De novo mutations in epileptic encephalopathies.

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders.

Health-care access among adults with epilepsy: The U.S. National Health Interview Survey, 2010 and 2013.

INTRODUCTION: Community-based and other epidemiologic studies within the United States have identified substantial disparities in health care among adults with epilepsy. However, few data analyses addressing their health-care access are representative of the entire United States. This study aimed to examine national survey data about adults with epilepsy and to identify barriers to their health care. MATERIALS AND METHODS: We analyzed data from U.S. adults in the 2010 and the 2013 National Health Interview Surveys, multistage probability samples with supplemental questions on epilepsy. We defined active epilepsy as a history of physician-diagnosed epilepsy either currently under treatment or accompanied by seizures during the preceding year. We employed SAS-callable SUDAAN software to obtain weighted estimates of population proportions and rate ratios (RRs) adjusted for sex, age, and race/ethnicity. RESULTS: Compared to adults reporting no history of epilepsy, adults reporting active epilepsy were significantly more likely to be insured under Medicaid (RR=3.58) and less likely to have private health insurance (RR=0.58). Adults with active epilepsy were also less likely to be employed (RR=0.53) and much more likely to report being disabled (RR=6.14). They experience greater barriers to health-care access including an inability to afford medication (RR=2.40), mental health care (RR=3.23), eyeglasses (RR=2.36), or dental care (RR=1.98) and are more likely to report transportation as a barrier to health care (RR=5.28). CONCLUSIONS: These reported substantial disparities in, and barriers to, access to health care for adults with active epilepsy are amenable to intervention.

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance--The U.S. E-37 Trial.

OBJECTIVES: The Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3-5-day Epilepsy Monitoring Unit (EMU) stay and long- term clinical outcomes of the device stimulating in all modes. MATERIALS AND METHODS: The E-37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR(®) in subjects with drug-resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events. RESULTS: Twenty implanted subjects (ages 21-69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six-months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3). CONCLUSIONS: The Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

Descriptive epidemiology of epilepsy in the U.S. population: A different approach.

OBJECTIVE: Determine prevalence and incidence of epilepsy within two health insurance claims databases representing large sectors of the U.S. METHODS: A retrospective observational analysis using Commercial Claims and Medicare (CC&M) Supplemental and Medicaid insurance claims data between January 1, 2007 and December 31, 2011. Over 20 million continuously enrolled lives of all ages were included. Our definition of a prevalent case of epilepsy was based on International Classification of Diseases, Ninth Revision, Clinical Modification-coded diagnoses of epilepsy or seizures and evidence of prescribed antiepileptic drugs. Incident cases were identified among prevalent cases continuously enrolled for ≥ 2 years before the year of incidence determination with no epilepsy, seizure diagnoses, or antiepileptic drug prescriptions recorded. RESULTS: During 2010 and 2011, overall age-adjusted prevalence estimate, combining weighted estimates from all datasets, was 8.5 cases of epilepsy/1,000 population. With evaluation of CC&M and Medicaid data separately, age-adjusted prevalence estimates were 5.0 and 34.3/1,000 population, respectively, for the same period. The overall age-adjusted incidence estimate for 2011, combining weighted estimates from all datasets, was 79.1/100,000 population. Age-adjusted incidence estimates from CC&M and Medicaid data were 64.5 and 182.7/100,000 enrollees, respectively. Incidence data should be interpreted with caution due to possible misclassification of some prevalent cases. SIGNIFICANCE: The large number of patients identified as having epilepsy is statistically robust and provides a credible estimate of the prevalence of epilepsy. Our study draws from multiple U.S. population sectors, making it reasonably representative of the U.S.-insured population.

Better object recognition and naming outcome with MRI-guided stereotactic laser amygdalohippocampotomy for temporal lobe epilepsy.

OBJECTIVES: Patients with temporal lobe epilepsy (TLE) experience significant deficits in category-related object recognition and naming following standard surgical approaches. These deficits may result from a decoupling of core processing modules (e.g., language, visual processing, and semantic memory), due to "collateral damage" to temporal regions outside the hippocampus following open surgical approaches. We predicted that stereotactic laser amygdalohippocampotomy (SLAH) would minimize such deficits because it preserves white matter pathways and neocortical regions that are critical for these cognitive processes. METHODS: Tests of naming and recognition of common nouns (Boston Naming Test) and famous persons were compared with nonparametric analyses using exact tests between a group of 19 patients with medically intractable mesial TLE undergoing SLAH (10 dominant, 9 nondominant), and a comparable series of TLE patients undergoing standard surgical approaches (n=39) using a prospective, nonrandomized, nonblinded, parallel-group design. RESULTS: Performance declines were significantly greater for the patients with dominant TLE who were undergoing open resection versus SLAH for naming famous faces and common nouns (F=24.3, p<0.0001, η2=0.57, and F=11.2, p<0.001, η2=0.39, respectively), and for the patients with nondominant TLE undergoing open resection versus SLAH for recognizing famous faces (F=3.9, p<0.02, η2=0.19). When examined on an individual subject basis, no SLAH patients experienced any performance declines on these measures. In contrast, 32 of the 39 patients undergoing standard surgical approaches declined on one or more measures for both object types (p<0.001, Fisher's exact test). Twenty-one of 22 left (dominant) TLE patients declined on one or both naming tasks after open resection, while 11 of 17 right (nondominant) TLE patients declined on face recognition. SIGNIFICANCE: Preliminary results suggest (1) naming and recognition functions can be spared in TLE patients undergoing SLAH, and (2) the hippocampus does not appear to be an essential component of neural networks underlying name retrieval or recognition of common objects or famous faces.

