NMDA Receptors and Brain Function
NMDA receptors are the brain’s and the indeed the body’s primary mechanism through which activity is initiated. NMDARs are excitatory receptors that bind with glutamate, the excitatory neurotransmitter. NMDARs, along with the AMPA receptor (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), a secondary excitatory receptor regulate all brain excitation. These receptors are located all over the brain, but are especially dense in the hippocampus, where learning and memory occur, and the frontal and prefrontal regions where planning, motivation, impulse control and emotional regulation take place.
NMDARs are also dense in subcortical regions, where all sorts of functions involving movement control, motivation and emotionality are controlled and in the brainstem, the region at the base of your brain where a set of nuclei called the medulla oblongata reside. The medulla oblongata control heart rate, respiration and vomiting reflex. Impair the functioning of the medulla oblongata by injury, by reducing NMDARs or even by alcohol poisoning, sedative or pain killer overdose, and heart rate and respiration will slow to a stop, until death becomes imminent.
Too much glutamate-NMDAR activity and seizures ensue. This is because brain’s major inhibitory neurotransmitter called GABA becomes ineffective at reducing brain excitation. Reduce glutamate/NMDAR activity and the perception of pain is also be reduced, but with far too many side-effects to make NMDAR antagonist likely therapeutics. Conversely, too little glutamate and NMDAR activity also will lead to seizures, psychosis, and even, cell death. It’s a complex balance between brain excitation and brain inhibition that must be maintained. When that balance is disrupted, serious illness occurs.
What is Anti-NMDAR Encephalitis?
As far as scientists can tell, anti-NMDAR encelphalitis begins with an illness, sometimes a virus or a vaccine, and in 60% of cases, an ovarian teratoma, that causes the body to have an immune reaction against the NMDA receptors. The immune reaction elicits the production of an antibody that tells certain types of NMDARs to involute into the cell so that they are no longer active. From the cases thus far, the disease process follows the path of the receptors attacked. It appears to begin in the frontal and temporal cortices and progress to the deeper brain regions and subcortical structures until it reaches the brain stem and mechanical ventilation is required. Flu like symptoms emerge first, hence the belief that the disease is triggered by illness, medication or vaccine. The flu-like symptoms are then followed by a memory deficits and rapid disintegration into psychosis, paranoia, delusions, hallucinations. Sometimes seizures occur, sometimes they do not. If untreated, within a period of weeks, the afflicted individual lands in ICU requiring mechanical ventilation. The mortality rate is approximately 4% and the median time from disease onset to death is 3-5 months. When treatment is initiated, the recovery process mirrors the disease onset stages, though in reverse. Recovery can take years.
The Connection between Anti-NMDAR Encephalitis and the Ovaries
One of the many striking components of this disease is the co-morbid presentation of ovarian teratomas, in 60% of the cases. Teratomas, sometimes referred to as dermoid cysts, are a unique type of tumor that contain germ cells that can grow into brain or nervous tissue, glands, fat, and even skin, teeth and hair. It is not uncommon for teratomas to have teeth or hair. Treatment and indeed survival of anti-NMDAR encephalitis is predicated upon tumor removal, in most cases.
Ovarian teratomas represent an error in germ cell division; germ cells being those cells handed down at birth from our parents that contain the genetic materials needed to form ovarian follicles (eggs) for women, sperm cells for men. The germ cells are pluripotent and contain all the ingredients to make skin, gland and other tissue, hence the nervous tissue, hair, nails and other components found in these tumors. Typically germs cells divide in a logical sequence that eventually results in oocyte, an egg, that will then become fertilized or not. In some women (and men), the cell division progresses unconventionally, producing the teratoma. In part, the teratoma develops as a result of epigenetic factors including the health and environmental exposures of our parents, even our grandparents. In utero exposures to medications, vaccines and other toxins can cause errors in germ cells, and as a result, many individuals are born with these errors, but not all are triggered. Germ cell division is very highly environmentally influenced suggesting that exposures later in life can trigger errors in germ cell development, as in a teratoma.
The Connection between Teratomas and Anti-NMDAR Encephalitis
What does an ovarian teratoma have to do encephalitis? Researchers don’t know for sure, but think that because the teratomas express nerve cells with NMDA receptors, when the immune system recognizes the teratoma as foreign and begins to attack, it also attacks brain NMDARs, mistakenly so. What they have observed is that if the teratoma is not removed, survival is difficult. They have also observed that in cases where no teratoma is found, recovery is more complicated and arduous than in cases where the teratoma is found and excised.
Symptoms of Anti-NMDAR Encephalitis
Approximately, 70% of cases begin with flu-like symptoms that include: headache, fever, nausea, vomiting, diarrhea and upper-respiratory symptoms. Within a few days to two weeks, this progresses to psychiatric and cognitive symptoms that include everything from anxiety and insomnia to hallucinations, delusions, mania, memory deficits, delirium, language difficulties to frank mutism. This is followed by autonomic instability (heart rate, blood pressure and temperature instability, incontinence), alternating periods of agitation and catatonia, oral/facial tics, limb jerking, posturing. Motor and complex seizures may develop, including status epilepticus (continuous seizures), coma can occur and mechanical ventilation is required to maintain breathing. In all cases, hospitalization is required during the acute phase, which can last 3-4 months. During the recovery phase, which can last many more months, hospitalization and/or direct supervision may also be required because of an on-going need for nocturnal ventilation assistance and also because of a unique dis-inihibition of frontal cortex functioning with high degrees of uncontrolled, impulsive behavior.
Diagnosing Anti-NMDAR Encephalitis
Diagnosing anti-NMDAR encephalitis is difficult because many of the traditional first line tests come back negative. Brain MRIs are normal in 50% of patients and mostly normal or only transiently abnormal in the remaining patients. This is in direct contrast to the severity of the patient’s illness. Brain biopsies are also unremarkable. The electrical activity of the brain is often abnormal with electroencephalograms (EEG) showing slow, non-specific and disorganized activity in general, with electrographic seizure and/or rhythmic delta-theta activity during catatonia, but this pattern not necessarily solely indicative of anti-NMDAR encephalitis. Blood tests for the anti-NMDAR antibodies also are often not indicative of the illness. From the research thus far, it appears that the most accurate test involved measuring the antibodies involved in anti-NMDAR encephalitis via cerebral spinal fluid (CSF). Antibody titres appear to follow the course of the disease and recovery, even relapse and remission.
If anti-NMDAR encephalitis is suspected in women, imaging for ovarian teratomas should be conducted, and if found, the teratomas should be removed.
How is Anti-NMDAR Treated?
Because anti-NMDAR encephalitis is an immune response, the goal of treatment is to reduce the concentration of anti-NMDAR antibodies. This is done with corticosteroids to reduce inflammation, plasmapheresis or plasma exchange to clear out the antibodies and intraveneous immunoglobulin (IVIG) treatment to boost the immune response. If an ovarian teratoma is present, it must be removed. If the teratoma is not removed, prognosis is poor, recovery is possible, but takes significantly longer. In general, treatment of the acute phase, where mechanical ventilation is required and recovery require months of hospitalization. Full recovery can take years. The disease also appears wax and wane with periods of remission and relapse.
The connection between anti-NMDAR encephalitis and ovarian teratomas is fascinating and though not fully delineated, presents one more bit of evidence that ovarian health is connected to total health. I suspect as the research progresses, our understanding of ovarian teratomas will expand exponentially and offer clues to a myriad of brain and autoimmune diseases currently unrecognized and often inappropriately treated. Who knows, perhaps the environmental factors, medication and vaccines influencing germ cell and teratoma development will garner more respect too.