SCT Encephalitis lethargica surveillance and
research programme at BICMS/QMUL: 2009 update
EL Surveillance Programme: The EL surveillance program was set
up in 2007, with the support of the Sophie Cameron Trust. The
aim of this is to monitor all reported UK cases of EL, and to
gain specific information on these cases. There are two arms to
this study; the paediatric surveillance programme commenced in
December 2007, and the adult surveillance programme commenced in
As of November 2009, 4 adult cases and 6 paediatric cases have
been confirmed following notifications received via the
surveillance programme. We are also requesting information from
consultants outside the UK, as this increases coverage and
enhances our understanding of the condition.
To date, 8 EL cases have been included on the database, and a
further 9 cases are to be included, pending informed consent
from the patients or their representatives. It is anticipated
that it may take several years of monitoring for the underlying
pattern of occurrence to become clear.
Research Programme: A research programme to investigate the
functional significance of anti-basal ganglia antibodies (ABGAs)
has been supported by a grant from the Sophie Cameron Trust.
This supported a laboratory project by Joseph Cohen, an
intercalated MBBCh-BSc student. This study was continued via
collaboration with Dr Jenny Pocock at University College London,
who supervised a project by Kathrin Hoffman, a German MSc
student. Further work to test the role of ABGAs will form a part
of the PhD project funded by the Sophie Cameron Trust, which
Priya Dua started in October 2008. Priya’s work is aiming to
establish a working model to study encephalitis lethargica and
related post-streptococcal movement disorders. In particular,
this will test the role of streptococcal infections and the
functional significance of anti-neuronal antibodies studied in
the previous project. An outline of her work has been presented
as a poster.
Priya will discuss this work at the SCT AGM on November 23rd.
Some thoughts on Joel Vilensky’s upcoming book
about encephalitis lethargica.
We are hoping that Joel’s book on encephalitis
lethargica will appear next year, nearly 80 years after the
publication of the English translation of von Economo’s classic
text, “Encephalitis Lethargica: its Sequelae and Treatment”,
which, coincidentally, was also published by Oxford University
Press. An obvious question to ask is, what has changed in the
past eight decades? Chapter II of von Economo’s book began with
the comment “There still remains … quite a variety of open
questions concerning the fundamental nature of encephalitis
lethargica”, and in this regard, little has changed – the
sentence would not be out of place in Joel’s book. However, the
practice of neurology has changed enormously.
In his Translator’s Preface to von Economo’s treatise, K.O. Newman
of New College, Oxford, noted that “The translator’s lot is not
a happy one. He is faced with the ungrateful, difficult and
wearisome task of sailing his craft, the book, across the wide
gulf which separates two languages.” Joel’s task is similar, but
the translation required is not only that of previously
untranslated material from French, German and Russian sources
into English, but also that from the theories and observations
of early 20th century neurology to those of early 21st century
neurology. The latter translation is by no means easy. For
example, the language of neurology has changed, as all living
languages do over time; consequently, some of the terminology of
the early 20th century neurologists has become archaic and its
meaning difficult to interpret in modern terms. Also, many of
the concepts underlying their ideas are no longer considered
valid. Simply put, we can say that if neurologists of the two
periods could discuss the issue of encephalitis lethargica, they
might find that they could not easily agree on their definitions
of the disease, or even on the most significant symptoms and
most appropriate diagnostic criteria. Thomas Kuhn, a historian
of science, would have considered that they would be living in
different scientific worlds – or, more precisely, in the same
world understood through different sets of canonical (standard)
techniques and theoretical possibilities, i.e., through
One reason for this is the development of modern medical
technology. For example, computed tomography or magnetic
resonance imaging (MRI) can now be used to visualize anatomical
structures of the living human brain in great detail; functional
MRI, positron emission tomography and near-infrared spectroscopy
can visualize changes of metabolism and brain activity in small
regions of the brain; polymerase chain reactions can allow the
definite identification of infectious agents from tiny amounts
of biological samples. These and many other tools were not
available to early 20th century neurologists. So, the kinds of
information now available to the physician, although similar in
part (for example, the presenting signs and symptoms), are in
other respects very different from those available then, and
would be interpreted in terms of different theoretical
understandings of pathological processes. The point is further
illustrated by the fact that, although tissue samples from
victims of the encephalitis lethargica pandemic were taken, and
some are still available, they were prepared and stored in ways
that have made them generally unsuitable for study with modern
techniques, so that the original cases can not easily be
reinterpreted. All of these considerations mean that we can not
even be sure that the encephalitis lethargica of the post World
War I pandemic is the same disease as the sporadic cases that
have been diagnosed in recent years. Indeed, Dale et al., in
their 2004 paper in Brain, preferred to use the term
encephalitis lethargica syndrome, reflecting the apparent
similarities but uncertain fundamental linkages between the old
and new forms of the disease as seen from a modern perspective.
