Anti-NMDA receptor encephalitis is a type of
brain inflammation caused by
antibodies
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
.
Early symptoms may include
fever
Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
, headache, and feeling tired.
[ This is then typically followed by ]psychosis
In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
which presents with false beliefs (delusions) and seeing or hearing things that others do not see or hear (hallucinations).[ People are also often agitated or confused.][ Over time, ]seizures
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
, decreased breathing, and blood pressure and heart rate variability typically occur.[ In some cases, patients may develop ]catatonia
Catatonia is a complex syndrome most commonly seen in people with underlying mood disorders, such as major depressive disorder, or psychotic disorders, such as schizophrenia. People with catatonia exhibit abnormal movement and behaviors, wh ...
.
About half of cases are associated with tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
, most commonly teratoma
A teratoma is a neoplasia, tumor made up of several types of biological tissue, tissue, such as hair, muscle, Human tooth, teeth, or bone. Teratomata typically form in the tailbone (where it is known as a sacrococcygeal teratoma), ovary, or test ...
s of the ovaries
The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
.[ Another established trigger is ]herpesviral encephalitis
Herpes simplex encephalitis (HSE), or simply herpes encephalitis, is encephalitis due to herpes simplex virus. It is estimated to affect at least 1 in 500,000 individuals per year, and some studies suggest an incidence rate of 5.9 cases per 100,00 ...
which is associated with over half of all identified pediatric cases, while the cause in other cases is unclear. The underlying mechanism is autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
, with the primary target being the GluN1 subunit of the N-methyl-D-aspartate receptors (NMDAR) in the brain.[ Diagnosis is typically based on finding specific antibodies in the ]cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
.[ ]MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
of the brain is often normal.[ Misdiagnosis is common.][
Treatment is typically with immunosuppresive medication and, if a tumor is present, surgery to remove it.][ With treatment, about 80% of cases have a good outcome.][ Outcomes are better if treatment is begun earlier.] Long-term mental or behavioral problems may remain.[ About 4% of those affected die from the condition.][ Recurrence occurs in about 10% of people.][
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.][ About 80% of those affected are female.][ It typically occurs in adults younger than 45 years old, but it can occur at any age.] The disease was first described by Josep Dalmau in 2007.[
]
Signs and symptoms
Prior to the development of a symptom complex that is specific to anti-NMDA receptor encephalitis, people may experience prodromal symptoms, including headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
s, flu-like illness, or symptoms similar to an upper respiratory infection. These symptoms may be present for weeks or months prior to disease onset. Beyond the prodromal
In medicine, a prodrome is an early Medical sign, sign or symptom (or set of signs and symptoms, referred to as prodromal symptoms) that often indicates the onset of a disease before more diagnostically specific signs and symptoms develop. More spe ...
symptoms, the disease progresses at varying rates, and patients may present with a variety of neurological symptoms. During the initial stage of the disease, symptoms vary slightly between children and adults. However, behavior changes are a common first symptom within both groups. These changes often include agitation, paranoia
Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety, suspicion, or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of co ...
, delusion
A delusion is a fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or some other m ...
s, psychosis
In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
, violent behaviors, and suicidal behaviors such as suicidal ideation and self-inflicted violence. Other common manifestations include seizures
A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
and bizarre movements, mostly of the lips and mouth, but also including pedaling motions with the legs or hand movements resembling playing a piano . Some other symptoms typical during the disease onset include impaired cognition, memory deficits, and speech problems (including aphasia
Aphasia, also known as dysphasia, is an impairment in a person's ability to comprehend or formulate language because of dysfunction in specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine, but aph ...
, perseveration
Perseveration, in the fields of psychology, psychiatry, and speech–language pathology, is the repetition of a particular response (such as a word, phrase, or gesture) regardless of the absence or cessation of a stimulus. It is usually caused by ...
or mutism
In human development, muteness or mutism is defined as an absence of speech, with or without an ability to hear the speech of others. Mutism is typically understood as a person's inability to speak, and commonly observed by their family members, c ...
).
The symptoms usually appear psychiatric in nature, which may confound the differential diagnosis. In many cases, this leads to the illness going undiagnosed. As the disease progresses, the symptoms become medically urgent and often include autonomic dysfunction, hypoventilation
Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide ( hypercap ...
, cerebellar ataxia, loss of feeling on one side of the body, loss of consciousness, or catatonia
Catatonia is a complex syndrome most commonly seen in people with underlying mood disorders, such as major depressive disorder, or psychotic disorders, such as schizophrenia. People with catatonia exhibit abnormal movement and behaviors, wh ...
