Epilepsy Foundation Research Articles

Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies

Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients' antibodies on neuronal cultures. In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy. Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3-63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2-74 years, median 26.5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients' antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor). High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable. The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.

Is Epilepsy a Cause of Cognitive Decline in Developing Brain

Abstract Epilepsy is a chronic noncommunicable disorder of the brain that affects people of all ages. Around 50 million people worldwide have epilepsy (WHO, 2012). 45,000 children under the age of 15, develop epilepsy each year (Epilepsy Foundation, 2010). Lower income was, however, associated with a higher incidence of epilepsy in all ethnic groups (Benn, et al., 2008). Neuropsychological impairment is an important co-morbidity of chronic epilepsy (Elger et al., 2004). Recent investigations have focused on the cumulative neurobiological burden associated with epilepsy and the risk of progressive cognitive impairment, but none have studied the effect of epilepsy on cognition on the developing brain, from India so far. Hence, the aim of the study was to study the effect of the temporal and extra temporal epilepsy on the cognitive functioning of children aged 7–12 years. Methodology: a cross-sectional study was carried out with a sample of 52 consenting children with an history of seizure (the 1st seizure occurred at least three months back i.e. the problem of seizure disorder was at least three months old) of neuropsychological assessment of epilepsy were administered with standardized neuropsychological tests, namely (Gesell’s Drawing Test- by Verma et al., 1972, PGI-Memory Scale for children- by Kohli et al., 1998) Results indicated significant findings in nine areas of neuropsychological functioning, namely immediate recall (p=0.001), followed by delayed recall (p=0.001), attention and concentration (p=0.001), recent memory (p=0.001), remote memory (p=0.001), visual retention (p=0.001), retention for similar pairs (p=0.001), mental balance (p=0.001), recognition (p=0.001) as compared to controls. Conclusion: results show that epilepsy does have a significant effect on cognition of children. However, a larger cohort study needs to be carried out to make substantiate claims.

EPILEPSY, DEPRESSION AND ANXIETY DISORDERS: A COMPLEX RELATION WITH SIGNIFICANT THERAPEUTIC IMPLICATIONS FOR THE THREE CONDITIONS

Andres M. Kanner is a senior attending physician at the department of Neurology and Director of the Comprehensive Epilepsy Center at the University of Miami, Miller School of Medicine, which...

