What is Anti-NMDAR Encephalitis?
Anti NMDA Receptor encephalitis is a brain inflammation condition caused by an immune response. It has complex mental and neurological symptoms. This condition is identified by the presence of certain antibodies, specifically Immunoglobulin G (IgG), that target a component of the NMDA receptors in the brain and spinal cord. These antibodies can typically be detected in either the blood or the fluid that surrounds the brain and spinal cord.
What Causes Anti-NMDAR Encephalitis?
This type of brain inflammation, known as autoimmune encephalitis, happens when certain antibodies, specifically IgG1 and G3, attach to a part of a protein called the NMDA receptor. This leads to changes in how nerve cells function, including a decrease in calcium movement into the cell and a reduction in activity linked to this receptor.
In some people, this process can be triggered by a specific type of ovarian tumor and very rarely, other types of tumors. Sometimes, brain inflammation due to a virus, especially the Herpes Simplex Virus, can lead to the creation of these antibodies. This tends to happen about three weeks later and leads to the development of autoimmune encephalitis.
In many cases, it’s not clear what triggers the production of these antibodies. However, no matter what causes it, this process leads to the overproduction of autoantibodies by cells in the brain’s spinal fluid.
Risk Factors and Frequency for Anti-NMDAR Encephalitis
Anti-NMDAR encephalitis is quite rare, affecting just one out of every 1.5 million people each year. However, it’s one of the most well-known and frequently occurring types of autoimmune encephalitis. In the California Encephalitis Project, it was seen to occur more often than any individual type of viral encephalitis. Cases of anti-NMDAR encephalitis have been observed in babies as young as two months old and in adult up to the age of 85. This condition is four times more likely to affect females, and is most commonly seen in young adult women between the ages of 25 and 35.
- Anti-NMDAR encephalitis is a rare condition, affecting one out of every 1.5 million individuals each year.
- Despite its rarity, it’s one of the most common types of autoimmune encephalitis.
- In one study, incidents of anti-NMDAR encephalitis were found to be greater than any type of viral encephalitis.
- People of any age can get this condition, from babies as young as two months old to adults as old as 85.
- Women are four times more likely to get this condition than men.
- It is most frequently seen in young adult women between the ages of 25 and 35.
onset of psychosis.
Signs and Symptoms of Anti-NMDAR Encephalitis
Anti NMDAR encephalitis is a disease that usually presents itself in five distinct stages: the prodromal phase, psychotic phase, unresponsive phase, hyperkinetic phase, and recovery phase. It initially starts off with symptoms similar to a common viral infection. As the disease progresses to the psychotic phase over weeks or a few months, it triggers complex neurological and psychiatric symptoms. These symptoms can vary between adults and children. Typically, adults show more psychiatric symptoms while children often display movement disorders or seizures.
For adults, some of the common symptoms include:
- Visual or auditory hallucination
- Sudden episodes of schizoaffective disorder, depression, mania
- Addictive or eating disorders
Patients with no prior psychiatric history can develop these symptoms quite rapidly, much faster than traditional psychiatric diseases. Some patients may require admission to psychiatric units due to the severity of their symptoms.
Anti-NMDAR encephalitis patients might display both positive and negative symptoms of schizophrenia. Besides these symptoms, they can also show signs such as apathy, anxiety, fluctuating consciousness, erratic behaviors, hypersexuality, and other bizarre behaviors. Seizures, both focal and general, are common, particularly in children and male adults. These seizures may be resistant to antiepileptic drugs and could potentially evolve into status epilepticus, a severe seizure condition.
The disease can worsen into an unresponsive phase, which is usually characterized by mutism, less motor activity, and catatonia. This then usually leads into the hyperkinetic phase with autonomic instability and severe movement disorders. In severe cases, these complications can lead to admission to the Intensive Care Unit, and patients may require ventilation support and a cardiac pacemaker.
The last phase is the recovery phase where patients, with adequate immunotherapy and supportive care, show improvement in their language function and behavior. However, this can take several months of treatment. Occasionally, these patients can develop demyelinating disorders such as Neuromyelitis Optica Spectrum Disorder, either simultaneously, before, or after the onset of encephalitis.
Testing for Anti-NMDAR Encephalitis
Routine lab tests may not be specific but are essential. The presence of Anti NMDAR IgG antibodies, identified through an indirect immunofluorescence test carried out on blood and cerebrospinal fluid (CSF), suggests a diagnosis of this disease. Antibodies are usually found in higher levels in the CSF. In some situations, only testing the CSF may reveal the disease even when the blood test results are negative. The CSF may also show a slight increase in cell count and specific protein bands.
Brain scans such as MRI may appear normal, but some changes might be present. These changes could include areas in the brain (commonly in the hippocampus) showing higher signal strength in the white and gray matter on T2/FLAIR imagery. Other reported findings include changes in water molecule movement and a shrinking cerebellum, which could be the only permanent radiological sign of this type of encephalitis.
