Steven C. Schachter

Vagus nerve stimulation therapy for partial-onset seizures A randomized active-control trial

Objective: The purpose of this multicenter, add-on, double-blind, randomized, active-control study was to compare the efficacy and safety of presumably therapeutic (high) vagus nerve stimulation with less (low) stimulation. Background: Chronic intermittent left vagus nerve stimulation has been shown in animal models and in preliminary clinical trials to suppress the occurrence of seizures. Methods: Patients had at least six partial-onset seizures over 30 days involving complex partial or secondarily generalized seizures. Concurrent antiepileptic drugs were unaltered. After a 3-month baseline, patients were surgically implanted with stimulating leads coiled around the left vagus nerve and connected to an infraclavicular subcutaneous programmable pacemaker-like generator. After randomization, device initiation, and a 2-week ramp-up period, patients were assessed for seizure counts and safety over 3 months. The primary efficacy variable was the percentage change in total seizure frequency compared with baseline. Results: Patients receiving high stimulation (94 patients, ages 13 to 54 years) had an average 28% reduction in total seizure frequency compared with a 15% reduction in the low stimulation group (102 patients, ages 15 to 60 year; p = 0.04). The high-stimulation group also had greater improvements on global evaluation scores, as rated by a blinded interviewer and the patient. High stimulation was associated with more voice alteration and dyspnea. No changes in physiologic indicators of gastric, cardiac, or pulmonary functions occurred. Conclusions: Vagus nerve stimulation is an effective and safe adjunctive treatment for patients with refractory partial-onset seizures. It represents the advent of a new, nonpharmacologic treatment for epilepsy.

Drug-Resistant Epilepsy

Nearly a quarter of patients with seizures have drug-resistant epilepsy. This review examines how this diagnosis should be established and how to recognize pseudoresistance. It explains possible mechanisms of drug-resistant epilepsy and presents treatment strategies.

Prospective Long-Term Study of Vagus Nerve Stimulation for the Treatment of Refractory Seizures

Summary: Purpose: To determine the long‐term efficacy of vagus nerve stimulation (VNS) for refractory seizures. VNS is a new treatment for refractory epilepsy. Two short‐term double‐blind trials have demonstrated its safety and efficacy, and one long‐term study in 114 patients has demonstrated a cumulative improvement in efficacy at 1 year. We report the largest prospective long‐term study of VNS to date.

Associations of handedness with hair color and learning disabilities.

Forms containing the Edinburgh handedness inventory and questions about learning disabilities, hair color, self-described handedness, age, gender, parental handedness and twinning were received from 1117 randomly selected professionals. Laterality scores (LS, range -100 to +100) were calculated for each respondent based on the handedness inventory and were correlated with the above variables. Among blonds, the frequency of non right-handedness (NRH, LS less than or equal to 70) was 44% compared to 24% of non-blonds (chi 2 = 23.5, P less than 0.0001). Learning disabilities (LD) were present in 9% of NRH (LS less than or equal to 70) as against 3% of those with LS greater than 70 (chi 2 = 22.1, P less than 0.0001). Associations between LS and self-described handedness, parental handedness, gender, and age are also presented. Possible explanations for the association of hair color and handedness are discussed in light of recent data on altered visual system pathways in albinos. Problems in the measurement of handedness are discussed.

Core Competencies in Integrative Medicine for Medical School Curricula: A Proposal

The authors present a set of curriculum guidelines in integrative medicine for medical schools developed during 2002 and 2003 by the Education Working Group of the Consortium of Academic Health Centers for Integrative Medicine (CAHCIM) and endorsed by the CAHCIM Steering Committee in May 2003. CAHCIM is a consortium of 23 academic health centers working together to help transform health care through rigorous scientific studies, new models of clinical care, and innovative educational programs that integrate biomedicine, the complexity of human beings, the intrinsic nature of healing, and the rich diversity of therapeutic systems. Integrative medicine can be defined as an approach to the practice of medicine that makes use of the best-available evidence taking into account the whole person (body, mind, and spirit), including all aspects of lifestyle. It emphasizes the therapeutic relationship and makes use of both conventional and complementary/alternative approaches. The competencies described in this article delineate the values, knowledge, attitudes, and skills that CAHCIM believes are fundamental to the field of integrative medicine. Many of these competencies reaffirm humanistic values inherent to the practice of all medical specialties, while others are more specifically relevant to the delivery of the integrative approach to medical care, including the most commonly used complementary/alternative medicine modalities, and the legal, ethical, regulatory, and political influences on the practice of integrative medicine. The authors also discuss the specific challenges likely to face medical educators in implementing and evaluating these competencies, and provide specific examples of implementation and evaluation strategies that have been found to be successful at a variety of CAHCIM schools.