The Evolution of Dietary Therapy for Neurologic Disorders

In the 4 years since the first international symposium devoted to the ketogenic diet, held in Phoenix, Arizona, there has been a significant increase in research and interest in this unique therapy. Ketogenic diet centers have started in many countries throughout the world, including developing nations. Evidence for success using dietary treatment for adults has grown and led to adult epilepsy diet centers being formed in several academic institutions. The traditional ketogenic diet itself continues to evolve with now 4 unique diets (classic ketogenic, mediumchain triglyceride diet, modified Atkins diet, and low glycemic index treatment) as well as research leading to less restrictive, safer, and easier diets to use for all age ranges. What is perhaps most dramatic since the Phoenix meeting in 2008 has been the remarkable increase in interest among neurologists and physicians in the use of this metabolism-based therapy for conditions other than epilepsy. Research in the past 4 years has shown potential benefits of low-carbohydrate, highfat diets for diabetes, metabolic syndrome, Alzheimer disease, cancer, amyotrophic lateral sclerosis, to name a few. Specialists in these conditions often look to pediatric epileptologists familiar with the ketogenic diet for advice as they embark on clinical trials. Conversely, pediatric epileptologists are often reviewing the medical literature for advice on keeping patients healthy on low-carbohydrate diets, especially when long-term use is required. As a result, Drs Thiele and Thio and I, along with Beth Zupec-Kania and Jim Abrahams from the Charlie Foundation, as the 5 co-organizers of this Third Symposium on dietary therapy, thought it was the appropriate time for a unique conference. We wanted to make this conference different, bringing together experts from fields outside of epilepsy to share their knowledge and help create potential collaborations for the future. Now, as we publish this Special Issue detailing the proceedings of this spectacular conference, we believe we succeeded. This Special Issue will begin with the Thursday morning of the Symposium, chaired by Dr Adam Hartman, and focusing on the emerging neurologic, but nonepilepsy uses of dietary therapy including as well diabetic nephropathy and cancer. Before delving into these topics, Dr Helen Cross will discuss the highlights of the past 2 years regarding the ‘‘traditional’’ use of dietary therapies for epilepsy in children. Three multiauthor reviews will then cover the Thursday afternoon breakout sessions, devoted to nutritional aspects (Beth Zupec-Kania first author), basic mechanisms of action (Dr Liu Lin Thio), and the growing uses of diets for adults (Dr Mackenzie Cervenka). Friday morning’s lectures returned to the field of epilepsy, with presentations on Dravet syndrome, glucose 1 transporter deficiency, and status epilepticus. This Special Issue will then close with 2 final articles regarding the future implications of dietary therapies and a parent’s perspective on how to continue to make these exciting and helpful treatments more widely available. This meeting would not have been possible without the support of the Charlie Foundation as well as many sponsors including Nutricia, Chicago Sun-Times, Matthew’s Friends, Lundbeck, Vitaflo, Sigma-Tau, Epilepsy Therapy Project, Carson Harris Foundation, Athena, Atkins, Protocol for Life Balance, Epilepsy Cure Initiative, Solace Nutrition, Anita Kaufmann Foundation, Dravet Syndrome Foundation, Epilepsy Foundation Greater Chicago, Citizens United for Research in Epilepsy, Glucose Transporter 1 Deficiency Foundation, Intractable Childhood Epilepsy alliance, Lennox Gastaut Syndrome Foundation, Tuberous Sclerosis Alliance, Johns Hopkins Hospital, and LeBonheur Children’s Hospital. We also gratefully thank Gary Taubes and Matt Vanderheiden for their Wednesday evening keynote lectures. In addition, the inspirational speeches and involvement by Meryl Streep and Jeff Garlin at the Friday night gala reception helped bring this incredible meeting to an uplifting close. This Special Issue was supported and encouraged by Dr Roger Brumback, the EditorIn-Chief of the Journal of Child Neurology. Lastly, all of the organizers and speakers mourn the tragic loss of Dr Marwan Maalouf, the speaker on the topic of ketogenic diets and Alzheimer disease, who passed away shortly after this meeting. On behalf of the organizers and all the authors of these reviews, we hope you enjoy reading about this research as much as we valued hearing about it in Chicago. The ketogenic diet is certainly evolving, and this Special Issue demonstrates it. We are all excited to see where this evolution takes the diet over the next 2 years, leading up to the fourth international symposium in October 2014 in Liverpool, United Kingdom.

Morris‐Coole Epilepsia Prize – 2012

Epilepsia is pleased to announce the winner of the 2012 Morris-Coole Epilepsia Prize—Mark R. Bower, Ph.D.—for the article “Spatiotemporal neuronal correlates of seizure generation in focal epilepsy” (Mark R. Bower, Matt Stead, Fredric B. Meyer, W. Richard Marsh, and Gregory A. Worrell, Epilepsia 53: 807–816, 2012). The research group is from the Mayo Clinic in Rochester, MN, U.S.A. The Morris-Coole Epilepsia Prize is supported by the International League Against Epilepsy (ILAE) and the Morris-Coole Trust. The Prize is awarded each year to the first author of a paper that presents high quality research (basic or clinical) with important implications for understanding and/or treating epilepsy-related phenomena. It is designed to encourage young scientists and/or clinicians to continue their work in epilepsy research. The Prize consists of $5,000 and a specially designed insignia pin. This year's Prizewinner will receive the award, and present a talk on his research, at the Awards Symposium of the 30th International Epilepsy Congress in Montreal on June 24, 2013. Selection of the Prizewinner starts with nominations from the Associate Editors of Epilepsia. From the set of nominated papers (full-length original research reports, published in a print issue of Epilepsia during 2012), a committee composed of the Co-Editors-in-Chief of Epilepsia and the President of ILAE chooses one study that the committee believes will have a particularly significant impact on the epilepsy field. Dr. Bower, the recipient of the 2012 (Epilepsia Volume 53) Prize, is Research Fellow in the Department of Neurology at Mayo Clinic, and a member of the Mayo Systems Electrophysiology Laboratory led by Drs. Matt Stead and Gregory A. Worrell. He received his Ph.D. in Neuroscience from the University of Arizona working with Dr. Bruce McNaughton on place cells and cognitive map formation in freely moving animals. His postdoctoral fellowship, with Dr. Paul Buckmaster at Stanford University, involved recording the activity of multiple single neurons prior to and during seizures in the pilocarpine model of epilepsy; he was awarded the Eric W. Lothman Fellowship by the Epilepsy Foundation for this work. At Mayo Clinic, Dr. Bower has helped translate the recording and analytical techniques developed in animal models to long-term, continuous recordings from patients undergoing treatment for epilepsy. His research centers on understanding how ongoing neuronal activity progresses into seizures, and on identifying robust biomarkers of impending seizures from the activity of multiple single neurons—with the goal of providing new therapies for patients with epilepsy.

