Editing Neuroleptic malignant syndrome

{{Infobox medical condition (new)
| name            = Neuroleptic malignant syndrome
| image           = Haloperidol (Haldol).jpg
| caption         = [[Haloperidol]], a known cause of NMS
| field           = [[Critical care medicine]], [[neurology]], [[psychiatry]], [[emergency medicine]]
| symptoms        = [[hyperpyrexia|High fever]], confusion, rigid muscles, variable blood pressure, sweating<ref name=Ber2011/>
| complications   = [[Rhabdomyolysis]], [[high blood potassium]], [[kidney failure]], [[seizures]]<ref name=Ber2011/><ref name=NORD2004/>
| onset           = Within a few weeks or days<ref name=NIH2017/>
| duration        =
| types           =
| causes          = [[Antipsychotic medication]]<ref name=Ber2011/>
| risks           = Dehydration, [[psychomotor agitation|agitation]], [[catatonia]]<ref name=Str2007/>
| diagnosis       = Based on symptoms in someone who has started on antipsychotics within the last month<ref name=NORD2004/>
| differential    = [[Heat stroke]], [[malignant hyperthermia]], [[serotonin syndrome]], [[lethal catatonia]]<ref name=NORD2004/>
| prevention      =
| treatment       = Stopping the offending medication, rapid cooling, starting other medications<ref name=NORD2004/>
| medication      = [[Dantrolene]], [[bromocriptine]], [[diazepam]]<ref name=NORD2004/>
| prognosis       = 10–15% risk of death<ref name=Str2007/>
| frequency       = 15 per 100,000 per year (on neuroleptics)<ref name=Ber2011/>
| deaths          =
}}
<!-- Definition and symptoms --> 
'''Neuroleptic malignant syndrome''' ('''NMS''') is a rare<ref name="aacnjournals.org">{{cite journal | first1 = Andrea M. | last1 = New | first2 = Sarah | last2 = Nelson | first3 = Jonathan G. | last3 = Leung | title = Psychiatric Emergencies in the Intensive Care Unit | journal = [[AACN Advanced Critical Care]] | publisher = American Association of Critical-Care Nurses | location = Aliso Viejo, California | volume = 26 | issue = 4 | pages = 285–293 | date = October 1, 2015 | pmid = 26484986 | doi = 10.4037/NCI.0000000000000104 }}</ref><ref name="Trollor_2009">{{cite journal | first1 = Julian N. |last1=Troller| first2 =  Xiaohua | last2 = Chen | first3 = Perminder S. |last3 = Sachdev | title = Neuroleptic malignant syndrome associated with atypical antipsychotic drugs | journal = [[CNS Drugs]] | publisher = [[Springer Nature]] | location= New York City | volume = 23 | issue = 6 | pages = 477–92 | date = February 2009 | pmid = 19480467 | doi = 10.2165/00023210-200923060-00003 | s2cid = 43859486 }}</ref> but life-threatening reaction that can occur in response to [[antipsychotic]]s (neuroleptic) or other drugs that block the effects of [[dopamine]].<ref name=Ber2011>{{cite journal | first = Brian D. | last= Berman | title = Neuroleptic malignant syndrome: a review for neurohospitalists | journal = The Neurohospitalist | publisher = [[SAGE Publications]] | location = New York City | volume = 1 | issue = 1 | pages = 41–47 | date = January 2011 | pmid = 23983836 | pmc = 3726098 | doi = 10.1177/1941875210386491 }}</ref><ref name="Wijdicks 2024" /> Symptoms include [[hyperpyrexia|high fever]], confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate.<ref name=Ber2011/> Complications may include muscle breakdown ([[rhabdomyolysis]]), [[high blood potassium]], [[kidney failure]], or [[seizures]].<ref name=Ber2011/><ref name=NORD2004>{{cite web |title=Neuroleptic Malignant Syndrome |url=https://rarediseases.org/rare-diseases/neuroleptic-malignant-syndrome/ |publisher=NORD (National Organization for Rare Disorders) |access-date=1 July 2017 |date=2004 |url-status=live |archive-url=https://web.archive.org/web/20170219085103/https://rarediseases.org/rare-diseases/neuroleptic-malignant-syndrome/ |archive-date=19 February 2017}}</ref>

<!-- Cause and diagnosis -->
Any medications within the family of antipsychotics can cause the condition, though [[typical antipsychotics]] appear to have a higher risk than [[atypical antipsychotics|atypicals]],<ref name="Ber2011" /> specifically [[first generation antipsychotic]]s like [[haloperidol]].<ref name="aacnjournals.org"/> Onset is often within a few weeks of starting the medication but can occur at any time.<ref name="Ber2011" /><ref name="NIH2017">{{cite web |title=Neuroleptic Malignant Syndrome Information Page |url=https://www.ninds.nih.gov/Disorders/All-Disorders/Neuroleptic-Malignant-Syndrome-Information-Page#disorders-r1 |publisher=National Institute of Neurological Disorders and Stroke | location = Bethesda, Maryland | access-date=1 July 2017|url-status=live |archive-url=https://web.archive.org/web/20170704215551/https://www.ninds.nih.gov/Disorders/All-Disorders/Neuroleptic-Malignant-Syndrome-Information-Page#disorders-r1 |archive-date=4 July 2017}}</ref> Risk factors include dehydration, [[psychomotor agitation|agitation]], and [[catatonia]].<ref name=Str2007/>

