View source for Medicine:Anti-NMDA receptor encephalitis

{{Short description|Rare disease which results in brain inflammation}}
{{Infobox medical condition (new)
| name            = Anti-NMDA receptor encephalitis
| synonyms        = NMDA receptor antibody encephalitis, anti-N-methyl-D-aspartate receptor encephalitis, anti-NMDAR encephalitis
| image           = NR1-NR2B subunit.png
| alt             =
| speciality      = [[Biology:Neurology|Neurology]]
| caption         = A schematic diagram of the [[Biology:NMDA receptor|NMDA receptor]]
| pronounce       =
| field           =
| symptoms        = '''Early''': [[Medicine:Fever|Fever]], headache, feeling tired, [[Medicine:Psychosis|psychosis]], agitated<ref name=Kay2016/><ref name=Kay2011/><br>'''Later''': Seizures, decreased breathing, blood pressure and heart rate variability<ref name=Kay2016/>
| complications   = Long term mental or behavioral problems<ref name=Kay2011/>
| onset           = Over days to weeks<ref name=Nie2013>{{cite book | vauthors = Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE |title= Abeloff's Clinical Oncology E-Book |date=2013 |publisher=Elsevier Health Sciences |isbn=9781455728817 |page=600 |url=https://books.google.com/books?id=nQ4EAQAAQBAJ&pg=PA600 |language=en}}</ref>
| duration        =
| types           =
| causes          =
| risks           = Ovarian teratoma, unknown<ref name=Kay2016/><ref name=Ven2017/>
| diagnosis       = Specific [[Biology:Antibodies|antibodies]] in the [[Biology:Cerebrospinal fluid|cerebrospinal fluid]]<ref name=Kay2016/>
| differential    = Viral encephalitis, acute psychosis, [[Medicine:Neuroleptic malignant syndrome|neuroleptic malignant syndrome]]<ref name=Kay2011/>
| prevention      =
| treatment       = Immunosuppresive medication, surgery<ref name=Kay2016/>
| medication      = Corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, [[Chemistry:Azathioprine|azathioprine]]<ref name=Kay2011/>
| prognosis       = Typically good (with treatment)<ref name=Kay2016/>
| frequency       = Rare <ref name=Kay2011/>
| deaths          = ~4% risk of death<ref name=Kay2011/>
}}
<!-- Definition and symptoms -->
'''Anti-NMDA receptor encephalitis''' is a type of [[Medicine:Encephalitis|brain inflammation]] caused by [[Biology:Antibodies|antibodies]].<ref name=Ven2017>{{cite journal | vauthors = Venkatesan A, Adatia K | title = Anti-NMDA-Receptor Encephalitis: From Bench to Clinic | journal = ACS Chemical Neuroscience | volume = 8 | issue = 12 | pages = 2586–2595 | date = December 2017 | pmid = 29077387 | doi = 10.1021/acschemneuro.7b00319 }}</ref> Early symptoms may include [[Medicine:Fever|fever]], headache, and feeling tired.<ref name=Kay2016/><ref name=Kay2011/> This is then typically followed by [[Medicine:Psychosis|psychosis]] which presents with false beliefs (delusions) and seeing or hearing things that others do not see or hear (hallucinations).<ref name=Kay2016/> People are also often agitated or confused.<ref name=Kay2016/> Over time, seizures, decreased breathing, and blood pressure and heart rate variability typically occur.<ref name=Kay2016/> In some cases, patients may develop [[Medicine:Catatonia|catatonia]].<ref>{{cite journal | vauthors = Wu H, Wu C, Zhou Y, Huang S, Zhu S | title = Catatonia in adult anti-NMDAR encephalitis: an observational cohort study | journal = BMC Psychiatry | volume = 23 | issue = 1 | pages = 94 | date = February 2023 | pmid = 36750806 | pmc = 9903498 | doi = 10.1186/s12888-022-04505-x | doi-access = free }}</ref>