Health behaviors among people with epilepsy--results from the 2010 National Health Interview Survey.

OBJECTIVES: This study aimed to estimate and compare the prevalence of selected health behavior-alcohol use, cigarette smoking, physical activity, and sufficient sleep-between people with and without a history of epilepsy in a large, nationally representative sample in the United States. METHODS: We used data from the 2010 cross-sectional National Health Interview Survey (NHIS) to compare the prevalence of each health behavior for people with and without epilepsy while adjusting for sex, age, race/ethnicity, and family income. We also further categorized those with epilepsy into active epilepsy and inactive epilepsy and calculated their corresponding prevalences. RESULTS: The percentages of adults with a history of epilepsy (50.1%, 95% CI=45.1%-55.2%) and with active epilepsy (44.4%, 95% CI=37.6%-51.5%) who were current alcohol drinkers were significantly lower than that of those without epilepsy (65.1%, 95% CI=64.2%-66.0%). About 21.8% (95% CI=18.1%-25.9%) of adults with epilepsy and 19.3% (95% CI=18.7%-19.9%) of adults without epilepsy were current smokers. Adults with active epilepsy were significantly less likely than adults without epilepsy to report following recommended physical activity guidelines for Americans (35.2%, 95% CI=28.8%-42.1% vs. 46.3%, 95% CI=45.4%-47.2%) and to report walking for at least ten minutes during the seven days prior to being surveyed (39.6%, 95% CI=32.3%-47.4% vs. 50.8%, 95% CI=49.9%-51.7%). The percentage of individuals with active epilepsy (49.8%, 95% CI=42.0%-57.7%) who reported sleeping an average of 7 or 8h a day was significantly lower than that of those without epilepsy (61.9%, 95% CI=61.2%-62.7%). CONCLUSIONS: Because adults with epilepsy are significantly less likely than adults without epilepsy to engage in recommended levels of physical activity and to get the encouraged amount of sleep for optimal health and well-being, promoting more safe physical activity and improved sleep quality is necessary among adults with epilepsy. Ending tobacco use and maintaining low levels of alcohol consumption would also better the health of adults with epilepsy.

Newer antiepileptic drug use and other factors decreasing hospital encounters.

A retrospective analysis was conducted in one claims database and was confirmed in a second independent database (covering both commercial and government insurance plans between 11/2009 and 9/2011) for the understanding of factors influencing antiepileptic drug (AED) use and the role of AEDs and other health-care factors in hospital encounters. In both datasets, epilepsy cases were identified by AED use and epilepsy diagnosis coding. Variables analyzed for effect on hospitalization rates were as follows: (1) use of first-generation AEDs or second-generation AEDs, (2) treatment changes, and (3) factors that may affect AED choice. Lower rates of epilepsy-related hospital encounters (encounters with an epilepsy diagnosis code) were associated with use of second-generation AEDs, deliberate treatment changes, and treatment by a neurologist. Epilepsy-related hospital encounters were more frequent for patients not receiving an AED and for those with greater comorbidities. On average, patients taking ≥1 first-generation AED experienced epilepsy-related hospitalizations every 684days, while those taking ≥1second-generation AED were hospitalized every 1001days (relative risk reduction of 31%, p<0.01). Prescriptions for second-generation AEDs were more common among neurologists and among physicians near an epilepsy center. Use of second-generation AEDs, access to specialty care, and deliberate efforts to change medications following epilepsy-related hospital encounters improved outcomes of epilepsy treatment based on average time between epilepsy-related hospital encounters. These factors may be enhanced by public health policies, private insurance reimbursement policies, and education of patients and physicians.

Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort.

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult-onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic-clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required.

Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability.