Rapidly decreasing the use of [[levodopa]] or other [[dopamine agonist]]s, such as [[pramipexole]], may also trigger the condition.<ref name="Ber2011" /><ref>{{cite journal | first1 = Aynur | last1 = Sahin | first2 = Mustafa | last2 = Cicek | first3 = Ozgen Gonenc | last3 = Cekic | first4 = Mucahit | last4 = Gunaydin | first5 = Demet Saglam | last5 = Aykut | first6 = Ozgur | last6 = Tatli | first7 = Yunus | last7 = Karaca | first8 = Mualla Aylin | last8 = Arici | title = A retrospective analysis of cases with neuroleptic malignant syndrome and an evaluation of risk factors for mortality | journal = Turkish Journal of Emergency Medicine | publisher =  Emergency Medicine Association of Turkey | location = Ankara, Turkey | volume = 17 | issue = 4 | pages = 141–145 | date = December 2017 | pmid = 29464217 | pmc = 5812912 | doi = 10.1016/j.tjem.2017.10.001 }}</ref> The underlying mechanism involves blockage of [[dopamine receptors]].<ref name="Ber2011" /> Diagnosis is based on symptoms.<ref name="NORD2004" />

<!-- Treatment -->
Management includes stopping the triggering medication, rapid cooling, and starting other medications.<ref name=NORD2004/> Medications used include [[dantrolene]], [[bromocriptine]], and [[diazepam]].<ref name=NORD2004/> The risk of death among those affected is about 10%.<ref name=Str2007>{{cite journal | vauthors = Strawn JR, Keck PE, Caroff SN | title = Neuroleptic malignant syndrome | journal = [[The American Journal of Psychiatry]] | volume = 164 | issue = 6 | pages = 870–876 | date = June 2007 | pmid = 17541044 | doi = 10.1176/ajp.2007.164.6.870 }}</ref> Rapid diagnosis and treatment is required to improve outcomes.<ref name=Ber2011/> Many people can eventually be restarted on a lower dose of antipsychotic.<ref name=NORD2004/><ref name=NIH2017/>

<!-- Epidemiology and history -->
As of 2011, among those in [[psychiatric hospitals]] on antipsychotics about 15 per 100,000 are affected per year (0.015%).<ref name=Ber2011/> In the second half of the 20th century rates were over 100 times higher at about 2% (2,000 per 100,000).<ref name=Ber2011/> Males appear to be more often affected than females.<ref name=Ber2011/> The condition was first described in 1956.<ref name=Ber2011/>

==Signs and symptoms==
NMS symptoms include:<ref name=Simon2022>{{cite book | vauthors = Simon LV, Hashmi MF, Callahan AL | chapter = Neuroleptic Malignant Syndrome. | date = August 2022 | title = StatPearls [Internet]. | location = Treasure Island (FL) | publisher = StatPearls Publishing | pmid = 29489248 | url = https://www.ncbi.nlm.nih.gov/books/NBK482282/ }}
</ref>
* [[Hyperpyrexia|Increased body temperature]] >38&nbsp;°C (>100.4&nbsp;°F)
* [[Delirium|Confused]] or [[altered state of consciousness|altered consciousness]]<ref name=Papadakis2023/>
* [[Hyperhidrosis|Excessive sweating]]<ref name=Papadakis2023>{{cite book | chapter = Neuroleptic malignant syndrome. | vauthors = Papadakis MA, McPhee SJ | date = 2023 | title = Quick Medical Diagnosis & Treatment | publisher = McGraw Hill | url = https://accessmedicine.mhmedical.com/content.aspx?bookid=3241&sectionid=271755113 }}</ref>
* Severely rigid muscles<ref name=Simon2022/>
* [[Dysautonomia|Autonomic imbalance]]<ref name=Simon2022/>

