On World Encephalitis Day, 22nd February, scientists raise awareness on the importance of studying this uncommon disease.

Encephalitis is a serious condition where the brain swells. Symptoms of encephalitis can range from mild (e.g., flu-like symptoms and headache) to more severe such as seizures and loss of consciousness. Long-term problems can follow, such as memory loss and seizures. It can be associated with high death rates too.

Encephalitis is caused by viral infections (including some that are spread by mosquitoes and ticks), autoimmune disorders that result in the immune system attacking the brain or, less commonly, bacterial and fungal infections. The disease cannot be passed from person to person. Distinguishing between the different forms of encephalitis is important to inform treatment, but this requires expertise. Some types of encephalitis (e.g., Japanese encephalitis, which has a high mortality rate) have no specific treatment but can be prevented with vaccinations.

Research to improve the understanding of the causes of encephalitis and how it is diagnosed and treated is essential. As part of World Encephalitis Day, the Institute of Infection interviewed Dr Nick Davies (clinical Consultant Neurologist and chair of the Encephalitis Society’s scientific advisory panel) and Dr Vanessa Sancho-Shimizu (Senior Lecturer in Paediatric Infectious Diseases) to help raise awareness of this condition.  

Encephalitis Society: Dr Nick Davies 

Tell me about yourself and your research? 

I am a full-time clinical consultant neurologist. I work mainly at Chelsea and Westminster and Charing Cross Hospitals. My current research is all collaborative. I was involved in the recent Dexenceph study [a clinical trial testing corticosteroid therapy in Herpes Simplex Virus encephalitis] and I am currently the external chair of the NIHR Enceph Ig study TSG. I also work with Professor Graham Taylor in the National Centre for Human Retrovirology clinic at St Mary’s and I am involved in clinical research relating to neurological infection with the human T-cell leukaemia virus HTLV-1.

What is the main problem in treating encephalitis, and how could interdisciplinary research help?

There are many problems associated with the treatment of encephalitis: the need for prompt recognition and accurate diagnosis; protection of the brain during the illness; and rehabilitation of an individual following what often results in an acquired brain injury. A range of disciplines of research is required: from laboratory diagnostics and understanding pathogenesis to clinical research on critical illness and rehabilitation.

Certain agents that cause encephalitis are arthropod-borne – is there a change in their frequency due to climate change?

Really interesting question. I am sure this is the case. Tick-borne Encephalitis (TBE – caused by a flavivirus transmitted by ticks common in central Europe) is now present in the UK. To date, there has only been a handful of indigenously transmitted cases. But be careful in the New Forest: UK ticks can transmit not only Lyme disease but also TBE! I strongly suspect that this has come about due to climate change causing an increase in tick prevalence.

Autoimmune encephalitis is often misdiagnosed; how do you think this can be improved?

This is where medical education needs to catch up with our ever-increasing knowledge base. Don’t forget that many of these syndromes have only been recognised and defined clinically in the last 10-15 years.

As chair of the Encephalitis Society’s scientific advisory panel, how is the society having an impact on the future of encephalitis?

The Encephalitis Society does a great job: it started by providing support to patients and their next of kin. It has now become a worldwide source for information relating to encephalitis. It has also achieved a major goal in pulling together researchers interested in encephalitis across the globe. Every year there is now an Encephalitis Conference held at the Royal College of Physicians here in London – do come (4^th-5^th December 2023)! The Society also sponsors PhD students and has seed funding for smaller projects. However, perhaps to date their biggest achievement is their work with the World health Organisation (WHO), which will result in a WHO technical report on encephalitis worldwide. This could be instrumental in ensuring diagnostic tools and medications for encephalitis are placed on the WHO’s essential lists. Hopefully this will make it more likely that encephalitis diagnostics and treatments will be available to all worldwide.

Childhood Encephalitis: Dr Vanessa Sancho-Shimizu

Tell me about yourself and your research

I work on the genetic basis of infectious diseases, with a particular focus on life-threatening infections of childhood including viral encephalitis. We try to identify inborn errors [i.e. congenital mutations] of immunity or other monogenic disorders that may make children susceptible to viral encephalitis (HSV-1 encephalitis and recurrent HSV-2 meningitis) or other severe infectious diseases.

What are the most common complications surrounding encephalitis?

The lifelong neurological consequences of herpes encephalitis are a common and debilitating problem. Infection by HSV-1 is destructive to brain tissue, and the damage caused can leave children with a range of neurological impairments, which may include developmental delay, intellectual disability, and seizures.

Why do certain people get encephalitis and not others?

We don’t fully understand why certain people develop encephalitis, although numerous factors can contribute, including the virulence of the virus and host factors including age, immune status and genetics. We have previously identified mutations in genes in an antiviral pathway that underlie susceptibility to childhood herpes encephalitis. These mutations are rare and disable the type 1 interferon pathway which is critical for viral clearance, and they explain a subset of childhood herpes encephalitis patients.

Does the genetics of a person make them more susceptible to either autoimmune or viral encephalitis and why – is there a way to test this?

As explained above, human genetic studies have helped us identify why certain individuals develop herpes encephalitis. Similar genetic approaches have also been successfully used to identify a different set of genes, controlling autophagy during viral infection, which is important in recurrent HSV-2 meningitis. This genetic approach is powerful because not only does it help us understand why the particular individual had life-threatening infection whilst the majority of people have mild or asymptomatic infection, but it also sheds light on which genes are essential for preventing these diseases. These findings can highlight different ways to manage the disease. On the other hand, the genetics underlying autoimmune encephalitis is not so clear yet. There are studies demonstrating that certain HLA haplotypes [i.e. the tissue type] are associated with autoimmune encephalitis: this is an area that is being actively explored.

What is next in research on the genetics of encephalitis?

Human genetic research gives us a unique perspective on what is essential for preventing encephalitis. Using assays with cells derived from patients, including the use of cerebral organoids [brain tissue grown in vitro] and cortical neurons derived from induced pluripotent stem cells, we can better model the disease process. These patient-derived organoids can help us understand how response to infection differs from healthy control derived organoids and we can also use them to test drugs and immunomodulatory treatments. Some of the genes and pathways implicated in herpes encephalitis have given us clues for new treatment strategies that may help to resolve the excessive inflammation associated with this infection that is thought to contribute to the devastating neurological consequences.

Learn more about World Encephalitis Day