Paper prepared by Dr Nicholas Davies, Clinical Research Fellow at Guy’s and
St Thomas’s Hospital, London, and Trustee of the Encephalitis Society" in
consultation with Professor Peter G E Kennedy, Burton Professor of Neurology at
Glasgow University and Dr Tom Solomon, Lecturer in Neurology at the University of
Liverpool. All are members of the Society’s expert Clinical Advisory Panel.
October 2003
In many ways research into viral encephalitis has lagged behind that of other diseases.
Encephalitis is not an easy disease to study because of the difficulties of diagnosis,
and because cases occur sporadically throughout the country.
We need a better understanding of the pathophysiology of encephalitis (i.e. how
the infection causes the disease). How important are seizures and raised intracranial
pressure? Should patients be given routine anticonvulsants to prevent seizures?
In herpes simplex encephalitis delays in the diagnosis and starting treatment are
known to be associated with a bad prognosis. We need better clinical predictors
of encephalitis so that treatment can be started early. Only with large prospective
clinical trials will such data be produced. Where-as steroids are not routinely
given for viral encephalitis, they are for the post-viral form ADEM. Often distinguishing
between these two is difficult, especially early in the disease. We need better
clinical predictors to distinguish between the two conditions. We also need trials
to assess the role of steroids in ADEM, and maybe even in acute viral encephalitis.
There is a long list of viruses that can cause encephalitis, most of which are impossible
to avoid, but which are the important ones? Acyclovir, the only established treatment,
is only effective for encephalitis due to herpes simplex virus type 1 (HSV). Although
this is the most commonly diagnosed cause of viral encephalitis in the West, HSV
only accounts for about 10-30% of all patients with suspected viral encephalitis.
In the remaining patients the diagnosis is usually uncertain, there is no treatment,
and until recently the outlook has been bleak.
The diagnosis of CNS infections has been revolutionized by the use of rapid diagnostic
techniques, including the polymerase chain reaction (PCR) and highly sensitive and
specific IgM capture ELISAs. In addition, treatment of previously untreatable viral
encephalitides is becoming a reality with the advent of new antiviral drugs, and
the wider application for older drugs. These drugs are effective in the laboratory,
and in animal models. Some have even been tried in a few humans with encephalitis,
but they need to be assessed properly in clinical trials.
Priorities for Research into Encephalitis
Encephalitis is a group of diseases about which little is known. It is an inflammation
of the brain that comes on suddenly and produces serious neurological disease. It
can have a variety of causes of which virus infection is the most frequent and important.
Even with currently available treatment, acyclovir, for one type of encephalitis,
Herpes Simplex Encephalitis - due to the cold sore virus – the mortality rate
from this and other types of virus encephalitis is very high; and even survivors
can be left with devastating disability that can profoundly affect both their own
lives and those of their loved ones.
In at least half of the cases of encephalitis, we do not know the cause (around
30% of cases are Herpes Simplex Encephalitis); and accurate information on both
the causes and the true incidence of encephalitis in the UK is not available and
is urgently needed.
We need research to address the following questions relating to encephalitis.
- What is the precise incidence and distribution of encephalitis?
- What is the precise burden of mortality and morbidity attributable to encephalitis?
- Which are the most frequent viruses and other organisms that cause encephalitis?
- Once we understand which organisms cause encephalitis, we need to know why encephalitis
occurs only in certain individuals, when many of the viruses involved can be detected
in so many normal unaffected people. Is this due mainly to something in the virus,
in the make-up of the affected individuals, or in both?
- How can we improve the recognition, diagnosis and treatment of those affected by
encephalitis; and can we predict outcome?
- Can we develop more specific and effective therapies to combat viral encephalitis
than are currently available?
- What is the best standard of care for patients affected by encephalitis?
- How can we improve outcome from encephalitis in terms of both mortality and morbidity?
- How can we improve the rehabilitation of patients who have been affected by encephalitis?
- Can we prevent this devastating disease? e.g. with prior immunisation with vaccines.
Much More Research Needed into Encephalitis
Peter G. Kennedy, MD, PhD, DSc, MLitt, MPhil, FRCP (London, Glasgow), FRCPath, FRSE,
FMedSci, Burton Professor of Neurology, and Head of Glasgow University Department
of Neurology
"Despite the fact that viral encephalitis can produce devastating brain disease
with severe long-term disability, we are still a long way from gaining a detailed
understanding of how this group of diseases occurs.
Even with early and specific anti-viral therapy for Herpes Simplex Encephalitis,
caused by the cold sore virus getting into the brain, patients can still die and
survivors can be left with profound disability that is a lifelong burden for both
themselves and their carers.
In many other cases, we don? t know the identity of the virus or other organism
that produces the inflammation of the brain. Much more research needs to go into
understanding the causes, epidemiology, treatment and prevention of viral encephalitis.
There is also a pressing need to increase general awareness of this disease, and
to improve significantly the rehabilitation of survivors and support for both patients
and their carers facing what can be a lifelong disability."
19 September 2003
Professor Kennedy is President of the International Society of Neuro-Virology, Chairman
of the Scientist Panel on Infections (including AIDS) of the European Federation
of Neurological Sciences, and is also a member of the Encephalitis Society"
s expert Clinical Advisory Panel.
Encephalitis – from laboratory bench to bedside
Encephalitis, in common with many other neurological conditions has traditionally
been a diagnosis of exclusion. That is to say physicians have not had a single test
to confirm the diagnosis; but instead have relied upon their experience, clinical
acumen and exclusion of other possible diagnoses before reaching the diagnosis of
encephalitis. In other fields of medicine, such as in genetic conditions, science
has provided detailed explanations as to the cause of disease resulting in simple,
reliable diagnostic tests. However, our understanding of how, why and which infections
cause inflammation of the brain is comparatively poorly understood. In fact, throughout
even the industrialised world the cause of the majority of encephalitis is unknown.
To begin to unravel the complexities of a diverse condition such as encephalitis,
one approach is to attempt to identify the culprit organisms responsible. This task
has been aided by the revolution biological science has undergone over the last
twenty years. Technical advances in the new science of “molecular biology”
allow the study of the biochemistry and genetics of individual cells. Such techniques
are now becoming reliable enough to use routinely in the pathology lab and offer
the advantage of being many times more sensitive than older technology. An example
of a new technique is the polymerase chain reaction (PCR). We are all familiar with
criminals being convicted on the evidence of their “genetic fingerprint”
being found in microscopic amounts at crime scenes. PCR is one of the techniques
used by forensic scientists to identify the unique “genetic fingerprint”.
Similarly, bugs such as viruses leave their “genetic fingerprints” at
the site of infection. In encephalitis, examination of the fluid that bathes and
nourishes the brain (cerebrospinal fluid) at lumbar puncture offers the chance to
spot the fingerprint and identify the infection.
However, one of the challenges of introducing new diagnostic tests is to understand
what the results mean in the context of the patient’s condition. Our ability
to find the fingerprints of bugs suggests that they may be involved in many more
disease processes than previously thought. The work of our collaboration aims to
capitalise upon these techniques to identify the causes of encephalitis rapidly
and reliably. In addition, we aim to increase our knowledge how test results correlate
with what the physician sees at the bedside. We hope that such endeavours will allow
greater understanding of the causes of encephalitis and direction of appropriate
treatments.
Dr Nicholas Davies
Neurology Clinical Research Fellow
Guy’s, King’s & St Thomas’ School of Medicine, London.