Anti-NMDA receptor encephalitis
Other namesNMDA receptor antibody encephalitis, anti-N-methyl-D-aspartate receptor encephalitis, anti-NMDAR encephalitis
A schematic diagram of the NMDA receptor
SpecialtyPsychiatry, Neurology
SymptomsEarly: Fever, headache, feeling tired, psychosis, agitated[1][2]
Later: Seizures, decreased breathing, blood pressure and heart rate variability[1]
ComplicationsLong term mental or behavioral problems[2]
Usual onsetOver days to weeks[3]
Risk factorsOvarian teratoma, unknown[1][4]
Diagnostic methodSpecific antibodies in the cerebrospinal fluid[1]
Differential diagnosisViral encephalitis, acute psychosis, neuroleptic malignant syndrome[2]
TreatmentImmunosuppresive medication, surgery[1]
MedicationCorticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, azathioprine[2]
PrognosisTypically good (with treatment)[1]
FrequencyRare [2]
Deaths~4% risk of death[2]

Anti-NMDA receptor encephalitis is a type of brain inflammation caused by antibodies.[4] Early symptoms may include fever, headache, and feeling tired.[1][2] This is then typically followed by psychosis which presents with false beliefs (delusions) and seeing or hearing things that others do not see or hear (hallucinations).[1] People are also often agitated or confused.[1] Over time, seizures, decreased breathing, and blood pressure and heart rate variability typically occur.[1] In some cases, patients may develop catatonia.[5]

About half of cases are associated with tumors, most commonly teratomas of the ovaries.[1][4] Another established trigger is herpesviral encephalitis, while the cause in others cases is unclear.[1][4][6] The underlying mechanism is autoimmune, with the primary target being the GluN1 subunit of the N-methyl D-aspartate receptors (NMDAR) in the brain.[1][7] Diagnosis is typically based on finding specific antibodies in the cerebral spinal fluid.[1] MRI of the brain is often normal.[2] Misdiagnosis is common.[7]

Treatment is typically with immunosuppresive medication and, if a tumor is present, surgery to remove it.[1] With treatment, about 80% of cases have a good outcome.[1] Outcomes are better if treatment is begun earlier.[2] Long-term mental or behavioral problems may remain.[2] About 4% of those affected die from the condition.[2] Recurrence occurs in about 10% of people.[1]

The estimated number of cases of the disease is one in 1.5 million people per year.[8][6] The condition is relatively common compared to other paraneoplastic disorders.[2] About 80% of those affected are female.[2] It typically occurs in adults younger than 45 years old, but it can occur at any age.[4][7] The disease was first described by Josep Dalmau in 2007.[1][9]

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 headaches, flu-like illness, or symptoms similar to an upper respiratory infection. These symptoms may be present for weeks or months prior to disease onset.[10] 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 agitation, paranoia, psychosis, and violent behaviors.[11] 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 . Some other symptoms typical during the disease onset include impaired cognition, memory deficits, and speech problems (including aphasia, perseveration or mutism).[12][13]

The symptoms usually appear psychiatric in nature, which may confound the differential diagnosis. In many cases, this leads to the illness going undiagnosed.[14] 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,[15] loss of consciousness, or catatonia.[16] 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.[12][13]

Pathophysiology

The condition is mediated by autoantibodies that target NMDA receptors in the brain.[17] 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 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 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.[18][19] 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.

  1. Passive access involves the diffusion of antibodies from the blood across a pathologically disrupted blood-brain barrier (BBB).[20] 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 on mast cells in acute stress has been shown to facilitate BBB penetration.[21] 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.
  2. Intrathecal production (production of antibodies in the intrathecal space) is also a possible mechanism.[22] 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 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.[23] 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.

  1. 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.[24]
  2. The direct antagonism of the NMDA receptor by the antibody, similar to the action of the classic dissociative anesthetics phencyclidine and ketamine.
  3. 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[25] 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 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.[26] EEG is abnormal in almost 90% of cases and typically shows general or focal slow wave activity.[27] CSF analysis often shows inflammatory changes with increased levels of white blood cells, total protein and the presence of oligoclonal bands.[28] 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.[29]

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.[12] 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.

