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Encephalitis | Anti-NMDA R Encephalitis

In the world of Neurology and Neurophysiology the term ‘Encephalitis’ is well known, and frequently used to describe tissues of the brain experiencing inflammation. As this area of the human body is vital, it is no surprise that any amount of inflammation can be quite detrimental to a person’s daily life. Symptoms can vary from a more mild headache, stiff neck and light sensitivities, but can quickly decline to mental confusion, delirium, and seizures. 

When describing encephalitis, two different sources for the inflammation can be noted - the first being, Infectious encephalitis. Infectious encephalitis is most commonly caused by viral infections, although in rare circumstances, bacteria, parasites, and fungi have been noted to cause this as well. The most common viral cause of encephalitis is herpes simplex virus (HSV) types 1 and 2, enteroviruses, and varicella zoster virus. Since the creation of vaccines for mumps, rubella, measles and chickenpox the rates of viral encephalitis have been reduced, since their introduction to society.

The second source of encephalitis is caused by a person's own antibodies attacking the brain. This is termed Autoimmune encephalitis. When the immune system is triggered the antibodies will begin to go after receptors and/or proteins in the brain such as the GABA-A and GABA-B receptors, and the anti-NMDA receptors just as an example. This is not fully understood yet in the neurological community, but it has been found to sometimes be the result of a tumor (both benign/cancerous,) or the body's reaction to a recent infection. 

Dalmau, et al, were the first to describe Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis back in 2007, after 12 patients were identified as presenting with ‘prominent neuropsychiatric symptoms.’ Symptoms were first described in 2005 when a group of women, who were diagnosed as having ovarian teratomas, were experiencing symptoms of a variety of psychotic disturbances and dyskinesia which is defined as uncontrollable movements of the face, arms or legs, also muscle spasms. It was at the University of Pennsylvania where Dalmau, and colleagues, began to put the pieces together to conclude the source of these changes in their patients. 

The NMDA receptor, in the human brain, is responsible for our moods, thoughts, and body movements. When the body’s immune system begins to attack this protein, it is no surprise that the symptoms will correlate, causing

changes such as: unusual behaviors and mood changes in patients, as well as hallucinations, agitation, etc. These symptoms begin to appear in the first 1-4 weeks, mainly affecting young people, of which are mostly female. In the following few weeks, patients will then begin to develop movement disorders, as well as issues with the body's ability to regulate blood pressures and heart rates. 

Diagnosis of this condition is done by evaluating the clinical symptoms followed by confirmation through serum and/or CSF testing. These tests will screen for the antibodies to the NMDA receptor. Other diagnostic testing includes MRI, tumor screening and EEG. With magnetic resonance imaging (MRI) of the brain it has been found that often 70% of images are reported normal, while the other cases have been found to have increased FLAIR or hyperintensities of the cerebellum, hippocampus, basal ganglia, etc. 

In the majority of females, 12 years or older, a teratoma has been found in conjunction with this condition. A teratoma is a germ cell type tumor typically found on the ovaries that can be made up of several different types of tissues such as hair, muscle, or even bone. Tumors of this nature can also be found to be malignant or benign. It is not unheard of to see testicular teratomas in males which can also elicit these symptoms. In cases where a tumor is suspected a tumor screening has been found to be beneficial following the anti-NMDAR diagnosis. If a tumor is found a patient's prognosis is found to be improved, as this can be removed via surgery.

Extreme Delta Brush in an Anti-NMDA patient in the ICU

Electroencephalogram or EEG, can be helpful in diagnosing Anti-NMDA. EEGs will typically have findings of ‘non-specific slowing’ or continuous slowing during the later stages of the illness. An interesting, and specific finding, that can be seen in some cases are what are known as ‘extreme delta brushes’ (beta-delta complexes) in about ⅓ of the patients. Patients with this finding are commonly seen in the ICU.

Once a patient has arrived at their diagnosis, the next steps are treatment. This will include tumor removal (if found), and starting immunotherapy medications such as corticosteroids with intravenous immunoglobulins (IVIG) or Plasmapheresis (plasma exchange). These treatments, in combination with one another, have been found to reduce the body’s inflammatory response, by inhibiting the binding of the harmful antibodies and removing them from the body all together. In the event that this treatment fails, a second treatment is utilized. This consists of using the chemotherapy drugs Rituximab and Cyclophosphamide, either individually or in combination with one another. These drugs work by suppressing the immune system. 

While long term deficits are not well studied at this point in time, it has been noted that some patients have been shown to have some cognitive impairment. Mostly noted to affect the memory and executive functions such as: concentration, reasoning, etc. Most long term deficits are dependent on how far advanced the patient had become, and the timeliness in which treatment was started. Recovery can vary from fully recovered to partially recovered.

In conclusion, encephalitis is inflammation of the brain and depending on the source of the inflammation, and degree of severity, the patient can have a variety of symptoms ranging from headaches, light sensitivity, etc., to more advanced symptoms that include seizures, cognitive decline, and in the worst cases, coma. Depending on the progression of the encephalitis, and the timeliness of treatment, a patient can go on to lead a normal life, but in some cases may be left with long term cognitive changes.







Sources

Barry, Helen, et al. “Anti-N-Methyl-d-Aspartate Receptor Encephalitis: Review of Clinical Presentation, Diagnosis and Treatment.” BJPsych Bulletin, U.S. National Library of Medicine, Feb. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4495821/#:~:text=treatment%20and%20prognosis.-,Anti%2DN%2Dmethyl%2Dd%2Daspartate%20(NMDA),antibodies%20to%20the%20NMDA%20receptor

“Chapter 11 / Diffuse EEG Abnormalities.” Practical Guide for Clinical Neurophysiologic Testing, by Thoru Yamada and Elizabeth Meng, Wolters Kluwer, 2018, pp. 252


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