Neuroleptic malignant syndrome: Difference between revisions

Jump to navigation Jump to search
 
(97 intermediate revisions by 15 users not shown)
Line 1: Line 1:
__NOTOC__
{{Infobox_Disease
{{Infobox_Disease
  | Name          = {{PAGENAME}}
  | Name          = {{PAGENAME}}
Line 8: Line 9:
  | ICDO          =  
  | ICDO          =  
  | OMIM          =  
  | OMIM          =  
  | MedlinePlus    =  
  | MedlinePlus    =
| eMedicineSubj  = emerg
| eMedicineTopic = 339
| eMedicine_mult = {{eMedicine2|med|2614}} {{eMedicine2|ped|1581}}
  | MeshID        =  
  | MeshID        =  
}}
}}
{{SI}}
{{SI}}
{{CMG}}; {{AE}} {{JH}} [[User:Qasim Khurshid|Qasim Khurshid, M.B.B.S.[2]]]


{{EH}}
'''''Keywords and synonyms:''''' NMS


'''Neuroleptic malignant syndrome (NMS)''' is a life-threatening, neurological disorder most often caused by an adverse reaction to [[antipsychotic|neuroleptic or antipsychotic drugs]].
==Overview==
The neuroleptic malignant syndrome is an uncommon adverse reaction to [[medications]] with [[dopamine]] receptor-antagonist properties or the rapid withdrawal of [[dopaminergic]] medications. The syndrome is characterized by severe rigidity, fever, [[tremor]], [[autonomic dysfunction]], [[altered mental status]], and elevated serum [[Creatinine phosphokinase|creatinine]] phosphokinase. This is a life-threatening condition, with difficulties in [[diagnosis]] and treatment. This syndrome can further complicates [[psychiatric]] treatment.
 
==Historical Perspective==
The first reported case of NMS appeared in 1956, shortly after the introduction of the [[Antipsychotics|antipsychotic]] drug [[chlorpromazine]] (Thorazine). Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the [[adverse effects]] of the newly introduced neuroleptic [[haloperidol]] and characterized a ‘‘syndrome malin des neuroleptiques.’’2 Pooled data from 1966 to 1997 suggested the [[incidence]] of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving [[neuroleptics]]; however, as physicians have become increasingly aware of the syndrome and with the advent of new neuroleptic medications, the [[incidence]] has decreased to around 0.01% to 0,02%.<ref>Ayd F. Fatal hyperpyrexia during chlorpromazine therapy. J Clin Exp Psychopathol. 1956;17(2):189-192.</ref><ref>Delay J, Pichot P, Lemperiere T. A non-phenothiazine and nonreserpine major neuroleptic, haloperidol, in the treatment of psychoses (in French). Ann Med Psychol (Paris). 1960;118(1): 145-152</ref><ref>Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49(9):1163-1172</ref><ref>Stubner S, Rustenbeck E, Grohmann R, et al. Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry. 2004;37(1):S54-S64.</ref>
==Classification==
There is no established system for the classification of NMS.
 
== Pathophysiology ==
The pathophysiologic mechanisms of NMS are complex and still under debate among physicians But the majority of physicians agree that sudden and significant reduction in central dopaminergic activity within the mesolimbic/cortical, the nigrostriatal, and hypothalamic pathways help explain the clinical features of the neuroleptic malignant syndrome. This theory is supported by the observation that the use of [[antipsychotic]] drugs that specifically block D 2 receptors primarily cause NMS and that the syndrome can also be induced by abrupt dopamine withdrawal.
 
Additionally, this theory is supported by the dopamine [[receptor]]imaging study of NMS patients in the acute phase which demonstrated a complete lack of D2 receptor binding. Another study demonstrated low levels of dopamine metabolite in the [[CSF]] of patients with NMS in the acute phase. However D2 receptor antagonism does not explain all the presenting [[signs]]] and [[symptoms]] of NMS, nor does it explain its occurrence with antipsychotic medications with lower D2 activity and [[medications]] without known antidopaminergic activity. Abnormalities in the sympathetic system are supported by the frequent presence of autonomic symptoms in NMS as well as demonstrated changes in the urine and plasma catecholamine levels in patients with NMS. Some have hypothesized that NMS shares pathophysiological similarities with [[malignant hyperthermia]] and that a defect in calcium regulatory proteins within sympathetic neurons may be the essential factor that brings about the onset of NMS. Another system that also appears to play a role in the signs and [[symptoms]] of NMS is the peripheral skeletal [[muscle]] system. The release of calcium is increased from the [[sarcoplasmic reticulum]] of muscle cells with antipsychotic usage, possibly leading to increased muscle contractility and rigidity, breakdown of muscle, and [[hyperthermia]]. However, these theories are unable to explain why only a small fraction of patients develop NMS after exposure to [[neuroleptics]].  Furthermore, it remains unknown why patients who develop NMS are usually able to continue being treated with similar [[medications]] and, at times, even the same offending agent.<ref>Adnet P, Lestavel P, Krivosic-Horber R. [https://doi.org/10.1093/bja/85.1.129 Neuroleptic malignant syndrome]. ''Br J Anaesth''. 2000;85(1):129-135. doi:10.1093/bja/85.1.129</ref><ref>Strawn JR, Keck PE Jr, Caroff SN. [https://doi.org/10.1176/ajp.2007.164.6.870 Neuroleptic malignant syndrome. ''Am J Psychiatr'']''y''. 2007;164(6):870-876. doi:10.1176/ajp.2007.164.6.870</ref><ref>Jauss, M., Krack, P., Franz, M., Klett, R., Bauer, R., Gallhofer, B. and Dorndorf, W. (1996), [https://doi.org/10.1002/mds.870110621 <nowiki>Imaging of dopamine receptors with [123I]iodobenzamide single‐photon emission–computed tomography in neuroleptic malignant syndrome</nowiki>]. Mov. Disord., 11: 726-728. doi:10.1002/mds.870110621</ref><ref>Nisijima K, Ishiguro T. Cerebrospinal-fluid levels of monoamine metabolites and gamma-aminobutyric-acid in neuroleptic malignant syndrome. J Psychiatr Res. 1995;29(3):233-244.</ref>
<br />


==Causes==
==Causes==
NMS is caused almost exclusively by antipsychotics, including all types of neuroleptic medicines along with newer antipsychotic drugs.<ref>{{cite web|url = http://www.emedicine.com/EMERG/topic339.htm|title = Neuroleptic Malignant Syndrome|publisher = Emedicine|author = Theodore I. Benzer, MD, PhD|year = 2005}}</ref>  The higher the [[Effective dose|dosage]], the more common the occurrence. Rapid and large increases in dosage can also trigger the development of NMS. Other [[drugs]], environmental or [[psychological]] factors, hereditary conditions, and specific demographics may cause greater risk, but to date no conclusive evidence has been found to support this. The disorder typically develops within two weeks of the initial treatment with the drug, but may develop at any time the drug is being taken.  NMS may also occur in people taking a class of drugs known as [[dopaminergic]]s when the dosage is reduced (i.e Levodopa).
Potent typical [[neuroleptics]] such as [[fluphenazine]], [[haloperidol]], [[trifluoperazine]], [[chlorpromazine]], and [[prochlorperazine]] have been most frequently associated with NMS and thought to confer the greatest risk. Although [[atypical neuroleptics]] appear to have reduced the risk of developing NMS compared to typical neuroleptics. But a significant number of cases have been reported with most [[atypical neuroleptics]] including [[clozapine]], [[risperidone]], [[olanzapine]], [[quetiapine]], [[aripiprazole]], [[olanzapine aripiprazole]], and [[ziprasidone]]. The neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as diatrizoate, droperidol, tetrabenazine, and metoclopramide. The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS, and there may be some risk of NMS associated with the abrupt withdrawal of [[Parkinson]] medications that are not known to have direct dopaminergic activity such as amantadine and tolcapone.
<ref>Khan FY, Qusad MJ. Neuroleptic malignant syndrome. Neurosciences. 2006;11(2):104-106</ref><ref>Pasa S, Sayhan MB, Boyraz T, Urakci Z, Altintas A. A case of neuroleptic malignant syndrome accompanied to an atypical antipsychotic agent: risperidone. Neurotoxicology. 2008;29(4): 750-751.</ref><ref>Pope HG, Cole JO, Choras PT, Fulwiler CE. Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nervous Mental Dis. 1986;174(8):493-495.</ref>
<br />
{| class="wikitable"
|+Neuroleptic and Nonneuroleptic Medications Associated With Neuroleptic Malignant Syndrome
!Typical Neuroleptics
!Atypical Neuroleptics
!Nonneuroleptics with  antidopaminergic activity
!Dopaminergics (withdrawal)
!Others
|-
|a. Haloperidol
b. Fluphenazine
 