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.[10]

Epidemiology

The estimated number of cases of the disease is 1.5 per million people per year.[6] According to the California Encephalitis Project, the disease has a higher incidence than its individual viral counterparts in patients younger than 30.[31] 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.[12] 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 teratomas. 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.[12]

Society and culture

Anti-NMDA receptor encephalitis is suspected of being an underlying cause of historical accounts of demonic possession.[32][33][34][35]

New York Post reporter Susannah Cahalan wrote a book titled Brain on Fire: My Month of Madness about her experience with the disease.[33] This has subsequently been turned into a film of the same name.[36]

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.[37]

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 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.[38][39][40]

In Hannibal, Will Graham was affected by NMDA receptor or antibody encephalitis, also known as anti-NMDAR encephalitis.[41]

The TV series Something's Killing Me featured an episode called "Into Madness" that featured two cases of the disease.[42]

Figures

An extreme delta brush in a patient. This EEG pattern is sometimes observed in anti-NMDAr encephalitis. From Mizoguchi et al., 2022.[43]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Kayser MS, Dalmau J (September 2016). "Anti-NMDA receptor encephalitis, autoimmunity, and psychosis". Schizophrenia Research. 176 (1): 36–40. doi:10.1016/j.schres.2014.10.007. PMC 4409922. PMID 25458857.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 Kayser MS, Dalmau J (2011). "Anti-NMDA Receptor Encephalitis in Psychiatry". Current Psychiatry Reviews. 7 (3): 189–193. doi:10.2174/157340011797183184. PMC 3983958. PMID 24729779.
  3. ↑ Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE (2013). Abeloff's Clinical Oncology E-Book. Elsevier Health Sciences. p. 600. ISBN 9781455728817.
  4. 1 2 3 4 5 Venkatesan A, Adatia K (December 2017). "Anti-NMDA-Receptor Encephalitis: From Bench to Clinic". ACS Chemical Neuroscience. 8 (12): 2586–2595. doi:10.1021/acschemneuro.7b00319. PMID 29077387.
  5. ↑ Wu H, Wu C, Zhou Y, Huang S, Zhu S (February 2023). "Catatonia in adult anti-NMDAR encephalitis: an observational cohort study". BMC Psychiatry. 23 (1): 94. doi:10.1186/s12888-022-04505-x. PMC 9903498. PMID 36750806.
  6. 1 2 3 Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, et al. (November 2019). "An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models". The Lancet. Neurology. 18 (11): 1045–1057. doi:10.1016/S1474-4422(19)30244-3. PMID 31326280. S2CID 197464804.
  7. 1 2 3 Minagar A, Alexander JS (2017). Inflammatory Disorders of the Nervous System: Pathogenesis, Immunology, and Clinical Management. Humana Press. p. 177. ISBN 9783319512204. Retrieved 14 July 2018.
  8. ↑ Samanta D, Lui F (2022). "Anti-NMDA Receptor Encephalitis". StatPearls. StatPearls. PMID 31869136.
  9. ↑ Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. (January 2007). "Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma". Annals of Neurology. 61 (1): 25–36. doi:10.1002/ana.21050. PMC 2430743. PMID 17262855.
  10. 1 2 Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. (December 2008). "Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies". The Lancet. Neurology. 7 (12): 1091–1098. doi:10.1016/S1474-4422(08)70224-2. PMC 2607118. PMID 18851928.
