1. Research aims and policy
According to our business plan, we aim to promote research
into the causes and treatment of EL and to promote awareness
of EL in the medical profession, as well as the general
public. Given our limited resources, we hope to achieve this
mainly by funding small-scale projects where success might
subsequently attract larger-scale funding from other sources,
or by supporting projects jointly funded together with other
organizations from the outset.
We also hope to encourage international collaboration as
far as possible. We have identified four key areas of research
that we should support, namely causes of EL, diagnosis,
currently available treatments, which are mostly palliative or
supportive, and potential future treatments. So far, we have
supported projects in the first three of those areas by
scientists and doctors in the UK, the USA and Russia.
We are always willing to consider requests for funding of
new research. However, in the interests of using our funds
efficiently, our policy is to consider only projects where
indirect or administrative costs will not exceed 10% of the
total funding requested.
2. Literature survey
Our initial literature survey was successful in finding papers about EL that have already been published in academic and medical journals, and we found that about 50 cases have been reported since 1980. The results were summarised in a
paper by Dr Richard Wharton in December 2003.
3. Research at the Institute of Neurology, University College London
In April 2003, we provided funding to Russell Dale and Andrew Church, working under Dr Gavin Giovannoni at the
Institute of Neurology, University College London, for a 3-year project to test their hypothesis that EL is an autoimmune disease. This work was designed to identify the brain proteins targeted by antibodies found in the blood of some EL patients.
In November 2007, we agreed to provide further funding for an extension of the work at The Institute of Neurology on brain antigens that may be related to EL. This work will be carried out by a group of researchers at The Institute of Neurology and The Institute of Cell and Molecular Science, led by Prof. Giovannoni. As described in an edited summary of their proposal,
one of the main aims is to investigate the distribution of
gamma/alpha enolase dimer, which is a target of anti-enolase autoantibodies. The anti-enolase autoantibodies are members of the class of anti-basal ganglia autoantibodies (ABGAs), which may be associated with recent streptococcal infection, and the research will also help to establish whether these antibodies play a role in the pathogenesis of EL.
In 2008, this work was taken forward by Joseph Cohen, an MBBCh-BSc
student, who did his laboratory project on this topic, and has
report of his results, and Kathrin Hoffman, a German MSc
student, who has been taken on for a further 8 months to
extend Joseph’s work.
Work on EL at the Institute of Neurology has been described in an article called “Encephalitis Lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity”, published in the leading journal “Brain” (vol. 127, no. 1, p.21-33, 2004). Dr Giovannoni gave a presentation describing this work and other aspects of EL at our 2005 AGM.
4. Physiotherapy research at the Royce Clinic
In July 2003, we initiated funding of a 3-year programme at the
Royce Clinic to evaluate the benefits of intensive physiotherapy for patients with severe brain injury. This important study was funded jointly with the Medlock Trust and the Brownsword Charitable Foundation, and has yielded valuable results.
Alison Felix and Royce Menezes at the Royce Clinic carried out an intensive case study with a single patient, examining the effects of a wide range of treatment modalities, including electrical stimulation of muscles, and passive and active exercise using an Oswestry frame, tilt table, motorised bicycle and treadmill with assistance. They finally developed an intensive programme of treatments for up to 25 hours a week, which resulted in improved mobility and function, thereby reducing the burden on carers. The methods they used and the results achieved are described in their report
“Developing a late rehabilitation programme for severe brain damage: A single-subject case study”. They suggested that acquisition of weightbearing ability may reduce the risk of complications, such as osteoporosis, urinary tract infections and pressure sores, and proposed that the cost of intensive physiotherapy for severely brain-damaged patients might be economically justified by reduced lifetime care and treatment costs.
5. Research at Indiana University School of Medicine, U.S.A.
In December 2005, we approved a grant to Professor Joel Vilensky of
Indiana University School of Medicine for preliminary work to develop a database of encephalitis lethargica signs and symptoms in a form that will be suitable for computerized statistical analysis. During 2007-2008, the Trust supporting further work to collate and analyze data about historical cases of EL. This should help lead to faster, more accurate diagnosis of EL. Professor Vilensky hopes that careful study of data from the
EL pandemic that followed the first world war will throw light on present day cases.