The first symptoms of neuroleptic malignant syndrome are usually [[muscle cramp]]s and [[tremor]]s, [[fever]], symptoms of [[autonomic nervous system]] instability such as unstable [[blood pressure]], and sudden changes in mental status (agitation, [[delirium]], or [[coma]]). Other possible symptoms include sweating, [[Dysphagia|trouble swallowing]], tremors, [[urinary incontinence|incontinence]], and [[muteness|mutism]]. Once symptoms appear, they may progress rapidly and reach peak intensity in as little as three days.<ref name=Simon2022/> These symptoms can last anywhere from eight hours to forty days, with the median duration of symptoms, with treatment, being nine days.<ref name=Str2007/><ref name="Wijdicks 2024">{{cite journal |last1=Wijdicks |first1=Eelco F.M. |last2=Ropper |first2=Allan H. |title=Neuroleptic Malignant Syndrome |journal=New England Journal of Medicine |date=26 September 2024 |volume=391 |issue=12 |pages=1130–1138 |doi=10.1056/NEJMra2404606|pmid=39321364 }}</ref> The median onset of symptoms is four days after initiating the offending medication, but in some cases symptoms may begin up to 30 days later.<ref name="Wijdicks 2024" />

Symptoms are sometimes misinterpreted by doctors as symptoms of mental illness which can result in delayed treatment.<ref>{{cite web | vauthors = Milbouer S | title = Quest for the truth | work = Nashua Telegraph | url = http://www.nashuatelegraph.com/apps/pbcs.dll/article?AID=/20050424/NEWS01/104240081 | archive-url = https://web.archive.org/web/20070927222612/http://www.nashuatelegraph.com/apps/pbcs.dll/article?AID=%2F20050424%2FNEWS01%2F104240081 |archive-date=2007-09-27 }}</ref> Symptoms may also be mistaken for similarly presenting conditions such as [[malignant hyperthermia]], [[serotonin syndrome]], or withdrawal from illicit drugs such as [[Alcohol (drug)|alcohol]], [[cocaine]], or [[MDMA]].<ref name="Wijdicks 2024" />

Neuroleptic malignant syndrome (NMS) usually presents with a "lead pipe rigidity" in which the muscles are stiffened and resistance is observed throughout the range of motion on testing. Severe cases may present as [[catatonia]] in which the person is not responsive to stimuli.<ref name="Wijdicks 2024" />

The [[deep tendon reflexes]] in NMS are usually preserved whereas serotonin syndrome presents with [[myoclonus]] or [[hyperreflexia|hyperactive muscle reflexes]].<ref name="Wijdicks 2024" />

==Causes==
NMS is usually caused by antipsychotic drug use, but other dopaminergic blocking drugs can also be a cause.<ref name=benzer>{{Emedicine|article|816018|Neuroleptic Malignant Syndrome}}</ref> Individuals using [[butyrophenone]]s (such as [[haloperidol]] and [[droperidol]]) or [[phenothiazine]]s (such as [[promethazine]] and [[chlorpromazine]]) are reported to be at greatest risk. However, various atypical antipsychotics such as [[clozapine]], [[olanzapine]], [[risperidone]], [[quetiapine]], and [[ziprasidone]] have also been implicated in cases.<ref name="Khaldi 2008">{{cite journal | vauthors = Khaldi S, Kornreich C, Choubani Z, Gourevitch R | title = [Neuroleptic malignant syndrome and atypical antipsychotics: a brief review] | language = fr | journal = L'Encephale | volume = 34 | issue = 6 | pages = 618–624 | date = December 2008 | pmid = 19081460 | doi = 10.1016/j.encep.2007.11.007 | trans-title = Neuroleptic malignant syndrome and atypical antipsychotics: A brief review }}</ref>

NMS may also occur in people taking [[dopaminergic]] drugs (such as [[levodopa]]) for Parkinson's disease, most often when the drug dosage is abruptly reduced.<ref>{{cite journal | vauthors = Keyser DL, Rodnitzky RL | title = Neuroleptic malignant syndrome in Parkinson's disease after withdrawal or alteration of dopaminergic therapy | journal = Archives of Internal Medicine | volume = 151 | issue = 4 | pages = 794–796 | date = April 1991 | pmid = 1672810 | doi = 10.1001/archinte.151.4.794 }}</ref> In addition, other drugs with anti-dopaminergic activity, such as the [[antiemetic]] [[metoclopramide]], can induce NMS.<ref>{{cite journal | vauthors = Friedman LS, Weinrauch LA, D'Elia JA | title = Metoclopramide-induced neuroleptic malignant syndrome | journal = Archives of Internal Medicine | volume = 147 | issue = 8 | pages = 1495–1497 | date = August 1987 | pmid = 3632154 | doi = 10.1001/archinte.147.8.1495 }}</ref> [[Tetracyclic]]s with anti-dopaminergic activity have been linked to NMS in case reports, such as the [[amoxapine]]s. Additionally, [[desipramine]], [[dothiepin]], [[phenelzine]], [[tetrabenazine]], and [[reserpine]] have been known to trigger NMS.<ref name=buckley>{{cite journal | vauthors = Buckley PF, Hutchinson M | title = Neuroleptic malignant syndrome | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 58 | issue = 3 | pages = 271–273 | date = March 1995 | pmid = 7897404 | pmc = 1073359 | doi = 10.1136/jnnp.58.3.271 }}</ref> Whether [[Lithium (medication)|lithium]] can cause NMS is unclear.<ref>{{cite book | vauthors = Aronson JK |title=Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions |date=2015 |publisher=Elsevier |isbn=978-0-444-53716-4 |page=607 |url=https://books.google.com/books?id=NOKoBAAAQBAJ&pg=RA3-PA607 |language=en}}</ref> However, concomitant use of lithium is associated with a higher risk of NMS when a person starts on an antipsychotic drug.<ref>{{cite journal | vauthors = Buckley PF, Hutchinson M | title = Neuroleptic malignant syndrome | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 58 | issue = 3 | pages = 271–273 | date = March 1995 | pmid = 7897404 | pmc = 1073359 | doi = 10.1136/jnnp.58.3.271 }}</ref>

