Sleep and Epilepsy: a Focused Review of Pathophysiology, Clinical Syndromes, Co-morbidities, and Therapy.

A healthy brain requires balancing of waking and sleeping states. The normal changes in waking and sleeping states result in neurophysiological conditions that either increase or decrease the tendency of seizures and interictal discharges to occur. This article reviews the manifold and complex relationships between sleep and epilepsy and discusses treatment of the sleep-related epilepsies. Several forms of epilepsy predominantly or exclusively manifest during sleep and seizures tend to arise especially from light NREM sleep. Diagnostic interictal epileptiform discharges on the electroencephalogram are also most likely to be activated during deep NREM sleep stage N3. Epileptiform discharges and antiepileptic medications may in turn detrimentally impact sleep. Co-morbid sleep disorders also have the potential to worsen seizure control. Sleep has an important key association with sudden unexpected death in epilepsy (SUDEP). Further research is necessary to understand the complex relationships between sleep and epileptic disorders and their treatments.

The impact of marriage and social support on persons with active epilepsy.

Persons with epilepsy (PWE) are more likely to report never being married than those without epilepsy. Social support, especially from marriage, may buffer the negative impact of stressful events and chronic health conditions. In 2005, sixteen U.S. states asked about epilepsy and social support in the Behavioral Risk Factor Surveillance System. A set of survey weight-adjusted logistic regression analyses were conducted to examine the impact of marriage and social support on self-rated health status and life satisfaction in persons with active epilepsy. PWE who were married with poor social support were less likely to report excellent/very good self-rated health status (OR=0.34) and better life satisfaction (OR=0.20), compared with those who were married with good support (reference group) after controlling for demographics and comorbid conditions. Once poor mental health status was controlled for, these differences were no longer significant. In contrast, persons with active epilepsy who were not married with poor support were significantly less likely to report better life satisfaction (OR=0.22) after controlling for demographics, comorbid conditions, and poor mental health status. Epilepsy practitioners need to address poor mental health through appropriate treatment and/or referral. Practitioners should also encourage PWE to improve their social support contacts.

Comparing patients' and practitioners' views on epilepsy concerns: a call to address memory concerns.

The objective was to compare practitioners' impressions of patients' concerns with those expressed by the patients themselves. Prior to clinical interaction, adult patients with epilepsy and their established practitioners were asked to choose their top five concerns via a modified version of the Epilepsy Foundation Concerns Index. Patients with epilepsy (n=257) with varying degrees of seizure control from the outpatient clinic practices of five prescribing practitioners completed the modified concerns index. The three most frequent concerns reported by patients were having a seizure unexpectedly, issues related to driving, and memory problems. These were similar to those reported by the practitioners, though memory was much less of a concern expressed by the practitioner. For the paired data, the concern with the largest gap from the patients' perspective was "your memory." Though there was an overlap, patients were concerned more about life issues and practitioners were concerned about clinical issues. This should serve as a major "wakeup call" to address memory problems in patients with epilepsy, regardless of seizure control.

Is it time to consider cognitive behavioral therapy for persons with epilepsy? Clues from pathophysiology, treatment and functional neuroimaging.

Depression is common in neurological conditions. Patients with epilepsy are significantly more likely to have depression than the general population. However, no published studies have examined the effects of antidepressants and psychotherapy on the brain in patients with epilepsy. A systematic review of 34 relevant neuroimaging articles was conducted on temporal lobe epilepsy (with and without depression), depression (with and without epilepsy), and cognitive behavioral therapy (CBT) and antidepressants through PET, functional MRI, SPECT or proton spectroscopic imaging. Results indicate hypoactivity in the frontal cortex and hippocampus, and hyperactivity in the left dorsomedial prefrontal cortex for depression (with and without epilepsy). Hypoactivity was consistently found in the frontal cortex and temporal region in temporal lobe epilepsy (with and without depression). Studies of nonepilepsy groups suggest that CBT impacts the frontal cortex, prefrontal cortex, temporal lobe, thalamus and hippocampus--all of these areas are dysfunctional in temporal lobe epilepsy with depression. The findings suggest that patients with epilepsy may benefit from CBT. More research is needed to establish CBT as evidence-based practice for epilepsy with depression.

