Researchers have identified a new form of autoimmune encephalitis characterized by high serum and CSF titers of antibodies against the gamma-aminobutyric acid A receptor (GABAAR) and a rapid onset of severe, refractory seizures or status epilepticus. The findings were published online ahead of print January 21 in Lancet Neurology.
In affected patients, these antibodies may cause a selective reduction of clusters of GABAAR at the synapses. Unlike the GABAB receptor, the GABAAR has never been recognized as a target of autoimmunity. Identifying this novel form of autoimmune epileptic disorder, which affected children and adults in this series, is important because, although it is not responsive to antiseizure measures, it is potentially treatable with other approaches, said Mar Petit-Pedrol of the August Pi i Sunyer Biomedical Research Institute, Barcelona, and associates.
The investigators first noted the disorder in two patients seen at their medical center within four months of each other. Both patients presented with encephalitis and severe, refractory seizures and showed serum and CSF cell-surface antibodies with a similar but unrecognized pattern of reactivity against the neuropil of rat brain. “The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunologic information from patients with similar symptoms,” the researchers wrote.
Serum and CSF Analysis
The study authors collected and examined serum and CSF samples from 1,134 patients around the world whose encephalitis and seizures were suspected to be autoimmune in origin and found 140 who had antibodies against the same unknown rat brain neuropil antigen. The investigators also examined samples from 75 healthy blood donors and 416 patients with a range of neurologic disorders.
Four of the 140 patients, in addition to the two index patients, showed high titers of antibodies to the GABAAR, but none of the control patients did. Among these six patients, three were children (ages 3, 4, and 16) and three were adults (ages 28, 51, and 63). All had a rapidly progressive encephalopathy preceded by or associated with a change in behavior or level of cognition. All patients developed refractory seizures, and five had status epilepticus. Five of the six patients had at least one CSF abnormality.
MRI Reveals Abnormal Findings
All six patients had abnormal findings on brain MRI, with extensive multifocal or diffuse cortical and subcortical involvement. It is not yet known if these anomalies were caused by the immune response or resulted from the lengthy seizures. However, they were different from the abnormalities seen in other forms of autoimmune encephalitis, the researchers noted. All six patients had abnormal EEG findings and multifocal seizures. Two also showed generalized periodic discharges.
This new form of encephalitis was not associated with any underlying tumor. In contrast, as much as 60% of patients with GABABR antibodies are found to have underlying small-cell lung cancer.
In addition to the GABAAR antibodies, three of these six patients had thyroid peroxidase antibodies, one had glutamic acid decarboxylase 65 (GAD65) antibodies, and two had GABABR antibodies. This result indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation, according to the researchers. Further supporting that connection, one patient had a history of idiopathic thrombocytopenic purpura, and another had a history of Hodgkin’s lymphoma, the investigators said.
Regarding treatment, one of the affected children received levetiracetam but no immunotherapy and showed “substantial recovery,” but three years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received immunotherapy and multiple antiepileptic drugs; three had a partial or total recovery, while two died from sepsis that developed during status epilepticus. In addition to these six patients who had high titers of GABAAR antibodies, 12 patients from the 140 global cases had low but detectable levels of GABAAR antibodies. Most of the 12 also had low titers of other antibodies, which “could explain the broader range of symptoms in this group,” noted the authors.
Of these 12 patients, six presented with encephalitis with refractory seizures, including a 2-year-old boy with status epilepticus and a 41-year-old man with epilepsia partialis continua. Of the remaining six patients, four presented with stiff-person syndrome and two with opsoclonus-myoclonus.
Testing for GABAAR Antibodies
These findings indicate that patients who have encephalitis or severe, refractory seizures thought to be autoimmune in origin with MRI and CSF abnormalities suggestive of an inflammatory process should be tested for GABAAR antibodies, the researchers advised. In addition, “future studies should establish, in a prospective manner, the incidence of serum and CSF GABAAR antibodies in patients with seizures or status epilepticus, opsoclonus-myo-clonus, and stiff-person syndrome,” the authors said.