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.

1. What is the precise incidence and distribution of encephalitis?
2. What is the precise burden of mortality and morbidity attributable to encephalitis?
3. Which are the most frequent viruses and other organisms that cause encephalitis?
4. 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?
5. How can we improve the recognition, diagnosis and treatment of those affected by encephalitis; and can we predict outcome?
6. Can we develop more specific and effective therapies to combat viral encephalitis than are currently available?
7. What is the best standard of care for patients affected by encephalitis?
8. How can we improve outcome from encephalitis in terms of both mortality and morbidity?
9. How can we improve the rehabilitation of patients who have been affected by encephalitis?
10. Can we prevent this devastating disease? e.g. with prior immunisation with vaccines.

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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

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.

Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections

NWS Davies, LJ Brown, J Gonde, D Irish, RO Robinson, AV Swan, J Banatvala, RS Howard
J Neural Neurosurg Psychiatry 2005;76:82-87. doi:10.1136/jnnp.2004.045336

Background:Polymerase chain reaction (PCR) is used to detect viruses in the cerebrospinal fluid (CSF) of patients with neurological disease. However data to assist its use or interpretation are limited.
Objective: We investigated factors possibly influencing viral detection in CSF by PCR which will also help clinicians interpret positive ad negative results.
Methods: CSF from patients with was tested for human herpesviruses types 1-6, JC virus, enteroviruses, and Taxoplasma gondii. The likelihood of central nervous (CNS) infection was classified as likely, possible, or unlikely. PCR findings in these categories were compared using single variable and logistic regression analysis.
Results: Of 787 samples tested, 97 (12%) were PCR postive for one or more viruses. Of episodes likely to be CNS viral infections, 30% were PCR positve compared to 5% categorised as unlikely. The most frequent positive findings were Epstein Barr virus (EBV), enteroviuses, and herpes simplex virus (HSV). Enteroviruses and HSV were found predominantly in the likely CNS viral infection group, whereas EBV was found mainly in the unlikely group. Positive PCR results were more likely when thre were 3-14 days between symptom onset and lumbar puncture, and when CSF white cells count was abnormal, although a normal CSF did not exclude a viral infection.
Conclusions: Th diagnostic yield of PCR can be maximised by using sensitive assays to detect a range of pathogens in approximetely timed CSF samples. PCR results, in particular EBV, should be interpreted cautiously when symptoms cannot readily be attributed to the virus detected.

Read more . . . http://jnnp.bmjjournals.com/