Brain Advance Access originally published online on October 21, 2003
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Brain, Vol. 127, No. 1, 21-33, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh008
Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity
1 Neurosciences Unit and 2 Neuropathology Department, Great Ormond Street Hospital and Institute of Child Health, 3 Department of Neuroinflammation, Institute of Neurology, University College London, 4 Reta Lila Weston Institute of Neurological Studies, Royal Free and UCLMS, London and 5 Department of Neurology, Radcliffe Infirmary, Oxford, UK
Correspondence to: Dr Russell Dale, Neurosciences unit, Meckelenburgh Square, Institute of Child Health, London WC1N 3JJ, UK E-mail: r.dale{at}ion.ucl.ac.uk
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.
Key Words: autoimmune encephalitis; Sydenham’s chorea; parkinsonism
Abbreviations: ASOT = anti-streptolysin-O titre; EL = encephalitis lethargica; GFAP = glial fibrillary acidic protein; OCB = oligoclonal band(s); PANDAS = paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections
Received July 7, 2003. Revised July 31, 2003. Accepted August 5, 2003.
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