In the pandemic period, many of the acute cases died. Among
survivors, less than one-third made a complete recovery, and
about one-third became chronic invalids. In the acute stage,
symptoms included tiredness, headache, fever, and a variety of
neuropsychiatric symptoms (anxiety, hallucinations, delirium,
confusion, bizarre behavior), as well as ocular disturbances,
motor disturbances (involuntary twitching or contractions,
unusual movements), sleep disturbances (such as sleep
inversion), respiratory disturbances, and seizure. Some patients
entered a coma-like state. Many patients subsequently developed
movement disorders (known as post-encephalitic parkinsonism),
such as rigidity and lack of expression, sometimes after a
period of months or even years. The course of the disease varied
enormously; symptoms sometimes appeared suddenly, and improved
or deteriorated very rapidly. Even now, though, it is not clear
how closely some of these symptoms are associated with EL, as
Joel will discuss in his book. Nevertheless, some patients were
hospitalized for decades. Physicians of the time found these
polymorphic signs and symptoms so perplexing that nearly 30
different types of the disease were proposed to exist.
Encephalitis lethargica is now considered a rare disease, though
sporadic cases continue to be reported from countries around the
world. In 1987, Howard and Lees proposed modern diagnostic
criteria that have been widely accepted. Briefly, they proposed
that an encephalitic illness could be diagnosed as encephalitis
lethargica if all known causes of encephalitis had been
excluded, and at least three of the following criteria were met:
signs of basal ganglia involvement, oculogyric crises,
ophthalmoplegia (paralysis or weakness of one or more of the
muscles that control eye movement), obsessive-compulsive
disorder, akinetic mutism (a coma-like state), respiratory
irregularity, and sleep disturbance.
One of the recent cases was that of Sophie, who returned from a
holiday in Venice feeling unwell. Several days later she was
admitted to hospital in a delirious state, and subsequently
developed many of the classical symptoms of encephalitis
lethargica, including oculogyric crises, respiratory
irregularity and coma. After months in intensive care, she was
finally discharged home late in 1999 in a minimally aware state.
Despite twenty-four-hour care from her family, as well as
intensive physiotherapy and other treatments, she sadly made
little progress, and she died suddenly on 30th May 2006.
As mentioned elsewhere on this site, friends of the Cameron family
established The Sophie Cameron Trust in 2001, aiming to help
people affected by encephalitis lethargica and their families,
to increase knowledge about encephalitis lethargica and its
implications among the medical profession and the general
public, and to encourage research into the management and causes
of encephalitis lethargica. The Trust has supported many studies
on various aspects of encephalitis lethargica by physicians and
research scientists in the UK, the USA and Russia, and some
results have already been published in leading medical journals.
The Trust also supports the national surveillance programme for
early identification and study of patients with encephalitis
lethargica in the UK, the only such programme currently
operating in the world. This programme is led by Professor Gavin
Giovannoni, who will also contribute a chapter to Joel’s book.