Interictal EEG, a test that monitors brain waves, can reveal specific patterns that can help diagnose this condition. One of these patterns is extreme delta brushes, bursts of beta activity on top of widespread delta activities, which is common in healthy premature babies. Other EEG changes that are commonly noticed but are not specific to this disease include a slowing of theta and delta waves, silent seizures, and non-convulsive status epilepticus.
Once the diagnosis is confirmed, a full-body check should be conducted to look for an underlying tumor. Scans like CT, MRI of the abdomen, and transvaginal ultrasound are typically used to detect tumors. The most critical test for young women with this condition is the transvaginal ultrasound due to the high possibility of an ovarian teratoma. Other options for detecting tumors include PET scans and exploratory surgery if the initial tests show nothing.
In case any tumor cannot be detected during the initial tests, further MRI scans of the abdomen and pelvis should be repeated every six months for at least four years.
Treatment Options for Anti-NMDAR Encephalitis
Early diagnosis and treatment of autoimmune encephalitis can lead to better outcomes. Quick treatment, even before the final diagnosis is confirmed, can be initiated based on suspicion and after collecting serum and spinal fluid samples.
First-line treatments include therapies aimed at moderating or suppressing the immune system, such as corticosteroids, immunoglobulin infusion, and a procedure called plasmapheresis to cleanse the blood of the damaging antibodies. If a tumor is involved, it will also be removed. It’s important to mention that the best order to initiate these treatments isn’t yet standardized or researched effectively.
Plasmapheresis tends to be used early on due to its ability to quickly remove the harmful autoantibodies. Recent studies have suggested that starting plasmapheresis before immunoglobulin infusion might improve outcomes. However, only around half of patients respond to the first line of treatment. If no improvement is seen after four weeks, different treatments like rituximab, cyclophosphamide, etc., are introduced. Infrequently, certain drugs can be beneficial in patients who are resistant to other treatments.
Managing seizures during this period can be challenging and needs anti-epileptic drugs along with immunotherapy. As the encephalitis improves, so do the seizures, which means the person doesn’t develop epilepsy. Anti-seizure medications can eventually be reduced and often stopped entirely within two years without seizures coming back. Antipsychotic medications are sometimes used to treat behavioral symptoms, and a high dose of sedative medications is needed to control the involuntary movements linked with this condition.
Intensive care is crucial during the severe phase of the disease. It helps manage complications like requiring airway protection, dealing with altered cognition and abnormal behavior, controlling seizures and involuntary movements as well as maintaining stable heart rate and temperature.
Herpes simplex encephalitis is the most common form of sudden onset encephalitis. Anyone showing symptoms of acute encephalitis should be given IV acyclovir, a medicine to stop the virus from replicating, while waiting for test results. Acyclovir is continued or discontinued based on these results. An early recurrence of HSV encephalitis can often be due to anti-NMDA receptor encephalitis triggered by the viral encephalitis.
What else can Anti-NMDAR Encephalitis be?
When doctors are trying to diagnose autoimmune encephalitis, there are a number of other conditions that might be considered because they have similar symptoms. These conditions include:
- Other types of autoimmune encephalitis
- Mental health disorders
- Viral inflammation of the brain (viral encephalitis)
- A potentially life-threatening reaction to certain psychiatric medications (neuroleptic malignant syndrome)
- Severe type of immobility related to mental disorders (catatonia)
- Inflammation of the brain and spinal cord that damages the myelin – the protective covering of nerve fibers (acute disseminated encephalomyelitis)
- A disorder that affects many of the body’s systems (mitochondrial encephalitis)
- Tumors or lesions in the brain
- Experiencing symptoms related to exposure to harmful drugs or toxins, or withdrawal symptoms from them
Each of these conditions needs to be carefully ruled out by the doctor in order to confirm a diagnosis of autoimmune encephalitis.
What to expect with Anti-NMDAR Encephalitis
Several factors can predict worse outcomes for patients. These include needing to stay in the Intensive Care Unit (ICU), treatment being delayed for more than four weeks, no improvements after four weeks of treatment, an abnormal brain MRI (a type of scan), and high white blood cell count (greater than 20 cells/microL). Each of these factors can be assigned one point to form a recovery score.
A higher score suggests a poorer health status one year after the onset of the disease. However, this score shouldn’t be used to decide on treatment plans or to predict the patient’s final health outcome. This is because one in three patients with a poor health status after one year may show improvement after two years.
Possible Complications When Diagnosed with Anti-NMDAR Encephalitis
About 20% of the patients with anti NMDAR encephalitis either develop specific health issues or unfortunately pass away. Chances are that around 10% of patients might see a recurrence within two years of the initial identification of the disease but mostly with milder symptoms. The most frequently reported long-term impacts are likely to affect attention, memory, and higher-level functions.
Preventing Anti-NMDAR Encephalitis
If doctors suspect a patient has a condition called anti-NMDAR encephalitis, they’ll need to conduct a procedure known as a lumbar puncture and check the fluids for certain antibodies. However, the patient’s treatment, which involves methods to stimulate their body’s immune response, should begin immediately. It should not be put on hold while waiting for the results from the antibody tests.