  11. ↑ Agarwal R, Gupta V (2022). "Anti-NMDA Receptor Encephalitis In Children". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 32965889. Retrieved 2023-02-24.
  12. 1 2 3 4 5 6 Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. (February 2013). "Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study". The Lancet. Neurology. 12 (2): 157–165. doi:10.1016/S1474-4422(12)70310-1. PMC 3563251. PMID 23290630.
  13. 1 2 Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (January 2011). "Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis". The Lancet. Neurology. 10 (1): 63–74. doi:10.1016/s1474-4422(10)70253-2. PMC 3158385. PMID 21163445.
  14. ↑ Greiner H, Leach JL, Lee KH, Krueger DA (April 2011). "Anti-NMDA receptor encephalitis presenting with imaging findings and clinical features mimicking Rasmussen syndrome". Seizure. 20 (3): 266–270. doi:10.1016/j.seizure.2010.11.013. PMID 21146427. S2CID 5839321.
  15. ↑ Cahalan S (2013). Brain on Fire-My Month of Madness. New York: Simon & Schuster.
  16. ↑ Eyre M, Kaushik A, Barrett E, King MD, Pollak T, Dale RC, et al. (2020). "Catatonic features in children and adolescents with N-methyl-d-aspartate receptor antibody encephalitis". BJPsych Open. 6 (4): e71. doi:10.1192/bjo.2020.55. ISSN 2056-4724. PMC 7443916.
  17. ↑ Li Y, Yang K, Zhang F, Wang J, Shen H, Liu M, et al. (2022). "Identification of cerebrospinal fluid biomarker candidates for anti-N-methyl-D-aspartate receptor encephalitis: High-throughput proteomic investigation". Frontiers in Immunology. 13: 971659. doi:10.3389/fimmu.2022.971659. PMC 9643472. PMID 36389787.
  18. ↑ Irani SR, Bera K, Waters P, Zuliani L, Maxwell S, Zandi MS, et al. (June 2010). "N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes". Brain. 133 (Pt 6): 1655–1667. doi:10.1093/brain/awq113. PMC 2877907. PMID 20511282.
  19. ↑ Suh-Lailam BB, Haven TR, Copple SS, Knapp D, Jaskowski TD, Tebo AE (June 2013). "Anti-NMDA-receptor antibody encephalitis: performance evaluation and laboratory experience with the anti-NMDA-receptor IgG assay". Clinica Chimica Acta; International Journal of Clinical Chemistry. 421: 1–6. doi:10.1016/j.cca.2013.02.010. PMID 23454475.
  20. ↑ Moscato EH, Jain A, Peng X, Hughes EG, Dalmau J, Balice-Gordon RJ (July 2010). "Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies". The European Journal of Neuroscience. 32 (2): 298–309. doi:10.1111/j.1460-9568.2010.07349.x. PMC 2955837. PMID 20646055.
  21. ↑ Rabchevsky AG, Degos JD, Dreyfus PA (June 1999). "Peripheral injections of Freund's adjuvant in mice provoke leakage of serum proteins through the blood-brain barrier without inducing reactive gliosis". Brain Research. 832 (1–2): 84–96. doi:10.1016/S0006-8993(99)01479-1. PMID 10375654. S2CID 27036707.
  22. ↑ Malviya M, Barman S, Golombeck KS, Planagumà J, Mannara F, Strutz-Seebohm N, et al. (November 2017). "NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody". Annals of Clinical and Translational Neurology. 4 (11): 768–783. doi:10.1002/acn3.444. PMC 5682115. PMID 29159189.
  23. ↑ Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, et al. (July 2009). "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents". Annals of Neurology. 66 (1): 11–18. doi:10.1002/ana.21756. PMC 2826225. PMID 19670433.
  24. ↑ Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, et al. (April 2010). "Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis". The Journal of Neuroscience. 30 (17): 5866–5875. doi:10.1523/JNEUROSCI.0167-10.2010. PMC 2868315. PMID 20427647.