c. Chlorpromazine
 
d. Prochlorperazine
 
e. Trifluoperazine


== Pathophysiology ==
f. Thioridazine
The mechanism is thought to depend on decreased levels of [[Dopamine|dopamine]] due to:
 
* [[Dopamine receptor]] blockade
g. Thiothixene
* Genetically reduced function of [[dopamine receptor]] D2<ref name="pmid12555236">{{cite journal |author=Mihara K, Kondo T, Suzuki A, ''et al'' |title=Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome |journal=Am. J. Med. Genet. B Neuropsychiatr. Genet. |volume=117 |issue=1 |pages=57-60 |year=2003 |pmid=12555236 |doi=10.1002/ajmg.b.10025}}</ref>
 
h. Loxapine
 
i. Perphenazine
 
J. Bromperido
 
k. Clopenthixol
 
l. Promazine
<br />
|a. Clozapine
b. Risperidone
 
c. Olanzapine
 
d. Quetiapine
 
e. Ziprasidone
 
f. Aripiprazole
|(1) Metoclopromide
2) Tetrabenazine
 
(3) Reserpine
 
4) Droperidol
 
(5) Promethazine
 
(6) Amoxapine


==Signs and Symptoms==
(7) Diatrizoate
The first [[symptom]] to develop is usually muscular rigidity, followed by high [[fever]] and changes in [[cognitive functions]].  Other symptoms can vary, but may be unstable [[blood pressure]], confusion, [[coma]], [[delirium]], [[tremor|muscle tremors]], etc.  Once symptoms do appear, they rapidly progress and can reach peak intensity in as little as three days.  These symptoms can last anywhere from eight hours to forty days.
|(1) Levodopa
2) Dopamine agonists


A raised [[creatine phosphokinase]] (CPK) plasma concentration will be reported due to increased muscular activity. The patient may be [[hypertensive]] and suffering from a [[metabolic acidosis]]. A non-generalised slowing on an [[EEG]] is reported in around 50% of cases.
(3) Amantadine


Unfortunately, symptoms of NMS are sometimes misinterpreted by doctors as symptoms of mental illness, delaying treatment.<ref> Stacy Milbouer, "Quest for the truth", <I>Nashua Telegraph</I> [http://www.nashuatelegraph.com/apps/pbcs.dll/article?AID=/20050424/NEWS01/104240081 http://www.nashuatelegraph.com/apps/pbcs.dll/article?AID=/20050424/NEWS01/104240081]</ref>
4) Tolcapone
|(1) Lithium
2) Phenelzine


===Mnemonic===
(3) Dosulepin
A [[mnemonic]] used to remember the features of NMS is: ''FEVER''.<ref>Identify neuroleptic malignant syndrome. schizophrenia.com URL: [http://www.schizophrenia.com/sznews/archives/002054.html http://www.schizophrenia.com/sznews/archives/002054.html]. Accessed: July 2, 2006.</ref>
*'''F''' - [[Fever]]
*'''E''' - [[Encephalopathy]]
*'''V''' - [[vital signs|Vital]]s unstable
*'''E''' - Elevated [[enzyme]]s (elevated CPK)
*'''R''' - Rigidity of [[muscles]]


==Prognosis==
4) Desipramine
As with most illnesses, the [[prognosis]] is best when identified early and treated aggressively.  In these cases NMS is usually not fatal, although there is currently no agreement on the exact mortality rate for the disorder.  Studies have given the disorder a mortality rate as low as 5% and as high as 76%, although most studies agree that the correct percentage is in the lower spectrum, perhaps between 10% - 15%.  Re-introduction to the drug that originally caused NMS to develop may also trigger a recurrence, although in most cases it does not.


==Treatment==
(5) Trimipramine
Although treatment is not always necessary, it will help to cure the disease and prevent fatal developments from occurring.  The first step in treatment is generally to remove the patient from any neuroleptic or antipsychotic drugs being taken and to treat fever aggressively.  Many cases require intensive care, or some kind of supportive care at the minimum.  Depending on the severity of the case, patients may require other treatments to contend with specific effects of the disorder.  These include circulatory and ventilatory support, the drugs [[dantrolene sodium]], [[bromocriptine]], [[apomorphine]] and [[electroconvulsive therapy]] (ECT) if medication fails.
|}
<br />


==Differential diagnosis==
==Differential Diagnosis==
*[[Infection]] ([[sepsis]], [[SIRS]])
*[[Infection]] ([[sepsis]], [[SIRS]])
*[[Serotonergic syndrome]]
* [[Serotonin syndrome]]
*[[Delirium tremens]]
*[[Delirium tremens]]
*[[Heat Stroke]]
*[[Heat Stroke]]
*[[Malignant hyperthermia]]
*[[Malignant hyperthermia]]<ref name="DSMV">{{cite book | title = Diagnostic and statistical manual of mental disorders : DSM-5 | publisher = American Psychiatric Association | location = Washington, D.C | year = 2013 | isbn = 0890425558 }}</ref>
 
===NMS and Serotonin Syndrome===


==NMS and serotonergic syndrome==
The clinical features of NMS and serotonergic syndrome are very similar.  This can make differentiating them very difficult.<ref>{{cite journal | author = Christensen V, Glenthøj B | title = [Malignant neuroleptic syndrome or serotonergic syndrome] | journal = Ugeskr Laeger | volume = 163 | issue = 3 | pages = 301-2 | year = 2001 | id = PMID 11219110}}</ref>   
The clinical features of NMS and [[serotonergic syndrome]] are very similar.  This can make differentiating them very difficult.<ref>{{cite journal | author = Christensen V, Glenthøj B | title = [Malignant neuroleptic syndrome or serotonergic syndrome] | journal = Ugeskr Laeger | volume = 163 | issue = 3 | pages = 301-2 | year = 2001 | id = PMID 11219110}}</ref>   


Features, classically present in NMS, that are useful for differentiating the two [[syndrome]]s are:<ref>{{cite journal | author = Birmes P, Coppin D, Schmitt L, Lauque D | title = Serotonin syndrome: a brief review. | journal = CMAJ | volume = 168 | issue = 11 | pages = 1439-42 | year = 2003 | id = PMID 12771076}} [http://www.cmaj.ca/cgi/content/full/168/11/1439 Full Free Text].</ref>  
Features, classically present in NMS, that are useful for differentiating the two [[syndrome]]s are:<ref>{{cite journal | author = Birmes P, Coppin D, Schmitt L, Lauque D | title = Serotonin syndrome: a brief review. | journal = CMAJ | volume = 168 | issue = 11 | pages = 1439-42 | year = 2003 | id = PMID 12771076}} [http://www.cmaj.ca/cgi/content/full/168/11/1439 Full Free Text].</ref>  
*Fever
*Fever
*Muscle rigidity
*Muscle rigidity
*Laboratory Values (WBC & CK)
*Laboratory values ([[WBC]] and [[CK]])
 