. During this acute phase, most patients require treatment in an intensive care unit to stabilize breathing, heart rate, and blood pressure. One distinguishing characteristic of anti-NMDA receptor encephalitis is the concurrent presence of many of the above listed symptoms. The majority of patients experience at least four symptoms, with many experiencing six or seven over the course of the disease.
Pathophysiology
The condition is mediated by autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
that target NMDA receptors in the brain. These 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
Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specif ...
can occur. Other autoimmune mechanisms are suspected for patients who do not have tumors. Whilst the exact pathophysiology of the disease is still debated, empirical evaluation of the origin of anti-NMDA receptor antibodies in serum and cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
leads to the consideration of two possible mechanisms.
These mechanisms may be informed by some simple observations. Serum NMDA receptor antibodies are consistently found at higher concentrations than cerebrospinal fluid antibodies, on average ten times higher. This strongly suggests the antibody production is systemic rather than in the brain or cerebrospinal fluid. When concentrations are normalized for total IgG, intrathecal synthesis is detected. This implies that there are more NMDA receptor antibodies in the cerebrospinal fluid than would be predicted given the expected quantities of total IgG.
# Passive access involves the diffusion
Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...
of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB). This cellular filter, separating the central nervous system from the circulatory system, normally prevents larger molecules from entering the brain. A variety of reasons for such a collapse in integrity have been suggested, with the most likely answer being the effects of acute inflammation of the nervous system. Likewise, the involvement of corticotropin releasing hormone
Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress (biology), stress responses. It is a releasin ...
on mast cells
A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...
in acute stress has been shown to facilitate BBB penetration. However, it is also possible that the autonomic dysfunction manifested in many patients during the later phases of the condition aids antibody entry. For example, an increase in blood pressure would force larger proteins, such as antibodies, to extravasate into the cerebrospinal fluid.
# Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism. Dalmau et al. demonstrated that 53 out of 58 patients with the condition had at least partially preserved BBBs, whilst having a high concentration of antibodies in the cerebrospinal fluid. Furthermore, cyclophosphamide
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
and rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
, 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.
A more sophisticated analysis of the processes involved in antibody presence in the cerebrospinal fluid hints at a combination of these two mechanisms in tandem.
Antibodies
Once the antibodies have entered the CSF, they bind to the NR1 subunit of the NMDA receptor. There are three possible methods in which neuronal damage occurs.
# 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.
# The direct antagonism of the NMDA receptor by the antibody, similar to the action of the classic dissociative anesthetics phencyclidine
Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...
and ketamine
Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...
.
# The recruitment of the complement cascade via the classical pathway (antibody-antigen interaction). Membrane attack complex (MAC) is one of the end products of this cascade and can insert into neurons as a molecular barrel, allowing water to enter. The cell subsequently lyses. Notably, this mechanism is unlikely as it causes the cell to die, which is inconsistent with current evidence.
Diagnosis
First and foremost is a high level of clinical suspicion, especially in young adults showing abnormal behavior as well as autonomic instability. Clinical examination may further reveal delusions and hallucinations, which can aid diagnostic efforts.
The initial investigation usually consists of clinical examination, MRI
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
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
Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, re ...
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 cell
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s, total protein and the presence of oligoclonal bands. NMDA receptor antibodies can be detected in serum and/or CSF. Whole body FDG-PET is usually performed as a part of tumor screening. Gynecological ultrasound or a pelvic MRI might be performed to search for an ovarian teratoma in women.
Diagnostic criteria for probable and definite anti-NMDA receptor encephalitis have been proposed to facilitate diagnosis at an early stage of the disease and help initiate early treatment.
Management
If a person is found to have a tumor, the long-term prognosis is generally better and the chance of relapse is much lower. This is because the tumor can be removed surgically, thus eradicating the source of autoantibodies. In general, early diagnosis and aggressive treatment is believed to improve patient outcomes, but this remains impossible to know without data from randomized controlled trials.
* If a tumor is detected, its removal should occur in conjunction with first-line immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
. This involves steroids
A steroid is an organic compound with four fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes that alter mem ...
to suppress the immune system, intravenous immunoglobulin
Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelinat ...
, and plasmapheresis
Plasmapheresis (from the Greek language, Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the ...
to physically remove autoantibodies. A study of 577 patients showed that over four weeks, about half the patients improved after receiving first-line immunotherapy.
* Second-line immunotherapy includes rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
, a monoclonal antibody
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Monoclonal antibodie ...
that targets the CD20
B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule.