In 2008, The Sophie Cameron Trust agreed to provide a grant for editorial assistance and translation expenses to help with the preparation of a new book on EL, which will be edited by Professor Vilensky,
and will include contributions from a number of eminent
physicians and scientists. This book, which is expected to be
called "Encephalitis Lethargica: During and After the
Epidemic" will be published by Oxford University Press in 2011. It is expected to provide a detailed, up-to-date examination of the clinical and pathological features of EL, based on a careful analysis of the thousands of scientific reports and books published during and after the pandemic period, as well as the considerable number published more recently. This will be the first comprehensive textbook on EL for many years, and we hope that it will become the definitive work on EL, in much the same way that von Economo’s classic text “Encephalitis Lethargica: its Sequelae and Treatment” was in the 1930’s. The Trust hopes that Professor Vilensky’s book will provide a new benchmark and a stimulus for further research on this still-mysterious disease.
The trust will contribute a foreword for the book, as an
acknowledgement of our financial support for its preparation.
Professor Vilensky has also kindly agreed that the book will
be dedicated to the memory of Sophie Cameron.
Professor Vilensky and his colleagues have recently published a number of scientific papers on encephalitis lethargica (EL). These include a review of the symptoms and classifications of various types of EL (Encephalitis lethargica: could this disease be recognised if the epidemic recurred? Practical Neurology 2006 6: 360-367). This article deals with the classifications that were developed during and after the EL pandemic that occurred following World War I, and discusses their relevance to modern diagnosis. They have also published an article entitled "Children and encephalitis lethargica. A historical review" (Pediatric Neurology 2007 37(2) 79-84), and a review article entitled “The relationship between encephalitis lethargica
and influenza: A critical analysis” (Journal of Neurovirology
2008 14(3): 177-185).
On 17th June 2008, Professor Vilensky gave a seminar
“Sleeping Princes and Princesses: The Encephalitis Lethargica
Epidemic of the 1920s and a Contemporary Evaluation of the
Disease” at the Wolfson Lecture Theatre, National Hospital
for Neurology and Neurosurgery, Queen Square, London. His
visit to London was supported by the Trust. The seminar was a
great success, being attended by about 80 people including a
number of eminent neurologists, such as Professor Andrew Lees,
who was a co-author of an important paper on the diagnostic
criteria for EL in the 1980s.
6. Research at Kazan State Medical University, Russia
In late 2006, the Trust approved a grant to Dr. Ravil Mukhamedzyanov of Kazan State Medical University, a leading medical school in Russia, to support him in translating Russian articles on encephalitis lethargica. EL in the Soviet Union had some unusual characteristics, the most significant of which was its persistence in epidemic form into the 1950s. Professor Vilensky and Dr. Mukhamedzyanov
are collaborating to prepare an annotated bibliography in
English of the Russian EL literature, most of which is not
currently available in English. The results of this work have
been published in an article entitled “Encephalitis lethargica
in the Soviet Union” (European Neurology 2008; 60: 113-121). This is in addition to Professor Vilensky’s other EL-related research (Indiana University School of Medicine).
7. Research at The London Metropolitan University
In 2007, the Trust agreed to fund a study by Dr Robert Dourmashkin at the Institute for Health, Research and Policy, The London Metropolitan University, to identify virus particles that have been observed in the brains of some EL patients. Dr Robert Dourmashkin has developed a reliable immunocytochemical technique for identifying viral antigens in the brain of patients with encephalitis lethargica and idiopathic Parkinson's disease. This study has included pathological material from Prof. Margaret Esiri at the Radcliffe Infirmary, Oxford, and Dr. Sherman McCall, formerly at the recently dissolved Armed Forces Institute of Pathology, Washington DC. Permission has also been obtained from the Institute of Neurology, Queen Square, for Dr.
Dourmashkin to examine tissue from a recent encephalitis lethargica patient.
The significance of Dr. Dourmashkin's findings have
to await confirmation that the results have not been
influenced by possible cross-reactions of the
immunocytochemical tests. This study will continue to
concentrate on this question. Dr. Dourmashkin is in frequent
contact with Prof. Esiri for scientific advice and technical
guidance, as well as with Dr. McCall. Dr. Dourmashkin's
studies by electron microscopy of encephalitis lethargica,
Parkinson's disease and Lytico-Bodig syndrome (a rare
neurodegenerative disease acquired from the ingestion of cycad
flour in Guam) are continuing.