At the molecular level, NMS is caused by a sudden, marked reduction in dopamine activity, either from withdrawal of dopaminergic agents or blockade of dopamine receptors.<ref>{{Cite web|title= Treatment of Schizophrenia | work =  TMedWeb: Medical Pharmacology | publisher = Tulane University |url=https://tmedweb.tulane.edu/pharmwiki/doku.php/rx_of_schizophrenia|access-date=2021-06-19 |language=en}}</ref>

===Risk factors===
The use of antipsychotics as well as how this class of medications is used is one of the most common risk factors for NMS. Use of high-potency antipsychotics, a rapid increase in the dosage of antipsychotics, use of long-acting forms of antipsychotics (such as haloperidol) or injectable formulations, or using multiple antipsychotics are all known to increase the risk of developing NMS.<ref>{{cite book | vauthors = Miller CS, Wiese JG | date = 2017 | chapter = Hyperthermia and fever. | veditors = McKean SC, Ross JJ, Dressler DD, Scheurer DB | title = Principles and Practice of Hospital Medicine | edition = 2nd | publisher = McGraw Hill | url = https://accessmedicine.mhmedical.com/content.aspx?bookid=1872&sectionid=146976769 | isbn = 978-0-07-184313-3 }}</ref><ref>{{cite journal | vauthors = Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA | title = Risk factors for neuroleptic malignant syndrome. A case-control study | journal = Archives of General Psychiatry | volume = 46 | issue = 10 | pages = 914–918 | date = October 1989 | pmid = 2572206 | doi = 10.1001/archpsyc.1989.01810100056011 }}</ref><ref name="Wijdicks 2024" /> Dehydration is a risk factor for the development of NMS.<ref name="Wijdicks 2024" /> There appears to be no relationship between duration of therapy and the development of NMS.<ref name="Trollor_2009" />

Use of the following agents is most commonly associated with the development of NMS:<ref name=Simon2022/>
* Typical antipsychotics: e.g. haloperidol, chlorpromazine.<ref>{{cite book | chapter = Key medications & interventions in psychiatry. | vauthors = Huppert LA, Dyster TG | date = 2021 | title = Huppert's Notes: Pathophysiology and Clinical Pearls for Internal Medicine. | publisher = McGraw Hill | chapter-url = https://accessmedicine.mhmedical.com/content.aspx?bookid=3072&sectionid=257403886 | isbn = 978-1-260-47007-9 }}</ref> 
* Anti-dopaminergic antiemetics: e.g. droperidol 
* Withdrawal of dopaminergic agents: e.g. [[levodopa]], [[amantadine]]<ref>{{cite book | chapter = Thermoregulation, hypothermia, & malignant hyperthermia. | vauthors = Butterworth IV JF, Mackey DC, Wasnick JD | date = 2022 | title = Morgan & Mikhail's Clinical Anesthesiology | edition = 7th | publisher = McGraw Hill | url = https://accessmedicine.mhmedical.com/content.aspx?bookid=3194&sectionid=266525430 | isbn = 978-1-260-47379-7 }}</ref>

It has been purported that there is a genetic risk factor for NMS.<ref>{{cite journal | vauthors = Velamoor VR | title = Neuroleptic malignant syndrome. Recognition, prevention and management | journal = Drug Safety | volume = 19 | issue = 1 | pages = 73–82 | date = July 1998 | pmid = 9673859 | doi = 10.2165/00002018-199819010-00006 | s2cid = 23303714 }}</ref> In one study, identical twins presented with NMS, and a mother and two of her daughters have presented with NMS in another case.<ref>{{cite journal | vauthors = Otani K, Horiuchi M, Kondo T, Kaneko S, Fukushima Y | title = Is the predisposition to neuroleptic malignant syndrome genetically transmitted? | journal = The British Journal of Psychiatry | volume = 158 | issue = 6 | pages = 850–853 | date = June 1991 | pmid = 1678666 | doi = 10.1192/bjp.158.6.850 | s2cid = 23185221 }}</ref>