  25. ↑ Abbas AK, Lichtman AH, Pillai S (2011). Cellular and Molecular Immunology (7th ed.). Elsevier Health Sciences. ISBN 978-1-4377-3573-4.
  26. ↑ Bacchi S, Franke K, Wewegama D, Needham E, Patel S, Menon D (June 2018). "Magnetic resonance imaging and positron emission tomography in anti-NMDA receptor encephalitis: A systematic review". Journal of Clinical Neuroscience. 52: 54–59. doi:10.1016/j.jocn.2018.03.026. PMID 29605275. S2CID 4565748.
  27. ↑ Gillinder L, Warren N, Hartel G, Dionisio S, O'Gorman C (February 2019). "EEG findings in NMDA encephalitis - A systematic review". Seizure. 65: 20–24. doi:10.1016/j.seizure.2018.12.015. PMID 30597400.
  28. ↑ Blinder T, Lewerenz J (2019-07-25). "Cerebrospinal Fluid Findings in Patients With Autoimmune Encephalitis-A Systematic Analysis". Frontiers in Neurology. 10: 804. doi:10.3389/fneur.2019.00804. PMC 6670288. PMID 31404257.
  29. ↑ Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, et al. (April 2016). "A clinical approach to diagnosis of autoimmune encephalitis". The Lancet. Neurology. 15 (4): 391–404. doi:10.1016/s1474-4422(15)00401-9. PMC 5066574. PMID 26906964.
  30. ↑ Liba Z, Sebronova V, Komarek V, Sediva A, Sedlacek P (May 2013). "Prevalence and treatment of anti-NMDA receptor encephalitis". The Lancet. Neurology. 12 (5): 424–425. doi:10.1016/S1474-4422(13)70070-X. PMID 23602156. S2CID 31746114.
  31. ↑ Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA (April 2012). "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". Clinical Infectious Diseases. 54 (7): 899–904. doi:10.1093/cid/cir1038. PMC 3297648. PMID 22281844.
  32. ↑ Lamas DJ (27 May 2013). "When the brain is under attack". The Boston Globe.
  33. 1 2 "A YoungReporter Chronicles Her 'Brain On Fire'". Fresh Air. WHYY; NPR. November 14, 2012. Retrieved September 20, 2013.
  34. ↑ Tam J, Zandi MS (July 2017). "The witchcraft of encephalitis in Salem". Journal of Neurology. 264 (7): 1529–1531. doi:10.1007/s00415-017-8546-4. PMID 28631128. S2CID 36151332.
  35. ↑ Sébire G (January 2010). "In search of lost time from "Demonic Possession" to anti-N-methyl-D-aspartate receptor encephalitis". Annals of Neurology. 67 (1): 141–142. doi:10.1002/ana.21928. PMID 20186949. S2CID 2366741.
  36. ↑ Hornaday A, O'Sullivan M. "What to watch with your kids: 'Ant-Man and the Wasp,' 'Leave No Trace' and more". Washington Post. Retrieved 14 July 2018.
  37. ↑ Whitmire K (2014-10-23). "Cowboys' Okoye returns to practice after battling rare brain disease". www.foxsports.com. FOX Sports Southwest. Retrieved 24 October 2014.
  38. ↑ Nuwer R (27 August 2015). "Knut the Polar Bear's Mysterious Death Finally Solved". Smithsonian.
  39. ↑ Armitage H (27 August 2015). "Death of beloved polar bear, Knut, solved". Science. doi:10.1126/science.aad1675.
  40. ↑ Prüss H, Leubner J, Wenke NK, Czirják GÁ, Szentiks CA, Greenwood AD (August 2015). "Anti-NMDA Receptor Encephalitis in the Polar Bear (Ursus maritimus) Knut". Scientific Reports. 5 (12805): 12805. Bibcode:2015NatSR...512805P. doi:10.1038/srep12805. PMC 4551079. PMID 26313569.
  41. ↑ Pitt A (21 February 2018). "Hannibal and Anti-NMDAR Encephalitis". Encephalitis Society. North Yorkshire.
  42. ↑ "Something's Killing Me Season 1".
  43. ↑ Mizoguchi T, Hara M, Hirose S, Nakajima H (2022). "Novel qEEG Biomarker to Distinguish Anti-NMDAR Encephalitis From Other Types of Autoimmune Encephalitis". Frontiers in Immunology. 13: 845272. doi:10.3389/fimmu.2022.845272. PMC 8885512. PMID 35242143.
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