All 32 patients for whom we describe clinical, serologic, and imaging findings had refractory epilepsy of presumed autoimmune basis. The intractability, high seizure frequency, and striking improvement in seizure control achieved following immunotherapy in many warrant emphasis: 81% had significant improvement in seizure status and 67% achieved seizure freedom, a majority of whom were AED resistant.
Our study supports previously noted links between neurologic autoimmunity and epilepsy.18–21,26–28
Recurrent seizures were the early and predominant clinical manifestation in the patients of our report. An autoimmune etiology is identified most readily in patients who present with the full syndrome of limbic encephalitis, characterized by subacute memory impairment with affective changes and temporal lobe seizures. The diagnosis of autoimmune limbic encephalitis is aided by detection of neural autoantibodies with radiological or pathological evidence of temporomedial inflammation and in some cases a history of neoplasia in the preceding 5 years.32
Limbic encephalitis has been suggested as a precedent of hippocampal sclerosis and adult-onset temporal lobe epilepsy.6,33
In our report, one-third of the patients had seizures as their exclusive presentation without other recognized clinical accompaniments of limbic encephalitis. Although the remaining two-thirds had additional neurologic problems, including cognitive and personality changes, they had presented with predominant concerns of high daily seizure burden. This prevented clear distinction of the contribution of inflammatory limbic lesions vs seizure activity to the evolving neurocognitive impairment. Furthermore, 15 patients had normal MRI brain scans at initial presentation, and among 12 patients who had subsequent MRIs, a median of 4 months elapsed before subsequent imaging showed development of inflammatory changes in 5.
The primary aim of this study was to report the clinical features and immunotherapy response in a cohort diagnosed with autoimmune epilepsy. The study was not designed to compare clinical features of this entity with those of epilepsy from other etiologies. The diagnosis of autoimmune epilepsy requires a high level of suspicion at initial evaluation. The clinical presentations in our patients were heterogeneous, but some general observations can be made. Data from the current cohort suggest that autoimmune investigation should be considered in the presence of 1 or more of the following: an unusually high seizure frequency, intraindividual seizure variability or multifocality, AED resistance, personal or family history of autoimmunity (either organ specific [eg, thyroid disease, diabetes mellitus, pernicious anemia, or celiac disease] or non–organ specific [rheumatoid arthritis or systemic lupus erythematosus]), or recent or past neoplasia. Serological testing is increasingly valuable as an aid to establishing the diagnosis of an autoimmune etiology. As illustrated in the patients we presented, other laboratory and radiological findings may be normal. Serial MRI findings were consistent with inflammation in several patients. When detected, these radiological findings (sometimes indistinguishable from medial temporal sclerosis) supported the diagnosis of autoimmune epilepsy. However, MRIs were normal in about half of patients. Cerebrospinal fluid was also normal in nearly half the patients despite the presence of an autoimmune neurologic disorder. Hence, the presence of normal CSF or MRI does not exclude an immune-mediated process. The role of brain FDG-PET in these patients warrants further study. While focal hypometabolism is more typically seen in the epilepsy population, focal hypermetabolism was fortuitously noted in this cohort who underwent whole-body FDG-PET primarily for malignancy purposes. It is our continuing observation that autoimmune epilepsies are underrecognized.
A majority of the patients in this study had neuronal VGKC complex autoantibodies. This serological marker aids the diagnosis of idiopathic and less commonly paraneoplastic autoimmune neurologic disorders. It is impressive that the seizure disorder was immunotherapy responsive in all seropositive patients. Voltage-gated potassium channel complex autoimmunity was first reported in patients with neuromyotonia34
(Isaacs syndrome), Morvan syndrome,35
and limbic encephalitis.36
A broader spectrum of neurologic phenotypes affecting all levels of the nervous system has been described.30,37
Two independent groups recently reported that the target autoantigens in these disorders are generally not VGKC complex channel proteins per se but neuronal proteins (Lgi1 and Caspr2) that respectively associate with a subset of Kv1 VGKC complexes at synapses and at juxtapara-nodes of myelinated axons.8,9
Lgi1 was the target antigen in 78% of our VGKC complex antibody–positive patients. One had antibodies targeting Caspr2. Previous reports have implicated Lgi1 as the principal target antigen in limbic encephalitis, while Caspr2 is more commonly, but not exclusively, associated with peripheral nervous system manifestations.8,9
Lgi1 is recognized as a causative gene in autosomal-dominant partial epilepsy with auditory features.38
It encodes a secreted protein that links 2 epilepsy-related receptors, ADAM22 and ADAM23, creating a complex that incorporates presynaptic potassium channels and postsynaptic AMPA receptor scaffolds. Fukata and colleagues39
demonstrated that disruption of the Lgi1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Recently, faciobrachial dystonic seizures were reported to precede Lgi1 antibody–associated encephalitis, suggesting that early immunotherapy could prevent the evolution to limbic encephalitis.22
We identified similar seizures in 6 of 14 (43%) Lgi1-seropositive patients in this cohort, often accompanied by other seizure semiologies. We also noted piloerection as a semiological feature in 4 of 14 (29%).
One patient in our study had NMDA receptor auto-antibodies.23
-methyl-D-aspartate receptor autoimmune encephalitis is often accompanied by ovarian teratoma and a stereotypic clinical evolution starting with a viral-like prodrome, psychiatric symptoms, memory impairment, dyskinesias, seizures, and progressing coma and hypoventilation.40
Most reported cases have had seizures at presentation,41
but these were overshadowed or accompanied by neurocognitive disturbances. Our patient presented with AED-intractable aphasic seizures and evolving left cortical inflammatory changes.
When autoimmune epilepsy is suspected on clinical grounds, CSF evaluation and comprehensive screening for neural autoantibodies are indicated. Selective auto-antibody testing is not advised because no single neural antibody is definitively associated with seizures. Failure to detect a neural antibody does not exclude the diagnosis of autoimmune epilepsy when other clinical clues exist. If autoimmune epilepsy is suspected, a trial of 6 to 12 weeks of immunotherapy (IVMP or IVIg daily for 3 days and then weekly) is justifiable in the absence of other treatment options and may serve as additional evidence for an autoimmune etiology when a favorable seizure response is observed.42
In 22 of 27 patients (81%), this therapeutic trial was positive, and early treatment was associated with a favorable outcome (P <
.05). Long-term immunosuppressive treatment, overlapping with gradual taper of IVMP or IVIg, should be considered for patients whose seizures respond favorably to the initial trial of immunotherapy. Despite this, relapses may still occur.
Our study is limited by its retrospective design and the fact that AED changes were not restricted during the period of immunotherapy. The patients’ poorly controlled seizures necessitated continuing AED changes during immunotherapy initiation, complicating interpretation of the contribution of immunotherapy to seizure control. However, the likelihood that such changes accounted for improved clinical response in these patients is well below the proportion of patients responding to immunotherapy trial.1
Clinical experience suggests that immunotherapy should not be used alone to control seizures but should be used in combination with AEDs to optimize seizure control. The clinical spectrum of auto-immune epilepsy is still unknown. In a series of patients with epilepsy, VGKC complex antibodies were detected in 10%; NMDA receptor antibodies, in 7% of newly diagnosed patients; and GAD65 antibodies, in 1.6% to 1.7%.43
It is conceivable that we are only identifying patients with the most severe presentations in this heterogeneous group, and the burden of this entity remains under appreciated in patients with milder epilepsies. Questions remaining unanswered 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.