HCN channels contribute to serotonergic modulation of chemoreceptors in the retrotrapezoid nucleus

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) provide a CO2‐dependent drive to breathe, and function as a key locus of respiratory control by integrating information from several respiratory centers including the medullary raphe. Recent evidence showed that mechanisms underlying serotonergic modulation of RTN neurons involves inhibition of KCNQ channels and activation of an unknown inward current. Evidence also shows that RTN neurons produce a hyperpolarization‐activated inward current (Ih) at negative potentials. HCN channels are the molecular correlate of Ih and have a high propensity for neuromodulation. Therefore, we hypothesize that HCN channels contribute to serotonergic modulation of RTN neurons. We investigated this in vitro and in vivo using selective blockers for KCNQ (XE991) and HCN (ZD7288) channels. Membrane potential recordings in rat brain slices show that serotonin application increased chemoreceptor activity by ~1 Hz. Consistent with our previous evidence, XE991 decreased serotonin‐responsiveness by ~50%. The residual serotonin‐sensitivity in XE991 was blocked by ZD7288. In anesthetized rats RTN injection of XE991 blunted serotonin‐responsiveness and together XE991 and ZD7288 completely eliminated the respiratory response to serotonin. These results indicate that HCN channels contribute to serotonergic modulation of RTN chemoreceptors and respiratory drive. Funding sources: CURE Epilepsy Foundation (AVT, DKM), NIH HL104101 (DKM), NS073981 (AVT), and the Sao Paulo Research Foundation (FAPESP) (ACT, TSM).

Epilepsy in Adults and Access to Care—United States, 2010

Epilepsy is a neurologic disorder that negatively affects the quality of life for millions of persons in the United States; however, nationally representative U.S. estimates of the prevalence of epilepsy are scant. To determine epilepsy prevalence among adults, assess their access to care, and provide baseline estimates for a Healthy People 2020 objective ("Increase the proportion of persons with epilepsy and uncontrolled seizures who receive appropriate medical care"), CDC analyzed data from the 2010 National Health Interview Survey (NHIS). The results of that analysis indicated that, in 2010, an estimated 1.0% of U.S. adults and 1.9% of those with annual family income levels ≤$34,999 had active epilepsy. In addition, only 52.8% of adults with active epilepsy reported seeing a neurologic specialist in the preceding 12 months. Public health agencies can work with Epilepsy Foundation state affiliates and other health and human service providers to eliminate identified barriers to care for persons with epilepsy.

Unlatched BAX Pairs for Death

Self-interacting BAX proteins permeabilize outer mitochondrial membranes to trigger apoptotic cell death. Czabotar et al. present two revealing structures of BAX dimers: one dimer has an activator BH3 helix bound into its canonical cleft, and the other dimer exposes a planar hydrophobic face potentially critical for membrane interactions.