The Trust is particularly pleased to have been able to provide
money to assist Joel in the preparation of this book, both with
the translation of material never before available in English,
and by funding a part-time editorial assistant to help him with
the organization and writing. And, Joel has kindly agreed that
the book will be dedicated to Sophie, and that the Trust will
contribute a Foreword. The book will be a comprehensive,
up-to-date examination of the epidemiological, clinical and
pathological features of encephalitis lethargica based on a
careful analysis of the thousands of scientific reports and
books published in the pandemic period, as well as others
published more recently. In the concluding chapter of his
classic textbook, von Economo commented that “Hardly ever has
the discovery of a disease … altered our outlook so radically.”.
The Trust hopes that Joel’s book will provide a new benchmark
and a stimulus for further research on this still-mysterious
lethargica surveillance and research programme: update
David Holden & Gavin Giovannoni
This report covers the first year of the surveillance and
research programme, from September 2007 to September 2008
1. The paediatric surveillance programme commenced in December
2007, and is being conducted through BPNSU. The adult
surveillance programme was delayed pending resolution of a query
sent by BNSU, but commenced in April 2008.
2. The EL database is being maintained at QMUL, stored on a
secure QMUL University server, which is backed-up on a daily
basis. Following a meeting with Dr Joel Vilensky in June 2008,
database design is based on a data collection pro-forma
originally designed for Dr Vilensky’s historical study. This
will allow comparison of comparison of current surveillance data
and historical data, and allow results to be available online
3. Mr David Holden and Professor Gavin Giovannoni attended 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. The presentation of an
EL poster at this meeting had the effect of raising awareness of
the disease, and placing it in the context of related
neuropsychiatric disorders. A flyer describing the surveillance
project was distributed at the meeting.
4. 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. A letter of support from the Sophie Cameron Trust has
been included with the information sent to patients identified
by the programme.
5. Professor Gavin Giovannoni has registered the domain name
www.encephalitislethargica.org to create a website for the SCT
EL surveillance and research programme. We plan to create a wiki
using this domain to allow user-generated material to be posted
on the site. We plan to go live with the wiki in 2009.
6. The SCT EL Surveillance Programme will generate added value
if it is continued indefinitely and if the surveillance
programme is widened to receive cases from outside the UK.
7. The Neuroimmunology Unit at ICMS-QMUL are conducting a
research programme to investigate the functional significance of
ABGA. This project is supported by the SCT. Further
investigations are likely to require further biological samples,
which will be obtained via the EL surveillance programme.
Attached is a report by Joseph Cohen, an intercalated MBBCh-BSc
student, who did his laboratory project on this aspect of the
research. Joseph results were very interesting and he was
sufficiently motivated to return for an 8 week period over his
summer holidays to continue the work and study additional cases.
8. In collaboration with Dr Jenny Pocock we have also taken on
Kathrin Hoffman, a German MSc student, for a further 8 months to
expand on Joseph’s work. Her research work is being sponsored by
the SCT grant.
9. We have also appointed Ms Priya Dua to the SCT PhD
Studentship for a period of 3 years. During this time Priya will
be trying to set-up an animal model of encephalitis lethargic
based on the streptococcal hypothesis.
4th November 2008
SEMINAR BY PROFESSOR VILENSKY
On 17th June 2008, Richard Steele and Richard Wharton, on behalf of the Sophie Cameron Trust, visited the Institute of Neurology in Queens Square, London. We had invited Professor Joel Vilensky of Indiana State University, USA to London to speak at the institute on encephalitis lethargica (EL). Prof. Vilensky has developed an encyclopaedic knowledge of the history and current state of the disease, and has unique access to records, documents and film footage from the epidemic in the 1920s. This has extended well beyond the USA, and he is in contact with researchers in Russia, Israel, South America, and elsewhere. He has documented the many recorded types of presentation of EL, and is developing a database which relates these to cases in a way which should help us understand the disease better. He has started work to write a definitive reference work on EL which will be published by Oxford University Press, hopefully in 2010. This work will be dedicated to Sophie, with a foreword by Richard Steele, and chapters will be contributed by many workers in this field including Professor Giovannoni, our scientific adviser. Research for the book is funded by SCT.
