Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune encephalitis characterized by antibodies targeting the GluN1 subunit of the NMDA receptor, leading to a multistage neuropsychiatric syndrome.
Anti-NMDA receptor encephalitis is a type of brain inflammation caused by antibodies.
The condition is mediated by autoantibodies that target NMDA receptors in the brain.
The estimated number of cases of the disease is one in 1.5 million people per year.
The condition is relatively common compared to other paraneoplastic disorders.
Symptoms Early: Fever, headache, feeling tired, psychosis, agitation.
Later: Seizures, decreased breathing, blood pressure and heart rate variability.
The disease predominantly affects children and young adults, especially women, and may be associated with ovarian teratomas in females aged 18–45 years.
Clinical presentation typically begins with psychiatric symptoms of agitation, hallucinations, psychosis, followed by cognitive dysfunction, seizures, abnormal movements/dyskinesias, language disintegration, and autonomic instability.
In severe cases, patients may progress to catatonia, decreased consciousness, and respiratory compromise.
Diagnosis relies on the detection of anti-NMDAR antibodies in cerebrospinal fluid (CSF) and/or serum, with CSF testing being more sensitive.
MRI findings are often normal or nonspecific.
Most patients respond favorably to first-line immunotherapy (corticosteroids, intravenous immunoglobulin, plasma exchange) and, when present, tumor resection.
Second-line agents include rituximab, cyclophosphamide for refractory cases.
Prognosis is generally good, with substantial recovery in over 75% of cases if treated promptly.
Deaths ~4% risk of death.
Relapses can occur: Recurrence occurs in about 10% of people.
About half of cases are associated with tumors, most commonly teratomas of the ovaries.
Long-term mental or behavioral problems may remain.
Another established trigger is herpesviral encephalitis which is associated with over half of all identified pediatric cases.
Other cases are unclear.
Diagnosis is typically based on finding specific antibodies in the cerebrospinal fluid.
MRI of the brain is often normal.
Misdiagnosis is common.
About 80% of those affected are female.
It typically occurs in adults younger than 45 years old, but it can occur at any age.
NMDA receptor encephalitis, patients people may experience prodromal symptoms, including headaches, flu-like illness, or symptoms similar to an upper respiratory infection.
Such symptoms may be present for weeks or months prior to disease onset.
Patients may present with a variety of neurological symptoms.
During the initial stage of the disease, symptoms vary slightly between children and adults.
Behavior changes are a common first symptom within both groups,and these changes often include agitation, paranoia, delusions, psychosis, violent behaviors, and suicidal behaviors such as suicidal ideation and self-inflicted violence.
Other common manifestations include seizures and bizarre movements, mostly of the lips and mouth, but also including pedaling motions with the legs or hand movements resembling playing a piano.
Other symptoms typical during the disease onset include impaired cognition, memory deficits, and speech problems including aphasia, perseveration or mutism.
The symptoms usually appear psychiatric in nature, which may confound the differential diagnosis leading to the illness going undiagnosed.
As the disease progresses, the symptoms often include autonomic dysfunction, hypoventilation, cerebellar ataxia, loss of feeling on one side of the body, loss of consciousness, or catatonia.
During this acute phase, most patients require treatment in an intensive care unit to stabilize breathing, heart rate, and blood pressure.
Characteristically of anti-NMDA receptor encephalitis is the concurrent presence of many symptoms.
The majority of patients experience at least four symptoms, with many experiencing six or seven over the course of the disease.
The process can be produced by cross reactivity with NMDA receptors in teratomas, which contain many cell types, including brain cells, and thus present a window in which a breakdown in immunological tolerance can occur.
Other autoimmune mechanisms are suspected for patients who do not have tumors.
Empirical evaluation of the origin of anti-NMDA receptor antibodies in serum and cerebrospinal fluid leads to the consideration of two possible mechanisms.
Serum NMDA receptor antibodies are consistently found at higher concentrations than cerebrospinal fluid antibodies, on average ten times higher, suggesting the antibody production is systemic rather than in the brain or cerebrospinal fluid.
Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB).
The blood brain barrier is a cellular filter, separating the central nervous system from the circulatory system, normally prevents larger molecules from entering the brain.
A collapse in its integrity is the end result of acute inflammation of the nervous system.
The involvement of corticotropin releasing hormone on mast cells in acute stress has been shown to facilitate BBB penetration.
An increase in blood pressure would force larger proteins, such as antibodies, to extravasate into the cerebrospinal fluid.
Cyclophosphamide and rituximab, drugs used to eliminate dysfunctional immune cells, have been shown to be successful second-line treatments in patients where first-line immunotherapy has failed.
These destroy excess antibody-producing cells in the thecal sac, thus alleviating the symptoms.
Once the antibodies have entered the CSF, they bind to the NR1 subunit of the NMDA receptor.
A reduction in the density of NMDA receptors on the post synaptic knob, due to receptor internalization once the antibody has bound.
This is dependent on antibodies cross linking.
Diagnosis: a high level of clinical suspicion, especially in young adults showing abnormal behavior as well as autonomic instability.
Examination may further reveal delusions and hallucinations, which can aid diagnostic efforts.
The initial investigation consists of clinical examination, MRI of the brain, an EEG, and a lumbar puncture for CSF analysis.
MRI of the brain may show abnormalities in the temporal and frontal lobes, but do so in less than half of cases.
A FDG-PET scan of the brain may show abnormalities in cases when the MRI scan is normal.
EEG is abnormal in almost 90% of cases and typically shows general or focal slow wave activity.
CSF analysis often shows inflammatory changes with increased levels of white blood cells, total protein and the presence of bands.
NMDA receptor antibodies can be detected in serum and/or CSF.
If a person is found to have a tumor, the long-term prognosis is generally better and the chance of relapse is much lower.
The tumor can be removed surgically, thus eradicating the source of autoantibodies.
If a tumor is detected, its removal should occur in conjunction with first-line immunotherapy.
This involves steroids to suppress the immune system, intravenous immunoglobulin, and plasmapheresis to physically remove autoantibodies.
Over four weeks, about half the patients improve after receiving first-line immunotherapy.
Second-line immunotherapy includes rituximab, a monoclonal antibody that targets the CD20 receptor on the surface of B cells, thus destroying the self-reactive B cells.
Cyclophosphamide, an alkylating agent that cross-links DNA and is used to treat both cancer and autoimmune diseases, has sometimes proven useful when other therapies have failed.
Recovery process from anti-NMDAR encephalitis can take many months depending on its form and severity.
The symptoms may reappear in reverse order: The patient may begin to experience psychosis again, leading many people to falsely believe the patient is not recovering.
As the recovery process continues on, the psychosis fades.
Lastly, social behavior and executive functions begin to improve.
In patients with herpesviral anti-NMDA encephalitis, the recovery process is typically met with poorer long-term outcomes due to extensive lesions caused by viral-indused necrosis in brain tissue.
The estimated number of cases of the disease is 1.5 per million people per year.
Anti-NMDA receptor encephalitis disease has a higher incidence than its individual viral counterparts in patients younger than 30.
Women make up 81% of cases.
Disease onset is skewed toward children, with a median age of diagnosis of 21 years.
Over a third of cases are children, while only 5% of cases were patients over the age of 45.
79% have a good outcome by 24 months, about 6% die and the rest are left with mild to severe deficits.
38% presenting with tumors, 94% of those presented with ovarian teratomas.