| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brain, Vol. 127, No. 1, 2-3, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh063
Encephalitis lethargica: part of a spectrum of post-streptococcal autoimmune diseases?
Encephalitis lethargica (EL) was first described by von Economo in 1917, shortly after the start of the 1916–1927 epidemic. The patients, mostly children of either sex, characteristically presented with headache and malaise, lethargy, insomnia, and ophthalmoplegia. Some recovered but the others either died during an acute fulminating disorder or developed, insidiously or after a variable period of time, movement and/or psychiatric disorders including Parkinsonism, oculogyric crises, chorea, myoclonus, mutism, catatonia or behavioural problems. Although linked by many observers to the influenza epidemic, the epidemic of EL began earlier and lasted longer, and flu virus has not been found in archival post-mortem tissue (e.g. McCall et al., 2001
; Lo and Geddes, 2003). Sporadic cases are still reported, but the acute fulminating form seems to have disappeared, and there have been no further reported epidemics.
The paper by Dale and colleagues in this issue of Brain describes 20 patients with a condition presenting with sleep disorder, lethargy, Parkinsonism and neuropsychiatric disorders, including mutism, anxiety, depression, obsessions and compulsions (Dale et al., 2004). The patients ranged between 2 and 69 years of age, but most were children or teenagers. Although we are not told the time between onset and study by the authors, half of the patients had a monophasic illness, and five have made a good recovery, but the others have continuing problems of movement or neuropsychiatric disorders at a follow-up period of <2 years. The clinical features, the course of the disease, cerebrospinal fluid and imaging studies, and histology in one case, are similar to those in cases of EL as originally or subsequently described, except that ophthalmoplegia and oculogyric crises were only found in a minority of Dale’s cases. The 20 cases were referred from tertiary neurological centres over a period of 3 years, suggesting a somewhat higher incidence of this EL-like illness than is apparent from the recent literature.
The main emphasis in their paper is the evidence for an autoimmune, possibly post-streptococal, aetiology. High signal changes were found on T2 imaging in 40% of the cases, predominantly in the deep grey matter, which resolved in a few cases examined during convalescence. Oligoclonal bands (OCB) were found in nine of the 13 examined; in five cases OCB were restricted to the cerebrospinal fluid (CSF) indicating intrathecal synthesis. These findings are consistent with those reported in sporadic cases; for instance, a recent case of EL showed plasma cell infiltrates in the brain and very high IgG levels in the CSF (Kiley and Esiri, 2001). But in four cases the OCB were detected in both CSF and serum, which suggests an immune response originating in the periphery. Indeed about half of the patients had a previous infection, either of the upper respiratory tract or tonsillitis, and raised titres of anti-streptolysin-O antibodies were present in 65%. Streptococcal infections were also present in some of the original patients with EL, and similarities to Sydenham’s chorea were noted during the epidemic. Remarkably, an EL like illness was induced in dogs by vaccination against streptococcus (von Economo, 1931).
Several authors have previously detected antibodies to neuronal antigens in neurological diseases associated, at least in part, with streptococcal infections including Sydenham’s chorea and PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; Kiessling et al., 1993; Singer et al., 1998; Church et al., 2002). Indeed, one recent study suggests that such antibodies to streptococcal antigens cross-react with lysogangliosides on the neuronal cell surface (Kirvan et al., 2003) In the present study Dale et al. (2004), detected antibodies, similar to those they have previously described as anti-basal-ganglia antibodies, by western blotting of soluble extracts of basal ganglia homogenates from human brain. The antibodies were detected at very low frequency in control groups but were found in 95% of EL sera and 4/5 of the CSFs tested. They bound to several different polypeptide bands, 40, 45, 60 and 98 kDa, of which the 40, 45 and 60 kDa bands appeared to be the same as those found previously, by the same team, in other post-streptococcal conditions. This raises issues of disease specificity but would be consistent with their hypothesis that EL is part of a spectrum of immune-mediated post-streptococcal basal ganglia disorders.
Western blotting is often used as a first test for anti-neuronal antibodies, but although it efficiently detects antibodies to non-conformational epitopes, it is likely to miss those potentially pathogenic antibodies that bind to conformational determinants. Moreover, it would have been more informative to use a whole tissue or membrane preparation, rather than soluble extract, since antibodies that exclusively recognise membrane targets would have been missed in the latter procedure. To see, therefore, whether there were serum antibodies binding to intact tissue, they performed immunofluorescence which demonstrated binding of antibodies to axons and neuronal cell cytoplasm. The results indicate the presence of antibodies predominantly to intracellular targets but do not exclude the possibility that there were also antibodies binding to the neuronal cell membranes. There are, however, questions regarding the regional specificity of the antibodies since a careful analysis of different parts of the brain was not done. Binding to bands in homogenates of whole rat brain and rat cerebellum were said to be similar, suggesting that the term ‘anti-basal ganglia antibody’ may prove to be misleading.
Thus there are some concerns about the neuronal specificity and pathogenic relevance of the antibodies detected, as the authors acknowledge. The presence of antibodies to different protein bands, varying between the individual patients, suggests that they may be secondary to an immune mediated condition rather than causative. In addition, it is not yet clear whether the antibodies to the basal ganglia antigens are cross-reactive with streptococcus A antigens. One would like to see, in future studies, evidence for antibodies binding to the surface of intact neurones derived from rat basal ganglia preparations, or other brain regions for comparison, and absorption experiments with streptococcal antigens to demonstrate cross-reactivity. Moreover, serial studies on individual patients comparing antibodies to streptococcal and neuronal antigens should be performed.