The lecture, at the Wolfson Lecture Theatre, National Hospital for Neurology and Neurosurgery, Queen Square, London, was attended by about 80 people including a number of eminent neurologists. It was co-chaired by Professors Andrew Lees and Roger Lemon. Prof. Lees is a co-author of an important paper on EL in the 1980s. Prof. Vilensky covered a huge amount in an hour, expounding the history, showing film of cases, and summarising the present position of cases and research. Particular aspects of EL which are almost unique include “false sleep”, where the patient appears to be asleep but is fully aware of and can remember events around them; and catatonia where they appear motionless for long periods, but can accurately catch a ball and throw it back. Cases in the 1920s included the centre forward of the national Hungarian football team, who later became catatonic. Another fascinating insight was the history of the disease in Samoa in the Pacific. During the worldwide flu epidemic, a ship from New Zealand docked in Western Samoa and flu spread through the islands, along with documented cases of EL. Meanwhile American Samoa nearby prevented the arrival of flu, and had no cases of EL at all. Researchers including Professor Oxford, who was in the audience, have tried for years to establish a link between the flu virus and EL, but have been unable to do so. Some of the discussion after the talk was quite technical, but Dr Gerald Stern, Emeritus Professor of Neurology, recalled the cases at Highland Hospital in north London which he had supervised and discussed with Oliver Sacks in the 1970s, and some of their bizarre behaviour.
All in all the talk was judged a great success, and SCT look forward to cooperating further with Prof. Vilensky in the future. Afterwards, he met with our team of Prof Giovannoni, Dr Annette Schrag, and David Holden, our research coordinator. The National Surveillance programme in the UK has started in March, and so far 15 cases of EL have been notified. This figure may be high, as neurologists may be recalling recent cases from the last few years, but we expect there to be a trickle of new cases as well. Where consent is obtained from patients, details can be logged using the database developed by Prof Vilensky in the USA. Each case will be sent details of the Sophie Cameron Trust. There is also growing evidence of cases all around the world, including 8 cases in Miami, Florida; a group in Israel; and new evidence from Thailand. Both professors have also been in touch with neurologists around the world about individual cases, especially in South America, and Dr Russell Dale, who co-wrote a paper we sponsored 3 years ago, is now based in Sydney. So we can see a worldwide research net into this rare disease developing.
Dr Andrew Church at ION still provides a test for antibodies to the basal ganglia in the brain, where movement is co-ordinated, and these antibodies are found in many cases of EL. Our next major research project is a three-year Ph. D. studentship to study these antibodies, known as ABGAs for short. Gavin Giovannoni will oversee this, and after interviewing a number of candidates, has appointed Ms Priyamvada Dua from Delhi, India. Ms Dua, who has taken an M.Sc. at Imperial College, London, will commence work in September. Gavin described her as an outstanding candidate, and hopes to arrange for us to meet her in the autumn. We will be covering her basic salary and some of the research costs for three years. Finally, we discussed how this explosion of research can best be coordinated and disseminated worldwide. It was suggested that the SCT website have a sister site designed for clinicians and maintained by the team in London, but with close links to SCT.
We will be pursuing this idea in the coming months. Overall, it
is astonishing how much the trust has achieved in the last few
years, and we anticipate the next few years will be equally
exciting. Many thanks to all our supporters and tireless workers
who have made this possible.
Richard Wharton and Richard Steele June 2008
Meeting at the Institute of Neurology following Dr Joel
Vilensky’s talk at the Wolfson Lecture Theatre, National
Hospital for Neurology and Neurosurgery, Queen Square, London.
Left to right: Richard Steele, Dr Anette Schrag, Professor Joel
Vilensky, Professor Gavin Giovannoni and David Holden. Photo
courtesy of Dr Richard Wharton.