<!-- Cause and diagnosis -->
About half of cases are associated with [[Medicine:Tumors|tumors]], most commonly [[Medicine:Teratoma|teratoma]]s of the ovaries.<ref name=Kay2016/><ref name=Ven2017/> Another established trigger is [[Medicine:Herpesviral encephalitis|herpesviral encephalitis]], while the cause in others cases is unclear.<ref name=Kay2016/><ref name=Ven2017/><ref name=Dal2019>{{cite journal | vauthors = Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ, Rosenfeld MR, Graus F | display-authors = 6 | title = An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models | journal = The Lancet. Neurology | volume = 18 | issue = 11 | pages = 1045–1057 | date = November 2019 | pmid = 31326280 | doi = 10.1016/S1474-4422(19)30244-3 | s2cid = 197464804 }}</ref> The underlying mechanism is [[Medicine:Autoimmune disease|autoimmune]], with the primary target being the GluN1 subunit of the N-methyl D-aspartate receptors (NMDAR) in the brain.<ref name=Kay2016>{{cite journal | vauthors = Kayser MS, Dalmau J | title = Anti-NMDA receptor encephalitis, autoimmunity, and psychosis | journal = Schizophrenia Research | volume = 176 | issue = 1 | pages = 36–40 | date = September 2016 | pmid = 25458857 | pmc = 4409922 | doi = 10.1016/j.schres.2014.10.007 }}</ref><ref name=Min2017/> Diagnosis is typically based on finding specific antibodies in the cerebral spinal fluid.<ref name=Kay2016/> MRI of the brain is often normal.<ref name=Kay2011/> Misdiagnosis is common.<ref name=Min2017/>

<!-- Treatment and prognosis -->
Treatment is typically with immunosuppresive medication and, if a tumor is present, surgery to remove it.<ref name=Kay2016/> With treatment, about 80% of cases have a good outcome.<ref name=Kay2016/> Outcomes are better if treatment is begun earlier.<ref name=Kay2011>{{cite journal | vauthors = Kayser MS, Dalmau J | title = Anti-NMDA Receptor Encephalitis in Psychiatry | journal = Current Psychiatry Reviews | volume = 7 | issue = 3 | pages = 189–193 | date = 2011 | pmid = 24729779 | pmc = 3983958 | doi = 10.2174/157340011797183184 }}</ref> Long-term mental or behavioral problems may remain.<ref name=Kay2011/> About 4% of those affected die from the condition.<ref name=Kay2011/> Recurrence occurs in about 10% of people.<ref name=Kay2016/>

<!-- Epidemiology, history and culture -->
The estimated number of cases of the disease is one in 1.5 million people per year.<ref>{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK551672/|title=StatPearls|chapter=Anti-NMDA Receptor Encephalitis|year=2022|publisher=StatPearls|pmid=31869136 | vauthors = Samanta D, Lui F }}</ref><ref name=Dal2019/> The condition is relatively common compared to other paraneoplastic disorders.<ref name=Kay2011/> About 80% of those affected are female.<ref name=Kay2011/> It typically occurs in adults younger than 45 years old, but it can occur at any age.<ref name=Ven2017/><ref name=Min2017>{{cite book | vauthors = Minagar A, Alexander JS |title=Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management |date=2017 |publisher=Humana Press |isbn=9783319512204 |page=177 |url=https://books.google.com/books?id=FoZtDgAAQBAJ&pg=PA177 |access-date=14 July 2018 |language=en}}</ref> The disease was first described by Josep Dalmau in 2007.<ref name=Kay2016/><ref>{{cite journal | vauthors = Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR | display-authors = 6 | title = Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma | journal = Annals of Neurology | volume = 61 | issue = 1 | pages = 25–36 | date = January 2007 | pmid = 17262855 | pmc = 2430743 | doi = 10.1002/ana.21050 }}</ref>

