Encephalitis a moving target for researchers, doctors

The simplest way to describe encephalitis is that it's a swelling or inflammation of the central nervous system. But encephalitis is far from simple. The complex neurological condition can strike out of the blue; it's difficult to diagnose and treat; and those who survive it often have to cope with devastating after-effects.

"There are, broadly speaking, two types of encephalitis," says Tom Solomon, chair of neurological sciences and head of the brain infections group at the University of Liverpool.

"One is caused by a virus or other pathogen entering the nervous system and directly causing inflammation. The other is indirect inflammation, often mediated by antibodies. One of the main issues is recognizing that a patient may have encephalitis, and then diagnosing it."

Encephalitis can result from a wide range of things — a brain injury, a drug reaction, a bite from a tick or mosquito carrying West Nile Virus or other diseases, and even an immune response triggered by common diseases such as mumps and measles.

It can hit quickly but often marks a patient for life.

"Although there are forms of encephalitis that are benign and do not cause long-term, permanent problems, most forms have a long-lasting effect on the brain, from seizures, to cognitive problems, to motor deficits, to sensory deficits, to death," says Dr. Jane M. R. Gillett, a neurologist and medical director of the acquired brain injury program at Hamilton Health Sciences. "Some can be associated with visual disturbances because of infection of the retina, and others because of the damage to the visual pathway in the brain or the occipital lobes. Hearing can also be affected, and balance."

Tracking encephalitis

There are no accurate statistics regarding the number of cases of encephalitis in Canada, because many factors influence how it is reported to the various provincial health units.

In the Simcoe-Muskoka area of Ontario, for example, if West Nile virus is detected as the infectious agent responsible for a case of encephalitis, it is reported as a case of West Nile virus and not encephalitis. The same goes for encephalitis caused by meningitis.

"There is no good overall Canadian data, as this is not a reportable condition," say Dr. Ari Bitnun, assistant professor of pediatrics at the University of Toronto and staff physician at the Hospital for Sick Children.

On the whole, the incidence of encephalitis is estimated to be between five and 10 cases per 100,000 people in the West and in tropical settings. According to a 2004 report on mortality statistics for encephalitis by country are derived from official causes of death on certificates of death.

"Rather than being a true indicator of the number of deaths attributed to a particular cause, mortality statistics reveal more about a particular country's reporting processes," the report says.

Difficult diagnosis

There are treatments that can help encephalitis patients, but they require fast diagnosis and action.

"Determining the cause of encephalitis can be quite difficult," says Bitnum. "In general, even with extensive investigations, a clear-cut etiology is identified in only a third of cases. In another third, a possible cause is identified, and in the final third, no specific pathogen is identified. In our institution, there is a standard microbiologic workup for encephalitis that includes cerebrospinal fluid, blood, stool and respiratory samples."

'As a caregiver for my husband, Daniel, I had no life for the first four or five years, just doctor's appointments and worry. This has changed my life, finances and life goals by degrees.' —MaryAnn Surridge

"One of the difficulties in both managing and treating patients with encephalitis is the vast number of causative agents," says Dr. Carol Glaser, chief of the encephalitis and special investigations section of the communicable disease and response branch at the California Department of Public Health. "Infectious causes are diverse, including viruses, bacteria, fungi and parasites, and the microbiology of encephalitis represents a moving target.

"Not all viral infections result in encephalitis. Why it does in some and not others is not at all clear."

Daniel Surridge, a 62-year-old from East Longmeadow, Mass., is all too aware of how tricky encephalitis can be to deal with. "I got encephalitis in 1997, and my life as I knew it changed overnight. The encephalitis was caused by a mosquito bite or from a flu shot I had received a week earlier."

Prior to getting encephalitis, Surridge was a computer operations manager running six government agencies in Boston. Now, he is unable to work. His family has also been affected.

"Encephalitis has infiltrated every part of my life," says his wife, MaryAnn. "As a caregiver for my husband, Daniel, I had no life for the first four or five years, just doctor's appointments and worry. This has changed my life, finances and life goals by degrees."