An Overview of the Facts, Myths and Treatment of the Disease Condition Known as “Epilepsy”

Epilepsy is sometimes called a seizure disorder. It is characterized by recurrent unprovoked seizures. There are over 40 different types of epilepsy and it affects people of all nations and cuts across all races. The Epilepsy Foundation of America defines it as, “a physical condition that occurs when there is a sudden, brief change in how the brain works”. Not all seizures are due to epilepsy. There are about fifty million people worldwide at any point in time with this disease and it is not contagious. According to a publication of the National Dissemination Center for Children with Disabilities, 2004, “about two million Americans have epilepsy; of the 125,000 new cases that develop each year, up to 50% are children and adolescents”. In most cultures, people with epilepsy have been discriminated against, stigmatized, shunned, or even imprisoned due to misconceptions and ignorance about the true nature of this disease condition. Epilepsy can occur in animals other than humans. Epilepsy is usually treated with medications prescribed by, a physician, primary caregivers, neurologists, and neurosurgeons. Anticonvulsants can be used to attenuate or abolish seizures. These chemical substances are heterogeneous in nature but they have a common structural feature known as anticonvulsant moiety or nucleus which consists of a nitrogen atom, a carbonyl group and a substituent group. In some cases the implantation of a stimulator of the vagus nerve, or a special diet can be helpful. Neurosurgical operations for epilepsy can be palliative, reducing the frequency or severity of seizures or in some cases an operation can be curative. In traditional systems, herbs have been used to manage and cure epilepsy as well.

1508 Spectrum of Neural Tube Defects after Prenatal Antiepileptic Drug Exposure: Extensive Case Series

BackgroundMost pregnant women with chronic active epilepsy need to use antiepileptic drugs (AEDs) during pregnancy to prevent epileptic seizures that may threaten maternal and fetal well-being. Valproic acid (VPA) and...

Correction: Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the General Population

There were errors in the Funding section. The correct funding information is as follows: HLT was supported by the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616), and the Dutch Medicines Evaluation Board (MEB/CBG). HLT, RDT, and JWS are supported by the National Epilepsy Foundation Netherlands (project number 10-07). The Arrest data collection was supported by an unconditional grant from Physio Control and a grant from the Netherlands Heart Foundation (grant 2006B179). Dr. Bardai was supported by the Netherlands Organization for Scientific Research (NWO, grant Mozaiek 017.003.084). RD Thijs and JW Sander are part of PRISM - the Prevention and Risk Identification of SUDEP Mortality Consortium which is funded by the NIH (NBIH/NINDS -1P20NS076965-01). The funders were not involved in: design, conduct of the study, collection, management, analysis, interpretation of the data, preparation, review or approval of the manuscript.

Psychosocial adjustment of epilepsy patients in Cyprus

This study investigated aspects of psychosocial adjustment in epilepsy patients in Cyprus. Sixty-three patients under 55years of age with idiopathic or symptomatic epilepsy and 89 neurologically matched healthy volunteers participated. Subjects completed the State and Trait Anxiety Inventory and the Beck Depression Inventory; patients with epilepsy also completed the Epilepsy Foundation Concerns Index. Results showed that patients with symptomatic epilepsy had significantly higher scores on state and trait anxiety and depressive symptoms. Sociodemographic characteristics including gender, marital status, and education levels contributed to differences in trait and state anxiety, depressive symptom scales, autonomy concerns, and fear for seizure recurrence. Variables such as poor seizure control and use of polytherapy were associated with lower adjustment scores and reduced psychosocial outcome. Finally, patients with epilepsy scored significantly higher on depression and anxiety symptoms. The results provide further evidence on challenges patients with epilepsy face and on the need for implementing psychosocial prevention programs.

Change in Prevalence of Chronic Conditions over a Period of 14 Years in Patients with Epilepsy (P07.123)