One the basis of stiffness and fever it can be differentiated from:
*[[Tetanus]]
*[[Stiff man syndrome]]
*[[Meningitis]]
*[[Tardive dyskinesia]]
*[[Parkinsonism]]


==History==
{| style="border: 2px solid #DCDCDC; font-size: 90%; width: 83%;"
NLM was known about as early as 1956, shortly after the introduction of the first [[phenothiazine]]s, and is derived from the French ''syndrome malin des neuroleptiques''.<ref>Friedberg JM. Neuroleptic malignant syndrome. URL: [http://www.idiom.com/~drjohn/biblio.html http://www.idiom.com/~drjohn/biblio.html]. Accessed: July 3, 2006.</ref>
|+ '''Differential Diagnosis of Fever and Stiffness'''
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" |Disease
! colspan="3" align="center" style="background:#4479BA; color: #FFFFFF;" |Diagnosis
! rowspan="2" align="center" style="background:#4479BA; color: #FFFFFF;" |Treatment
|-
! align="center" style="background:#4479BA; color: #FFFFFF;" |Symptoms
! align="center" style="background:#4479BA; color: #FFFFFF;" |Signs
! align="center" style="background:#4479BA; color: #FFFFFF;" |Laboratory Findings
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Tetanus]]<ref name="pmid27538652">{{cite journal| author=Woldeamanuel YW, Andemeskel AT, Kyei K, Woldeamanuel MW, Woldeamanuel W| title=Case fatality of adult tetanus in Africa: Systematic review and meta-analysis. | journal=J Neurol Sci | year= 2016 | volume= 368 | issue=  | pages= 292-9 | pmid=27538652 | doi=10.1016/j.jns.2016.07.025 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27538652  }} </ref><ref name="pmid26598719">{{cite journal| author=Thwaites CL, Loan HT| title=Eradication of tetanus. | journal=Br Med Bull | year= 2015 | volume= 116 | issue=  | pages= 69-77 | pmid=26598719 | doi=10.1093/bmb/ldv044 | pmc=4674006 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26598719  }} </ref>
| style="background: #DCDCDC; padding: 5px;" |
*Tonic contraction of muscles between the spasmodic episodes
*[[Trismus]] or lockjaw
* [[Neck stiffness]]
* [[Swallowing difficulty]]
* Stiffening of the calf and pectoral muscle groups
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
* [[Opisthotonos]]
* Leg [[extension]] with arm [[flexion]]
* [[Risus sardonicus]]
* [[respiratory distress]]
| style="background: #DCDCDC; padding: 5px;" |
* Not significant
| style="background: #DCDCDC; padding: 5px;" |
* [[Diazepam]]
* [[Magnesium]] 
* Human TIG
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Neuroleptic malignant syndrome|Neuroleptic Malignant Syndrome]] <ref name="pmid28533580">{{cite journal| author=Hosseini S, Elyasi F| title=Olanzapine-Induced Neuroleptic Malignant Syndrome. | journal=Iran J Med Sci | year= 2017 | volume= 42 | issue= 3 | pages= 306-309 | pmid=28533580 | doi= | pmc=5429500 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28533580  }} </ref><ref name="pmid28488314">{{cite journal| author=Leenhardt F, Perier D, Pinzani V, Giraud I, Villiet M, Castet-Nicolas A et al.| title=Pharmacist intervention to detect drug adverse events on admission to the emergency department: Two case reports of neuroleptic malignant syndrome. | journal=J Clin Pharm Ther | year= 2017 | volume=  | issue=  | pages=  | pmid=28488314 | doi=10.1111/jcpt.12531 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28488314  }} </ref>
| style="background: #DCDCDC; padding: 5px;" |
*History of intake of offending drugs e.g [[neuroleptics]] like:
**[[Fluphenazine]]
**[[Haloperidol]]
**[[Olanzapine]]
**[[Risperidone]]
*[[Autonomic instability]]
*[[Stiffness|Rigidity]]
*[[Disorientation]]
*[[Fever]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
* [[Dysphagia]]
* [[Pallor]]
* [[Dyspnea]]
* [[Shuffling gait]]
* [[Agitation]]
| style="background: #DCDCDC; padding: 5px;" |
** [[Myoglobinemia]]
** Elevated [[LDH]]
** Elevated [[creatine kinase]]
** [[Hyperkalemia]]
** Elevated [[AST]] and [[ALT]]
** [[Hyperphosphatemia]]
** Elevated [[alkaline phosphatase]]
** [[Hyperuricemia]]
| style="background: #DCDCDC; padding: 5px;" |
* Supportive therapy
* Stop the offending agent
* Medical Therapy
** [[Dantrolene]]
** [[Amantadine]]
** [[Bromocriptine]]
|-
| style="background: #F5F5F5; padding: 5px;" | [[Meningitis|Viral Meningitis]]<ref name="pmid24326618">{{cite journal| author=Chow E, Troy SB| title=The differential diagnosis of hypoglycorrhachia in adult patients. | journal=Am J Med Sci | year= 2014 | volume= 348 | issue= 3 | pages= 186-90 | pmid=24326618 | doi=10.1097/MAJ.0000000000000217 | pmc=4065645 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24326618  }} </ref><ref name="pmid22880096">{{cite journal| author=Leen WG, Willemsen MA, Wevers RA, Verbeek MM| title=Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice. | journal=PLoS One | year= 2012 | volume= 7 | issue= 8 | pages= e42745 | pmid=22880096 | doi=10.1371/journal.pone.0042745 | pmc=3412827 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22880096  }} </ref><ref name="pmid15319091">{{cite journal| author=Tyler KL| title=Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. | journal=Herpes | year= 2004 | volume= 11 Suppl 2 | issue=  | pages= 57A-64A | pmid=15319091 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15319091  }} </ref>
| style="background: #DCDCDC; padding: 5px;" |
* [[Fever]]
* [[Irritability]]
* Lack of appetite
* [[Lethargy]]
* Disoriented
 
* High grade [[fever]]
* Severe [[headache]]
* [[Stiff neck]]
* [[Photophobia|Sensitivity to bright light]]
* [[Nausea]]
* [[Vomiting]]
| style="background: #F5F5F5; padding: 5px;" |
*[[Headache]]
*[[Photophobia]]
*Phonophopia
*[[Pharyngitis]] in case of [[enterovirus]] infeciton
*[[Orchitis]] (In mumps)
*[[Vesicular]] or [[macular]] [[skin rash]]
*[[Petechia|Petichiae]]
*[[Nuchal rigidity]]
*Signs of [[meningeal irritation]]:
**[[Kernig's sign]]
**[[Brudzinski's sign]]
*[[Altered mental status]]
*[[Hypotonia]]
 
