Wednesday, January 13, 2016

Autoimmune epilepsy

In our study, we looked at patients with autoimmune epilepsy due to multiple types of antibodies. We identified four patients who had Ma2 antibodies, targeting an intracellular antigen, and eight patients with LGI1 antibodies, targeting an antigen on the cell surface. These were patients who had seizures as their predominant clinical feature, and we looked at their clinical and EEG features.

The main findings were that patients with Ma2 antibodies tended to have a more severe clinical course. They frequently required intensive care unit admission and more frequently progressed to status epilepticus. They also had a variety of associated neurologic symptoms, including psychiatric disturbance, cognitive impairment, eye movement abnormalities, and parkinsonism. The patients with LGI1 antibodies, on the other hand, only had accompanying psychiatric disturbance and cognitive impairment.

In addition, patients with Ma2 antibodies tended to have an associated malignancy, most frequently a testicular tumor, whereas patients with LGI1 antibodies did not. Mesiotemporal hyperintensities were seen in both groups, but more frequently in the Ma2 antibody group. The main difference was the presence of early hippocampal atrophy, which was much more frequent in patients with Ma2 antibodies and may indicate a destructive process leading to neuronal loss early on in the disease.

In terms of their seizure presentation, there was a specific seizure type seen in LGI1 antibodies: focal tonic or faciobrachial dystonic seizures. In addition, pilomotor seizures, a seizure type now shown \ to suggest autoimmune epilepsy, were also noted in one patient with LGI1 antibodies. Both groups had focal dyscognitive seizures, suggestive of a temporal lobe onset, and some of the patients in each group had secondary generalized tonic/clonic seizures.

In terms of the EEG features, the main finding in the Ma2 antibody group was the presence of multifocal interictal discharges indicating a process not simply confined to the temporal lobes, as opposed to patients with LGI1 antibodies, who had unusual EEGs with very frequent subclinical temporal lobe seizures despite no captured clinical temporal lobe seizures on several days of EEG monitoring. They also had electrodecremental events before the focal tonic or faciobrachial dystonic seizures, which gives further support to these representing tonic seizures in terms of their classification.

In terms of treatment, both groups demonstrated resistance to anticonvulsants—with an average of 4.5 anticonvulsants trialed in the Ma2 antibody group and 3.2 anticonvulsants in the LGI1 antibody group. The main treatment difference was that the patients with Ma2 antibodies did not tend to respond to immunotherapy (which was done with a combination of steroids, intravenous immunoglobulins, plasmapheresis, and/or rituximab) while patients with LGI1 antibodies exhibited an impressive response to immunotherapy. This may be related to the fact that cerebral dysfunction in patients with antibodies targeting intracellular antigens, such as Ma2 antibodies, tends to be T-cell mediated, whereas that associated with cell surface receptor antibodies, such as LGI1 antibodies, tends to be B-cell mediated. Indeed, conventional immunotherapy predominantly targets the B-cell response and may not be getting at the root immunologic pathology in diseases associated with antibodies targeting intracellular antigens.

This work helps to set a foundation for further studies looking at patients with autoimmune epilepsy. Rather than lumping all autoimmune epilepsies together, a more refined goal may be to differentiate what the different clinical features and treatment responses are within various antibody groups (antibodies targeting intracellular antigens vs antibodies targeting cell-surface receptor antigens). We may be dealing with a variety of diseases rather than one disease, and it may be that each should be suspected in potentially different clinical scenarios and treated with different methods of immunotherapy...

Antineuronal antibodies have been found in 5%-10% of cases of drug-resistant epilepsy cohorts. With increasing awareness, testing availability, and discovery of new antibodies associated with epilepsy, that number may continue to rise. One of the key next steps is to find out what clinically distinguishes the 5%-10% subgroup of patients, to help us understand which patients we need to test for antibodies.

Steriade C, Mirsattari S, Tang-Wai DF, Wennberg R. In or out: differences between patients with intracellular versus cell-surface receptor antibodies in autoimmune epilepsy. Program and abstracts of the American Epilepsy Society Annual Meeting; December 4-8, 2015; Philadelphia, Pennsylvania. Abstract 3.153.

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