Epilepsy affects more than two million individuals of all ages in the U.S. alone and at least 50 million worldwide. It is characterized by the occurrence of spontaneous, unpredictable seizures, which can interfere with daily life, cause physical injury, and lead to brain cell damage. For many patients the seizures are not controlled by currently available medical therapies. Treatment options are limited for these patients to include epilepsy surgery, vagus nerve stimulation, or experimental therapies. While much information is available about the abnormal communication of neuronal networks in epilepsy, the basic mechanisms of epilepsies that involve both genetic and acquired causes are not fully understood.
Basic scientists are studying how specific changes in the brain eventually produce epilepsy and how brief or prolonged seizures directly alter brain function. These include changes in gene expression, "rewiring" of brain connections, and the death or birth of specific brain cells. Researchers are also studying how seizures start, spread, and stop; why certain types of seizures occur at specific ages or in response to distinct stimuli; and how antiepileptic medications work on brain cells to block seizures.
Mayo Clinic researchers are studying many areas of epilepsy and have made milestone advances. Some of the ongoing research and their accomplishments are listed below.
Gregory Worrell, M.D., is leading a laboratory team focused on investigating electrophysiological signatures of epileptogenic brain and the transition from normal brain activity to seizures (ictogenesis). Electrophysiological biomarkers of epileptogenic brain and precursor signals that precede the onset of clinical seizures may make seizure warning devices possible, as well as lead to improvements in the efficacy of epilepsy surgery and brain stimulation.
Gregory Cascino, M.D., is focusing on the care and management of patients with intractable epilepsy. The goals of the research are to render these individuals seizure-free without treatment-induced adverse effects to allow the patients to become participating and productive members of society. This includes the diagnostic evaluation involving structural and functional neuroimaging, long-term EEG monitoring, and intracranial EEG recordings. His team has been assessing the importance of hippocampal volumetric studies and subtraction ictal SPECT co-registered to SPECT (SISCOM) in the identification of surgically remediable epileptic syndromes. The introduction of MRI-based hippocampal volumetry in patients with temporal lobe epilepsy by Clifford R. Jack, M.D., and colleagues at Mayo Clinic has confirmed the presence of focal pathology in patients being considered for surgical treatment. SISCOM has been developed by Elson L. So, M.D., and colleagues. These neuroimaging techniques may be used to select potential operative candidates with intractable partial epilepsy.
Treatment options for intractable epilepsy include epilepsy surgery, vagus nerve stimulation, ketogenic diet, and investigational therapies. They are evaluating the safety and efficacy of electrical stimulation using responsive neurostimulation (NeuroPace, Inc.) for intractable partial epilepsy.
Gregory Cascino, M.D., is also a principal investigator at Mayo Clinic in the National Institutes of Health-funded study Epilepsy Phenome/Genome Project (EPGP) that began in 2007. The goal of this investigation is to understand the pathophysiology and clinical expression of idiopathic (genetic) epileptic syndromes. The Epilepsy Phenome/Genome Project is a large-scale, national, multi-institutional, collaborative research project aimed at advancing our understanding of the genetic basis of the most common forms of idiopathic and cryptogenic epilepsies and a subset of symptomatic epilepsy; i.e., epilepsies that are likely related to genetic predispositions or developmental anomalies rather than endogenous, acquired factors such as CNS infection, head trauma, or stroke. The overall strategy of EPGP is to collect extremely detailed phenotypic information on a large population of patients with epilepsy, and to use state-of-the-art bioinformatics to identify the potential contribution of genomic and somatic variability to the epilepsy phenotype, to developmental anomalies of the central nervous system, and to the varied therapeutic response of patients treated with antiepileptic drug medication.
Joseph I. Sirven, M.D., is conducting research that pertains to all facets of the diagnosis and management of seizures and epilepsy. Dr. Sirven has studied various therapeutic modalities in this age group, including epilepsy surgery, electrical stimulation, and antiepileptic drugs. Currently, he is involved in evaluating the impact of antiseizure drugs on balance function. Dr. Sirven chairs the Seniors and Seizures Task Force for the Epilepsy Foundation of America.