| style="background: #DCDCDC; padding: 5px;" |
*[[CSF]] / [[plasma glucose]] ratio (>0.6)
*[[Lactate]] (mmols/l) (<2.1)
*[[Lymphocytes]] > [[granulocytes]]
| style="background: #DCDCDC; padding: 5px;" |
* Supportive
** [[Analgesics]] for [[pain]].
** [[Acetaminophen]] for [[fever]].
* Anti-viral therapy:
** [[Acyclovir]]
** [[Pleconaril]]
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Stiff man syndrome]]
| style="background: #DCDCDC; padding: 5px;" |
* Marked rigidity
* [[Spasms]]
** Intermittent
** Painful
** Absent during sleep
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
* [[Diaphoresis]]
* [[Arterial hypertension]]
* [[Tachypnea]]
* [[Cyanosis]]
* [[Apnea]], [[tachypnea]]
* [[Respiratory arrest]]
* Dilatation of the pupils
* [[Tachycardia]]
| style="background: #DCDCDC; padding: 5px;" |
* [[CSF]] has
** Elevated [[IgG]]
** [[Oligoclonal bands]]
* Positive anti-GAD antibodies
* Elevated [[creatine kinase]]
* Normal CBC & ESR
| style="background: #DCDCDC; padding: 5px;" |
* [[Benzodiazepines]]
* B[[Baclofen|aclofen]]
* [[Vigabatrin]] 
* [[Valproic Acid]], [[Neurontin]]
* Injected [[botulinum toxin]] 
* [[Prednisone]], [[plasmapheresis]], [[IVIG]] ( some success)
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Drug]] induced  [[Tardive dyskinesia|(Tardive dyskinesia]])<ref name="pmid28552340">{{cite journal| author=Deng ZD, Li DY, Zhang CC, Pan YX, Zhang J, Jin H et al.| title=Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia. | journal=Parkinsonism Relat Disord | year= 2017 | volume=  | issue=  | pages=  | pmid=28552340 | doi=10.1016/j.parkreldis.2017.05.010 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28552340  }} </ref><ref name="pmid28520698">{{cite journal| author=| title=Valbenazine (Ingrezza) for tardive dyskinesia. | journal=Med Lett Drugs Ther | year= 2017 | volume= 59 | issue= 1521 | pages= 83-84 | pmid=28520698 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28520698  }} </ref><ref name="pmid28510661">{{cite journal| author=Voelker R| title=Tardive Dyskinesia Drug Approved. | journal=JAMA | year= 2017 | volume= 317 | issue= 19 | pages= 1942 | pmid=28510661 | doi=10.1001/jama.2017.5537 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28510661  }} </ref>
| style="background: #DCDCDC; padding: 5px;" |
*History of intake of the offending drug for at least one month
**[[Neuroleptics]] ([[antipsychotics]])
**[[Metoclopramide]]
*Eye deviation
*Head and neck jerky movements
*No tonic contraction of the muscles between the spasms
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
* [[Dyskinesia]] of the tongue and lips
* [[Dyskinesia]] of the limbs
* [[Dyskinesia]] of the neck
| style="background: #DCDCDC; padding: 5px;" |
* It is a clinical diagnosis depending on
** [[Dyskinetic|Dyskinetic movements]]
** Hx of > 1 month of [[Antipsychotics|antipsychotic]] use
* Labs may be done to rule out other differentials
| style="background: #DCDCDC; padding: 5px;" |
* Stop the offending agent
* [[Benztropine]]
* [[Benzodiazepines]]
* Injection of [[botulinum toxin]]
* Valbenzine
* [[Tetrabenazine]]
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Strychnine poisoning]]<ref>{{Cite journal
| author = [[Charlotte Duverneuil]], [[Geoffroy Lorin de la Grandmaison]], [[Philippe de Mazancourt]] & [[Jean-Claude Alvarez]]
| title = Liquid chromatography/photodiode array detection for determination of strychnine in blood: a fatal case report
| journal = [[Forensic science international]]
| volume = 141
| issue = 1
| pages = 17–21
| year = 2004
| month = April
| doi = 10.1016/j.forsciint.2003.12.010
| pmid = 15066709
}}</ref><ref>{{Cite journal
| author = [[B. A. Smith]]
| title = Strychnine poisoning
| journal = [[The Journal of emergency medicine]]
| volume = 8
| issue = 3
| pages = 321–325
| year = 1990
| month = May-June
| pmid = 2197324
}}</ref><ref>{{Cite journal
| author = [[B. J. Maron]], [[J. R. Krupp]] & [[B. Tune]]
| title = Strychnine poisoning successfully treated with diazepam
| journal = [[The Journal of pediatrics]]
| volume = 78
| issue = 4
| pages = 697–699
| year = 1971
| month = April
| pmid = 5547830
}}</ref><ref>{{Cite journal
| author = [[B. Oberpaur]], [[A. Donoso]], [[C. Claveria]], [[C. Valverde]] & [[M. Azocar]]
| title = Strychnine poisoning: an uncommon intoxication in children
| journal = [[Pediatric emergency care]]
| volume = 15
| issue = 4
| pages = 264–265
| year = 1999
| month = August
| pmid = 10460082
}}</ref>
   
| style="background: #DCDCDC; padding: 5px;" |
*Hx of up to date tetanus immunizations
*History of intentional or accidental intake
**''Strychnos nux vomica seeds''
**Rodenticide
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
* Hypervigilance
* Anxiety
* Mydriasis
* Hypereflexia
* Clonus
* Facial and neck stiffness
| style="background: #DCDCDC; padding: 5px;" |
* Blood assay
* Tissue assay
* Urine assay
| style="background: #DCDCDC; padding: 5px;" |
* Initial stabilization
* High dose [[Benzodiazepines]]
* Intubation and airway securing
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Hypocalcaemia]]<ref name="pmid27065735">{{cite journal| author=Chhabra P, Rana SS, Sharma V, Sharma R, Bhasin DK| title=Hypocalcemic tetany: a simple bedside marker of poor outcome in acute pancreatitis. | journal=Ann Gastroenterol | year= 2016 | volume= 29 | issue= 2 | pages= 214-20 | pmid=27065735 | doi=10.20524/aog.2016.0015 | pmc=4805743 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27065735  }} </ref><ref name="pmid24171002">{{cite journal| author=Desai M, Kolla PK, Reddy PL| title=Calcium unresponsive hypocalcemic tetany: gitelman syndrome with hypocalcemia. | journal=Case Rep Med | year= 2013 | volume= 2013 | issue=  | pages= 197374 | pmid=24171002 | doi=10.1155/2013/197374 | pmc=3792521 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24171002  }} </ref>
| style="background: #DCDCDC; padding: 5px;" |
**[[Muscle]] [[twitching]] and [[cramping]]
**Circumoral and extremity [[paresthesia]] or [[tingling]]
** [[Altered mental status]]
** [[Irritability]]
** [[Depression]]
** [[Psychosis]]
** [[Seizure]]
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
** [[Tetany (medical sign)|Tetany]] (carpopedal spasm)
** Latent tetany
*** [[Trousseau sign of latent tetany]] 
*** [[Chvostek's sign]] 
** Hyperactive tendon reflexes
| style="background: #DCDCDC; padding: 5px;" |
* Decreased blood [[calcium]] levels
| style="background: #DCDCDC; padding: 5px;" |
* Two [[Ampule|ampules]] of [[intravenous]] [[calcium gluconate]] 10% is given slowly in a period of 10 minutes, or
* If hypocalcemia is severe, [[calcium chloride]] is given instead
* Maintenance doses of both calcium and [[vitamin-D]]
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;" | [[Parkinson's disease]]<ref name="pmid11402154">{{cite journal| author=Olanow CW, Watts RL, Koller WC| title=An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. | journal=Neurology | year= 2001 | volume= 56 | issue= 11 Suppl 5 | pages= S1-S88 | pmid=11402154 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11402154  }} </ref><ref name="pmid24756517">{{cite journal| author=Connolly BS, Lang AE| title=Pharmacological treatment of Parkinson disease: a review. | journal=JAMA | year= 2014 | volume= 311 | issue= 16 | pages= 1670-83 | pmid=24756517 | doi=10.1001/jama.2014.3654 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24756517  }} </ref>
| style="background: #DCDCDC; padding: 5px;" |
* [[Stiffness]]
* Inability to write
* Jerky movements at rest
* [[Constipation]]
* Sleeping difficulty
* Walking difficulty
| style="background: #F5F5F5; padding: 5px; text-align: center;" |
* [[Tremor]]
* Rigidity
* [[Bradykinesia]]
* [[Postural instability]]
* Shuffling gait
| style="background: #DCDCDC; padding: 5px;" |
* Clinical diagnosis
* Improvement with dopaminergic therapy confirms diagnosis
| style="background: #DCDCDC; padding: 5px;" |
* Symptomatic therapy
* [[Dopamine agonists]]
* [[Levodopa]]
* [[Amantadine]]
* [[MAO inhibitors]]
* COMT inhibitors
* [[Anticholinergics]]
|}
 
