Recent Updates in Anti-NMDA Receptor Encephalitis Research
Imagine that your body suddenly began destroying itself on purpose, attacking its own cells as if they were foreign invaders. The consequences would be life-threatening. This is what happens in anti-NMDA receptor encephalitis, a rare autoimmune disease that attacks NMDA receptors in the brain.1,2 Every single person carries thousands of receptors on their cells that control every aspect of the body, from moving a finger to forming memories. One key receptor, N-methyl-D-aspartate (NMDA), controls critical cognitive behavioural functions such as perception of reality and human interaction as well as autonomic functions such as breathing and swallowing.1 Currently, steroidal and immunosuppressive treatments are the only therapeutic interventions available for patients, both of which are generally ineffective for those with severe forms of the disease.1 However, researchers from Charité - Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) recently stumbled upon an innovative treatment that may just be the final cure for every single anti-NMDA patient.2
The pathophysiology of anti-NMDA receptor encephalitis is highly implicated in the development of antibodies against the NMDA receptor. In normal immune responses to bacteria, viruses or tumours, antibodies play an important role in defense of the host (or infected person). However, in those with autoimmune disorders, the body’s immune system has begun producing antibodies against its own tissues, resulting in severe consequences for the patients.1,3 Since NMDA receptors are found in most abundance within the brain, it is here that the most damage is done by the disease.4
So why would the body produce antibodies to kill its own healthy tissue? Unfortunately, it is still not understood why the body develops these antibodies against the NMDA receptors. Looking at the statistical prevalence of the disease, approximately 80% of patients are women, and in those greater than 18 years of age, ~50% have an underlying tumor, most often an ovarian teratoma.5 Moreover, lung cancer, thyroid tumours, breast cancer, colon cancer, and neuroblastoma have also all been implicated in the onset of the disease.1 Current research suggests that these tumours contain neural tissue identical to the tissue found in the brain.2-4 Thus, it is presumed that the antibodies are formed within the tumours, and are then excreted into the body, going on to attack similar-looking NMDA receptors within the brain.2-4
Nonetheless, with or without the tumour, the course of the disease is quite similar in all cases, with four distinct symptomatic phases present (Figure 1).5,6 The first phase, or prodrome, encompasses the onset of viral-like symptoms including lethargy, headache, upper respiratory symptoms, nausea, diarrhea, muscle pain, and fever.6 One patient, Kimberly, explained the beginning symptoms, saying “I started having headaches, insomnia, anxiety, that escalated quickly.”1 These symptoms soon give way to more severe psychotic symptoms such as anxiety and paranoia and then short-term memory loss after several weeks.1,5,6 Within a short time, the disease has already spread through the entire brain, and severe physical and behavioural changes take place. Kimberly explained these symptoms in the most severe point in her illness, saying “I lost control of my bodily functions, I couldn’t talk, read, write, I could barely walk.”1 Seizures, hypoventilation and dysautonomia continue to progress with the disease until a treatment, or even diagnosis, is finally made for many patients like Kimberly.5,6 However, even after the acute stages of illness, patients with anti-NMDA receptor encephalitis take considerable time to return to their baseline function, with cognitive deficits and behavioural changes lasting months to years.5,6 Kimberly professed the difficult recovery from the disease, saying “After I got home, I had to relearn everything.” In many cases, full recovery never occurs, as many treatments are still ineffective for severe cases of anti-NMDA receptor encephalitis and fatalities are high due to heart attacks, or complications associated with the use of powerful immune suppressing medications.5,6
Remarkably, new research published in the journal Neurology by researchers from DZNE describes significant progress in treating the disease, including in patients who did not previously respond to treatment.2 In the study, anti-NMDA patients were treated with a new drug, bortezomib, which functions as a proteasome inhibitor, previously used to treat blood cancer.2 Proteasomes are protein bundles inside of cells which degrade damaged proteins.7 The proteasome inhibitor bortezomib works by inhibiting the breakdown of these proteins within the cells, causing a buildup of unwanted proteins in plasma cells (cells that produce the antibodies), ultimately bursting them open due to accumulated waste.7 As explained by the study’s first author, Franziska Scheibe, "Bortezomib is capable of treating the causes of the disease by eliminating plasma cells. This makes it a valuable new treatment option in cases of anti-NMDA receptor encephalitis that have so far proven resistant to treatment,"2 Five patients with severe anti-NMDA receptor encephalitis, who had no improvements on the regularly administered immunosuppressive treatments, were completely treated with bortezomib, demonstrating its superiority to any current treatment available.2
The implications of this discovery are huge, not only for those with the disease but for the families and loved ones affected by anti-NMDA receptor encephalitis. Now, future research is focused on finding specific biomarkers to detect severe forms of the disease earlier and whether physicians can initiate bortezomib treatment sooner on in the progression of the disease.2 Dave, a current anti-NMDA patient, explained the countless treatments he had received, including “IVIG (immunoglobulin therapy), Rituximab (a drug used to treat autoimmune disorders and certain types of cancers), MRIs, countless EEGs, and, when there was no progress after a year, Cyclophosphamide.”1 Many patients have a similar experience to Dave’s, trying countless drugs that create more harm than good in most instances. Perhaps this research will be the final treatment that anti-NMDA patients need to fully recover their health and their life once again.
1. What is Anti-NMDA Receptor Encephalitis? (In English, French & Spanish) - The Anti NMDA Receptor Encephalitis Foundation Inc. The Anti NMDA Receptor Encephalitis Foundation Inc. 2017. Available at: http://www.antinmdafoundation.org/the-illness/what-is-anti-nmda-receptor-encephalitis/.
2. Scientists find new treatment option for rare autoimmune disease. News-Medicalnet. 2017. Available at: http://www.news-medical.net/news/20170106/Scientists-find-new-treatment-option-for-rare-autoimmune-disease.aspx.
3. Whittingham S McNeilage L. Antinuclear antibodies as molecular and diagnostic probes. Molecular and Cellular Probes. 1988;2(3):169-179. doi:10.1016/0890-8508(88)90001-1.
4. Ikonomidou C. Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain. Science. 1999;283(5398):70-74. doi:10.1126/science.283.5398.70.
5. S. Kayser M Dalmau J. Anti-NMDA Receptor Encephalitis in Psychiatry. Current Psychiatry Reviews. 2011;7(3):189-193. doi:10.2174/157340011797183184.
6. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld M, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. The Lancet Neurology. 2011;10(1):63-74. doi:10.1016/s1474-4422(10)70253-2.
7. ADAMS J. The proteasome: structure, function, and role in the cell. Cancer Treatment Reviews. 2003;29:3-9. doi:10.1016/s0305-7372(03)00081-1.
Cite This Article:
McKee H., Zheng K., Chan G., Ho J. Recent Updates in Anti-NMDA Receptor Encephalitis Research. Illustrated by C. Nguyen. Rare Disease Review. February 2017. DOI:10.13140/RG.2.2.14304.28167.