity of EEG in the elderly compared with younger age groups

Following a recommendation from a Good Practice Guide published in Scotland stating that EEG should not be routinely used in the diagnosis of epilepsy in the elderly, we conducted a retrospective study to ascertain the effects this recommendation had. We found that predating the recommendation, there had already been a decline in the use of EEG in people aged 65 and over. Detailed examination of a 3.5-year epoch which straddled 2 years before the recommendation and 1.5 years after its publication revealed no evidence of a change in the type of referrals but just in the number of referrals. Comparison with 2 younger cohorts showed that EEG in the elderly had the same specificity and sensitivity as in the younger age groups and was of particular use in picking up previously unsuspected non-convulsive status. We conclude the EEG remains an important diagnostic adjunct in the elderly.

'If you're gonna die, you're gonna die': Young adults' perceptions of sudden unexpected death in epilepsy.

Objectives To explore the views and experiences of young adults with epilepsy on the risks associated with, and information giving in relation to sudden unexpected death in epilepsy (SUDEP). Methods In-depth interviews with 27 young adults (aged 18–29 years) with epilepsy. Results Participants reported everyday experiences of seeking to control the risk of seizure occurrence or injury from seizures. In contrast, SUDEP was reported in more fatalistic terms as a risk that was considered to be largely unpreventable. Participants stated that information on SUDEP should be given to those with epilepsy, in a consultation, at or soon after the diagnosis, though clinical judgement on patients’ readiness was considered important in timing decisions. Many had a limited, sometimes incorrect understanding of SUDEP, yet were satisfied with the information they had received. Very few engaged in independent information seeking on SUDEP, and many deliberately avoided searching for further information. Discussion Our findings suggest that SUDEP was bracketed off from other aspects of participants’ epilepsy, in terms of the meanings attributed to it, perceptions of risk status and ways of coping. SUDEP is a case through which to consider how people give meaning to information about risk of sudden death related to chronic conditions.