== Epidemiology and Demographics ==
The [[incidence]] of neuroleptic malignant syndrome is 0.02 % to 3% among patients taking [[antipsychotic medications]]. This wide range in the incidence probably reflects differences among population samples and differences in the surveillance methods used.<ref>Levenson JL. [https://doi.org/10.1176/ajp.142.10.1137 Neuroleptic malignant syndrome]. ''Am J Psychiatry''. 1985;142(10):1137-1145. doi:10.1176/ajp.142.10.1137</ref>
 
The majority of the patients is of adult populations but this rare disorder has been documented in all age groups from 0.9 to 78 years.Age is not a risk factor. In most studies, men outnumber women twofold.
 
==Risk Factors==
Following are the major [[risk factors]] for the development of NMS.<ref>Berardi D, Amore M, Keck PE, Troia M, Dell’Atti M. Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study. Biol Psychiatry. 1998;44(8): 748-754.</ref><ref>Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA. Risk-factors for neuroleptic malignant syndrome—a casecontrol study. Arch Gen Psychiatry. 1989;46(6):914-918.</ref><ref>Kuno S, Mizuta E, Yamasaki S. Neuroleptic malignant syndrome in parkinsonian patients: Risk factors. Eur Neurol. 1997; 38(2):56-59.</ref>
 
* Initiation or dose escalation of [[neuroleptioc medication]]
* Use of high dose, high potency [[intramuscular]] neuroleptics
* Concurrent use of multiple neuroleptics
* physical exhaustion
* [[Heat stroke]]
* [[Dehydration]]
* [[hyponatremia]]
* [[thyrotoxicosis]]
* [[psychoactive substances]]
* presence of a structural or functional brain disorder such as [[encephalitis]], [[tumor]], [[delirium]], or [[dementia]]
 
== Screening ==
There is insufficient evidence to recommend routine screening for NMS.
 
*
 
==Natural History, Complication and Prognosis==
Most cases of neuroleptic malignant syndrome resolve within two weeks. The reported mean recovery time is 7 to 11 days. Depot [[antipsychotic]] use with concomitant structural [[brain]] disease is a risk factor for prolonged illness. Most patients recover without [[neurologic sequela]] if there is no prolonged [[hypoxic]] brain damage.
The [[mortality]] rate of NMS varies from 5 to 20%. Delay in diagnosis or treatment can prolong the recovery time that may result in [[parkinsonism]] or an increase in [[morbidity]] secondary to [[cardiopulmonary]] or renal complications.  When a death occurs in NMS patients that are due to [[DIC]], [[arrhythmias]], or [[cardiovascular complications]].
 
==Diagnosis==
===Diagnostic Study of Choice===
 
{| border="1"
! Diagnostic criterion !! Priority score* 
|-
| Exposure to dopamine antagonist, or dopamine agonist withdrawal, within past 72 hours
| 20
|-
| Hyperthermia (>100.4°F or >38.0°C on at least 2 occasions, measured orally
| 18
|-
| Rigidity
| 17
|-
|Mental status alteration
| 13
|-
|Creatine kinase elevation
|10
|-
|Sympathetic nervous system lability, defined as at least 2 of the following:
Blood pressure elevation (systolic or diastolic ≥25 percent above baseline)
Blood pressure fluctuation (≥20 mmHg diastolic change or ≥25 mmHg systolic change within 24 hours)
Diaphoresis
Urinary incontinence
|10
|-
|Hypermetabolism, defined as heart-rate increase (≥25 percent above baseline) AND respiratory-rate increase (≥50 percent above baseline)
|5
|-
|Negative work-up for infectious, toxic, metabolic, or neurologic causes
|7
|-
|
!Total 100
|}
 
===History and Symptoms===
The tetrad of neuroleptic malignant symptoms usually evolves in one to three days. About 97-100% of the patients have the following features.
* Almost 82% of the patients present with mental status change
* Generalized muscle [[rigidity]] that is often extreme
* Hyperthermia, almost 87% of patients have a [[temperature]] of more than 38°C a but even higher temperatures, greater than 40°C, is present in 40%
* [[Autonomic instability]] typically takes the form of [[tachycardia]] (88%), labile or high [[blood pressure]] (61-77 %), and [[tachypnea]] (73%). [[Dysrhythmias]] may occur. [[Diaphoresis]] is often profuse.
 
===Physical Examination===
*[[Altered mental status]]
* [[Muscle rigidity]]
* [[Hyperthermia]]
* [[Diaphoresis]]
* [[Tachycardia]]
* [[Tachypnea]]
* [[Increased or labile blood pressure]]
* [[Dystonia]]
* [[Dyskinesia]]
* [[Resting tremor]]
 
===Laboratory Findings===
* Elevated serum [[CK]]
* [[Leukocytosis]]
* Mild elevations of [[LDH]], [[ALP]], and liver transaminases are common
* Electrolyte abnormalities: [[Hypocalcemia]], [[metabolic acidosis]], [[hypo]] or hypernatremia are common.
* Elevated creatinine may result from [[rhabdomyolysis]]
 
===Electrocardiogram===
[[Electrolyte imbalances]] can cause [[cardiac arrhythmias]] that can cause [[cardiac arrest]] if not treated in a timely fashion. Both classes of [[antipsychotic]] drugs can cause serious cardiac side effects regardless of the electrolyte imbalances. One of the adverse side effects of [[antipsychotics]] is a prolongation of the [[QT interval]] that can convert into [[torsades de pontes]] causing [[sudden cardiac death]].
 
===X-ray===
There are no [[x-ray]] findings associated with NMS.
 
===Echocardiography or Ultrasound===
There are no [[echocardiography]]/ultrasound findings associated with NMS.
 
===CT scan===
Imaging studies with [[scans]] do not provide any diagnostic information for NMS. However, the [[CT brain]] may be helpful to rule out other conditions.
 
===MRI===
MRI brain does not provide any diagnostic information for NMS but can be used to rule out other conditions.
 
===Other Imaging Findings===
There are no other imaging findings associated with NMS.
 
===Other Diagnostic Studies===
There are no other diagnostic studies associated with NMS.
 
==Treatment==
 
=== Medical Therapy ===
The management of patients with NMS should be based upon a hierarchy of [[clinical]] severity and diagnostic certainty. When manifestations are [[severe]], intensive care unit monitoring and treatment are required.
 
==== Stop causative agent ====
The single most important step in the treatment of NMS is removal os causative [[agents]]. If possible, other potential contributing [[psychotropic]] agents should also be stopped. When the precipitant is the discontinuation of dopaminergic therapy, it should be reinstituted.
 
'''Supportive care'''
 
Complications of the NMS are often fatal and following supportive treatment is required in the intensive care unit.
 