Dr. Sirven's research also includes social issues as they pertain to epilepsy. He has extensively studied the stigma of epilepsy as it is portrayed in the media, as laws are written on the topic for the Federal Aviation Administration and on Complementary and alternative medicine for epilepsy. Dr. Sirven is also involved in research involving seizures in the Hispanic population. In 2005, he published the first national survey of U.S. Hispanic attitudes and knowledge about epilepsy and seizures, and his research continues in this endeavor.
Dr. Sirven is also studying epilepsy as it pertains to new therapeutic modalities for seizure treatment with either new drugs or devices. He is actively involved in research using devices that deliver electrical stimulation for epilepsy as well as several research trials involving new anti-seizure medications. He is also working with a new device to help predict when seizures are likely to occur.
In a study entitled "Does co-morbid ADHD predispose to seizure activity in children?" William Barbaresi, M.D., Slavica Katusic, M.D., and Elaine Wirrell, M.D., are investigating the frequency of seizure activity (febrile, unprovoked, and epilepsy) in a previously identified population-based birth cohort of ADHD cases compared to case-controls. Their primary hypothesis is that there is a higher frequency of unprovoked seizures and epilepsy in ADHD cases than in non-ADHD controls. The secondary hypotheses are:
- The highest frequency of epilepsy will be found among the subgroup with "definite ADHD," and a lower frequency of epilepsy will be identified in the subgroup with "intermediate-risk ADHD."
- ADHD with other neurodevelopmental disorders or cognitive impairment will have a higher frequency of epilepsy than ADHD without these co-morbidities.
- Epilepsy will be more frequent in those with ADHD-inattentive subtype than those with ADHD-hyperactive/impulsive subtype or ADHD-combined subtype.
From this study they also hope to describe the characteristics of seizures, including the severity of epilepsy, response to treatment, EEG findings, and underlying etiology in the ADHD cases compared to non-ADHD controls. They will also assess the temporal relationship of ADHD diagnosis and onset of seizure activity in the subgroup of ADHD cases with co-morbid seizures.
Elson So, M.D., is researching diagnostic tests and treatment approaches in the management of patients with seizure disorders. Dr. So has recently been investigating the development of advanced techniques of imaging for localizing the seizure focus for epilepsy surgery. He is also conducting research on the morbidity and mortality in persons with epilepsy, especially injuries due to seizures and the phenomenon of sudden unexplained death in epilepsy (SUDEP). Dr. So led the effort at Mayo Clinic for the development of SISCOM studies. The use of peri-ictal SPECT in patients with intractable partial epilepsy has been shown to be of diagnostic and prognostic importance in individuals being considered for surgical treatment.
Katherine Nickels, M.D., is conducting research in pediatric epilepsy, where one of the most concerning risks of withdrawal of medication is the recurrence of seizures. Furthermore, these seizures may be intractable. According to previous studies, the risk of developing intractable epilepsy following withdrawal of antiepileptic medication is between 1 and 20 percent. However, these studies did not include all seizure types. Neuroimaging and EEGs were not consistently used to determine if antiepileptic medications should be withdrawn. Failure to account for abnormalities in neuroimaging and EEG may lead to premature medication withdrawal. Furthermore, the majority of previous studies were not population-based. This could lead to an increased frequency of children who develop intractable epilepsy and may over-estimate the risk of developing intractable epilepsy following discontinuation of antiepileptic medications in seizure-free children with epilepsy. Dr. Nickels is conducting a retrospective chart review to 1) report on the number of children with epilepsy in a population-based cohort who were able to discontinue antiepileptic medications due to seizure-free status; 2) examine the number of children who, after discontinuation of antiepileptic medication due to seizure-free status, developed recurrence of seizures; 3) determine the risk of developing intractable epilepsy following discontinuation of antiepileptic medication in seizure-free children with epilepsy; and 4) determine the risk factors for developing intractable epilepsy following discontinuation of antiepileptic medication in seizure-free children with epilepsy.
Mayo Clinic researchers have made significant progress and discoveries in diagnosis and treatment of epilepsy. This section contains some of their milestones in conquering this disease.