Objective: To examine changes in the prevalence of chronic comorbid conditions in patients with epilepsy (PWE) over time. Background PWE have high prevalence of chronic conditions. However, temporal changes in the prevalence of these conditions remain unknown. Design/Methods: The Ohio Medicaid claims data from 1992 to 2008 was used to form a cohort of PWE and control. Individuals aged ≥18 year old with at least two years of look-back and follow-up periods were included. Our epilepsy cohort consisted of 6,390 individuals with at least one visit of a diagnosis of epilepsy (ICD-9-CM: 345.xx) or at least two visits of non-febrile convulsions (ICD-9-CM: 780.3 or 780.39) and at least one pharmacy dispensing of antiepileptic drugs. Control cohort consisted of 83,067 individuals without the diagnostic code of epilepsy or non-febrile convulsion. Individuals who enrolled in both Medicaid and Medicare programs or managed care program, who had a period of spend down, or who had less than 80% of expected enrollment were excluded. We measured the prevalence of 38 common conditions that were selected based on their commonality in the general population and their impact on the patient9s outcome every 2 year interval. Results: PWE had significantly higher prevalence of chronic comorbid conditions, especially during the first 10 years after epilepsy diagnosis. In generalized estimating equations logistic regression models adjusting for sex, race, age and time, PWE continued to have high prevalence of these conditions. Regression models demonstrated that the prevalence ratio of these conditions significantly decreased over time. However, the prevalence ratio of congestive heart failure;cardiac arrhythmia;peripheral vascular disorders;liver disease;coagulopathy;deficiency anemia;hypothyroidism;fluid and electrolyte disorders;paralysis and other neurological diseases other than epilepsy;weight loss;pain;depression;suicide;alcohol abuse;and psychosis remained >1 throughout a period of 14 years. Conclusions: PWE have several chronic comorbid conditions. These conditions put significant health risks to PWE. Supported by: The Epilepsy Foundation. Disclosure: Dr. Kaiboriboon has nothing to disclose. Dr. Bakaki has nothing to disclose. Dr. Sattar has nothing to disclose. Dr. Schiltz has nothing to disclose. Dr. Kosachunhanun has nothing to disclose. Dr. Koroukian has nothing to disclose.

Prevalence Ratios for Unintended Pregnancy on Various Contraceptive Methods and AEDs in Women with Epilepsy: Interim Analysis from the Epilepsy Birth Control Registry (IN5-1.006)

Objective: To determine the prevalence of unintended pregnancy associated with various contraceptive methods (CMs) and categories of antiepileptic drugs (AEDs) in women with epilepsy (WWE). Background Contraception requires special consideration in WWE because contraceptive hormones have reciprocal interactions with AEDs that may affect seizures and CM efficacy. The relative efficacy of CMs in WWE in the community, however, has received little systematic investigation. Design/Methods: These retrospective data come from the first 350 WWE in the community, 18-47 years old, who completed the Epilepsy Birth Control Registry web-based survey that collected demographic, reproductive, contraceptive, epilepsy and AED data. We calculated prevalence ratios (probability of unplanned pregnancy on method / probability of unplanned pregnancy not on method) for CMs used by the survey population. We carried out univariate ANOVA to determine whether AED category (enzyme inducing EIAED, glucuronidated [lamotrigine, valproate] GLUAED, non enzyme inducing NEIAED and no AED) was a predictor of hormonal v non-hormonal CM failure. Results: Unintended pregnancies occurred in 125 (85.6%) of the 146 women who had pregnancies. Of the 340 pregnancies, 63.2%, were unintended as compared to 49% in a general U.S. population survey of 7,643 women (p = .0001). Prevalence ratios for unplanned pregnancy on various CMs is presented in decreasing order: no contraception - 10.45, withdrawal - 4.20, male condom - 0.72, oral contraceptive - 0.41 and depomedroxyprogesterone - 0.40. Prevalence ratios for AED categories was EIAED - 2.88, no AED - 0.91, GLUAED - 0.32, NEIAED - 0.28. In this interim analysis, ANOVA did not find AED category to be a significant predictor of hormonal versus non-hormonal CM failure. Conclusions: Unintended pregnancy may be more common among WWE than in the general population. Both the CM type and AED category impact the prevalence ratios of unintended pregnancies in WWE. Supported by: Epilepsy Foundation. Disclosure: Dr. Herzog has nothing to disclose. Dr. Davis has received personal compensation for activities with Bayer Pharmaceuticals and Schering Plough as an advisory board member.Dr. Davis has received research support from Bayer Pharmaceuticals. Dr. Hauser has received personal compensation for activities with Pfizer Inc, Ovation Pharmaceuticals, Inc., Valeant Pharmaceuticals as consultant. Dr. Saporta has nothing to disclose. Dr. Cahill has nothing to disclose. Dr. Fowler has nothing to disclose.