BACKGROUND: Cerebral palsy is a heterogeneous group of neurodevelopmental brain disorders resulting in motor and posture impairments often associated with cognitive, sensorial, and behavioural disturbances. Hypoxic-ischaemic injury, long considered the most frequent causative factor, accounts for fewer than 10% of cases, whereas a growing body of evidence suggests that diverse genetic abnormalities likely play a major role. METHODS AND RESULTS: This report describes an autosomal recessive form of spastic tetraplegic cerebral palsy with profound intellectual disability, microcephaly, epilepsy and white matter loss in a consanguineous family resulting from a homozygous deletion involving AP4E1, one of the four subunits of the adaptor protein complex-4 (AP-4), identified by chromosomal microarray analysis. CONCLUSION: These findings, along with previous reports of human and mouse mutations in other members of the complex, indicate that disruption of any one of the four subunits of AP-4 causes dysfunction of the entire complex, leading to a distinct 'AP-4 deficiency syndrome'.

Clinical and economic impact of vagus nerve stimulation therapy in patients with drug-resistant epilepsy.

We evaluated long-term medical and economic benefits of vagus nerve stimulation (VNS) therapy in drug-resistant epilepsy. A pre-post analysis was conducted using multistate Medicaid data (January 1997-June 2009). One thousand six hundred fifty-five patients with one or more neurologist visits with epilepsy diagnoses (ICD-9 345.xx, 780.3, or 780.39), one or more procedures for vagus nerve stimulator implantation, one or more antiepileptic drugs (AEDs), and 6 or more months of continuous Medicaid enrollment pre- and post-VNS were selected. The pre-VNS period was 6 months. The post-VNS period extended from implantation to device removal, death, Medicaid disenrollment, or study end (up to 3 years). Incidence rate ratios (IRRs) and cost differences ($2009) were estimated. Mean age was 29.4 years. Hospitalizations decreased post-VNS compared with pre-VNS (adjusted IRR=0.59, P<0.001). Grand mal status events decreased post-VNS compared with pre-VNS (adjusted IRR=0.79, P<0.001). Average total health care costs were lower post-VNS than pre-VNS ($18,550 vs $19,945 quarterly, P<0.001). VNS is associated with decreased resource utilization and epilepsy-related clinical events and net cost savings after 1.5 years.

Economic burden associated with the use of generic antiepileptic drugs in the United States.

This study quantifies the economic burden associated with generic-versus-branded use of antiepileptic drugs (AEDs) in the United States. Adult patients with epilepsy receiving carbamazepine, gabapentin, phenytoin, primidone, or zonisamide were selected from the PharMetrics database. By use of an open-cohort design, patients were classified into mutually exclusive periods of generic-versus-branded AED use. Annualized cost differences (CDs) between periods were estimated using multivariate regressions. Results were stratified into stable versus unstable epilepsy and newer-generation versus older-generation AEDs. A total of 33,625 patients (52% male, mean age=51 years) were observed. Periods of generic AED treatment were associated with higher medical service costs (adjusted CD [95% CI]=$3186 [$2359; $4012]), stable pharmacy costs ($69 [$-34; $171]), and greater total costs ($3254 [$2403; $4105]) versus brand use. Epilepsy-related costs represented 30% of incremental costs. Similar findings were observed for patients with stable and unstable epilepsy and users of newer-generation and older-generation AEDs. Significantly higher health care costs were observed during generic AED use across seizure control and AED subgroups.

Vagus nerve stimulation and magnet use: optimizing benefits.

More than 10 years ago, the vagus nerve stimulator became the first device approved by the Food and Drug Administration for use in persons with epilepsy. The vagus nerve stimulator has subsequently served to spearhead the concept of neurostimulation for seizures. Chronic intermittent electrical stimulation of the left vagus nerve is the foundation for vagus nerve stimulation, yet little is known about its capability to deliver acute, on-demand, activation of stimulation through use of a magnet. Thus far, clinical use of magnet-induced vagus nerve stimulation has not been elucidated. In an effort to help guide management, we highlight current and potential uses of acute abortive therapy with vagus nerve stimulation. We review the current evidence that is available for vagus nerve stimulator magnet use, discuss potential clinical applications that exist, offer a protocol for magnet application within the institutional setting, provide our approach to titrating the magnet parameters, and make recommendations for magnet use that support an evolving standard of care.

An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability.

Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABAA receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFS+). A novel mutation, R859C, in the Nav1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFS+. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Nav1.1 channel alpha subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Nav1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFS+ sodium channel mutations, which have changes predicted to increase neuronal firing.

Hormonal consequences of epilepsy.

Epilepsy is a common disorder in childhood. The effects of recurrent seizures and the use of antiepileptic drugs (AEDs) during childhood and adolescence on reproductive endocrine health are poorly defined. We review effects of hormones on epilepsy and vice versa along with the effects of treatment (AEDs) on hormones in children.