Demographically, it appears that males, especially those under forty, are at greatest risk for developing NMS, although it is unclear if the increased incidence is a result of greater antipsychotic use in men under forty.<ref name=benzer/> It has also been suggested that postpartum women may be at a greater risk for NMS.<ref>{{cite journal | vauthors = Alexander PJ, Thomas RM, Das A | title = Is risk of neuroleptic malignant syndrome increased in the postpartum period? | journal = The Journal of Clinical Psychiatry | volume = 59 | issue = 5 | pages = 254–255 | date = May 1998 | pmid = 9632037 | doi = 10.4088/JCP.v59n0509a | doi-access = free }}</ref>

Antipsychotic use in those with [[Lewy body dementia]] is a risk factor for NMS. These people are extremely sensitive to antipsychotics. As a result, antipsychotics should be used cautiously in all cases of dementia.<ref>{{cite journal | vauthors = Steinberg M, Lyketsos CG | title = Atypical antipsychotic use in patients with dementia: managing safety concerns | journal = The American Journal of Psychiatry | volume = 169 | issue = 9 | pages = 900–906 | date = September 2012 | pmid = 22952071 | pmc = 3516138 | doi = 10.1176/appi.ajp.2012.12030342 }}</ref>

==Pathophysiology==
The mechanism is commonly thought to depend on decreased levels of [[dopamine]] activity due to:
* [[Dopamine receptor]] blockade
* Genetically reduced function of dopamine receptor [[Dopamine receptor D2|D<sub>2</sub>]]<ref name=pmid12555236>{{cite journal | vauthors = Mihara K, Kondo T, Suzuki A, Yasui-Furukori N, Ono S, Sano A, Koshiro K, Otani K, Kaneko S | display-authors = 6 | title = Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 117B | issue = 1 | pages = 57–60 | date = February 2003 | pmid = 12555236 | doi = 10.1002/ajmg.b.10025 | s2cid = 44866985 }}</ref>
*Sympathoadrenal hyperactivity and autonomic dysfunction

It has been proposed that blockade of D<sub>2</sub>-like (D<sub>2</sub>, D<sub>3</sub> and D<sub>4</sub>) receptors induce massive glutamate release, generating catatonia, [[neurotoxicity]] and myotoxicity.<ref>{{cite journal | vauthors = Kornhuber J, Weller M, Riederer P | title = Glutamate receptor antagonists for neuroleptic malignant syndrome and akinetic hyperthermic parkinsonian crisis | journal = Journal of Neural Transmission. Parkinson's Disease and Dementia Section | volume = 6 | issue = 1 | pages = 63–72 | year = 1993 | pmid = 8105799 | doi = 10.1007/bf02252624 | s2cid = 45530847 }}</ref><ref>{{cite journal | vauthors = Chatterjee A | title = Glutamate-based magnetic resonance spectroscopy in neuroleptic malignant syndrome | journal = Annals of Indian Academy of Neurology | volume = 17 | issue = 1 | pages = 123–124 | date = January 2014 | pmid = 24753679 | pmc = 3992752 | doi = 10.4103/0972-2327.128579 | doi-access = free }}</ref> Additionally, the blockade of diverse serotonin receptors by atypical antipsychotics and activation of 5-HT<sub>1</sub> receptors by certain of them reduces GABA release and indirectly induces glutamate release, worsening this syndrome.<ref>{{cite journal | vauthors = Odagaki Y | title = Atypical neuroleptic malignant syndrome or serotonin toxicity associated with atypical antipsychotics? | journal = Current Drug Safety | volume = 4 | issue = 1 | pages = 84–93 | date = January 2009 | pmid = 19149529 | doi = 10.2174/157488609787354387 | citeseerx = 10.1.1.334.241 }}</ref>

The muscular symptoms are most likely caused by blockade of the [[dopamine receptor D2|dopamine receptor D<sub>2</sub>]], leading to abnormal function of the [[basal ganglia]] similar to that seen in [[Parkinson's disease]].<ref name=uptodate.com>{{Cite web | vauthors = Wijdicks EF | date = 26 May 2022 | veditors = Aminoff MJ, Rabinstein AA, Wilterdink JL |url= https://www.uptodate.com/contents/neuroleptic-malignant-syndrome|title=Neuroleptic malignant syndrome | work = UpToDate }}</ref>