* Discontinue any precipitating [[antipsychotic medication]]
* Maintain [[cardiorespiratory]] stability. [[Mechanical ventilation]] and cardio consultation may be required.
* Maintain euvolemic state through the administration of [[intravenous fluids]],
* If CK is elevated then [[urine alkalinization]] with high volume fluid should be done to prevent renal failure from [[rhabdomyolysis]]
* Cooling blankets should be used to lower [[fever]], more aggressive measures such as ice water [[gastric lavage]]may be required.
* Lower [[blood pressure]] if markedly elevated. [[clonidine]]may be used.
* Prescribe heparin or [[LMWH]] to prevent [[deep venous thrombosis]]
* If needed, use benzodiazepines (eg, [[lorazepam]] 0.5 to 1 mg) to control agitation
 
==== Pharmacotherapy ====
Recommendations for the treatment of NMS are based on clinical experience and case reports and [[randomized control trials]] were never done.  [[Dantrolene]], [[amantadine]], and [[bromocriptine]] are commonly used [[medications]].  These agents are used in more severe cases and the dose is escalated if the patient gets worse.  A reasonable approach is to start with [[benzodiazepines]] ([[lorazepam]] or [[diazepam]]) along with dantrolene in moderate or severe cases, followed by the addition of [[bromocriptine]] or [[amantadine]].
 
===Surgery===
Surgical intervention is not recommended for the management of NMS.
===Primary Prevention===
Prevention is the most important aspect of treatment. This includes reducing the [[risk factors]], early recognization of the [[disease]], and prompt discontinuation of the causative [[agent]].
 
===Secondary Prevention===
There are no established measures for the secondary [[prevention]] of NMS.


==References==
==References==
<div class="references-small">
{{reflist|2}}
<references />
</div>
 
==External links==
* [http://www.cmdg.org/Movement_/drug/Neuroleptic_Malignant_Syndrome/neuroleptic_malignant_syndrome.htm Canadian Movement Disorder Group] - cmdg.org.
* [http://counsellingresource.com/medications/medication-types/about-nms.html NMS] - counsellingresource.com.
* [http://www.ninds.nih.gov/disorders/neuroleptic_syndrome/neuroleptic_syndrome.htm NINDS Neuroleptic Malignant Syndrome Information Page] - [[NIH]].
* [http://www.currentpsychiatry.com/article_pages.asp?AID=704&UID=187 NMS] - currentpsychiatry.com


{{Diseases of the nervous system}}
{{Diseases of the nervous system}}
Line 84: Line 555:
[[Category:Psychiatry]]
[[Category:Psychiatry]]
[[Category:Syndromes]]
[[Category:Syndromes]]
[[Category:Emergency medicine]]


[[de:Malignes Neuroleptisches Syndrom]]
[[fr:Syndrome malin des neuroleptiques]]
[[nl:Maligne neuroleptica syndroom]]
[[ja:悪性症候群]]
[[pl:Złośliwy zespół neuroleptyczny]]
{{WikiDoc Sources}}
{{WikiDoc Sources}}

Latest revision as of 18:37, 24 August 2020

Neuroleptic malignant syndrome
ICD-10 G21.0
ICD-9 333.92
DiseasesDB 8968

WikiDoc Resources for Neuroleptic malignant syndrome

Articles

Most recent articles on Neuroleptic malignant syndrome

Most cited articles on Neuroleptic malignant syndrome

Review articles on Neuroleptic malignant syndrome

Articles on Neuroleptic malignant syndrome in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Neuroleptic malignant syndrome

Images of Neuroleptic malignant syndrome

Photos of Neuroleptic malignant syndrome

Podcasts & MP3s on Neuroleptic malignant syndrome

Videos on Neuroleptic malignant syndrome

Evidence Based Medicine

Cochrane Collaboration on Neuroleptic malignant syndrome

Bandolier on Neuroleptic malignant syndrome

TRIP on Neuroleptic malignant syndrome

Clinical Trials

Ongoing Trials on Neuroleptic malignant syndrome at Clinical Trials.gov

Trial results on Neuroleptic malignant syndrome

Clinical Trials on Neuroleptic malignant syndrome at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Neuroleptic malignant syndrome

NICE Guidance on Neuroleptic malignant syndrome

NHS PRODIGY Guidance

FDA on Neuroleptic malignant syndrome

CDC on Neuroleptic malignant syndrome

Books

Books on Neuroleptic malignant syndrome

News

Neuroleptic malignant syndrome in the news

Be alerted to news on Neuroleptic malignant syndrome

News trends on Neuroleptic malignant syndrome

Commentary

Blogs on Neuroleptic malignant syndrome

Definitions

Definitions of Neuroleptic malignant syndrome

Patient Resources / Community

Patient resources on Neuroleptic malignant syndrome

Discussion groups on Neuroleptic malignant syndrome

Patient Handouts on Neuroleptic malignant syndrome

Directions to Hospitals Treating Neuroleptic malignant syndrome

Risk calculators and risk factors for Neuroleptic malignant syndrome

Healthcare Provider Resources

Symptoms of Neuroleptic malignant syndrome

Causes & Risk Factors for Neuroleptic malignant syndrome

Diagnostic studies for Neuroleptic malignant syndrome

Treatment of Neuroleptic malignant syndrome

Continuing Medical Education (CME)

CME Programs on Neuroleptic malignant syndrome

International

Neuroleptic malignant syndrome en Espanol

Neuroleptic malignant syndrome en Francais

Business

Neuroleptic malignant syndrome in the Marketplace

Patents on Neuroleptic malignant syndrome

Experimental / Informatics

List of terms related to Neuroleptic malignant syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2] Qasim Khurshid, M.B.B.S.[2]

Keywords and synonyms: NMS

Overview

The neuroleptic malignant syndrome is an uncommon adverse reaction to medications with dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. The syndrome is characterized by severe rigidity, fever, tremor, autonomic dysfunction, altered mental status, and elevated serum creatinine phosphokinase. This is a life-threatening condition, with difficulties in diagnosis and treatment. This syndrome can further complicates psychiatric treatment.

Historical Perspective

The first reported case of NMS appeared in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (Thorazine). Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the adverse effects of the newly introduced neuroleptic haloperidol and characterized a ‘‘syndrome malin des neuroleptiques.’’2 Pooled data from 1966 to 1997 suggested the incidence of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics; however, as physicians have become increasingly aware of the syndrome and with the advent of new neuroleptic medications, the incidence has decreased to around 0.01% to 0,02%.[1][2][3][4]

Classification

There is no established system for the classification of NMS.

Pathophysiology

The pathophysiologic mechanisms of NMS are complex and still under debate among physicians But the majority of physicians agree that sudden and significant reduction in central dopaminergic activity within the mesolimbic/cortical, the nigrostriatal, and hypothalamic pathways help explain the clinical features of the neuroleptic malignant syndrome. This theory is supported by the observation that the use of antipsychotic drugs that specifically block D 2 receptors primarily cause NMS and that the syndrome can also be induced by abrupt dopamine withdrawal.