The impact of social support on health related quality of life in persons with epilepsy.

Previous studies have found that psychosocial factors have the greatest impact on health-related quality of life (HRQOL). Social support can buffer the negative impact of stressful events and chronic health conditions. To date, no population studies have examined the association between social support and epilepsy. In the 2003 California Health Interview Survey (CHIS), four questions were used to assess social support. A set of survey weight-adjusted logistic regression analyses were conducted with self-rated health status as the outcome. In those regression models, we examined the effect of epilepsy status, social support, and their interactions, after controlling for demographics. Analyses examining the interaction between epilepsy and social support showed a significant interaction between epilepsy and "availability of someone to love you and make you feel wanted." Once demographics were controlled for, persons without epilepsy and poor affectionate support reported fair/poor self-rated health status (odds ratio=1.7). Persons with epilepsy and good affectionate support also reported fair/poor self-rated health status (odds ratio=3.3). Persons with epilepsy and poor affectionate support were the most likely to report fair/poor self-rated health status (odds ratio=9.1). Persons with epilepsy need encouragement to actively seek and sustain supportive personal relationships that may help improve their quality of life.

The impact of 'social determinants of health' on epilepsy prevalence and reported medication use.

There is a limited understanding of the complex relationship between poverty and epilepsy. To address the complex interaction of environmental and psychosocial factors in epilepsy a 'social determinants of health' model is presented where individual factors are influenced through three pathways (social environment, work and material factors). In the 2005 California Health Interview Survey, 246 of 604 (41%) persons with a history of epilepsy were in poverty, defined as <200% Federal Poverty Level (FPL). Multivariable logistic regression analyses revealed persons in poverty are not more likely to report a history of epilepsy compared to those not in poverty. However, persons with a history of epilepsy in poverty were significantly less likely than those not in poverty to report taking medication for epilepsy (OR 0.5) once material factors (annual income and living situation) and healthcare access were controlled for in the final sequential model. Healthcare practitioners must continue to recognize that connection to social services and the cost of medications are significant barriers to optimal care in persons with epilepsy. Improved connection to patient advocacy organizations and medication assistance programs may help close these gaps.

Serious psychological distress and health outcomes for persons with epilepsy in poverty.

Epidemiology literature demonstrates socioeconomic status as an important variable for outcomes in persons with epilepsy. However, no previous studies have analyzed the association between poverty and epilepsy in the United States. Forty-one percent (246/604) of persons with a history of epilepsy (PWHE) in the 2005 California Health Interview Survey (n=43,020) had an annual income <200% Federal Poverty Level (FPL), adjusted lifetime prevalence rate 0.5% [98.33% CI 0.4-0.7]. Four groups are presented in the analyses: (1) those with a history of epilepsy <200% FPL, (2) those with a history of epilepsy > or =200% FPL, (3) those not reporting a history of epilepsy <200% FPL and (4) those not reporting a history of epilepsy > or =200% FPL. PWHE in poverty reported significantly higher amounts of serious psychological distress, based on the validated Kessler 6 (K6) scale, than both non-epilepsy populations. After adjusting for demographics and other comorbid conditions, logistic regression analyses show PWHE in poverty are significantly more likely to report fair or poor self-rated health status when compared to the PWHE not in poverty and both non-epilepsy populations. PWHE in poverty are also more likely to report > or =14 generally unhealthy days and > or =14 physically unhealthy days in the past 30 days compared to the PWHE not in poverty and both non-epilepsy populations. Psychological well-being needs to be incorporated into any comprehensive treatment strategy for managing epilepsy.

Exercise, diet, health behaviors, and risk factors among persons with epilepsy based on the California Health Interview Survey, 2005.

Based on the 2005 California Health Interview Survey, persons with a history of epilepsy report lower educational attainment, lower annual income, and poorer health status, similar to other state-based epidemiological surveys. Previous studies have found persons with epilepsy exercise less and smoke more than the nonepilepsy population. The medical literature has also shown that antiepileptic drugs may cause nutritional deficiencies. Persons with a history of epilepsy in the 2005 CHIS report they walk more for transportation, drink more soda, and eat less salad than the nonepilepsy population. Exercise and dietary behaviors at recommended levels have been found to reduce mortality from many comorbid conditions such as cardiovascular disease, stroke, depression, anxiety, and osteoporosis for which persons with epilepsy are at increased risk. Health professionals in the epilepsy field should step up their efforts to engage patients in health promotion, especially in the areas of exercise, diet, and smoking cessation.