In the past, research and clinical studies seemed to corroborate the D<sub>2</sub> receptor blockade theory in which antipsychotic drugs were thought to significantly reduce dopamine activity by blocking the D<sub>2</sub> receptors associated with this neurotransmitter. The introduction of atypical antipsychotic drugs, with lower affinity to the D<sub>2</sub> dopamine receptors, was thought to have reduced the incidence of NMS. However, recent studies suggest that the decrease in mortality may be the result of increased physician awareness and earlier initiation of treatment rather than the action of the drugs themselves.<ref name=pmid15119907/> NMS induced by atypical drugs also resembles "classical" NMS (induced by "typical" antipsychotic drugs), further casting doubt on the overall superiority of these drugs.<ref>{{cite journal | vauthors = Hasan S, Buckley P | title = Novel antipsychotics and the neuroleptic malignant syndrome: a review and critique | journal = The American Journal of Psychiatry | volume = 155 | issue = 8 | pages = 1113–1116 | date = August 1998 | pmid = 9699705 | doi = 10.1176/ajp.155.8.1113 }}</ref>

However, the failure of D<sub>2</sub> dopamine receptor antagonism, or dopamine receptor dysfunction, do not fully explain the presenting symptoms and signs of NMS, as well as the occurrence of NMS with [[atypical antipsychotic]] drugs with lower D<sub>2</sub> dopamine activity.<ref name=pmid15119907>{{cite journal | vauthors = Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T | title = Neuroleptic malignant syndrome and atypical antipsychotic drugs | journal = The Journal of Clinical Psychiatry | volume = 65 | issue = 4 | pages = 464–470 | date = April 2004 | pmid = 15119907 | doi = 10.4088/JCP.v65n0403 | s2cid = 32752143 }}</ref> This has led to the hypothesis of sympathoadrenal hyperactivity (results from removing tonic inhibition from the [[sympathetic nervous system]]) as a mechanism for NMS.<ref name=pmid9989551>{{cite journal | vauthors = Gurrera RJ | title = Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome | journal = The American Journal of Psychiatry | volume = 156 | issue = 2 | pages = 169–180 | date = February 1999 | pmid = 9989551 | doi = 10.1176/ajp.156.2.169 | s2cid = 31276121 }}</ref> Release of calcium is increased from the sarcoplasmic reticulum with antipsychotic usage. This can result in increased muscle contractility, which can play a role in the breakdown of muscle, muscle rigidity, and hyperthermia. Some antipsychotic drugs, such as [[typical antipsychotics]], are known to block dopamine receptors; other studies have shown that when drugs supplying dopamine are withdrawn, symptoms similar to NMS present themselves.<ref name=Str2007/>

In support of the sympathoadrenal hyperactivity model, it has been hypothesized that a defect in calcium regulatory proteins within the sympathetic neurons may bring about the onset of NMS.<ref>{{cite journal | vauthors = Gurrera RJ | title = Is neuroleptic malignant syndrome a neurogenic form of malignant hyperthermia? | journal = Clinical Neuropharmacology | volume = 25 | issue = 4 | pages = 183–193 | year = 2002 | pmid = 12151905 | doi = 10.1097/00002826-200207000-00001 | s2cid = 29010904 }}</ref> This model of NMS strengthens its suspected association with [[malignant hyperthermia]] in which NMS may be regarded as a neurogenic form of this condition which itself is linked to defective calcium-related proteins.{{citation needed|date=December 2020}}

There is also thought to be considerable overlap between malignant catatonia and NMS in their pathophysiology, the former being idiopathic and the latter being the drug-induced form of the same syndrome.<ref>{{cite journal | vauthors = Northoff G | title = Catatonia and neuroleptic malignant syndrome: psychopathology and pathophysiology | journal = Journal of Neural Transmission | volume = 109 | issue = 12 | pages = 1453–1467 | date = December 2002 | pmid = 12486486 | doi = 10.1007/s00702-002-0762-z | s2cid = 12971112 | citeseerx = 10.1.1.464.9266 }}</ref>

The [[Leukocytosis|raised white blood cell count]] and [[creatine phosphokinase]] (CPK) plasma concentration seen in those with NMS is due to increased muscular activity and [[rhabdomyolysis]] (destruction of muscle tissue).<ref>{{cite journal | vauthors = Latham J, Campbell D, Nichols W, Mott T | title = Clinical inquiries. How much can exercise raise creatine kinase level--and does it matter? | journal = The Journal of Family Practice | volume = 57 | issue = 8 | pages = 545–547 | date = August 2008 | pmid = 18687233 | url = http://www.jfponline.com/home/article/how-much-can-exercise-raise-creatine-kinase-level-and-does-it-matter/86f4f4fd65053888a3d529aca00eb455.html | url-status = live | archive-url = https://web.archive.org/web/20160601202531/http://www.jfponline.com/home/article/how-much-can-exercise-raise-creatine-kinase-level-and-does-it-matter/86f4f4fd65053888a3d529aca00eb455.html | archive-date = 2016-06-01 }}</ref> Someone may experience [[hypertensive crisis]] and [[metabolic acidosis]].