Diurnal and Sleep/Wake Patterns of Evolutions to Tonic-Clonic Seizures in Pediatric Epilepsy (P04.019)

Objective: To investigate the sleep/wake and 24-hour periodicity of evolutions into generalized tonic-clonic seizures. Background Generalized tonic-clonic seizures may evolve from seizures of variable semiology. These seizures constitute a risk factor for accidents, status epilepticus and sudden unexpected death in epilepsy. Design/Methods: Charts of 407 consecutive patients with epilepsy aged 0-21 years undergoing continuous video-EEG monitoring were reviewed for the presence of evolution into generalized tonic-clonic seizures. Seizures were characterized according to 2001 ILAE terminology. Charts were reviewed for EEG localization, MRI lesions, and seizure timing in 3-hour time blocks, out of sleep or wakefulness, and during the day (6AM-6PM) or night. Analysis was done with binomial testing. Results: Seventy-one patients (32 girls, mean age 12.63±5.3 years) had 223 seizures with evolutions into tonic-clonic semiology. Sleep/wakefulness was more related to seizure evolution than time of day, with more evolutions during sleep (p Conclusions: Evolutions to generalized tonic-clonic seizures from focal epilepsy occur more frequently out of sleep and in the morning. These findings contribute to the pathophysiological understanding of seizures and towards individualized therapies, including differential dosing and light therapy. Disclosure: Dr. Ramgopal has nothing to disclose. Dr. Shah has nothing to disclose. Dr. Vendrame has nothing to disclose. Dr. Zarowski has nothing to disclose. Dr. Alexopoulos has received personal compensation for activities with UCB Pharma as a speaker. Dr. Wyllie has nothing to disclose. Dr. Kothare has nothing to disclose. Dr. Loddenkemper has received personal compensation for activities with Eisai Inc. as a consultant. Dr. Loddenkemper has received research support from NIH/NINDS, The Epilepsy Foundation of America, CIMIT/DOD, Harvard Medical School Office of Faculty Development, and the Children9s Hospital Program for Patient Safety and Quality Improvement.

Sleep/Wake and Diurnal Variations of Seizure Evolution in Pediatric Patients (P02.167)

Objective: To investigate the relationship between clinical seizure evolution based on time of day and wakefulness/sleep in pediatric patients. Background ILAE seizure terminology permits characterization of seizure phases, such as evolution into generalized tonic-clonic seizures and other clinical presentations. This evolution may be dependent on clock time, sleep/wake status, and circadian rhythms. Design/Methods: Charts of 955 patients undergoing video-EEG monitoring for epilepsy were reviewed. Seizure evolution was characterized according to ILAE seizure terminology, EEG localization, and for timing in 3-hour blocks, during the day (6AM-6PM) or night, and in relation to sleep/wake status. Analysis was done with binomial testing, taking P values below 0.01 as significant. Results: 226 pediatric patients (107 girls, age 10.83 years 5.74) had 912 second-phase seizures. Of these, 93 patients (41 girls, age 11.69 years 5.73) had an additional 334 third-phase seizures. Evolutions into clonic seizures (28.5%), generalized tonic-clonic seizures (18.3%) and automotor seizures (13.3%) were most common. Peak times for evolutions were seen for different seizures, including clonic (6AM-9AM; p Conclusions: Diurnal and sleep/wake timing of seizure evolution varies based on clinical seizure type and localization. Our data assist in elucidating 24-hour seizure patterns, potentially providing new treatment approaches such as differential medication dosing. Disclosure: Dr. Loddenkemper has received personal compensation for activities with Eisai Inc. as a consultant. Dr. Loddenkemper has received research support from NIH/NINDS, The Epilepsy Foundation of America, CIMIT/DOD, Harvard Medical School Office of Faculty Development, and the Children9s Hospital Program for Patient Safety and Quality Improvement. Dr. Ramgopal has nothing to disclose. Dr. Shah has nothing to disclose. Dr. Zarowski has nothing to disclose. Dr. Vendrame has nothing to disclose. Dr. Alexopoulos has received personal compensation for activities with UCB Pharma as a speaker. Dr. Wyllie has nothing to disclose. Dr. Kothare has nothing to disclose.