Dr Dourmashkin has published a number of related scientific papers, including some in collaboration with the well-known virologist, Professor John Oxford.
Unfortunately this work had not yielded any conclusive results
by 2009, and funding has been discontinued.
8. Research at Queen Mary University London
Dr Giovannoni, who recently moved from the Institute of Neurology to become Professor of Neurology at the Institute of Cell and Molecular Science, Queen Mary University London, has started a
national surveillance programme for
encephalitis lethargica in the whole of the UK. The Trust has been encouraging and supporting planning for this project for about 2 years, and will be playing a key role in funding part of the salary of the research manager who will administer it. The proposal has received ethical approval from the UK's Medical Research Ethics Committee. The principal investigators will be Dr Anette Schrag (consultant neurologist at the Royal Free Hospital) and Dr Cheryl Hemmingway (paediatric consultant neurologist at Great Ormond Street Hospital).
The purpose of the study is to gain near-complete surveillance of the disease across the UK. At present it is anticipated that the surveillance programme will run for 10 years. The information obtained from this study may help us to better diagnose and treat future patients with EL. In addition, long-term follow-up will provide better information about outcomes, and may lead to better treatment options for the patients.
The paediatric surveillance programme commenced in December
2007, and is being conducted through the British Pediatric
Neurological Surveillance Unit (BPNSU). The adult surveillance
programme was delayed pending resolution of a query sent by
the British Neurological Surveillance Unit (BNSU), but
commenced in April 2008. The EL database is being maintained
at Queen Mary University London on a secure University server.
As of October 2008, 15 paediatric EL cases have been notified
through the BPNSU scheme and confirmed through the
surveillance programme – a feature of both the BPNSU and BNSU
schemes is that a number of erroneous cases are initially
reported. Four adult EL cases have been notified via the BNSU
scheme, one of which has been confirmed to date. The current
notification rate is approaching the expected 20 cases per
year; however, this is likely to include a backlog of cases
from 2007 and previous years.
In November 2007, we agreed to provide further funding for an extension of the work at The Institute of Neurology on brain antigens that may be related to EL. This work will be carried out by a group of researchers at The Institute of Neurology and The Institute of Cell and Molecular Science, led by Prof. Giovannoni. As described in an
edited summary of their proposal, one of the main aims is to investigate the distribution of gamma/alpha enolase dimer, which is a target of anti-basal ganglia autoantibodies that are thought to be associated with recent streptococcal infection. This research will also help to establish whether these antibodies play a role in the pathogenesis of EL.In
2008, the SCT grant has so far contributed to supporting
Joseph Cohen, an MBBCh-BSc student, who did his laboratory
project on this topic, and has written a
report of his results, and Kathrin Hoffman, a German MSc
student, who has been taken on for a further 8 months to
extend Joseph’s work.
The Trust also provided some funding for a symposium on the role of autoimmunity in Tourette’s syndrome and related disorders, as part of the Italian Movement Disorders National Congress, in Bari, April 4-5 2008. David Holden presented a poster entitled
“Encephalitis lethargica: surveillance and immunological studies”. This described the EL surveillance programme, and related investigations into the immunological basis of this disease, both of which are supported by funding from the Sophie Cameron Trust.
In 2008, the Trust agreed to provide funding for a 3-year Ph.D. studentship at Queen Mary University London, to be supervised by Professors Giovanonni and Baker at the Institute of Cell and Molecular Science. This grant, to be called The Sophie Cameron Trust Ph.D. Studentship, will allow a research student to work full-time for the degree of Ph.D, on a project entitled “Functional effects of anti-basal ganglia antibodies in patients with encephalitis lethargica and related disorders associated with streptococcal infection”. An edited summary of the proposal is available
here. The research will focus on the hypothesis that autoimmune mechanisms play an important role in EL, as they are thought to do in other neuropsychiatric disorders, including Sydenham’s chorea, PANDAS, Tourette’s syndrome (TS) and obsessive compulsive disorder (OCD). As auto-antibody-mediated diseases respond to immunomodulatory therapy, identifying and defining the pathogenesis of these disorders is important so that patients can be appropriately treated.
Progress during 2009 is described in the “Latest news”
What is Encephalitis Lethargica
The "Spanish" influenza
epidemic of 1918 and EL