The fever seen with NMS is believed to be caused by hypothalamic dopamine receptor blockade. Antipsychotics cause an increased calcium release from the [[sarcoplasmic reticulum]] of muscle cells which can result in rigidity and eventual cell breakdown. No major studies have reported an explanation for the abnormal [[Electroencephalogram|EEG]], but it is likely also attributable to dopamine blockage leading to changes in neuronal pathways.<ref name=benzer/>

==Diagnosis==
===Differential diagnosis===
Due to the comparative rarity of NMS, it is often overlooked. Immediate treatment for the syndrome should not be delayed as it has a high mortality of between 10-20%.<ref name =Stringer2017>{{cite book | chapter = Antipsychotics or neuroleptics. | veditors = Stringer JL | date = 2017 | title = Basic Concepts in Pharmacology: What You Need to Know for Each Drug Class | edition = 5th | publisher = McGraw Hill | chapter-url = https://accessmedicine.mhmedical.com/content.aspx?bookid=2147&sectionid=161351718 | isbn = 978-1-259-86107-9 }}</ref>  Differentiating NMS from other neurological disorders can be very difficult.

The diagnosis is suggested on patients with a history of drug exposure to the most common inducing agents such as strong antidopaminergic medications.<ref name="Trollor_2009" /><ref>{{cite book | vauthors = Yandle G, deBoisblanc BP | date = 2014 | chapter = Persistent fever | veditors = Hall JB, Schmidt GA, Kress JP | title = Principles of Critical Care | edition = 4th | publisher = McGraw Hill | chapter-url = https://accessmedicine.mhmedical.com/content.aspx?bookid=1340&sectionid=80033832 | isbn = 978-0-07-173881-1 }}</ref> The [[differential diagnosis]] includes [[serotonin syndrome]],<ref>{{cite journal | vauthors = Christensen V, Glenthøj BY | title = [Malignant neuroleptic syndrome or serotonergic syndrome] | journal = Ugeskrift for Laeger | volume = 163 | issue = 3 | pages = 301–302 | date = January 2001 | pmid = 11219110 }}</ref> [[encephalitis]], [[toxic encephalopathy]], [[status epilepticus]], [[heat stroke]], [[catatonia]] and [[malignant hyperthermia]]. Drugs such as [[cocaine]] and [[amphetamine]] may also produce similar symptoms.<ref name=Str2007/><ref>{{cite journal | vauthors = Sachdev PS | title = A rating scale for neuroleptic malignant syndrome | journal = Psychiatry Research | volume = 135 | issue = 3 | pages = 249–256 | date = June 2005 | pmid = 15996751 | doi = 10.1016/j.psychres.2005.05.003 | s2cid = 25728796 | hdl = 1959.4/unsworks_46263 | hdl-access = free }}</ref><ref name="Trollor_2009" /> Features which distinguish NMS from serotonin syndrome include [[bradykinesia]], muscle rigidity, and a high white blood cell count.<ref>{{cite journal | vauthors = Birmes P, Coppin D, Schmitt L, Lauque D | title = Serotonin syndrome: a brief review | journal = CMAJ | volume = 168 | issue = 11 | pages = 1439–1442 | date = May 2003 | pmid = 12771076 | pmc = 155963 | url = http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=12771076 }}</ref>

==Treatment==
NMS is a medical emergency and can lead to death if untreated. The first step is to stop the culprit medication and treat the [[hyperthermia]] aggressively, such as with cooling blankets or ice packs to the axillae and groin. [[Acetaminophen]] is commonly used as an anti-pyretic. Supportive care in an intensive care unit capable of circulatory and ventilatory support is crucial. In those unable to control their secretions, or who have muscle spams of the respiratory muscles, mechanical ventilation may be needed.<ref name="Wijdicks 2024" /> 

The best pharmacological treatment is still unclear.  [[Dantrolene]] has been used when needed to reduce muscle rigidity, and dopamine pathway medications such as [[bromocriptine]] have shown benefit.<ref>{{cite journal | vauthors = Dhib-Jalbut S, Hesselbrock R, Mouradian MM, Means ED | title = Bromocriptine treatment of neuroleptic malignant syndrome | journal = The Journal of Clinical Psychiatry | volume = 48 | issue = 2 | pages = 69–73 | date = February 1987 | pmid = 3804991 }}</ref> Dantrolene may act centrally on thermoregulatory pathways to lower the temperature.<ref name="Wijdicks 2024" /> Dantrolene also inhibits calcium release from the muscle sarcoplasmic reticulum to cause muscle relaxation.<ref name="Wijdicks 2024" />
[[Amantadine]] is another treatment option due to its dopaminergic and anticholinergic effects.
[[Apomorphine]] may be used however its use is supported by little evidence.<ref name=uptodate.com/> [[Benzodiazepine]]s may be used to control [[wikt:agitation|agitation]]. Highly elevated blood [[myoglobin]] levels from muscle breakdown (rhabdomyolysis) can result in [[kidney]] damage, therefore aggressive intravenous hydration with diuresis may be required.  When recognized early NMS can be successfully managed; however, up to 10% of cases can be fatal.<ref name=Str2007/>