Additionally, this theory is supported by the dopamine receptorimaging study of NMS patients in the acute phase which demonstrated a complete lack of D2 receptor binding. Another study demonstrated low levels of dopamine metabolite in the CSF of patients with NMS in the acute phase. However D2 receptor antagonism does not explain all the presenting signs] and symptoms of NMS, nor does it explain its occurrence with antipsychotic medications with lower D2 activity and medications without known antidopaminergic activity. Abnormalities in the sympathetic system are supported by the frequent presence of autonomic symptoms in NMS as well as demonstrated changes in the urine and plasma catecholamine levels in patients with NMS. Some have hypothesized that NMS shares pathophysiological similarities with malignant hyperthermia and that a defect in calcium regulatory proteins within sympathetic neurons may be the essential factor that brings about the onset of NMS. Another system that also appears to play a role in the signs and symptoms of NMS is the peripheral skeletal muscle system. The release of calcium is increased from the sarcoplasmic reticulum of muscle cells with antipsychotic usage, possibly leading to increased muscle contractility and rigidity, breakdown of muscle, and hyperthermia. However, these theories are unable to explain why only a small fraction of patients develop NMS after exposure to neuroleptics. Furthermore, it remains unknown why patients who develop NMS are usually able to continue being treated with similar medications and, at times, even the same offending agent.[5][6][7][8]

Causes

Potent typical neuroleptics such as fluphenazine, haloperidol, trifluoperazine, chlorpromazine, and prochlorperazine have been most frequently associated with NMS and thought to confer the greatest risk. Although atypical neuroleptics appear to have reduced the risk of developing NMS compared to typical neuroleptics. But a significant number of cases have been reported with most atypical neuroleptics including clozapine, risperidone, olanzapine, quetiapine, aripiprazole, olanzapine aripiprazole, and ziprasidone. The neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as diatrizoate, droperidol, tetrabenazine, and metoclopramide. The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS, and there may be some risk of NMS associated with the abrupt withdrawal of Parkinson medications that are not known to have direct dopaminergic activity such as amantadine and tolcapone. [9][10][11]

Neuroleptic and Nonneuroleptic Medications Associated With Neuroleptic Malignant Syndrome
Typical Neuroleptics Atypical Neuroleptics Nonneuroleptics with antidopaminergic activity Dopaminergics (withdrawal) Others
a. Haloperidol

b. Fluphenazine

c. Chlorpromazine

d. Prochlorperazine

e. Trifluoperazine

f. Thioridazine

g. Thiothixene

h. Loxapine

i. Perphenazine

J. Bromperido

k. Clopenthixol

l. Promazine

a. Clozapine

b. Risperidone

c. Olanzapine

d. Quetiapine

e. Ziprasidone

f. Aripiprazole

(1) Metoclopromide

2) Tetrabenazine

(3) Reserpine

4) Droperidol

(5) Promethazine

(6) Amoxapine

(7) Diatrizoate

(1) Levodopa

2) Dopamine agonists

(3) Amantadine

4) Tolcapone

(1) Lithium

2) Phenelzine

(3) Dosulepin

4) Desipramine

(5) Trimipramine


Differential Diagnosis

NMS and Serotonin Syndrome

The clinical features of NMS and serotonergic syndrome are very similar. This can make differentiating them very difficult.[13]

Features, classically present in NMS, that are useful for differentiating the two syndromes are:[14]

  • Fever
  • Muscle rigidity
  • Laboratory values (WBC and CK)

One the basis of stiffness and fever it can be differentiated from:

Differential Diagnosis of Fever and Stiffness
Disease Diagnosis Treatment
Symptoms Signs Laboratory Findings
Tetanus[15][16]
  • Not significant
Neuroleptic Malignant Syndrome [17][18]
Viral Meningitis[19][20][21]
Stiff man syndrome
  • Marked rigidity
  • Spasms
    • Intermittent
    • Painful
    • Absent during sleep
Drug induced (Tardive dyskinesia)[22][23][24]
  • History of intake of the offending drug for at least one month
  • Eye deviation
  • Head and neck jerky movements
  • No tonic contraction of the muscles between the spasms
Strychnine poisoning[25][26][27][28]
  • Hx of up to date tetanus immunizations
  • History of intentional or accidental intake
    • Strychnos nux vomica seeds
    • Rodenticide
  • Hypervigilance
  • Anxiety
  • Mydriasis
  • Hypereflexia
  • Clonus
  • Facial and neck stiffness
  • Blood assay
  • Tissue assay
  • Urine assay
  • Initial stabilization
  • High dose Benzodiazepines
  • Intubation and airway securing
Hypocalcaemia[29][30]
Parkinson's disease[31][32]
  • Clinical diagnosis
  • Improvement with dopaminergic therapy confirms diagnosis

Epidemiology and Demographics

The incidence of neuroleptic malignant syndrome is 0.02 % to 3% among patients taking antipsychotic medications. This wide range in the incidence probably reflects differences among population samples and differences in the surveillance methods used.[33]

The majority of the patients is of adult populations but this rare disorder has been documented in all age groups from 0.9 to 78 years.Age is not a risk factor. In most studies, men outnumber women twofold.

Risk Factors

Following are the major risk factors for the development of NMS.[34][35][36]

Screening

There is insufficient evidence to recommend routine screening for NMS.

Natural History, Complication and Prognosis

Most cases of neuroleptic malignant syndrome resolve within two weeks. The reported mean recovery time is 7 to 11 days. Depot antipsychotic use with concomitant structural brain disease is a risk factor for prolonged illness. Most patients recover without neurologic sequela if there is no prolonged hypoxic brain damage. The mortality rate of NMS varies from 5 to 20%. Delay in diagnosis or treatment can prolong the recovery time that may result in parkinsonism or an increase in morbidity secondary to cardiopulmonary or renal complications. When a death occurs in NMS patients that are due to DIC, arrhythmias, or cardiovascular complications.

Diagnosis

Diagnostic Study of Choice

Diagnostic criterion Priority score*
Exposure to dopamine antagonist, or dopamine agonist withdrawal, within past 72 hours 20
Hyperthermia (>100.4°F or >38.0°C on at least 2 occasions, measured orally 18
Rigidity 17
Mental status alteration 13
Creatine kinase elevation 10
Sympathetic nervous system lability, defined as at least 2 of the following:

Blood pressure elevation (systolic or diastolic ≥25 percent above baseline) Blood pressure fluctuation (≥20 mmHg diastolic change or ≥25 mmHg systolic change within 24 hours) Diaphoresis Urinary incontinence

10
Hypermetabolism, defined as heart-rate increase (≥25 percent above baseline) AND respiratory-rate increase (≥50 percent above baseline) 5
Negative work-up for infectious, toxic, metabolic, or neurologic causes 7
Total 100

History and Symptoms

The tetrad of neuroleptic malignant symptoms usually evolves in one to three days. About 97-100% of the patients have the following features.

Physical Examination

Laboratory Findings

Electrocardiogram

Electrolyte imbalances can cause cardiac arrhythmias that can cause cardiac arrest if not treated in a timely fashion. Both classes of antipsychotic drugs can cause serious cardiac side effects regardless of the electrolyte imbalances. One of the adverse side effects of antipsychotics is a prolongation of the QT interval that can convert into torsades de pontes causing sudden cardiac death.

X-ray

There are no x-ray findings associated with NMS.

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with NMS.

CT scan

Imaging studies with scans do not provide any diagnostic information for NMS. However, the CT brain may be helpful to rule out other conditions.

MRI

MRI brain does not provide any diagnostic information for NMS but can be used to rule out other conditions.

Other Imaging Findings

There are no other imaging findings associated with NMS.

Other Diagnostic Studies

There are no other diagnostic studies associated with NMS.

Treatment

Medical Therapy

The management of patients with NMS should be based upon a hierarchy of clinical severity and diagnostic certainty. When manifestations are severe, intensive care unit monitoring and treatment are required.

Stop causative agent

The single most important step in the treatment of NMS is removal os causative agents. If possible, other potential contributing psychotropic agents should also be stopped. When the precipitant is the discontinuation of dopaminergic therapy, it should be reinstituted.

