In 1916, von Economo first described
encephalitis lethargica (EL), a CNS disorder presenting with
pharyngitis followed by
sleep disorder, basal ganglia signs (particularly
parkinsonism) and neuropsychiatric sequelae. Since the 1916-1927 epidemic, only sporadic cases have been described. Pathological studies revealed an
encephalitis of the midbrain and basal ganglia, with lymphocyte (predominantly plasma cell) infiltration. The EL epidemic occurred during the same time period as the 1918
influenza pandemic, and the two outbreaks have been linked in the medical literature. However, von Economo and other contemporary scientists thought that the 1918 influenza virus was not the cause of EL. Recent examination of archived EL brain material has failed to demonstrate
influenza RNA, adding to the evidence that EL was not an invasive
influenza encephalitis. By contrast, the findings of intrathecal
oligoclonal bands (OCB) and beneficial effects of
steroid treatments have provoked the hypothesis that EL may be immune-mediated. We have recently seen 20 patients with a similar EL phenotype, 55% of whom had a preceding
pharyngitis. The patients had remarkable similarity to the historical descriptions of EL:
sleep disorder (
somnolence, sleep inversion or
insomnia),
lethargy,
parkinsonism,
dyskinesias and neuropsychiatric symptoms. CSF examination commonly showed elevated
protein and OCB (75 and 69% respectively). Investigation found no evidence of
viral encephalitis or other recognized causes of rapid-onset
parkinsonism. MRI of the brain was normal in 60% but showed inflammatory changes localized to the deep grey matter in 40% of patients. We investigated the possibility that this phenotype could be a postinfectious autoimmune CNS disorder, and therefore similar to
Sydenham's chorea. Anti-
streptolysin-O titres were elevated in 65% of patients. Furthermore, western immunoblotting showed that 95% of EL patients had
autoantibodies reactive against human basal ganglia
antigens. These
antibodies were also present in the CSF in four patients tested. By contrast,
antibodies reactive against the basal ganglia were found in only 2-4% of child and adult controls (n = 173, P < 0.0001). Rather than showing polyspecific binding, these
antibodies bound to common neural
autoantigens of molecular weight 40, 45, 60 and 98 kDa. Regional tissue comparisons showed that the majority of these
autoantigens were specific to or enriched in CNS tissue. Immunohistochemistry with secondary staining localized antibody binding to neurons rather than glial populations. Further investigation is required to determine whether these
antibodies affect neuronal function (i.e. whether they are pathogenic anti-neuronal
antibodies). Histopathology in one case demonstrated striatal
encephalitis with perivenous B- and T-lymphocytic infiltration. We believe an EL-like syndrome is still prevalent, and propose that this syndrome may be secondary to autoimmunity against deep grey matter neurons.