Should the affected person subsequently require an antipsychotic, trialing a low dose of a low-potency atypical antipsychotic is recommended.<ref name=Str2007/>

[[Electroconvulsive therapy]] may be used in life threatening cases of NMS that are refractory to first line treatments.<ref name="Wijdicks 2024" />

==Prognosis==
The [[prognosis]] is best when identified early and treated aggressively. In earlier studies the mortality rates of NMS ranged from 20%–38%, but by 2009 mortality rates were reported to have fallen below 10% over the previous two decades due to early recognition and improvements in management.<ref name=niraj>{{cite journal | vauthors = Ahuja N, Cole AJ |title=Hyperthermia syndromes in psychiatry |journal=Advances in Psychiatric Treatment |volume=15 |issue=3 |year=2009 |pages=181–91 |doi=10.1192/apt.bp.107.005090|doi-access=free }}</ref> Re-introduction of antipsychotics after NMS may trigger a recurrence, although in most cases it does not. With recurrence rate being 4.2% in a small, population based study.<ref name="Wijdicks 2024" /><ref name="Guinart 2021">{{cite journal |last1=Guinart |first1=Daniel |last2=Taipale |first2=Heidi |last3=Rubio |first3=Jose M |last4=Tanskanen |first4=Antti |last5=Correll |first5=Christoph U |last6=Tiihonen |first6=Jari |last7=Kane |first7=John M |title=Risk Factors, Incidence, and Outcomes of Neuroleptic Malignant Syndrome on Long-Acting Injectable vs Oral Antipsychotics in a Nationwide Schizophrenia Cohort |journal=Schizophrenia Bulletin |date=21 October 2021 |volume=47 |issue=6 |pages=1621–1630 |doi=10.1093/schbul/sbab062|pmid=34013325 |pmc=8530388 }}</ref>

==Epidemiology==
Pooled data suggest the incidence of NMS is between 0.2%–3.23%.<ref name=neuro8>{{cite journal | vauthors = Pelonero AL, Levenson JL, Pandurangi AK | title = Neuroleptic malignant syndrome: a review | journal = Psychiatric Services | volume = 49 | issue = 9 | pages = 1163–1172 | date = September 1998 | pmid = 9735957 | doi = 10.1176/ps.49.9.1163 }}</ref> However, greater awareness coupled with increased use of atypical anti-psychotics have likely reduced the prevalence of NMS.<ref name=benzer/> Additionally, young males are particularly susceptible and the male to female ratio has been reported to be as high as 2:1.<ref name=benzer/><ref name=neuro8/><ref>{{cite journal | vauthors = Hernández JL, Palacios-Araus L, Echevarría S, Herrán A, Campo JF, Riancho JA | title = Neuroleptic malignant syndrome in the acquired immunodeficiency syndrome | journal = Postgraduate Medical Journal | volume = 73 | issue = 866 | pages = 779–784 | date = December 1997 | pmid = 9497946 | pmc = 2431511 | doi = 10.1136/pgmj.73.866.779 }}</ref>

==History==
NMS was known about as early as 1956, shortly after the introduction of the first [[phenothiazine]]s.<ref>{{cite web | vauthors = Friedberg JM | title = Neuroleptic malignant syndrome | url=http://www.idiom.com/~drjohn/biblio.html |access-date=2006-07-03 |url-status=dead |archive-url=https://web.archive.org/web/20061016043024/http://www.idiom.com/~drjohn/biblio.html |archive-date=October 16, 2006 }} {{self-published source|date=April 2016}}</ref>{{self-published inline|date=April 2016}} NMS was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterized the condition that was associated with the side effects of haloperidol "''syndrome malin des neuroleptiques''", which was translated to neuroleptic malignant syndrome.<ref name=buckley/>

== References ==
{{Reflist}}

== External links ==
* [https://www.ninds.nih.gov/Disorders/All-Disorders/Neuroleptic-Malignant-Syndrome-Information-Page NINDS Neuroleptic Malignant Syndrome Information Page]—[[NIH]].
{{Medical resources
|  DiseasesDB      = 8968
|  ICD10           = {{ICD10|G|21|0|g|20}}
|  ICD9            = {{ICD9|333.92}}
|  eMedicineSubj   = emerg
|  eMedicineTopic  = 339
|  eMedicine_mult  = {{eMedicine2|med|2614}}{{eMedicine2|ped|1581}}
|  MeshID          = D009459
}}

{{Diseases of the nervous system}}

{{DEFAULTSORT:Neuroleptic Malignant Syndrome}}
[[Category:Antipsychotics|*]]
[[Category:Extrapyramidal and movement disorders]]
[[Category:Medical emergencies]]
[[Category:Rare syndromes]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Adverse effects of psychoactive drugs]]
[[Category:Wikipedia emergency medicine articles ready to translate]]