Highlights of the 2005 Joint Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society

December 2-6, 2005; Washington, DC

Andrew N. Wilner, MD, FAAN, FACP

February 02, 2006

The American Epilepsy Society (AES) and the American Clinical Neurophysiology Society (ACNS) held their joint annual meeting in Washington, DC, December 2-6, 2005. Clinicians and scientists came together to share the latest research data in epilepsy and neurophysiology. Abstracts based on these presentations were published in the 2005 issue of Epilepsia Volume 46, Supplement 8 (registration required).

Introduction

This year's AES and ACNS joint meeting featured the Annual Courses, Lennox Lecture, Merritt-Putman Symposium, National EpiFellows Foundation Scientific Forum, Investigator Workshops, Neurobehavioral Fellows Program, Plenary Sessions, Practice Resource and Management Courses Presidential Symposium, the 3rd Judith Hoyer Lecture in Epilepsy, and Special Symposia on AED Pharmacology, "Hot Topics," Impaired Consciousness, Pediatric State of the Art, Professionals in Epilepsy Care, Resective Epilepsy Surgery, a Spanish Symposium on New Antiepileptic Drugs, and the AET Symposium. In addition, there were 20 special interest groups, 36 platform presentations, and 1000 poster presentations. It's safe to say that even those who stayed for all 5 days could not attend every session. A few of the more interesting presentations are summarized in this report.

Herbs and Botanicals

One of the new special interest group meetings this year was herbs and botanicals (ie, Botanicals as Anticonvulsant Therapy), coordinated by Steven Schachter, MD, Professor of Neurology, Harvard Medical School Osher Institute, Boston, Massachusetts.

Dr. Schachter introduced the concept that herbs and botanicals may represent an economical and effective resource for modern epilepsy treatment. Natural products are contained in more than half of the best-selling US prescription drugs, such as aspirin (willow bark), digitalis (foxglove), galantamine (daffodil bulbs), and paclitaxel (Pacific yew tree bark). Over 100 drugs have been studied in the Far East for the treatment of epilepsy. More than 70% of people with epilepsy use herbs for their general health, and some try to treat their epilepsy with natural products.

Nicholas Sucher, MD, Children's Hospital and Harvard Medical School, Boston, described his basic science research in traditional Chinese medicine (TCM) treatments for stroke and epilepsy. Dr. Sucher explained the 4 major components of a TCM prescription: Jun ("Ruler") attacks the main cause or disease symptom; Chen ("Minister") is directed at the underlying cause, symptoms, and complications; Zuo ("Assistant") treats secondary symptoms and counteracts potential adverse effects of the primary drugs; and Shi ("Enabler") directs the action of all the other drugs into the correct channels. Each formulation contains a combination of approximately 7 drugs, which must be specially prepared by soaking and boiling. One TCM prescription, "Tian Ma Gou Teng Yin," which is prescribed to "calm excessive endogenous wind," contains 11 different drugs and is used for seizures, stroke, and hypertension. Dr. Sucher's studies revealed multiple mechanisms of action, including NMDA antagonism with a non-magnesium-type block, blockade of caspase-8 (an enzyme involved in programmed cell death), and neuroprotective properties. Dr. Sucher suggested that herbal medicines act with low affinity at multiple targets and may be more effective when used in combination.

Siegward-M. Elsas, MD, Assistant Professor of Neurology, Oregon Health and Science University, Portland, Oregon, noted that herbal epilepsy treatments are found throughout the world in native cultures. These include Ayurvedic medicine (Withaniasomnifera), the Pacific Islands (kava [Piper methysticum]), TCM (Piper nigrum, Cynanchum otophyllum), native North and South America (Passiflora incarnata), and Europe (valerian). Dr. Elsas observed that these compounds possess biochemical activity that warrants further research. For example, valepotriates from valerian inhibit gamma-aminobutyric acid (GABA) metabolism and may bind to GABA receptors. Passiflora incarnata enhances GABAA receptor ligand binding and is a partial GABAA agonist, inhibiting pentylenetetrazol-induced seizures in rodents. Kava enhances GABAA receptor ligand binding, inhibits voltage-gated Na+ and Ca++ channels, and inhibits strychnine-induced seizures in rodents.

