Pauline Anderson

December 07, 2015

PHILADELPHIA — Researchers are identifying an increasing number of antibodies that are the culprit behind seizure disorders in adults.

There's now a "very big list" of such antibodies that target the inside or the outside of the neuronal cell, said Claude Steriade, MD, Division of Neurology, University of Toronto, Ontario, Canada.

"Over the past few years, there has been increasing recognition that some forms of epilepsy are immune mediated; they're associated with antibodies that target neurons," said Dr Steriade.

At a press briefing during the American Epilepsy Society (AES) 69th Annual Meeting here, Dr Steriade presented a study illustrating that different antibodies can lead to very different diseases.

It's well known that antineuronal antibodies cause a variety of neurologic symptoms, from gait and coordination difficulties to rapidly progressing dementia, as well as seizures, said Dr Steriade. But it's only recently that researchers are recognizing that epilepsy can be the predominant feature, she said.

It's not clear how these antibodies get triggered, although some cases are associated with an underlying tumor that the immune response targets.

"As a side effect of this immune response, antibodies are created that then cross the blood-brain barrier, recognize proteins within the brain, and cause cerebral dysfunction," explained Dr Steriade.

Not all these antibodies are the same, however. Some target proteins inside the cell (intracellular antigens) and others target proteins on the surface of the cell (cell-surface receptor antigens).

Immunologic factors appear to separate these two types of antibodies. Those that target intracellular antigens are associated with a T-cell immune response and with cancer, while the ones targeting proteins on the cell surface are typically associated with a B-cell response and are not associated with an underlying cancer.

"The difference between these antibodies in terms of their immunology translates into different clinical pictures and different treatment response," said Dr Steriade.

This was reflected in her study that took a closer look at the differences between the "in" and the "out" antibodies.

The study included patients with autoimmune epilepsy as the predominant neurologic feature, so their main presenting symptom was seizures. Four of these patients had antibodies to an intracellular antigen (MA2) and eight had antibodies targeting a protein outside the cell (leucine-rich glioma inactivated-1 or [LGI1]).

The patient population was "representative of what we know about these antibodies," Dr Steriade noted. For example, those with MA2 antibodies tended to have a more severe course.

"They were often admitted to the intensive care unit; they often had other neurological symptoms, including narcolepsy, eye movement abnormalities, and signs of parkinsonism; and they also had psychiatric disturbances, which ranged from mood disorders to quite severe psychosis, as well as cognitive impairment, which ranged from mild dysfunction to quite severe dementia."

Cognitive and psychiatric disturbances were also common in the group with LGI1.

Some 75% of the MA2 patients and none of the LGI1 patients had an underlying malignancy.

Almost all the MA2 patients and half of those in the LGI1 group had mesial temporal hyperintensities, "which correlates with them having seizures and cognitive impairment," said Dr Steriade. However, she added, the MA2 group tended to have more hippocampal atrophy, "which sort of implies that the destructive process is more active and malignant."

For the most part, only the MA2 antibody group had status epilepticus, again "portending a poorer and more malignant clinical course," said Dr Steriade.

Patients with LGI1 antibodies had very unusual seizure types that were highly suggestive of an autoimmune cause, she said. For example, some had focal tonic or faciobrachial dystonic seizures involving contractions of the arm, face, and leg.

"This type of seizure is only ever seen with this type of antibody, and is now widely known as highly suggestive of this disease," said Dr Steriade.

Electroencephalogram (EEG) data revealed "striking" findings, said Dr Steriade. For example, many MA2 patients had multifocal interictal discharges, while those with LGI1 were more likely to have multiple subclinical temporal lobe seizures.

"This means that the LGI1 patients had seizure activity on their EEG but no external signs of a seizure," she said. "This is very unique and not seen in other types of epilepsy."

Both groups were refractory to anticonvulsants, with many in the LGI1 group developing a severe rash from these drugs. "This may be related to a unique immune genetic makeup," said Dr Steriade.

Different Immune Responses

However, response to immune suppressants, such steroids, intravenous immunoglobulins, plasma exchange, or rituximab, was different. MA2 patients responded poorly to these drugs, while those with LGI1 antibodies responded quite well.

Which patients should be tested for antibodies? According to Dr Steriade, those with "explosive" late-onset (over age 40 years) resistant epilepsy with atypical psychiatric features, such as psychosis.

Certain radiologic features, such as edema, may also be suggestive, she said.

Having other coexisting autoimmune diseases, such as type 1 diabetes, might offer another clue, said Mar Carreño, MD, PhD, professor and epileptologist, Hospital Clinic, Barcelona, Spain.

Dr Carreño's own study of 13 patients with drug-resistant epilepsy due to autoimmune encephalitis showed that surgery may be a good option. She and her colleagues also showed that there was no apparent correlation between antibody type (they looked at anti-MA2, anti-LGI1, and four others).

Invited to comment on this research, Jeffrey W. Britton, MD, professor of neurology, and chair, Division of Epilepsy, Mayo Clinic, Rochester, Minnesota, agreed that seizure disorders caused by autoimmune mechanisms are increasingly being recognized. Technological advances, he said, have led to the discovery of more neuronal antibody types.  

Dr Britton attributed much of the increased awareness surrounding autoimmune epilepsies to the publication of Brain on Fire, journalist Susannah Cahalan's best-selling account of her autoimmune encephalitis and seizures. 

The new study confirms previous observations made by other investigators, including Dr Britton's group. "We also found that the potential for response to immunotherapy is greater for autoimmune epilepsies due to antibodies targeting neuronal surface structures than for those targeting intracellular proteins."

The exact prevalence of autoimmune causes of epilepsy is not known. According to Dr Britton, a few studies have suggested that neurologic antibodies are present in 1% to 5% of patients with seizures.

"However, these antibodies, especially when present at low levels, are sometimes coincidental and not causative of the epilepsy," he said.

Dr Steriade estimated that 5% to 10% of all drug-resistant focal epilepsies are linked to antibodies.

American Epilepsy Society (AES) 69th Annual Meeting. Abstracts 3.153 and 2.320.


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