A quicker diagnosis and medical intervention might have meant a different outcome, she said. "An earlier diagnosis could have prevented some, if not all, of the residuals, because the antiviral meds would have killed the infection before it damaged my husband's brain. He would possibly be able to work today. He was sent home from the hospital twice and languished for two or three days at home before they decided that it wasn't just the flu." 

Finding the source

Researchers around the world are trying to develop faster ways to identify, treat and track encephalitis.

The Hospital for Sick Children in Toronto has maintained a registry of all patients admitted with acute encephalitis since 1994. It sees 10 to 20 acute cases each year.

"The purpose of this registry is to provide a standardized framework for the investigation of acute encephalitis in children in our institution," says Dr. Bitnun, who is in charge of the registry.

In the U.S., the California Encephalitis Project (CEP) was initiated in 1998 to identify the causes and symptoms of encephalitis. To date, more than 4,000 cases have been referred to the CEP from more than 220 facilities in California for testing.

"At the Johns Hopkins Encephalitis Center, we have established a multidisciplinary group of neuro-infectious disease specialists, neuro-critical care experts, infectious disease physicians, laboratory pathologists and rehabilitation specialists to improve the diagnosis and treatment of patients with encephalitis," says Dr. Arun Venkatesan of Johns Hopkins. 

"We recognize that prompt recognition of the condition combined with advanced diagnostic and therapeutic modalities is likely to impact patients' lives and decrease morbidity and mortality.

"Using newly developed technology will allow for the identification of previously unrecognized organisms. Identifying these organisms is the first step toward developing effective treatments."     Dr. W. Ian Lipkin, director of the Center for Infection and Immunity and a professor of epidemiology, neurology and pathology at the Mailman School of Public Health and College of Physicians and Surgeons at Columbia University, New York,  is internationally recognized for his work with West Nile virus and SARS. Dr. Lipkin and his team have developed several new technologies to identify pathogens linked to encephalitis, including:     

• Degenerate Polymerase Chain Reaction, a sensitive method for detecting a type of microbe (virus, bacterium, fungus or parasite) that may vary in gene sequence.
• MassTag PCR, a method that is sensitive, inexpensive and allows many tests to be run simultaneously. It's particularly useful for situations where many different infectious agents may result in a similar disease (like encephalitis). There are panels for distinguishing up to 30 different causes each of respiratory, brain, and enteric infections. A typical test costs $150 US and takes four hours.
• GreeneChips, slides coated with probes for all known viruses that have the potential to identify any virus in a sample. The tradeoff for this breadth is in sensitivity. A typical test costs $400 US and takes 14 hours. 
• Unbiased High Throughput Sequencing, which can detect any microbe. However, it is much more expensive and requires significant expertise. A typical test costs $5,000 US and takes several days.

"MassTag PCR may become widely available in the next few years because of investments in making smaller, user-friendly equipment," Lipkin says. "GreeneChips and sequencers will be confined to reference labs and major medical centres for the foreseeable future. Thus, their first impact will be on epidemiology of encephalitis. However, results obtained will direct development of specific, degenerate and MassTag PCR assays that can be more widely used, as well as spurring development of new therapeutics."

"A greater understanding of the pathogenesis [how the virus causes the disease] and the pathophysiology [how the disease affects the body] leads to better patient management and the development of new treatments," adds Solomon. His team has been working with the World Health Organization and others to improve the diagnosis of Japanese encephalitis, a leading cause of viral encephalitis in Asia with up to 50,000 clinical cases reported annually.

MaryAnn Surridge hopes the research will result in earlier diagnosis and treatment so that others don't have to go through what she and her husband have experienced.

"The impact of encephalitis on me, the only family member caring for Daniel — the survivor — is by far the worst thing that has ever happened to me in my entire life," Surridge said. "I am not someone to give up easily, but encephalitis has beaten me. Over the years, it has taken more and more of my life from me. I cannot express the fear I face every day, the fear of losing my husband to this illness."