Of importance, Dr. Elsas stated that botanicals are not without health risks. For example, kava may cause liver toxicity and ephedra and Ginko biloba may precipitate seizures. Dr. Elsas recommended that formal clinical trials need to be conducted to further investigate the use of herbs and botanicals in the treatment of epilepsy, and that compounds should elicit at least a 50% responder rate in order to qualify for further study.

Sudden Death

Sudden unexpected death in epilepsy (SUDEP) represents one of the gravest complications of epilepsy. Potential risk factors include abnormal electroencephalograms (EEGs), alcohol abuse, low antiepileptic drug (AED) levels, male sex, mental disability, noncompliance, the use of psychotropic medications, severe epilepsy, structural brain abnormalities, symptomatic epilepsy, unwitnessed nocturnal seizures, and young age. Patients are often found dead in their beds, presumably dying of respiratory or cardiac arrest.[1,2]

According to Maromi Nei, MD, Assistant Professor, Jefferson Comprehensive Epilepsy Center, Philadelphia, Pennsylvania, "SUDEP occurs with an overall risk of 6%, with several cases per year at high volume epilepsy centers. One proposed hypothesis for the etiology of SUDEP is that repetitive cardiac ischemia may occur during repeated seizures that renders the heart susceptible to fatal arrhythmias during seizures.[3]" In order to determine the frequency of cardiac abnormalities in people with epilepsy, Dr. Nei and her colleagues monitored 14 patients (9 men, 5 women; age, 18-49) with partial or generalized refractory epilepsy with a subcutaneous implanted electrocardiographic (ECG) recorder for 1.5-14 months (mean follow-up, 9.9 months). None of the patients had cardiac symptoms, such as presyncope, syncope, or palpitations. The device was set to record episodes of bradycardia (< 30 beats/minutes) or tachycardia (> 180 beats/minute) and could also be activated by the patient during a seizure. The number of seizures per patient during the monitoring period ranged from 3 to 236. During seizures, the mean ictal heart rate was 110 beats/minute (range, 76-198). Two patients had T-wave inversions during seizures. One patient had ST-segment elevation during seizures, and 1 patient had frequent atrial premature contractions postictally. One patient experienced a sinus arrest lasting 4.8 seconds during sleep, which was not associated with a seizure.

Dr. Nei made the following statements about the results:

 

Cardiac abnormalities during seizures tended to recur with other seizures, but not always. There was no correlation between seizure type and cardiac abnormality. These data do suggest that these patients might be at increased risk for cardiac ischemia in association with their seizures. I think it would be helpful for SUDEP patients to get an autopsy with a microscopic cardiac evaluation.

Dr. Nei also stated: "We need to define how important an issue SUDEP is and find the predictors in order to properly advise patients. Long-term follow-up and more collaboration with cardiologists and pulmonologists would help us learn more about these patients. We would like to do a multicenter study."

Epilepsy Education

Patient education is considered a mainstay in the treatment of any disease. In order to facilitate coping and compliance, people with seizures need to understand basic information about epilepsy and how to effectively manage their seizure disorder. One tool for epilepsy education is the Seizures and Epilepsy (S.E.E.) program*, a 2-day psychosocial program started 23 years ago by Robert Mittan, PhD, at the UCLA Comprehensive Epilepsy Center, Los Angeles, California. To date, the S.E.E. program has been attended by over 2000 people in 4 countries. To determine the effectiveness of the S.E.E. program for adolescents and their parents, Cheryl Shore, PhD, RN; Joan Austin, DNS, RN, Indiana University School of Nursing, Bloomington; and Susan Perkins, PhD, Indiana University School of Medicine, Indianapolis, conducted an outcomes study that measured child (ages 12-19 years) and parent outcomes 6 months after attending the program with self-report questionnaires.[4] There was no control group.

Subjects included 12 mothers (mean age, 42.2), 6 fathers (mean age, 45), and 10 children (mean age, 15.5). Outcomes for parents at 6 months that significantly improved from baseline were global health, role emotional-behavioral, bodily pain, behavior, mental health, parental impact-emotional, family activities, unmet needs for information, worry, and epilepsy knowledge. In addition, fewer unscheduled clinic visits (P = .0455) and child absences (P = .0469) were observed. Outcomes for children at 6 months that significantly improved from baseline were behavior, global behavior, mental health, self-esteem, change in health, family activities, and the child depression index.