==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 [[Medicine:Headache|headache]]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.<ref name="ReferenceA">{{cite journal | vauthors = Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR | display-authors = 6 | title = Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies | journal = The Lancet. Neurology | volume = 7 | issue = 12 | pages = 1091–1098 | date = December 2008 | pmid = 18851928 | pmc = 2607118 | doi = 10.1016/S1474-4422(08)70224-2 }}</ref> Beyond the prodromal 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 [[Medicine:Agitation (dementia)|agitation]], [[Medicine:Paranoia|paranoia]], [[Medicine:Psychosis|psychosis]], and violent behaviors.<ref>{{cite book | vauthors = Agarwal R, Gupta V | chapter = Anti-NMDA Receptor Encephalitis In Children |date=2022 |url=http://www.ncbi.nlm.nih.gov/books/NBK562218/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32965889 |access-date=2023-02-24 }}</ref> 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 {{Citation needed|date=February 2023}}. Some other symptoms typical during the disease onset include impaired cognition, memory deficits, and speech problems (including [[Medicine:Aphasia|aphasia]], [[Medicine:Perseveration|perseveration]] or mutism).<ref name="ReferenceB"/><ref name="Dalmau_2011">{{cite journal | vauthors = Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R | title = Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis | journal = The Lancet. Neurology | volume = 10 | issue = 1 | pages = 63–74 | date = January 2011 | pmid = 21163445 | pmc = 3158385 | doi = 10.1016/s1474-4422(10)70253-2 }}</ref>

The symptoms usually appear psychiatric in nature, which may confound the differential diagnosis. In many cases, this leads to the illness going undiagnosed.<ref>{{cite journal | vauthors = Greiner H, Leach JL, Lee KH, Krueger DA | title = Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome | journal = Seizure | volume = 20 | issue = 3 | pages = 266–270 | date = April 2011 | pmid = 21146427 | doi = 10.1016/j.seizure.2010.11.013 | s2cid = 5839321 | doi-access = free }}</ref> As the disease progresses, the symptoms become medically urgent and often include autonomic dysfunction, hypoventilation, cerebellar ataxia, loss of feeling on one side of the body,<ref>{{cite book | vauthors = Cahalan S | title = Brain on Fire-My Month of Madness | location = New York | publisher = Simon & Schuster | date = 2013 }}</ref> loss of consciousness, or [[Medicine:Catatonia|catatonia]].<ref>{{Cite journal | vauthors = Eyre M, Kaushik A, Barrett E, King MD, Pollak T, Dale RC, Byrne S, Lim M | display-authors = 6 |date=2020 |title=Catatonic features in children and adolescents with N-methyl-d-aspartate receptor antibody encephalitis |journal=BJPsych Open |language=en |volume=6 |issue=4 |pages=e71 |doi=10.1192/bjo.2020.55 |issn=2056-4724 |pmc=7443916}}</ref> During this acute phase, most patients require treatment in an intensive care unit to stabilize breathing, heart rate, and blood pressure.{{Citation needed|date=November 2015}} 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.<ref name="ReferenceB"/><ref name="Dalmau_2011"/>

==Pathophysiology==

The condition is mediated by autoantibodies that target NMDA receptors in the brain.<ref>{{cite journal | vauthors = Li Y, Yang K, Zhang F, Wang J, Shen H, Liu M, Guo J, Wang J | display-authors = 6 | title = Identification of cerebrospinal fluid biomarker candidates for anti-N-methyl-D-aspartate receptor encephalitis: High-throughput proteomic investigation | journal = Frontiers in Immunology | volume = 13 | pages = 971659 | date = 2022 | pmid = 36389787 | pmc = 9643472 | doi = 10.3389/fimmu.2022.971659 | doi-access = free }}</ref> These can be produced by [[Biology:Cross-reactivity|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. Whilst the exact pathophysiology of the disease is still debated, empirical evaluation of the origin of anti-NMDA receptor antibodies in [[Biology:Serum (blood)|serum]] and [[Biology:Cerebrospinal fluid|cerebrospinal fluid]] leads to the consideration of two possible mechanisms.{{cn|date=July 2021}}

