Autoimmune Etiology Suggested for Subset of Epilepsy Diagnoses

b cell lyphocyte
b cell lyphocyte
A subset of epilepsy cases of unknown etiology may be secondary to the production of autoantibodies.

Autoimmune mechanisms are highly underrecognized as causes of epilepsy and may represent a target for immunotherapy in as many as 20% of epilepsies with unknown etiologies, according to a study reported in JAMA Neurology.1

The study investigators reviewed 112 epilepsy cases from 2 large neurology centers in Dallas, Texas — the University of Texas (UT) Southwestern Medical Center and the Parkland Health and Hospital System — and found the presence of serum neurologic autoantibodies (Abs) suggesting potential autoimmune causes in 39 patients (34.8%).

Within the cohort, 77 patients (68.8%) had epilepsy of unknown etiology that had been diagnosed a mean of 12.7 years earlier, while the remaining 35 patients (31.2%) had newly diagnosed epilepsy. Serum Abs were more likely to be detected in patients with newly diagnosed epilepsy (13 of 35, 37.1%) compared with patients with established epilepsy (10 of 77, 13.0%; odds ratio [OR] 3.4; 95% CI, 1.5-7.8; P =.004).

Of the total cohort, 7 (6.3%) patients tested positive for the presence of more than 1 serum Ab; combinations included thyroperoxidase antibody (TPO-Ab) and voltage-gated potassium channel complex antibody (VGKCc-Ab), glutamic acid decarboxylase 65 antibody (GAD65-Ab) and VGKCc-Ab, TPO-Ab and GAD65-Ab , and antineuronal nuclear antibody type 1(ANNA-1 or anti-Hu) and GAD65-Ab. Because TPO-Ab is regarded as controversial in the pathogenesis of autoimmune epilepsy, the investigators excluded data from 11 patients with only that marker from further analysis.2

Immunotherapy was initiated in 15 of the 23 patients who tested Ab-seropositive (65.2%), resulting in better seizure outcomes than in seronegative patients who did not receive immunotherapy.

Treated patients (n = 9, 39.1%) were more likely to be seizure free after only 1 clinic visit than seronegative patients (n = 16, 18.0%; OR, 3.3; 95% CI, 1.2-8.9; P =.02). The best outcomes were achieved with intravenous methylprednisolone (OR = 8.25; 95% CI, 1.2-59.0;

P =.04) or plasmapheresis (OR = 32.5; 95% CI, 1.6-673.8; P =.02).

Previous studies have indicated low rates of autoimmune epilepsies, with only 34 cases reported in a large-scale retrospective review.3 The current study, however, indicates a much higher potential for autoimmune causes of unknown etiology than previously suspected, as indicated by the significant percentage of Ab-seropositive patients (n = 19, 82.6% ) with antibody prevalence in epilepsy (APE) scores of 4 or higher compared with seronegative patients (n = 17,  19.1%; OR, 21.7; 95% CI, 6.5-72.4; P <.001).

“Autoimmune epilepsy should be considered in the differential diagnosis,” study coinvestigator Steven Vernino, MD, PhD, of the department of neurology and neurotherapeutics, UT Southwestern Medical Center, told Neurology Advisor. “However, there are certain clinical features that seem to increase the likelihood of an autoimmune cause. These features are encoded in the APE score (especially autonomic features, psychiatric/behavioral changes, and facial dyskinesias).” 

The researchers pointed to the use of APE scores as a tool for the selection of patients for antibody testing. “Antibody testing should be considered, especially in new-onset unexplained epilepsy with some of these features,” Dr Vernino said, adding that “the presence of neurological antibodies certainly suggests an autoimmune encephalitis but does not prove that diagnosis.” 


  1. Dubey D, Alqallaf A, Hays R, et al. Neurological autoantibody prevalence in epilepsy of unknown etiology [published online February 6, 2017]. JAMA Neurol. doi:10.1001/jamaneurol.2016.5429 
  2. Ferracci F, Bertiato G, Moretto G. Hashimoto’s encephalopathy: epidemiologic data and pathogenetic considerations. J Neurol Sci 2004;217(2):165-168.
  3. Dubey D, Sawhney A, Greenberg B, et al. The spectrum of autoimmune encephalopathies. J Neuroimmunol. 2015;287:93-97.