On the basis of the results, Dr. Shore concluded: "Healthcare providers can recommend the S.E.E. program and reasonably expect that attendance will result in improved quality-of-life and seizure condition management."

*More information can be obtained at: www.theseeprogram.com

Vagus Nerve Stimulation for Children

Most patients with epilepsy are effectively treated with AEDs. For those who don't respond to medications, resective epilepsy surgery may be a curative option. However, many patients with intractable epilepsy are not good surgical candidates due to diffuse or multifocal epileptic foci or other reasons. For these patients, therapeutic alternatives include the ketogenic diet, clinical trials with new AEDs, and vagus nerve stimulation (VNS).

Approved by the US Food and Drug Administration (FDA) for the treatment of epilepsy in 1997, VNS is indicated as adjunctive therapy for adults and adolescents over 12 years of age with refractory partial-onset seizures. (More recently, VNS has also received FDA approval as adjunctive treatment for refractory depression in adults.) Because the options for treatment of younger children with refractory epilepsy are relatively limited, VNS has also been used "off-label" in this population.

Marcio Sotero de Menezes, MD, Associate Professor in the Department of Neurology and Pediatrics, University of Washington, Children's Hospital and Regional Medical Center, Seattle, Washington, and his colleagues presented a review of 43 children (24 boys, 19 girls) less than 12 years old with intractable epilepsy who had received VNS therapy for a mean of 18 months (range, 7-40 months).[5] Seizure types included generalized (N = 20), mixed (N = 15), and partial (N = 8). The median seizure frequency was 105/month. The children had tried an average of 5.6 AEDs; many had failed the ketogenic diet; and none were candidates for resective epilepsy surgery.

Overall, the median reduction in seizures was 84%. Twenty-two patients (51%) had a 50% or greater reduction in seizures; this level of reduction did not seem to be dependent on the seizure type. Although none of the patients became seizure-free, 16 had a 90% or greater reduction in seizures. Thirteen (30%) patients had less than a 50% reduction in seizures and 8 (19%) had an increase in seizure frequency. Complications included 2 infections, worsening of respiratory symptoms, and device failure.

On the basis of these results, Dr. Sotero de Menezes concluded: "The vagus nerve stimulator is an option for all intractable epilepsy patients who are not good resective epilepsy surgery candidates. The device has a very high retention rate."

EEG and Functional Magnetic Resonance Imaging Detect Epileptic Activity

The gold standard in the diagnosis of epilepsy is epileptic activity recorded by the EEG during an epileptic seizure. The detection and mapping of epileptic activity is critical for successful epileptic surgery and to make a secure diagnosis of nonepileptic seizures. However, sometimes epileptic activity goes undetected on routine EEG.

Bassel Abou-Khalil, MD, an epileptologist at Vanderbilt University Medical Center, Nashville, Tennessee, explained:

 

Scalp EEG only detects a small percentage of epileptic activity in the brain. It misses hippocampal activity and dipoles parallel to the surface, like mesial frontal activity. Unlike EEG, fMRI is not limited by depth and distance from the electrode. If you could find epileptic activity with fMRI, that would be an advantageous approach, which could overcome some of the limitations of EEG.

Dr. Abou-Khalil and colleagues, from the Montreal Neurological Institute, Montreal, Quebec, Canada, led by Victoria Morgan, PhD, explored the use of functional magnetic resonance imaging (fMRI) in 22 patients with temporal lobe epilepsy.[6] Fifteen patients had unilateral and 7 had bilateral independent temporal lobe spikes on EEG. The researchers compared 2 fMRI techniques, EEG-BOLD (blood oxygen level-dependent) and 2dTCA-BOLD (2-dimensional temporal lobe clustering) that may detect epileptic activity. TCA has the advantage of not requiring EEG information for analysis. Results revealed that the 2 techniques were complementary. The 2dTCA-BOLD technique identified 9 patients with epileptic activity missed by EEG-BOLD, but missed 2 that were identified by EEG-BOLD. However, it is important to note that the 2dTCA-BOLD method lacks specificity in regard to the sources of the detected activations.