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.<ref name=Irani>{{cite journal | vauthors = Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, Friese MA, Galea I, Kullmann DM, Beeson D, Lang B, Bien CG, Vincent A | display-authors = 6 | title = N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes | journal = Brain | volume = 133 | issue = Pt 6 | pages = 1655–1667 | date = June 2010 | pmid = 20511282 | pmc = 2877907 | doi = 10.1093/brain/awq113 }}</ref><ref>{{cite journal | vauthors = Suh-Lailam BB, Haven TR, Copple SS, Knapp D, Jaskowski TD, Tebo AE | title = Anti-NMDA-receptor antibody encephalitis: performance evaluation and laboratory experience with the anti-NMDA-receptor IgG assay | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 421 | pages = 1–6 | date = June 2013 | pmid = 23454475 | doi = 10.1016/j.cca.2013.02.010 }}</ref> 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.{{cn|date=July 2021}}

# Passive access involves the [[Physics:Diffusion|diffusion]] of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB).<ref>{{cite journal | vauthors = Moscato EH, Jain A, Peng X, Hughes EG, Dalmau J, Balice-Gordon RJ | title = Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies | journal = The European Journal of Neuroscience | volume = 32 | issue = 2 | pages = 298–309 | date = July 2010 | pmid = 20646055 | pmc = 2955837 | doi = 10.1111/j.1460-9568.2010.07349.x }}</ref> 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 [[Biology:Corticotropin-releasing hormone|corticotropin releasing hormone]] on mast cells in acute stress has been shown to facilitate BBB penetration.<ref>{{cite journal | vauthors = Rabchevsky AG, Degos JD, Dreyfus PA | title = Peripheral injections of Freund's adjuvant in mice provoke leakage of serum proteins through the blood-brain barrier without inducing reactive gliosis | journal = Brain Research | volume = 832 | issue = 1–2 | pages = 84–96 | date = June 1999 | pmid = 10375654 | doi = 10.1016/S0006-8993(99)01479-1 | s2cid = 27036707 }}</ref> 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.<ref name="pmid29159189">{{cite journal | vauthors = Malviya M, Barman S, Golombeck KS, Planagumà J, Mannara F, Strutz-Seebohm N, Wrzos C, Demir F, Baksmeier C, Steckel J, Falk KK, Gross CC, Kovac S, Bönte K, Johnen A, Wandinger KP, Martín-García E, Becker AJ, Elger CE, Klöcker N, Wiendl H, Meuth SG, Hartung HP, Seebohm G, Leypoldt F, Maldonado R, Stadelmann C, Dalmau J, Melzer N, Goebels N | display-authors = 6 | title = NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody | journal = Annals of Clinical and Translational Neurology | volume = 4 | issue = 11 | pages = 768–783 | date = November 2017 | pmid = 29159189 | pmc = 5682115 | doi = 10.1002/acn3.444 }}</ref> 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, [[Chemistry:Cyclophosphamide|cyclophosphamide]] and [[Chemistry:Rituximab|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.<ref>{{cite journal | vauthors = Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, Campen CJ, Moss H, Peter N, Gleichman AJ, Glaser CA, Lynch DR, Rosenfeld MR, Dalmau J | display-authors = 6 | title = Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents | journal = Annals of Neurology | volume = 66 | issue = 1 | pages = 11–18 | date = July 2009 | pmid = 19670433 | pmc = 2826225 | doi = 10.1002/ana.21756 }}</ref> These destroy excess antibody-producing cells in the [[Biology:Thecal sac|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.{{cn|date=July 2021}}

===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.<ref>{{cite journal | vauthors = Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ | display-authors = 6 | title = Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis | journal = The Journal of Neuroscience | volume = 30 | issue = 17 | pages = 5866–5875 | date = April 2010 | pmid = 20427647 | pmc = 2868315 | doi = 10.1523/JNEUROSCI.0167-10.2010 }}</ref>
# The direct [[Biology:Receptor antagonist|antagonism]] of the NMDA receptor by the antibody, similar to the action of the classic dissociative anesthetics [[Chemistry:Phencyclidine|phencyclidine]] and [[Chemistry:Ketamine|ketamine]].
# 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<ref>{{cite book | vauthors = Abbas AK, Lichtman AH, Pillai S |title=Cellular and Molecular Immunology |url=https://books.google.com/books?id=qtJY05rIUKQC |date=2011 |publisher=Elsevier Health Sciences |edition=7th |isbn=978-1-4377-3573-4}}</ref> 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.{{cn|date=July 2021}}