Health status and behavioral risk factors among persons with epilepsy in Ohio based on the 2006 Behavioral Risk Factor Surveillance System.

In 2006, Ohio added questions to the Centers for Disease Control and Prevention's yearly Behavioral Risk Factor Surveillance System (BRFSS) survey to assess epilepsy prevalence. Ninety-seven of 5506 respondents reported a history of epilepsy, yielding a weight-adjusted prevalence rate of 1.48% (95% CI=0.9-2.1), which is supportive of previous state-based epidemiology estimates. Persons with a history of epilepsy report double the rate of cigarette smoking than the population without epilepsy. Persons with both active epilepsy and a history of epilepsy report poor physical and mental health. Health screening behaviors were comparable to or higher than those of the population without epilepsy. Data from previous BRFSS surveys are used to identify major risk factor trends, as well as to explore the health promotion implications for people with epilepsy. Assessments reveal a need for smoking cessation and increased physical activity for persons with a history of epilepsy in Ohio.

The validity and reliability of the Knowledge of Women's Issues and Epilepsy (KOWIE) Questionnaires I and II.

The Knowledge of Women's Issues in Epilepsy (KOWIE) Questionnaires I and II were developed to assess what women with epilepsy (WWE) and practitioners know about relevant topics and concerns. Prior to disseminating any tool, an instrument should be both valid and reliable. The purpose of this study was to report the validity and reliability of the KOWIE Questionnaires I and II. To establish validity, the original KOWIE was sent to five experts who critiqued the relevance of each item. A content validity inventory (CVI) was developed later and sent to 20 additional epilepsy experts across the country. Tool stability was evaluated by test-retest procedures. Patients and practitioners completed corresponding tools on day one, and 24 hours later, on day two. Participants were asked to not review information on the topic of interest until after study procedures were completed. Sixteen of 20 expert responses were included in data analysis; 4 were excluded due to incomplete data. The CVI correlation coefficient was 0.92. Test-retest results from all 9 patients and 18 of 20 healthcare professionals were included in data analysis. Correlation coefficients were 0.88 and 0.83 for the KOWIE I and II, respectively, confirming these questionnaires are valid and reliable. While future knowledge may require altering both tools, the current instrument may be used as an assessment tool and guide intervention as it pertains to outcomes in WWE.

Use of verapamil as a potential P-glycoprotein inhibitor in a patient with refractory epilepsy.

OBJECTIVE: To describe a patient in whom we used adjunctive verapamil therapy was used for its P-glycoprotein inhibitory effects. CASE SUMMARY: Verapamil was added to the antiepileptic drug regimen of a 24-year-old woman with intractable epilepsy. The average time interval between hospitalizations for complex partial status doubled. The addition of verapamil greatly improved overall seizure control and subjective quality of life in this pharmacoresistant patient. DISCUSSION: The overexpression of P-glycoprotein in the central nervous system may be one mechanism of pharmacoresistance in patients with epilepsy. The calcium-channel blocker verapamil is a known inhibitor of P-glycoprotein and may function to block P-glycoprotein-modulated efflux of antiepileptic drugs in the brain, thereby raising the intracellular concentration of antiepileptic drugs and ultimately decreasing seizure burden in patients with refractory epilepsy. CONCLUSIONS: Verapamil may offer pharmacoresistant patients hope of improved seizure control due to its potential P-glycoprotein inhibitory effects.

Newer therapies in the drug treatment of epilepsy.

