Brain Network Disorders Review explores biomarkers linked to rare autoimmune brain disease

Encephalitis is a potentially life-threatening condition that involves inflammation of the brain. While some cases of encephalitis are caused by a bacterial or viral infection, other cases of ‘autoimmune’ encephalitis result when the body’s own immune system attacks the brain. One type of autoimmune encephalitis is characterized by antibodies (protective proteins produced by the immune system) that target N-methyl-D-aspartate (NMDA) receptors, or NMDARs, which play an important role in the transmission of signals between neurons in the nervous system.

This type of encephalitis, known as anti-NMDAR encephalitis, typically affects younger women and children and has a higher incidence in Asian populations. In fact, around 12.9% of unexplained encephalitis cases in China were found to be cases of autoimmune encephalitis – of which 90% were anti-NMDAR encephalitis cases. Despite this, there are few reviews that discuss the biological markers that characterize anti-NMDAR encephalitis.

To better understand the biological markers of this disease, two researchers, Dr. Honghao Wang and Dr. Minchao He from The Second Affiliated Hospital of South China University of Technology, Guangzhou, China, conducted a comprehensive review of the biomarkers and mechanisms associated with anti-NMDAR encephalitis. Their findings were made available online on May 13, 2025, and were published in Volume 1, Issue 2 of the journal Brain Network Disorders in June 2025.

In this review, the authors begin by describing the clinical characteristics, underlying mechanisms, and related conditions associated with anti-NMDAR encephalitis. They identify eight main symptom categories commonly seen in patients: psychiatric abnormalities, seizures, memory deficits, consciousness disorders, movement dysfunction, autonomic dysregulation (malfunction of nerves that control involuntary functions like heart rate and digestion), speech disturbances, and central hypoventilation (a condition in which the brain fails to control breathing properly).

What causes this form of encephalitis? The authors explain that it can be triggered by tumors, viral infections, and certain vaccines such as H1N1 influenza and tetanus. In affected individuals, NMDARs present on tumor cells or on the surface of neurons are mistakenly identified by the immune system as threats. This activates B cells in the lymph nodes, which multiply and migrate across the blood-brain barrier into the brain. There, they mature into plasma cells that release large amounts of antibodies targeting NMDA receptors. These antibodies interfere with normal brain signaling, resulting in the neurological and psychiatric symptoms characteristic of the disease.

The authors then review key biomarkers that can help in diagnosing and managing anti-NMDAR encephalitis. “If clinical manifestations suggest that the patient may have anti-NMDAR encephalitis, the first step must be to check for NMDAR antibodies and their levels in the blood and cerebrospinal fluid,” explains Dr. Wang.

If NMDA antibodies are absent or present at low levels, clinicians are advised to look for additional clinical indicators. These include uric acid, C-reactive protein, 25-hydroxyvitamin D (the primary form of vitamin D in the body), and various thyroid-related hormones in the blood. Abnormal results for these indicators can support the diagnosis. Electroencephalogram tests, which detect irregular brain activity, may also help identify the condition.

Finally, a technique called a lumbar puncture is required to obtain a sample of cerebrospinal fluid (CSF)–a fluid that surrounds the brain and spinal cord. After the CSF is obtained, tests for other markers such as interleukins and chemokines (proteins associated with the immune system and inflammation) can be conducted depending on the equipment available. In addition, molecules such as microRNAs and circular RNAs can be used for further detection.

“In the future, we will need to search for more anti-NMDAR encephalitis biomarkers, review controversial biomarkers, and examine the strength of the evidence for existing biomarkers–further summary and refinement of these indicators are also directions for future research,” says Dr. Wang.

The authors hope their review will serve as a valuable resource for clinicians and researchers working to improve diagnosis and treatment of anti-NMDAR encephalitis.

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Reference
DOI: 10.1016/j.bnd.2025.03.001