Nailing the Suspect: The Prevalence of Autoimmune Encephalitis Compared with Infectious Encephalitis

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For people with encephalitis, rapid treatment of their acute brain inflammation is critical for avoiding devastating physical and cognitive deficits. But appropriate treatment requires identifying the culprit causing the symptoms.

For years, the prime suspects were infections, particularly those caused by the Herpes simplex virus and mosquito- or tick-borne pathogens. But in the past decade, Mayo Clinic has been at the forefront of demonstrating that encephalitis can also be caused by the body’s immune system attacking the brain. This “autoimmune encephalitis” has been considered much less common than encephalitis resulting from an infection.

Now, in a groundbreaking population-based study, Mayo Clinic has found that autoimmune encephalitis is as common as its infectious disease counterpart. The finding underlines the need for precise diagnostic testing for people with encephalitis, as the autoimmune and infectious diseases require different treatments.

“When physicians see a patient with encephalitis, it’s very important to test for an autoimmune cause in addition to considering infections,” says Eoin Flanagan, M.B., B.Ch., an autoimmune neurologist at Mayo Clinic in Rochester, Minnesota, and the study’s senior author.

“If an autoimmune cause isn’t considered, the patient may not receive immunotherapy. That can be detrimental—as patients often respond well to immunotherapy, but the longer the delay in receiving it, the worse the outcomes.”

Mayo Medical Laboratories offers an Autoimmune Encephalopathy Evaluation (Test ID: ENS2/ENC2) to test for autoimmune encephalitis. Dr. Flanagan notes that physicians ordering the panel should submit both patient serum and cerebral spinal fluid samples when highly suspicious.

“We need to test both because some antibodies are better picked up in serum and others in the spinal fluid,” he says. “These patients are often very sick. We do a comprehensive analysis upfront because rapid diagnosis and treatment result in better outcomes.”

Heavy Disease Burden

Encephalitis can cause considerable morbidity with patients experiencing confusion, altered consciousness, memory loss, seizures, and movement disorders. Hospitalizations for the disease cost $2 billion in the United States in 2010.*

Timely immunotherapy can often help patients regain function. “But depending on the antibody involved, recovery can be quick in the order of weeks or be prolonged and take more than six months,” Dr. Flanagan says.

Previous epidemiology studies of encephalitis have focused mostly on infectious causes, with “immune-mediated” syndromes occasionally analyzed as a subgroup. Mayo Clinic’s study is the first to determine the epidemiology of autoimmune encephalitis at a population level.

To identify cases of encephalitis, the study used data from the Rochester Epidemiology Project, a medical-records database of all medical providers in Olmsted County (where Mayo Clinic’s campus in Minnesota is located). In that study population, the prevalence of autoimmune encephalitis was 13.7 cases per 100,000 people, compared with 11.6 cases per 100,000 people for infectious encephalitis.

“Extrapolating our results to the world population suggests that about one million people are affected with autoimmune encephalitis,” Dr. Flanagan says. “The disease burden for autoimmune encephalitis—a condition that just 10 years ago went unrecognized—is significant.”

The study also found a nearly three-times higher incidence of autoimmune encephalitis for African-Americans: 38.3 cases per 100,000 people in the population group, which is largely of northern European descent. That finding is consistent with previous Mayo research showing a predisposition for certain other autoimmune neurology disorders among African-Americans. The researchers note that further studies are needed in populations with a higher proportion of African-Americans. 

In this epidemiology study, the researchers took several steps to avoid overestimating the frequency of autoimmune encephalitis. “We used diagnostic criteria from a 2016 position paper that are quite strict, and we included in the study only patients with definite or probable autoimmune encephalitis. To be extra cautious, we excluded cases of possible autoimmune encephalitis,” says Divyanshu Dubey, M.B.B.S., an autoimmune neurologist at Mayo Clinic’s campus in Minnesota who also participated in the study.

In addition, only antibodies highly specific for autoimmune encephalitis were included. “Other antibodies can be seen in small numbers of healthy individuals,” Dr. Flanagan says. “We excluded those antibodies because we didn’t want to over-diagnose.

“The prevalence that we report may actually be an underestimate,” he adds.

“We are discovering new antibodies all the time. Over the last 15 years, we have probably gone from one or two neural antibodies to 20 to 30 neural antibodies now available for testing. This allows us to diagnose autoimmune encephalitis more easily. Our ability to diagnose is likely to increase over time, so the prevalence of autoimmune encephalitis will also increase.”

The study also found that autoimmune encephalitis has a higher risk of relapse or recurrent hospitalization than infectious encephalitis. The risk varies according to the antibody involved but can be as high as 30%.

Pioneers in Autoimmune Neurology

Mayo Clinic has a distinguished history of translating discoveries about neural antibodies into advances in patient diagnosis and care. Much of the antibody testing in the encephalitis epidemiology study was conducted at Mayo’s Autoimmune Neurology Laboratory.

The most common antibody found in the study was myelin oligodendrocyte glycoprotein auto-antibody, also known as MOG IgG. That antibody is associated with acute disseminated encephalomyelitis, a disorder that often affects children. Other antibodies that were found include GAD-65, LGI-1, CRMP-5, NMDA-receptor, ANNA-2, and GFAP.

Clues to a possible autoimmune encephalitis diagnosis include:

• New onset of epilepsy without an apparent underlying cause.
• Autonomic dysfunction.
• MRI findings of mesial-temporal-lobe involvement or inflammation in the white matter.
• Recent diagnosis of cancer, which can trigger an immune response.
• Faciobrachial dystonic seizures, which are associated with LGI1 antibodies.

“Knowing the antibody that’s involved in autoimmune encephalitis can give you a sense of the patient’s prognosis,” Dr. Flanagan says. “Some patients respond very rapidly to immunotherapy. They can go from being very confused to back to normal in a week. Antibody testing can help these patients to get their lives back.”

*Vora NM, Holman RC, Mehal, JM, et al. Burden of encephalitis-associated hospitalizations in the United States, 1998-2010. Neurology. 2014;82(5):443-451. www.ncbi.nlm.nih.gov/pubmed/24384647. DOI: https://n.neurology.org/content/82/5/443.

Barbara J. Toman

Barbara J. Toman is a Senior Communications Specialist at Mayo Clinic Laboratories. She is also the science writer for Mayo’s Neurosciences Update newsletter, which helps referring physicians to stay informed about Mayo’s treatment and research. Barbara has worked at Mayo Clinic since 2007. She enjoys international travel and cooking.