The initial investigation usually consists of clinical examination, [[Physics:Magnetic resonance imaging|MRI]] of the brain, an [[Biology:Electroencephalography|EEG]], and a [[Medicine:Lumbar puncture|lumbar puncture]] for [[Biology:Cerebrospinal fluid|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 [[Physics:Positron emission tomography|FDG-PET]] scan of the brain may show abnormalities in cases when the MRI scan is normal.<ref>{{cite journal | vauthors = Bacchi S, Franke K, Wewegama D, Needham E, Patel S, Menon D | title = Magnetic resonance imaging and positron emission tomography in anti-NMDA receptor encephalitis: A systematic review | journal = Journal of Clinical Neuroscience | volume = 52 | pages = 54–59 | date = June 2018 | pmid = 29605275 | doi = 10.1016/j.jocn.2018.03.026 | s2cid = 4565748 | url = https://www.repository.cam.ac.uk/handle/1810/276054 }}</ref> EEG is abnormal in almost 90% of cases and typically shows general or focal slow wave activity.<ref>{{cite journal | vauthors = Gillinder L, Warren N, Hartel G, Dionisio S, O'Gorman C | title = EEG findings in NMDA encephalitis - A systematic review | journal = Seizure | volume = 65 | pages = 20–24 | date = February 2019 | pmid = 30597400 | doi = 10.1016/j.seizure.2018.12.015 | doi-access = free }}</ref> CSF analysis often shows inflammatory changes with increased levels of [[Biology:White blood cell|white blood cell]]s, total protein and the presence of [[Biology:Oligoclonal band|oligoclonal band]]s.<ref>{{cite journal | vauthors = Blinder T, Lewerenz J | title = Cerebrospinal Fluid Findings in Patients With Autoimmune Encephalitis-A Systematic Analysis | journal = Frontiers in Neurology | volume = 10 | pages = 804 | date = 2019-07-25 | pmid = 31404257 | pmc = 6670288 | doi = 10.3389/fneur.2019.00804 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J | display-authors = 6 | title = A clinical approach to diagnosis of autoimmune encephalitis | journal = The Lancet. Neurology | volume = 15 | issue = 4 | pages = 391–404 | date = April 2016 | pmid = 26906964 | pmc = 5066574 | doi = 10.1016/s1474-4422(15)00401-9 }}</ref>

==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.<ref name="ReferenceB"/> Given that the majority of patients are initially seen by psychiatrists, it is critical that all physicians (especially psychiatrists) consider anti-NMDA receptor encephalitis as a possible cause of acute psychosis in young patients with no past neuropsychiatric history.{{cn|date=July 2021}}
* If a tumor is detected, its removal should occur in conjunction with first-line [[Medicine:Immunotherapy|immunotherapy]]. This involves steroids to suppress the immune system, intravenous immunoglobulin, and [[Medicine:Plasmapheresis|plasmapheresis]] to physically remove autoantibodies. A study of 577 patients showed that over four weeks, about half the patients improved after receiving first-line immunotherapy.<ref name="ReferenceB"/>
* Second-line immunotherapy includes [[Chemistry:Rituximab|rituximab]], a [[Biology:Monoclonal antibody|monoclonal antibody]] that targets the [[Biology:CD20|CD20]] receptor on the surface of B cells, thus destroying the self-reactive B cells. [[Chemistry:Cyclophosphamide|Cyclophosphamide]], an [[Chemistry:Alkylating antineoplastic agent|alkylating agent]] that cross-links DNA and is used to treat both [[Medicine:Cancer|cancer]] and autoimmune diseases, has sometimes proven useful when other therapies have failed.
* Other medications, such as [[Chemistry:Alemtuzumab|alemtuzumab]], remain experimental.<ref>{{cite journal | vauthors = Liba Z, Sebronova V, Komarek V, Sediva A, Sedlacek P | title = Prevalence and treatment of anti-NMDA receptor encephalitis | journal = The Lancet. Neurology | volume = 12 | issue = 5 | pages = 424–425 | date = May 2013 | pmid = 23602156 | doi = 10.1016/S1474-4422(13)70070-X | s2cid = 31746114 | doi-access = free }}</ref>