Functional difficulties and school limitations of children with epilepsy: findings from the 2009-2010 National Survey of Children with Special Health Care Needs.

BACKGROUND: Epilepsy is a common serious neurologic disorder in children. However, most studies of children's functional difficulties and school limitations have used samples from tertiary care or other clinical settings. OBJECTIVE: To compare functional difficulties and school limitations of a national sample of US children with special health care needs (CSHCN) with and without epilepsy. METHODS: Data from the 2009-2010 National Survey of CSHCN for 31,897 children aged 6-17 years with and without epilepsy were analyzed for CSHCN in two groups: 1) CSHCN with selected comorbid conditions (intellectual disability, cerebral palsy, autism, or traumatic brain injury) and 2) CSHCN without these conditions. Functional difficulties and school limitations, adjusted for the effect of sociodemographic characteristics, were examined by epilepsy and comorbid conditions. RESULTS: Three percent of CSHCN had epilepsy. Among CSHCN with epilepsy 53% had comorbid conditions. Overall CSHCN with epilepsy, both with and without comorbid conditions, had more functional difficulties than CSHCN without epilepsy. For example, after adjustment for sociodemographic characteristics a higher percentage of children with epilepsy, compared to children without epilepsy, had difficulty with communication (with conditions: 53% vs. 37%, without conditions: 13% vs. 5%). Results for school limitations were similar. After adjustment, a higher percentage of children with epilepsy, compared to children without epilepsy, missed 11 + school days in the past year (with conditions: 36% vs. 18%, without conditions: 21% vs. 15%). CONCLUSION: CSHCN with epilepsy, compared to CSHCN without epilepsy, were more likely to have functional difficulties and limitations in school attendance regardless of comorbid conditions.

Vagus nerve stimulation therapy, epilepsy, and device parameters: scientific basis and recommendations for use.

Our understanding of a precise dose-response relationship for vagus nerve stimulation (VNS) therapy in the treatment of seizures is still evolving. Because several parameters are involved in VNS therapy, the individual contribution of each is not well understood. This review discusses the efficacy of stimulation parameters used in the VNS clinical trials. The background, influence on safety and efficacy, and role in helping to achieve seizure control are discussed for each VNS device parameter: output current, pulse duration, frequency, and duty cycle. Finally, we provide an algorithm for the adjustment of VNS device settings (see Appendices).

Epilepsy in the elderly.

BACKGROUND: Epilepsy is one of the most common neurologic diseases that affect the elderly population. Underlying etiologies as well as diagnostic and treatment issues vary from that of younger adults and deserve special consideration. REVIEW SUMMARY: The substantially increased risk of seizures and epilepsy in the elderly is associated with medical conditions that affect this group such as stroke, dementia, and metabolic disturbances. In addition, there is an increased incidence and associated mortality of status epilepticus among seniors. Distinguishing epilepsy from paroxysmal nonepileptic events can be a particular challenge. As in the general adult population, EEG and MRI are the cornerstones of diagnostic assessment; however, the clinician must be aware of nonspecific changes associated with aging that do not necessarily indicate an underlying predisposition for epilepsy. Finally, there are unique challenges to the treatment of epilepsy in this population, but fortunately there are multiple treatment options available, including nonpharmacological therapies. CONCLUSIONS: Knowledge of the unique challenges in identifying and treating the elderly patient with epilepsy is important for effective management as well as maximizing quality of life. However, further studies in this area are still needed to establish optimal treatment strategies.

Observations on the use of vagus nerve stimulation earlier in the course of pharmacoresistant epilepsy: patients with seizures for six years or less.

BACKGROUND: This study retrospectively compared the effectiveness of vagus nerve stimulation (VNS) therapy among a constant cohort of patients in the patient outcome registry, which systematically monitors outcomes of patients receiving VNS therapy. Patients in the study had pharmacoresistant seizures for 6 years or less (early treatment group) or more than 6 years (late treatment group) before initiation of VNS therapy, and results are provided after both 3 and 12 months. REVIEW SUMMARY: Of 405 patients, 51 were in the early and 354 in the late treatment groups. Median age at onset of seizures was 7 years in the early and 4.5 years in the late treatment group. Seizure reduction of 100% was reported in 7.8% (early) and 3.7% (late) patients at 3 months and 11.8% (early) and 4.5% (late) at 12 months (P = 0.033). Reductions in seizure frequency greater than or equal to 90% for early and late treatment groups were similar: 11.8% (early) and 11.0% (late) at 3 months and 23.5% (early) and 17.0% (late) at 12 months. CONCLUSIONS: Patients treated earlier with VNS therapy were twice as likely to report no seizures as patients who had seizures for more than 6 years before they received VNS therapy. The effectiveness of VNS therapy should be assessed among other patients with pharmacoresistant seizures and lesser cumulative seizure loads.