Sept. 17, 2014
Autoimmune disorders have long been recognized as potential causes of seizures. In the extreme, autoimmune mechanisms can lead to limbic encephalitis, an acute disorder. However, accumulating evidence indicates that autoimmune factors may play a bigger role in seizure disorders than previously suspected, often without full features of limbic encephalitis. Patients with such disorders may respond to immunosuppressant therapies.
PET scan of woman experiencing frequent focal seizures and memory disturbance
Fluorodeoxyglucose positron emission tomography scan of a 62-year-old woman experiencing frequent focal seizures and severe memory disturbance. Marked hypermetabolism is visible in both hippocampi (arrow). The patient was found to have high titers of anti-GAD 65 antibody.
Mayo Clinic researchers have developed a new approach to diagnosing and treating autoimmune epilepsy. In research published in Neurology in 2014, 29 patients at Mayo Clinic with suspected autoimmune epilepsy were given an immunotherapy trial. The patients presented with epilepsy of recent onset, but often lacked other features of limbic encephalitis. The majority was found to have an anti-neural autoantibody.
Eighteen study participants (62 percent) achieved a reduction in seizure frequency of at least 50 percent. Ten patients (34 percent) became seizure-free. The findings provide evidence of a causative role for autoimmunity epilepsy and justification for continuing long-term immune suppression in some cases.
"Our work suggests that less-severe, more-pure epilepsy presentations may occur in people with neural antibodies, and these patients may respond quite well to immunotherapy," says Jeffrey W. Britton, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Rochester, Minnesota.
Importance of early diagnosis
Patients in the retrospective study were tested at Mayo's autoimmune neurology clinic. An autoimmune cause was suspected based on frequent or medically intractable seizures and the presence of at least one neural antibody, inflammatory changes indicated in spinal fluid or on MRI, or a personal or family history of autoimmunity. The time from onset of seizures to the start of immunotherapy was significantly shorter in patients who responded to treatment, indicating early therapy favors a beneficial response.
Mayo Clinic has a distinguished history in the research, diagnosis and treatment of autoimmune neurological disorders. "The discovery of antibodies targeting channels or receptors on the surface of nerve cells in the brain has really exploded in the past few years," says Sean J. Pittock, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Rochester, Minnesota. "We are now recognizing many disorders of the nervous system previously considered degenerative or idiopathic to be autoimmune."
MRI of woman experiencing frequent focal seizures and memory disturbance
MRI scans of a 62-year-old woman experiencing frequent focal seizures and severe memory disturbance. A. Coronal fluid-attenuated inversion recovery (FLAIR) imaging before treatment shows hyperintensity involving the bilateral orbitofrontal (bracket), right hypothalamic (white arrow) and bilateral hippocampal (yellow arrow) regions. B. Four months after treatment, orbitofrontal and hypothalamic abnormalities are shown to be resolved; however, both hippocampi show significant hyperintensity (yellow arrow).
For patients with medically intractable epilepsy, the implications are significant: Their conditions may be reversed or significantly improved with immunotherapies. "Having a biomarker for these patients is revolutionary, and paramount to understanding and treating them," says Joseph F. Drazkowski, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Phoenix, Arizona.
The prevalence of autoimmune epilepsy isn't known. Recent research suggests that people with autoimmune disease are almost four times likelier to have epilepsy than are people without autoimmune disorders. "Autoimmune-mediated epilepsy is probably a lot more common than we think," Dr. Britton says.
In addition to the presence of neural antibodies, clinical features suggestive of autoimmune epilepsy include:
- Acute to subacute onset, with seizures occurring every three months or less
- Multiple types of seizures or faciobrachial dystonic seizures
- Resistance to anti-seizure medication
- Personal or family history of autoimmunity
- History of recent or past neoplasia
- Viral prodrome
- Evidence of CNS inflammation
Dr. Britton notes that autoimmune-mediated seizures are often thought to occur only in conjunction with cancer. However, he says, many people with autoimmune epilepsy don't have cancer. Nonetheless, at Mayo, patients with a positive neural antibody test are assessed further to exclude cancer.
"We often see depression, anxiety, personality changes and memory dysfunction out of proportion to the amount of epilepsy the patient is experiencing," says Matthew T. Hoerth, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Phoenix, Arizona.
The '3 M's' of treatment
Mayo's standardized approach is based on three M's:
- Maximum reversibility of seizures
- Maintenance of reversibility
- Minimal therapeutic dosage
Patients receive high-dose immunotherapy, usually for six to 12 weeks, with objective testing at baseline and after therapy to define the extent of reversibility. "We want seizure freedom or at least seizure reduction for each patient," Dr. Pittock explains.
Reversibility is maintained with oral immunosuppressants such as prednisone, azathioprine, mycophenolate, methotrexate or rituximab — at the minimum effective dosage, to minimize side effects. The results are generally positive if patients are selected correctly. "Most of the patients get at least some benefit from immunotherapy. Prior to this they were having absolutely no results from anti-seizure drug therapy," Dr. Hoerth says.
Mayo's autoimmune epilepsy group is refining its standardized diagnostic and treatment protocol and designing randomized controlled trials to help better define the clinical characteristics suggestive of autoimmune epilepsy and the treatments required.
Dr. Britton notes that when he began practicing neurology 20 years ago, antibody-mediated neurological disorders were considered unresponsive to therapy. "But it's very clear that's not true," he says. "There are some patients who respond extremely well. That gives some hope to people who have autoimmunity as a possible cause of their epilepsy."
For more information
Toledano M, et al. Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy. Neurology. 2014;82:1578.
Autoimmune epilepsy evaluation
A comprehensive autoimmune epilepsy evaluation for serum and cerebral spinal fluid is available from Mayo Medical Laboratories. "This evaluation provides neurologists with cutting-edge neural autoantibody testing for patients with unexplained medically intractable epilepsy," says Dr. Pittock. "The serum evaluation includes approximately 20 antibodies specifically relevant to autoimmune epilepsy."
Mayo Clinic neurologists provide interpretation of test results and are available for consultation with referring physicians. Testing must be ordered by a hospital laboratory.