Dr. Abou-Khalil stated: "This technology is very, very promising, but has challenges. It could potentially replace depth electrode testing for presurgical epilepsy candidates."

EEG and MEG

Another approach to detect epileptic activity is magnetoelectroencephalography (MEG). According to Anthony Bailey, BSc, MBBS, FRCPsych, DCH, Cheryl and Reece Scott Professor of Psychiatry at the University of Oxford, London, United Kingdom, "MEG complements EEG, but the superior spatial resolution of MEG allows the resolution of abnormalities not clearly resolvable using EEG."

William Nowack, MD, Associate Professor of Neurology, Kansas University Medical Center, Kansas City, Kansas, and Jeffrey Lewine, PhD, of the Hoglund Brain Imaging Center, Kansas University Medical Center, presented their comparative study of MEG and EEG in 10 adults with autistic spectrum disorder.[7] Dr. Nowack explained that the detection of subclinical epileptic activity in people with autism is important because it may contribute to language compromise and other neurologic deficits.

Two of the patients had a history of seizures, but none of the patients had active epilepsy or were taking AEDs. There were 7 men and 3 women, aged 22-51 years. Nearly all of the patients were high-functioning. Patients underwent MEG and EEG for 20 minutes. Of the 10 patients, 3 had epileptic activity on both MEG and EEG. A fourth patient had epileptic activity on MEG that could only be found on EEG in hindsight. In the fifth patient, MEG picked up epileptic activity from more regions than the EEG.

Dr. Nowack stated the following: "The current expense of MEG (about $5000) has limited population studies. If the cost decreases, we could use MEG to screen for interictal epileptic activity." On the basis of the results from this study, he concluded: "MEG picks up some activity that EEG does not. It may be worthwhile to do a controlled investigation of antiepileptic drugs in these patients to see whether or not they improve."

Conclusion

These conference highlights merely scratch the surface of the wealth of scientific research presented at this year's joint meeting of the AES and ACNS. The selected presentations illustrate the continuing progress and evolution of epilepsy research: Alternative and complementary medicine in the form of herbs and botanicals is now formally addressed as a potential resource for new and economical epilepsy treatment. The use of VNS has extended to very young children. The troublesome issue of sudden death in epilepsy is receiving more research and promoting collaboration with our cardiology colleagues. An objective assessment of the S.E.E. Educational Program endorses its long-term effectiveness. New technologies, such as MEG and fMRI, are complementing traditional EEG detection of epileptic activity. All of these advances promise to enrich our diagnostic and therapeutic tools for the care of people with epilepsy.

References

  1. Ben-Menachem E. Sudden death and epilepsy. Epilepsy Curr. 2005;5:223-224.

  2. Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology. 2005;64:1131-1133.

  3. Nei M, Ho RT, Payne M, Morales M, Wicks T, Sperling MR. Long-term cardiac rhythm abnormalities in refractory epilepsy. Program and abstracts of the 2005 Joint Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society; December 2-6, 2005; Washington, DC. Abstract 3.219.

  4. Shore CP, Perkins SM, Austin JK. Efficacy of the seizures and epilepsy (S.E.E.) program on quality of life, seizure management, and cost savings for adolescents with epilepsy and their parents. Program and abstracts of the 2005 Joint Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society; December 2-6, 2005; Washington, DC. Abstract 1.023.

  5. Saneto R, Sotero de Menezes MA, Ojemann J, et al. Vagus nerve stimulation therapy for medically intractable seizures in children under 12 years of age. Program and abstracts of the 2005 Joint Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society; December 2-6, 2005; Washington, DC. Abstract 2.408.

  6. Morgan V, Kobayashi E, Bagshaw A, et al. Concordance of EEG-BOLD and TCA-BOLD in temporal lobe epilepsy. Program and abstracts of the 2005 Joint Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society; December 2-6, 2005; Washington, DC. Abstract 3.125.

  7. Lewine JD, Nowack W. Magnetoencephalography (MEG) reveals epileptiform activity in adults with autism spectrum disorders. Program and abstracts of the 2005 Joint Meeting of the American Epilepsy Society and the American Clinical Neurophysiology Society; December 2-6, 2005; Washington, DC. Abstract 3.148.