In April 2003, The Sophie Cameron Trust finalised funding for a study by Dr Russell Dale and Andrew Church, working under the direction of Dr Gavin Giovannoni at the Institute of Neurology, University College London. In the last few years, they have found that patients who develop certain neurological conditions after infections can produce anti-brain antibodies, which are rarely found in healthy adults or children. These antibodies bind to specific proteins in the brain, and one of them seems to be relatively specific to encephalitis lethargica. They planned to identify the protein involved, using well established methods. Edited extracts from their proposal are given below.
Their related research has led to the development of a diagnostic test for anti-basal ganglia antibodies, and the Institute has made this test available to doctors in the UK and elsewhere to help in the diagnosis of neurological disorders. Some of their work is described in a recent paper (ref. 1).
(1) Dale RC, Candler PM, Church AJ, Wait R, Pocock JM, Giovannoni G. Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease. J Neuroimmunol. 2006 Mar;172(1-2):187-97.
Identification of brain proteins involved in Encephalitis Lethargica
Russell Dale and Andrew Church
Encephalitis lethargica (EL) is a disease that has been described for many centuries. EL is best remembered for the last major outbreak between 1916 and 1927. During this time, many thousands of individuals throughout the world were affected. There is no doubt that an infectious disease is associated with EL, although no virus or bacteria has been clearly implicated. Indeed, recent attempts to identify a virus in the brain have failed to implicate influenza or any recognised virus. It is our hypothesis that EL is caused by an immune attack against the brain after infection, rather than a direct invasion of the brain by a virus or bacteria.
EL has continued to be reported since the 1920’s, although only single cases have been reported in the literature. Over the last 4 years, we have seen both children and adults with a disease identical to EL. We have seen approximately 30 children and adults with an acute encephalitic illness. The patients presented with a movement disorder (Parkinsonism typically), psychiatric disorder (emotional disorders), sleep disorder (somnolence) and brainstem features (eye movement and cardiorespiratory disorders). The patients often had brain scan changes localised to the deep grey matter (basal ganglia and brainstem). Although the spinal fluid analysis was abnormal with elevated antibodies and protein, no viruses were found, suggesting that this syndrome was not caused by a virus directly entering and attacking the brain. These patients showed symptoms remarkably similar to the historical descriptions of EL, and those described by Von Economo 1. We have presented these findings to the International Movement Disorder Society, the British Neurologists Association and the British Paediatric Neurology Association. The findings have been received with great interest. Our manuscript describing this work is currently being considered for publication by the journal Brain.
Over the last 4 years, we have been investigating a group of neurological conditions that present after infections (post-infectious disorders); specifically movement disorders (chorea, tics and Parkinsonism) and psychiatric disorders (obsessive-compulsive disorder and depression) after Streptococcal throat infections 2,3. We have developed methods for measuring antibodies produced by the patient that bind to brain proteins. These anti-brain antibodies are found in patients with movement and psychiatric disorders after infections, including patients with EL. These antibodies are rarely found in healthy adults, healthy children and children with other neurological diseases. So far we know the following about these antibodies:
1. The antibodies bind to 4 main proteins in a specific part of the brain. We know the size of these proteins (40, 45, 60 and 98 kDa). The 98-kDa protein is relatively specific to the EL phenotype.
2. The antibodies are present when the patient is unwell, and disappear when the patient improves. The antibodies re-appear if the patient has a relapse.
3. The antibodies recognise proteins in the brain and proteins on the surface of Streptococcus bacteria.
4. Other investigators have shown that these antibodies can produce disease in animals 4.
5. Previous reports (and our scientific research) suggest that removing these antibodies with treatments could lead to an improvement in the clinical condition 5.
It is our aim to identify the brain proteins involved in these conditions. Identification will greatly improve our understanding of these disorders. In addition, this will allow us to create a specific, diagnostic assay. This in turn will allow a carefully controlled trial to be devised that will assess the most appropriate treatments.
In summary, the aim of this project is to identify the 98-kDa brain protein. This will require the use of appropriate methods to separate and identify the brain proteins and demonstrate specific antibody responses. We will use techniques that have previously been successfully used in other immune-mediated disorders. Assuming that these steps yield positive results, we should be able to identify the brain protein involved in antibody binding. This protein will therefore act as a diagnostic marker for EL. In addition, it may provide essential information about how the brain is impaired or damaged by this disease. Only when the disease is better understood will we be able to create appropriate treatment protocols.
(1) Von Economo C. Encephalitis lethargica. Its sequelae and treatment. Translated by Newman KO. Oxford University Press, 1931.
(2) Dale RC, Church AJ, Cardoso F, Goddard E, Cox TC, Chong WK, et al.. Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies. Ann Neurol. 2001 Nov; 50(5): 588-95.
(3) 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: 227-231.
(4) Hallett JJ, Harling-Berg CJ, Knopf PM, Stopa EG, Kiessling LS. Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction. J Neuroimmunol. 2000 Nov 1; 111(1-2): 195-202.
(5) 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 Oct 2; 354 (9185):1153-8.
What is encephalitis lethargica
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