Combination of Ictal EEG and Seizure Semiology Provides 24-Hour Seizure Susceptibility Profile (P04.018)

Objective: To investigate the occurrence of seizures based on sleep/wake status and electrographic localization in pediatric epilepsy. Background We previously described diurnal and sleep/wake patterns of seizures based on clinical presentation and electrographic localization. In this study, we investigated in a larger patient series whether the sleep/wake state of seizure onset can predict EEG localization of seizures with different semiology. Design/Methods: Charts of 955 consecutive patients with epilepsy undergoing continuous video-EEG monitoring were reviewed for EEG localization, seizure occurrence out of wakefulness or sleep and for clinical seizure type. Seizures were characterized according to 2001 ILAE terminology. Proportions were compared using binomial methods. Odds ratios were used to compare seizure localization based sleep/wake state. Results: 407 patients aged 0-21 (194 girls, mean age 9.2 ± 6.0 years) had 1,754 seizures. The majority of seizures occurred out of wakefulness (58%, p Conclusions: Sleep/wake states at seizure onset can predict EEG localization of seizures with certain semiology. Clonic, dyscognitive and myoclonic seizures have more likely a generalized EEG onset when occurring during wakefulness, and a focal EEG onset when occurring out of sleep. Disclosure: Dr. Ramgopal has nothing to disclose. Dr. Loddenkemper has received personal compensation for activities with Eisai Inc. as a consultant. Dr. Loddenkemper has received research support from NIH/NINDS, The Epilepsy Foundation of America, CIMIT/DOD, Harvard Medical School Office of Faculty Development, and the Children9s Hospital Program for Patient Safety and Quality Improvement. Dr. Vendrame has nothing to disclose. Dr. Shah has nothing to disclose. Dr. Zarowski has nothing to disclose. Dr. Alexopoulos has received personal compensation for activities with UCB Pharma as a speaker. Dr. Wyllie has nothing to disclose. Dr. Kothare has nothing to disclose.

Depiction of Seizure First Aid Management in Medical Television Dramas

The objective of this study was to investigate whether medical television dramas portray proper seizure first aid. Episodes of the four highest-rated US medical dramas ("Grey's Anatomy," "House M.D.", "Private Practice," and "ER") were screened for the presence of seizures. "Patient" age, sex, semiology, and etiology were recorded. The appropriateness of seizure first aid management was determined by comparison to the Epilepsy Foundation of America (EFA) guidelines. Among 364 television programs, 65 seizures (in 59 individuals) were identified (30 males; 29 females). Seizures were primary or secondarily generalized tonic-clonic in 53 (81.5%) cases. Other seizure types included complex partial (5, 7.7%), simple partial (1, 1.5%), myoclonic (1, 1.5%), absence (1, 1.5%), and psychogenic (1, 1.5%). On 63 occasions (96.9%), first aid was performed by a health care professional. First aid management was judged appropriate in 21 (32.3%) seizures, inappropriate in 28 (43.1%), and indeterminate in 16 (24.6%). Inappropriate practices included holding the person down (17, 26.2%), trying to stop the involuntary movements (10, 15.4%) and putting something in the person's mouth (11, 16.9%). The first aid management of seizures performed by actors portraying health care professionals was inappropriate in nearly half of all cases. Inaccurate depiction of seizure first aid management may contribute to misinformation of the general public. The television industry could easily incorporate the simple first aid EFA seizure guidelines as a public service without sacrificing dramatic impact.