==Prognosis==
The recovery process from anti-NMDAR encephalitis can take many months. 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.<ref name="ReferenceA" />

==Epidemiology==
The estimated number of cases of the disease is 1.5 per million people per year.<ref name=Dal2019/> According to the California Encephalitis Project, the disease has a higher incidence than its individual viral counterparts in patients younger than 30.<ref>{{cite journal | vauthors = Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA | title = The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project | journal = Clinical Infectious Diseases | volume = 54 | issue = 7 | pages = 899–904 | date = April 2012 | pmid = 22281844 | pmc = 3297648 | doi = 10.1093/cid/cir1038 }}</ref> 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.<ref name="ReferenceB">{{cite journal | vauthors = Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, Honig LS, Benseler SM, Kawachi I, Martinez-Hernandez E, Aguilar E, Gresa-Arribas N, Ryan-Florance N, Torrents A, Saiz A, Rosenfeld MR, Balice-Gordon R, Graus F, Dalmau J | display-authors = 6 | title = Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study | journal = The Lancet. Neurology | volume = 12 | issue = 2 | pages = 157–165 | date = February 2013 | pmid = 23290630 | pmc = 3563251 | doi = 10.1016/S1474-4422(12)70310-1 }}</ref> 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 [[Medicine:Teratoma|teratoma]]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.<ref name="ReferenceB" />

==Society and culture==
Anti-NMDA receptor encephalitis is suspected of being an underlying cause of historical accounts of [[Unsolved:Demonic possession|demonic possession]].<ref>{{cite web | vauthors = Lamas DJ | url = https://www.bostonglobe.com/lifestyle/health-wellness/2013/05/26/when-brain-attacks-newly-discovered-disease-can-mimic-psychosis/dyixxnwdHJJIUITsNYJC3O/story.html | title = When the brain is under attack | work = The Boston Globe | date = 27 May 2013 }}</ref><ref name = "npr" /><ref>{{cite journal | vauthors = Tam J, Zandi MS | title = The witchcraft of encephalitis in Salem | journal = Journal of Neurology | volume = 264 | issue = 7 | pages = 1529–1531 | date = July 2017 | pmid = 28631128 | doi = 10.1007/s00415-017-8546-4 | s2cid = 36151332 }}</ref><ref>{{cite journal | vauthors = Sébire G | title = In search of lost time from "Demonic Possession" to anti-N-methyl-D-aspartate receptor encephalitis | journal = Annals of Neurology | volume = 67 | issue = 1 | pages = 141–142 | date = January 2010 | pmid = 20186949 | doi = 10.1002/ana.21928 | s2cid = 2366741 }}</ref>

''New York Post'' reporter Susannah Cahalan wrote a book titled ''[[Medicine:Brain on Fire|Brain on Fire: My Month of Madness]]'' about her experience with the disease.<ref name = "npr">{{cite web |title=A YoungReporter Chronicles Her 'Brain On Fire' | work = Fresh Air |publisher=WHYY; NPR |date=November 14, 2012 |url=https://www.npr.org/2012/11/14/165115921/a-young-reporter-chronicles-her-brain-on-fire |access-date=September 20, 2013}}</ref> This has subsequently been turned into a film of the same name.<ref>{{cite news | vauthors = Hornaday A, O'Sullivan M |title=What to watch with your kids: 'Ant-Man and the Wasp,' 'Leave No Trace' and more |url=https://www.washingtonpost.com/goingoutguide/movies/what-to-watch-with-your-kids-ant-man-and-the-wasp-leave-no-trace-and-more/2018/07/05/2734a31c-7a4e-11e8-80be-6d32e182a3bc_story.html?noredirect=on |access-date=14 July 2018 |newspaper=Washington Post |language=en}}</ref>