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:  Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy

Nearly one-third of patients with epilepsy continue to have seizures despite optimal medication management. Systems employed to detect seizures may have the potential to improve outcomes in these patients by allowing more tailored therapies and might, additionally, have a role in accident and SUDEP prevention. Automated seizure detection and prediction require algorithms which employ feature computation and subsequent classification. Over the last few decades, methods have been developed to detect seizures utilizing scalp and intracranial EEG, electrocardiography, accelerometry and motion sensors, electrodermal activity, and audio/video captures. To date, it is unclear which combination of detection technologies yields the best results, and approaches may ultimately need to be individualized. This review presents an overview of seizure detection and related prediction methods and discusses their potential uses in closed-loop warning systems in epilepsy.

Depression and epilepsy: Epidemiologic and neurobiologic perspectives that may explain their high comorbid occurrence☆

Depression is the most frequent psychiatric comorbidity in people with epilepsy (PWE) with lifetime prevalence rates ranging between 30 and 35%. Multifactorial variables play a pathogenic role in the high comorbid occurrence of these two disorders. These variables were critically examined during an international symposium held in Chicago in September 2010, the results of which are presented in two companion manuscripts. The first manuscript summarizes new epidemiologic data highlighting the bidirectional relation between depression and epilepsy and related methodological issues in studying this relationship. An examination of the neurobiologic aspects of primary mood disorders, mood disorders in PWE and pathogenic mechanisms of epilepsy derived from studies in animal models and humans is allowing a better understanding of the complex relation between the two conditions. In the first manuscript, we review data from animal models of epilepsy in which equivalent symptoms of depression and anxiety disorders develop and, conversely, animal models of depression in which the kindling process is facilitated. Data from structural and functional neuroimaging studies in humans provide a further understanding of potential common pathogenic mechanisms operant in depression and epilepsy that may explain their high comorbidity. The negative impact of depression on the control of seizure disorders has been documented in various studies. In this manuscript, these data are reviewed and potential mechanisms explaining this phenomenon are proposed.

Oxcarbazepine Double-blind, randomized, placebo-control, monotherapy trial for partial seizures

Objective: To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. Methods: A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. Results: Analysis of the primary efficacy variable—time to meeting one of the exit criteria—showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables—percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)—were also statistically significant in favor of oxcarbazepine. Conclusion: These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.OBJECTIVE To evaluate the efficacy and safety of oxcarbazepine in a placebo-control trial. METHODS A multicenter, double-blind, randomized, placebo-control, two-arm parallel group, monotherapy design was used to compare oxcarbazepine administered 1,200 mg twice daily to placebo in hospitalized patients with refractory partial seizures, including simple and complex partial seizures and partial seizures evolving to secondarily generalized seizures. Patients exited the trial after completing the 10-day double-blind treatment phase or after experiencing four partial seizures, two new-onset secondarily generalized seizures, serial seizures, or status epilepticus, whichever came first. RESULTS Analysis of the primary efficacy variable--time to meeting one of the exit criteria--showed a statistically significant effect in favor of oxcarbazepine (p = 0.0001). The secondary efficacy variables--percentage of patients who met one of the exit criteria (p = 0.0001) and total partial seizure frequency per 9 days during the double-blind treatment (p = 0.0001)--were also statistically significant in favor of oxcarbazepine. CONCLUSION These results demonstrate that oxcarbazepine given as monotherapy is effective and safe for the treatment of partial seizures in this paradigm.

Drug treatment of epilepsy in adults

Epilepsy is a serious, potentially life shortening brain disorder, the symptoms of which can be successfully treated in most patients with one or more antiepileptic drug. About two in three adults with new onset epilepsy will achieve lasting seizure remission on or off these drugs, although around half will experience mild to moderately severe adverse effects. Patients with epilepsy, especially the 20-30% whose seizures are not fully controlled with available drugs (drug resistant epilepsy), have a significantly increased risk of death, as well as psychiatric and somatic comorbidities, and adverse effects from antiepileptic drugs. Newer drugs have brought more treatment options, and some such as levetiracetam cause fewer drug interactions and less hypersensitivity than older ones. However, they do not reduce the prevalence of drug resistant epilepsy or prevent the development of epilepsy in patients at high risk, such as those with a traumatic brain injury. The development of antiepileptic drugs urgently needs to be revitalized so that we can discover more effective antiseizure drugs for the treatment of drug resistant epilepsy, including catastrophic forms. Antiepileptogenic agents to prevent epilepsy before the first seizure in at risk patients and disease modifying agents to control ongoing severe epilepsy associated with progressive underlying disease are also needed.