Health Advocacy Organizations and Evidence-Based Medicine

STRONG AND INDEPENDENT NOT-FOR-PROFIT ADVOcacy organizations are vital to a democratic society. At their best, they stand apart from the interests of the marketplace and the government, helping to promote diverse public concerns. The scope of their activities is extensive. Some not-for-profit advocacy organizations spearhead campaigns to eliminate discriminatory legislation and improve the life chances of vulnerable groups. Others challenge economic interests to better protect the environment. Still others work to advance civil and human rights. Health advocacy organizations are part of this sector. They speak for targeted populations affected by a variety of diseases such as epilepsy, breast cancer, mental illness, and autism. They effectively communicate their priorities to legislators, regulators, private and public funders, and the media. Their initiatives often highlight needs that might otherwise be overlooked. However, some health advocacy organizations, as shall be illustrated, are so committed to securing diagnostic and treatment interventions for their targeted populations that they minimize the value of evidence-based medicine (EBM) and comparative effectiveness research. They also ignore the potential effects of their advocacy on health care costs. Many health advocacy organizations responded to a recent Institute of Medicine survey, the goal of which was to identify criteria for determining the essential health benefits package. They contended that EBM should serve merely as an aid in medical decision making, not as the basis for it. Outcome data, they insist, should not limit patient choice or restrict available services. The Epilepsy Foundation of America, for example, opposed the use of EBM “to broadly establish coverage rules that trump an individual’s circumstances and specific needs.” It should be “a tool for practitioners, patients and caregivers not applied across the patient population as a final decision on coverage.” So too, the National Alliance on Mental Illness states that EBM should be “a tool for practitioners, patients and caregivers, not a bright-line decision applied across the board.” The National Coalition of Cancer Survivorship also supports “an individualized approach to medical necessity, relying on evidence-driven decisions made by patients and physicians.” Some health advocacy organizations are so committed to promoting patient choice that they insist on unfettered access to branded drugs, regardless of the availability of generic products, and access to still unproven interventions. They oppose policies such as Fail First, which require a trial on less expensive medications before moving to brand name and other costly products; and they resist prior authorization requirements and the establishment of closed formularies on the grounds that they limit physician prerogatives and patient preferences. Mental Health America, for example, opposes these stipulations, stating they “fail to acknowledge that physicians and consumers should make individualized treatment decisions, recognizing the unique and non-interchangeable nature of human beings and psychotropic medications.” Moreover, some health advocacy organizations urge unlimited access to screening technologies regardless of evidence of efficacy or cost. They frame advocacy for early detection in more universal terms by emphasizing how many individuals are at risk for the disease. Mammography screening is a case in point. The American Cancer Society maintains that since 1 in 8 women have a lifetime risk of developing cancer of the breast, annual mammograms for all women older than 40 years are essential. This calculation, however, blurs the lines between the harms and benefits of screening a population with a low prevalence of the disease (women aged 40 to 49 years) and screening and surveillance of those with a higher risk (women older than 50 years). This approach to screening led some health advocacy organizations to oppose the recommendations of United States Preventive Services Task Force (USPSTF) when it recommended against “routine screening mammography in women aged 40 to 49 years.” The USPSTF stated that “although false-positive test results, overdiagnosis, and unnecessary earlier treatment are problems for all age groups, false-positive results are more common for women aged 40 to 49 years.”

Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry

Prenatal exposure to antiepileptic drugs is associated with a greater risk of major congenital malformations, but there is inadequate information on the comparative teratogenicity of individual antiepileptic drugs and the association with dose. We aimed to establish the risks of major congenital malformations after monotherapy exposure to four major antiepileptic drugs at different doses. The EURAP epilepsy and pregnancy registry is an observational cohort study representing a collaboration of physicians from 42 countries. We prospectively monitored pregnancies exposed to monotherapy with different doses of four common drugs: carbamazepine, lamotrigine, valproic acid, or phenobarbital. Our primary endpoint was the rate of major congenital malformations detected up to 12 months after birth. We assessed pregnancy outcomes according to dose at the time of conception irrespective of subsequent dose changes. After excluding pregnancies that ended in spontaneous abortions or chromosomal or genetic abnormalities, those in which the women had treatment changes in the first trimester, and those involving other diseases or treatments that could affect fetal outcome, we assessed rates of major congenital malformations in 1402 pregnancies exposed to carbamazepine, 1280 on lamotrigine, 1010 on valproic acid, and 217 on phenobarbital. An increase in malformation rates with increasing dose at the time of conception was recorded for all drugs. Multivariable analysis including ten covariates in addition to treatment with antiepileptic drugs showed that the risk of malformations was greater with a parental history of major congenital malformations (odds ratio 4·4, 95% CI 2·06-9·23). We noted the lowest rates of malformation with less than 300 mg per day lamotrigine (2·0% [17 events], 95% CI 1·19-3·24) and less than 400 mg per day carbamazepine (3·4% [5 events], 95% CI 1·11-7·71). Compared with lamotrigine monotherapy at doses less than 300 mg per day, risks of malformation were significantly higher with valproic acid and phenobarbital at all investigated doses, and with carbamazepine at doses greater than 400 mg per day. The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential. Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, Netherlands Epilepsy Foundation, Stockholm County Council, and ALF.