Immunotherapy Promising for Intractable Epilepsy

Allison Shelley

March 29, 2012

March 29, 2012 — Immunotherapy may be effective in treating medically intractable epilepsy in patients with specific clinical and serologic markers, new research suggests.

The seizure freedom we saw in our study is better than any antiepileptic drug ever studied.

According to investigators a "striking" 67% of patients with daily seizures who were resistant to treatment with 2 or more antiepileptic drugs (AEDs) were free of seizures after receiving immunotherapy.

"The seizure freedom we saw in our study is better than any antiepileptic drug ever studied," senior investigator Sean Pittock, MD, from the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News.

"This is very exciting and there is growing literature to support autoimmunity, not just in epilepsy, but in other areas of neurology as well — dementia, movement disorders, and neurodegenerative diseases."

The results, published online March 26 in the Archives of Neurology, suggest an autoimmune basis for intractable epilepsy.

History of Autoimmune Disease

Dr. Pittock noted many of the patients he sees have a personal history of autoimmune thyroid problems, lupus, or type 1 diabetes or a family history of rheumatoid arthritis.

"There is something different about these patients," he said, pointing out that his team found neural autoantibodies in most patients.

Table 1. Neural Autoantibodies

Antibody Percentage
Voltage-gated potassium channel complex 56
Glutamic acid decarboxylase 65 22
Collapsin response-mediator protein 5 6

The researchers led by Amy Quek, MBBS, also at the Mayo Clinic, found Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.

The observational retrospective case series included 32 patients with partial seizures. Most (81%) had failed treatment with 2 or more AEDs and 38% had seizure semiologies that were multifocal or changed with time.

Head magnetic resonance imaging was normal in 47% of patients at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20 patients, electrographic seizures in 15, and focal slowing in 13.

Patients received immunotherapy with intravenous methylprednisolone, intravenous immune globulin, and combinations of these drugs with plasmapheresis or cyclophosphamide.

New Subspecialty

After a median of 17 months, 81% of patients reported postimmunotherapy improvement. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05).

Table 2. Epilepsy Outcomes (n=27)

Outcome Percentage
Seizure freedom 67
Seizure improvement 15
No change 18

All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection and another responded to antiepileptic drug change alone.

When autoimmune epilepsy is suspected on clinical grounds, the authors suggest cerebrospinal fluid evaluation and comprehensive screening for neural autoantibodies are indicated.

Selective autoantibody testing is not advised because no single neural antibody is definitively associated with seizures.

In the absence of other treatment options, a trial of 6 to 12 weeks of immunotherapy is justified, the authors suggest. Long-term immunosuppressive treatment, overlapping with gradual taper, should be considered for patients whose seizures respond favorably to the initial trial of immunotherapy.

Clinical experience suggests that immunotherapy should not be used alone to control seizures, but should be used in combination with antiepileptic drugs to optimize seizure control.

Many questions remain, Dr. Pittock told Medscape Medical News. These include the natural history of autoimmune epilepsy, the selection criteria for patients with epilepsy most likely to benefit from an autoimmune evaluation, the timing for immunotherapy trial, and optimal duration of long-term immunotherapy maintenance.

"There's a whole new subspecialty emerging in neurology," Dr. Pittock said. "It's known as autoimmune neurology and we are working with the American Academy of Neurology (AAN) to launch courses exploring this area."

Dr. Pittock will be teaching a course on this topic next month at the AAN's 64th Annual Meeting in New Orleans, Louisiana. He will be presenting with Drs. Josep Dalmau, Andrew McKeon, and Mark Keegan.


Perhaps the failure of new antiepileptic drugs is because some of these patients have autoimmune-mediated epilepsy.

In an accompanying editorial, Gregory Bergey, MD, from Johns Hopkins University in Baltimore, Maryland, noted that although the study was not a placebo-controlled trial and all patients were treated, two-thirds achieved seizure freedom for a median of 10 months and 44% became seizure free within 12 months of treatment.

"The typical investigational antiepileptic drug trial produces seizure freedom in fewer than 10% of patients even if seizure freedom is defined as only a 12-week period," Dr. Bergey writes.

Screening for autoantibodies is not required for entry into investigational antiepileptic drug trials, he pointed out.

"Perhaps the failure of new antiepileptic drugs is because some of these patients have autoimmune-mediated epilepsy," he writes.

Dr. Bergey added that the study is another reminder that "we need to broaden our concept of symptomatic chronic epilepsy from the structural realm into more dynamic processes not limited to acute inflammatory or infectious pathologies."

Although not part of a controlled series, the subjects in the current study represent an extensive group of patients with diverse autoantibodies treated with immunotherapy.

"What is the true scope of autoimmune epilepsy in our populations of drug-resistant epilepsy? This is not known, but certainly at present it is probably being underdiagnosed," he writes.

If a clear symptomatic cause for a patient's epilepsy is identified such as mesial temporal sclerosis, cortical dysplasia, or cavernous malformation, then autoantibody testing is probably unnecessary, he noted.

"However, if imaging is unrevealing or suggests inflammation or focal swelling, then such screening may be warranted."

EUROIMMUN provided assay kits for identifying autoantibodies in this study. Dr. Pittock is a named inventor on patents that relate to functional assays. He receives research support from Alexion Pharmaceuticals, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. Editorialist Dr. Bergey has disclosed no relevant financial relationships.

Arch Neurol. Published online March 26, 2012.


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