The two most convincing criteria of an antibody-mediated disorder, even in the absence of the detection of specific antibodies, are the response to immunosuppressive therapies and passive transfer of disease to experimental animals. PANDAS has been shown to respond to plasma exchange (Perlmutter et al., 1999), and corticosteroids have been found effective in individual cases of EL (e.g. Blunt et al., 1997) although they were not apparently tested in these patients. Recently, a Tourette’s-like syndrome has been transferred to rats by intracerebral injections (Hallett et al., 2000; Taylor et al., 2002). If EL is indeed immune-mediated, it should be possible to show a clinical response to plasma exchange and other immunotherapies, at least early in the course of the disease before permanent changes take place, and successful transfer of disease to experimental animals by immunoglobulin injection. Although passive transfer is still not routinely performed for CNS disorders, the growing number of conditions in which an antibody-mediated aetiology is now suspected (reviewed in Lang et al., 2003), and preliminary studies in which functional effects of antibodies on CNS neurons are being shown (e.g. DeGiorgio et al., 2001; Kirvan et al., 2003), means that further approaches to demonstrate the roles and mechanisms of action of peripherally-induced antibodies in causing CNS diseases need to be developed. However, one should not forget the possibility that the anti-neuronal antibodies may be markers for a destructive process, either T cell-mediated or due to direct toxicity from the infectious agents or the activated immune system. This paper, in suggesting a role for the immune system in EL and in other disorders that appear to form part of a spectrum of post-streptococcal autoimmune diseases, highlights the need for more experimental work in this important area.
1 Neurosciences Group, Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford UK
References
Blunt SB, Lane RJ, Turjanski N, Perkin GD. Clinical features and management of two cases of encephalitis lethargica. Mov Disord 1997; 12: 354–9.[CrossRef][ISI][Medline]
Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ, Giovannoni G. Anti-basal ganglia antibodies in acute and persistent Sydenham’s chorea. Neurology 2002; 59: 227–31.
Dale RC, Church AJ, Surtees RAH, Lees AJ, Adcock JE, Harding B, Neville BGR and Giovannoni G. Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain 2004; 127: 21–33. Brain Advance Access published October 21, 2003, 10.1093/brain/awh008.
DeGiorgio LA, Konstantinov KN, Lee SC, Hardin JA, Volpe BT, Diamond B. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med 2001; 7: 1189–93.[CrossRef][ISI][Medline]
Hallett JJ, Harling-Berg CJ, Knopf PM, Stopa EG, Kiessling LS. Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction. J Neuroimmunol 2000; 111: 195–202.[CrossRef][ISI][Medline]
Kiessling LS, Marcotte AC, Culpepper L. Antineuronal antibodies in movement disorders. Pediatrics 1993; 92: 39–43.
Kiley M, Esiri MM. A contemporary case of encephalitis lethargica. Clin Neuropathol 2001; 20: 2–7.[ISI][Medline]
Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. Mimicry and auto antibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med 2003; 9: 914–20.[CrossRef][ISI][Medline]
Lang B, Dale RC, Vincent A. New autoantibody mediated disorders of the central nervous system. Curr Opin Neurol 2003; 16: 351–7.[CrossRef][ISI][Medline]
Lo KC, Geddes JF, Daniels RS, Oxford JS. Lack of detection of influenza genes in archived formalin-fixed, paraffin wax-embedded brain samples of encephalitis lethargica patients from 1916 to 1920. Virchows Arch 2003; 442: 591–6.[CrossRef][ISI][Medline]
McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases. J Neuropathol Exp Neurolol 2001; 60: 696–704.[ISI][Medline]
Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, et al. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive–compulsive disorder and tic disorders in childhood. Lancet 1999; 354: 1153–8.[CrossRef][ISI][Medline]
Singer HS, Giuliano JD, Hansen BH, Hallett JJ, Laurino JP, Benson M, et al. Antibodies against human putamen in children with Tourette syndrome. Neurology 1998; 50: 1618–24.[Abstract]
Taylor JR, Morshed SA, Parveen S, Mercadante MT, Scahill L, Peterson BS, et al. An animal model of Tourette’s syndrome. Am J Psychiatry 2002; 159: 657–60.
von Economo C. Encephalitis lethargica. Its sequelae and treatment. Translated by K. O. Newman. London: Oxford University Press; 1931.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. A Vilensky and S. Gilman Encephalitis lethargica: could this disease be recognised if the epidemic recurred? Practical Neurology, December 1, 2006; 6(6): 360 - 367. [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Rippel, J. J. Hong, D. Y. Yoon, P. N. Williams, and H. S. Singer Methodologic Factors Affect the Measurement of Anti-basal Ganglia Antibodies Ann. Clin. Lab. Sci., April 1, 2005; 35(2): 121 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Millichap Encephalitis Lethargica Presenting as Post-Streptococcal Autoimmune Disease AAP Grand Rounds, April 1, 2004; 11(4): 41 - 42. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||