A neurology team from Mayo Clinic's Jacksonville and Arizona campuses led by Katherine Noe, M.D., Ph.D., found that the young men with epilepsy who have normal bone density measurements are at risk of developing seizure-related vertebral fractures, and that tests that generally predict bone weakening and osteoporosis did not predict the risk of compression fractures in young men. Joseph Sirven, M.D., and Sara Schrader, M.D. are other investigators on the team. The patients' T-scores--the bone mineral density measurements--were within normal ranges. Yet, all felt acute back pain after well-documented seizures, and X-rays confirmed the presence of vertebrae fractured from the mechanical stress of seizures. The vertebral compression fractures appear to result from bone demineralization caused by anticonvulsants prescribed to control seizures. The team is the first to identify a new potential negative side effect of some seizure medications by noting that traditional bone density measurements do not adequately predict the risk of compression fractures.
Gregory Cascino, M.D., and other Mayo Clinic researchers found that 81 percent of patients with intractable epilepsy become totally or nearly seizure-free six months following epilepsy surgery. Ten years later, 72 percent remained totally or nearly seizure-free. In one of the largest epilepsy surgery studies ever conducted, the results show that seizure surgery is durable and remains effective and safe over time.
Elaine Wirrell, M.D., and colleagues investigated the time of onset of ketosis and the efficacy of a ketogenic diet when the classic ketogenic diet is initiated at full calories without a prior fast in children with epilepsy. They did a retrospective hospital and neurology clinic chart review of 14 children on the classic ketogenic diet at full calories without a prior fast to determine time to ketosis, time to good ketosis (urine ketones >=80 mg/dL), and success of the ketogenic diet. Median age at diet initiation was 63 months (25th-75th percentile, 47-149 months). There were 7 girls and 7 boys. Four had symptomatic generalized epilepsy, whereas the remainder had partial seizures with secondary generalization. Twelve of 14 children suffered seizures on a daily basis prior to the ketogenic diet. Six were commenced on the diet as outpatients, whereas 8 were admitted to hospital. No patients were fasted. All admitted patients were started on a 1:1 ketogenic ratio at full calories for the first 24 hours and advanced to a 3:1 or 4:1 ratio over 3 to 4 days, while outpatients were started on a 1:1 or 2:1 ratio and similarly advanced. They found that the ketogenic diet can be effectively initiated without a fast in children with epilepsy. Time to ketosis and diet efficacy are similar to protocols that use a fast. (E Wirrell, HZ Darwish, C Williams-Dyjur, M Blackman, V Lange. Is a fast necessary when initiating the ketogenic diet? J Child Neuro 2002;17:179-82.)
Dr. Wirrell and her colleagues compared sleep patterns in children with epilepsy with those of their non-epileptic siblings to determine which epilepsy-specific factors predict greater sleep disturbance. They conducted a case-control study of 55 children with epilepsy and their nearest-aged non-epileptic sibling. Parents or caregivers completed the Sleep Behavior Questionnaire and Child Behavior Checklist for patients and controls, and the Quality of Life in Childhood Epilepsy for patients. They concluded that children with epilepsy in this current study had significantly greater sleep problems than their non-epileptic siblings. (E Wirrell, M Blackman, K Barlow, J Mah, L Hamiwka. Sleep disturbances in children with epilepsy compared to their nearest aged siblings. Dev Med Child Neurol 2005;47:754-759.)
Dr. Wirrell also studied whether children and teens with epilepsy participate in less physical activity and have higher body mass index (BMI) percentiles for age than do their siblings without epilepsy; and what epilepsy-specific factors limit their participation. They found that programs that promote exercise in adolescents with epilepsy should be encouraged to improve their physical, psychological, and social well-being. (J Wong*, E Wirrell. Physical activity in children with epilepsy compared to their siblings without epilepsy. Epilepsia 2006;47:631-639.)
Dr. Wirrell and colleagues studied to determine the range of diagnoses and the prevalence of previous seizures in children presenting to a first seizure clinic. They studied 127 children who were seen in a tertiary care first seizure clinic, looking at referring physician specialty; child's age, gender, and developmental status; and clinical diagnosis of the epileptologist (non-epileptic vs. epileptic). They found that diagnostic inaccuracy is common in a first seizure. One quarter of children were incorrectly diagnosed as having a seizure, while the diagnosis of epilepsy was missed in over one-third of children. (LD Hamiwka, N Singh, J Niosi, E Wirrell. Diagnostic inaccuracy in children presenting with "first seizure": role for a first seizure clinic. Epilepsia 2007;48:1062-6.)