OBJECTIVE: To provide a review of recent developments in the pharmacotherapy of epilepsy. DATA SOURCES: A MEDLINE search was performed to identify pertinent literature (1966-June 2001). Selected articles emphasized those published from 1997 to 2001. Bibliographies of identified articles were also evaluated. STUDY SELECTION AND DATA EXTRACTION: All identifiable sources written in English. DATA SYNTHESIS: Epilepsy is a common neurologic disorder, and antiepileptic drugs (AEDs) are the mainstays of therapy. The focus of this article is on the 3 latest AEDs--levetiracetam, oxcarbazepine, and zonisamide. We discuss human data published as both original studies and reviews from the last 4 years, except where noted. We apply a general template for all 3 drugs and provide information on clinical trials, adverse effects, pharmacokinetics, drug interactions, and clinical use. CONCLUSIONS: Levetiracetam, oxcarbazepine, and zonisamide are reasonable options for many patients whose seizures are not yet controlled or who suffer from intolerable adverse effects. All 3 agents are approved for adjunctive use in patients with partial seizures. Oxcarbazepine also has approval for monotherapy in partial seizures. All 3 drugs are well tolerated by most patients and have characteristics that potentially make them easier to use with medications other than the older AEDs. Further clinical experience is needed before specific recommendations can be given for their place among older and newer AEDs.

An Evaluation of the Effects of Methylphenidate on Outcomes in Adult Epilepsy Patients.

Purpose. To determine if methylphenidate (MPH) therapy can improve cognition in adult epilepsy patients on multiple antiepileptic drugs (AEDs), we assessed the impact of MPH on seizure activity, quality of life, cognition, and fatigue in patients with a primary diagnosis of localization-related epilepsy.Methods. This was an open-label, nonrandomized 3-month study. MPH (Ritalin) was added to patients' current antiepileptic drug regimens. Outcome measures included seizure activity, select AED serum concentrations, quality of life (via Quality of Life in Epilepsy-89 questions (QOLIE-89)), cognition (via Microcog), and fatigue (via a visual analog scale) at baseline and at monthly intervals for the treatment phase.Results. Eleven patients were enrolled and eight completed this pilot study. Of the eight completing the study, five were seizure-free at baseline and throughout the study. One patient had an increase, one a decrease, and one no change in seizure activity. No serious adverse events were observed. On average, serum AED concentrations changed <10% from baseline to the end of the study. Mean overall QOLIE-89 scores and select domains improved significantly from baseline. All Microcog domains improved from baseline. Fatigue also improved significantly.Conclusions. Adult epilepsy patients received relief from sedation with MPH and showed an improved quality of life, without significant alteration of seizure control.

A Prospective Evaluation of the Effects of a 12-Week Outpatient Exercise Program on Clinical and Behavioral Outcomes in Patients with Epilepsy.

Purpose. We hypothesized that patients randomized to an exercise program would demonstrate a measurable improvement in behavioral outcomes with no adverse clinical outcomes, as compared with control patients.Methods. This randomized, prospective, parallel, and controlled study spanned 12 weeks. Twenty-eight patients were randomized either to participate in a supervised exercise program (Exercise) or to continue their current level of activity with no planned intervention (Control). The Exercise group worked with an exercise physiologist three times per week. At specific intervals, behavioral (QOLIE-89, POMS, PSDQ, Self-Esteem) and clinical (seizure activity, antiepileptic drug (AED) concentrations) outcomes were measured.Results. Twenty-three patients completed the study (Exercise n = 14, Control n = 9). Of the four patients in the Exercise group with active seizures, two had no change, one had an increase, and one had a decrease in seizure activity. Of the three patients in the Control group with active seizures, one had no change, one had an increase, and one had a decrease in seizure activity. In all patients, there was <26% coefficient of variation in AED concentrations over the 12-week study, suggesting little or no impact of the exercise intervention. The overall quality of life and two domain scores improved from baseline to Week 12 in the Exercise group (P = 0.031), while the Control group score did not change (P = 0.943). In the Exercise group, there were several measures of physical self-concept and vigor that improved and total mood disturbance decreased from the beginning to the end of the program.Conclusion. This is the first randomized, controlled study of exercise in patients with epilepsy. Behavioral outcomes are positively influenced by moderate exercise and there is no impact on seizure frequency. This suggests that exercise should not be discouraged in the care of epilepsy patients. The ability to offer an exercise program adds a health promotion component to the current plan of care provided by our comprehensive epilepsy program.