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 and a rapid onset of severe, refractory seizures or status epilepticus in a series of six patients.
It appears that in affected patients these antibodies cause a selective reduction of clusters of gamma-aminobutyric acid-A receptor (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 4 months of each other. Both presented with encephalitis and severe, refractory seizures, and both showed serum and cerebrospinal fluid (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 immunological information from patients with similar symptoms," they wrote.
They 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. They also examined samples from 75 healthy blood donors (controls) and 416 patients with a range of neurological disorders.
Four of the 140 patients, in addition to the 2 index patients, showed high titers of antibodies to the GABAAR, whereas none of the control patients did.
Among these six patients, three were children (aged 3 years, 4 years, and 16 years) and three were adults (aged 28 years, 51 years, and 63 years). All had a rapidly progressive encephalopathy either preceded by or associated with a change in behavior or level of cognition. All developed refractory seizures, and five had status epilepticus.
Five of the six had at least one CSF abnormality.
All six 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 those seen in other forms of autoimmune encephalitis, the researchers noted (Lancet Neurol. 2014 Jan. 22 [doi:10.1016/S1474-4422(13)70299-0]).
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, up to 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 indicates that patients with this new form of encephalitis have a propensity for autoimmunity or immune dysregulation. Further supporting that connection, one of the six patients 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 3 years later still requires antiseizure medication to prevent a recurrence of epilepsy. The other five patients received both 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 6 patients who had high titers of GABAAR antibodies, another 12 from the 140 global cases had low but still 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."
Of these 12 patients, 6 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.
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, Petit-Pedrol and associates said.
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-myoclonus, and stiff-person syndrome," they said.