It is a 33-37 kDa non-glycosylated protein. CD20 is expressed on the surface of B-cells from the pre-B phase, the expression is lost in terminally differentiated plasm ...
receptor on the surface of B cells
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
, thus destroying the self-reactive B cells. Cyclophosphamide
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
, an alkylating agent Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
that cross-links DNA and is used to treat both cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
and autoimmune diseases, has sometimes proven useful when other therapies have failed.
* Other medications, such as alemtuzumab, remain experimental.
Prognosis
The 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, the person's 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.
Epidemiology
The estimated number of cases of the disease is 1.5 per million people per year.[ According to the California Encephalitis Project, the disease has a higher incidence than its individual viral counterparts in patients younger than 30. The largest case series as of 2013 characterized 577 people with anti-NMDA receptor encephalitis. The data were limited, but provides the best approximation of disease distribution. It found that 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 were children, while only 5% of cases were patients over the age of 45. This same review found that 394 out of 501 patients (79%) had a good outcome by 24 months.] 30 people (6%) died, and the rest were left with mild to severe deficits. The study mentioned that of the 38% presenting with tumors, 94% of those presented with ovarian teratoma
A teratoma is a neoplasia, tumor made up of several types of biological tissue, tissue, such as hair, muscle, Human tooth, teeth, or bone. Teratomata typically form in the tailbone (where it is known as a sacrococcygeal teratoma), ovary, or test ...
s. Within that subset, African & Asian women were more likely to have a tumor, but this was not relevant to the prevalence of the disease within those racial groups.
Society and culture
Anti-NMDA receptor encephalitis is suspected of being an underlying cause of historical accounts of demonic possession
Spirit Possession is an altered state of consciousness and associated behaviors which are purportedly caused by the control of a human body and its functions by Supernatural#Spirit, spirits, ghosts, demons, angels, or Deity, gods. The concept ...
.
''New York Post
The ''New York Post'' (''NY Post'') is an American Conservatism in the United States, conservative
daily Tabloid (newspaper format), tabloid newspaper published in New York City. The ''Post'' also operates three online sites: NYPost. ...
'' reporter Susannah Cahalan wrote a book titled '' Brain on Fire: My Month of Madness'' about her experience with the disease. This has subsequently been turned into a film of the same name.
Dallas Cowboys
The Dallas Cowboys are a professional American football team based in the Dallas–Fort Worth metroplex. The Cowboys compete in the National Football League (NFL) as a member of the National Football Conference (NFC) NFC East, East division. T ...
defensive lineman Amobi Okoye spent 17 months battling anti-NMDA receptor encephalitis. In addition to three months in a medically-induced coma, he experienced a 145-day memory gap and lost 78 pounds. He returned to practice on October 23, 2014.
In the Japanese movie called '' The 8-Year Engagement'', a young Japanese woman ends up being in a coma due to anti-NMDA receptor encephalitis.
Knut
Knut ( Norwegian and Swedish), Knud ( Danish), or Knútur ( Icelandic) is a Scandinavian and German first name, of which the anglicised form is Canute. In Germany both "Knut" and "Knud" are used. In Spanish and Portuguese Canuto is used which ...
, a polar bear
The polar bear (''Ursus maritimus'') is a large bear native to the Arctic and nearby areas. It is closely related to the brown bear, and the two species can Hybrid (biology), interbreed. The polar bear is the largest extant species of bear ...
at the Berlin Zoological Garden
The Berlin Zoological Garden (, ) is the oldest surviving and best-known zoo in Germany. Opened in 1844, it covers and is located in Berlin's Tiergarten (park), Tiergarten. With about 1,380 different species and over 20,200 animals, the zoo pre ...
that died on 19 March 2011, was diagnosed with anti-NMDA receptor encephalitis in August 2015. This was the first case discovered in a non-human animal.
In ''Hannibal
Hannibal (; ; 247 – between 183 and 181 BC) was a Punic people, Carthaginian general and statesman who commanded the forces of Ancient Carthage, Carthage in their battle against the Roman Republic during the Second Punic War.
Hannibal's fat ...
'', Will Graham was affected by NMDA receptor or antibody encephalitis, also known as anti-NMDAR encephalitis.
The TV series '' Something's Killing Me'' featured an episode called "Into Madness" that featured two cases of the disease.
Figures
See also
* Anti-glutamate receptor antibodies
* Neuromyelitis optica spectrum disorder
Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of autoimmune diseases characterized by acute inflammation of the optic nerve (optic neuritis, ON) and the spinal cord (myelitis).Banerjee S, Butcher R. Rituximab for the Treatment of ...
References
External links
* — about her experience with the disease
{{Paraneoplastic syndromes
Encephalitis
Demonic possession
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