Dallas Cowboys 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.<ref>{{cite web | vauthors = Whitmire K |title= Cowboys' Okoye returns to practice after battling rare brain disease |url=http://www.foxsports.com/southwest/story/cowboys-okoye-returns-to-practice-after-battling-rare-brain-disease-102314|website=www.foxsports.com|publisher=FOX Sports Southwest|access-date=24 October 2014|date=2014-10-23}}</ref>

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, a [[Biology:Polar bear|polar bear]] at the Berlin Zoological Garden 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.<ref>{{cite web | vauthors = Nuwer R |title=Knut the Polar Bear's Mysterious Death Finally Solved|url=http://www.smithsonianmag.com/science-nature/knut-polar-bears-mysterious-death-finally-solved-180956414/|publisher=Smithsonian |date=27 August 2015}}</ref><ref>{{cite journal | vauthors = Armitage H |title=Death of beloved polar bear, Knut, solved |journal=Science |date=27 August 2015 |doi=10.1126/science.aad1675 |url=https://www.science.org/content/article/death-beloved-polar-bear-knut-solved}}</ref><ref>
{{cite journal | vauthors = Prüss H, Leubner J, Wenke NK, Czirják GÁ, Szentiks CA, Greenwood AD | title = Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut | journal = Scientific Reports | volume = 5 | issue = 12805 | pages = 12805 | date = August 2015 | pmid = 26313569 | pmc = 4551079 | doi = 10.1038/srep12805 | bibcode = 2015NatSR...512805P }}</ref>

In ''Hannibal'', Will Graham was affected by NMDA receptor or antibody encephalitis, also known as anti-NMDAR encephalitis.<ref>{{Cite web | vauthors = Pitt A | work = Encephalitis Society | location = North Yorkshire |url=https://www.encephalitis.info/blog/hannibal-and-anti-nmdar-encephalitis|title = Hannibal and Anti-NMDAR Encephalitis| date = 21 February 2018 }}</ref>

The TV series ''Something's Killing Me'' featured an episode called "Into Madness" that featured two cases of the disease.<ref>{{Cite web|url=https://www.radiotimes.com/tv-programme/e/g6nwfg/somethings-killing-me--s1-e1-into-madness/|title=Something's Killing Me Season 1}}{{Dead link|date=September 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>

==Figures==

[[File:Extreme delta brush in anti-NMDAr encephalitis.png|700px|center|thumb|An ''extreme delta brush'' in a patient. This EEG pattern is sometimes observed in anti-NMDAr encephalitis. From Mizoguchi et al., 2022.<ref name="pmid35242143">{{cite journal | vauthors = Mizoguchi T, Hara M, Hirose S, Nakajima H | title = Novel qEEG Biomarker to Distinguish Anti-NMDAR Encephalitis From Other Types of Autoimmune Encephalitis | journal = Frontiers in Immunology | volume = 13 | issue =  | pages = 845272 | date = 2022 | pmid = 35242143 | pmc = 8885512 | doi = 10.3389/fimmu.2022.845272 | doi-access = free }}</ref>]]

== See also ==
* Anti-glutamate receptor antibodies
* [[Medicine:Neuromyelitis optica spectrum disorder|Neuromyelitis optica spectrum disorder]]

== References ==
{{reflist}}

== External links ==
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* {{cite news | vauthors = Cahalan S |title=My mysterious lost month of madness |newspaper=New York Post |date=4 October 2009 |url=http://www.nypost.com/p/news/local/my_mysterious_lost_month_of_madness_OseCEXxo6axZ8Uyig17QKL}} — about her experience with the disease


[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Anti-NMDA receptor encephalitis}}