Supportive care

Complications of the NMS are often fatal and following supportive treatment is required in the intensive care unit.

Pharmacotherapy

Recommendations for the treatment of NMS are based on clinical experience and case reports and randomized control trials were never done. Dantrolene, amantadine, and bromocriptine are commonly used medications. These agents are used in more severe cases and the dose is escalated if the patient gets worse. A reasonable approach is to start with benzodiazepines (lorazepam or diazepam) along with dantrolene in moderate or severe cases, followed by the addition of bromocriptine or amantadine.

Surgery

Surgical intervention is not recommended for the management of NMS.

Primary Prevention

Prevention is the most important aspect of treatment. This includes reducing the risk factors, early recognization of the disease, and prompt discontinuation of the causative agent.

Secondary Prevention

There are no established measures for the secondary prevention of NMS.

References

  1. Ayd F. Fatal hyperpyrexia during chlorpromazine therapy. J Clin Exp Psychopathol. 1956;17(2):189-192.
  2. Delay J, Pichot P, Lemperiere T. A non-phenothiazine and nonreserpine major neuroleptic, haloperidol, in the treatment of psychoses (in French). Ann Med Psychol (Paris). 1960;118(1): 145-152
  3. Pelonero AL, Levenson JL, Pandurangi AK. Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998;49(9):1163-1172
  4. Stubner S, Rustenbeck E, Grohmann R, et al. Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry. 2004;37(1):S54-S64.
  5. Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth. 2000;85(1):129-135. doi:10.1093/bja/85.1.129
  6. Strawn JR, Keck PE Jr, Caroff SN. Neuroleptic malignant syndrome. Am J Psychiatry. 2007;164(6):870-876. doi:10.1176/ajp.2007.164.6.870
  7. Jauss, M., Krack, P., Franz, M., Klett, R., Bauer, R., Gallhofer, B. and Dorndorf, W. (1996), Imaging of dopamine receptors with [123I]iodobenzamide single‐photon emission–computed tomography in neuroleptic malignant syndrome. Mov. Disord., 11: 726-728. doi:10.1002/mds.870110621
  8. Nisijima K, Ishiguro T. Cerebrospinal-fluid levels of monoamine metabolites and gamma-aminobutyric-acid in neuroleptic malignant syndrome. J Psychiatr Res. 1995;29(3):233-244.
  9. Khan FY, Qusad MJ. Neuroleptic malignant syndrome. Neurosciences. 2006;11(2):104-106
  10. Pasa S, Sayhan MB, Boyraz T, Urakci Z, Altintas A. A case of neuroleptic malignant syndrome accompanied to an atypical antipsychotic agent: risperidone. Neurotoxicology. 2008;29(4): 750-751.
  11. Pope HG, Cole JO, Choras PT, Fulwiler CE. Apparent neuroleptic malignant syndrome with clozapine and lithium. J Nervous Mental Dis. 1986;174(8):493-495.
  12. Diagnostic and statistical manual of mental disorders : DSM-5. Washington, D.C: American Psychiatric Association. 2013. ISBN 0890425558.
  13. Christensen V, Glenthøj B (2001). "[Malignant neuroleptic syndrome or serotonergic syndrome]". Ugeskr Laeger. 163 (3): 301–2. PMID 11219110.
  14. Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review". CMAJ. 168 (11): 1439–42. PMID 12771076. Full Free Text.
  15. Woldeamanuel YW, Andemeskel AT, Kyei K, Woldeamanuel MW, Woldeamanuel W (2016). "Case fatality of adult tetanus in Africa: Systematic review and meta-analysis". J Neurol Sci. 368: 292–9. doi:10.1016/j.jns.2016.07.025. PMID 27538652.
  16. Thwaites CL, Loan HT (2015). "Eradication of tetanus". Br Med Bull. 116: 69–77. doi:10.1093/bmb/ldv044. PMC 4674006. PMID 26598719.
  17. Hosseini S, Elyasi F (2017). "Olanzapine-Induced Neuroleptic Malignant Syndrome". Iran J Med Sci. 42 (3): 306–309. PMC 5429500. PMID 28533580.
  18. Leenhardt F, Perier D, Pinzani V, Giraud I, Villiet M, Castet-Nicolas A; et al. (2017). "Pharmacist intervention to detect drug adverse events on admission to the emergency department: Two case reports of neuroleptic malignant syndrome". J Clin Pharm Ther. doi:10.1111/jcpt.12531. PMID 28488314.
  19. Chow E, Troy SB (2014). "The differential diagnosis of hypoglycorrhachia in adult patients". Am J Med Sci. 348 (3): 186–90. doi:10.1097/MAJ.0000000000000217. PMC 4065645. PMID 24326618.
  20. Leen WG, Willemsen MA, Wevers RA, Verbeek MM (2012). "Cerebrospinal fluid glucose and lactate: age-specific reference values and implications for clinical practice". PLoS One. 7 (8): e42745. doi:10.1371/journal.pone.0042745. PMC 3412827. PMID 22880096.
  21. Tyler KL (2004). "Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's". Herpes. 11 Suppl 2: 57A–64A. PMID 15319091.
  22. Deng ZD, Li DY, Zhang CC, Pan YX, Zhang J, Jin H; et al. (2017). "Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia". Parkinsonism Relat Disord. doi:10.1016/j.parkreldis.2017.05.010. PMID 28552340.
  23. "Valbenazine (Ingrezza) for tardive dyskinesia". Med Lett Drugs Ther. 59 (1521): 83–84. 2017. PMID 28520698.
  24. Voelker R (2017). "Tardive Dyskinesia Drug Approved". JAMA. 317 (19): 1942. doi:10.1001/jama.2017.5537. PMID 28510661.
  25. Charlotte Duverneuil, Geoffroy Lorin de la Grandmaison, Philippe de Mazancourt & Jean-Claude Alvarez (2004). "Liquid chromatography/photodiode array detection for determination of strychnine in blood: a fatal case report". Forensic science international. 141 (1): 17–21. doi:10.1016/j.forsciint.2003.12.010. PMID 15066709. Unknown parameter |month= ignored (help)
  26. B. A. Smith (1990). "Strychnine poisoning". The Journal of emergency medicine. 8 (3): 321–325. PMID 2197324. Unknown parameter |month= ignored (help)
  27. B. J. Maron, J. R. Krupp & B. Tune (1971). "Strychnine poisoning successfully treated with diazepam". The Journal of pediatrics. 78 (4): 697–699. PMID 5547830. Unknown parameter |month= ignored (help)
  28. B. Oberpaur, A. Donoso, C. Claveria, C. Valverde & M. Azocar (1999). "Strychnine poisoning: an uncommon intoxication in children". Pediatric emergency care. 15 (4): 264–265. PMID 10460082. Unknown parameter |month= ignored (help)
  29. Chhabra P, Rana SS, Sharma V, Sharma R, Bhasin DK (2016). "Hypocalcemic tetany: a simple bedside marker of poor outcome in acute pancreatitis". Ann Gastroenterol. 29 (2): 214–20. doi:10.20524/aog.2016.0015. PMC 4805743. PMID 27065735.
  30. Desai M, Kolla PK, Reddy PL (2013). "Calcium unresponsive hypocalcemic tetany: gitelman syndrome with hypocalcemia". Case Rep Med. 2013: 197374. doi:10.1155/2013/197374. PMC 3792521. PMID 24171002.
  31. Olanow CW, Watts RL, Koller WC (2001). "An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines". Neurology. 56 (11 Suppl 5): S1–S88. PMID 11402154.
  32. Connolly BS, Lang AE (2014). "Pharmacological treatment of Parkinson disease: a review". JAMA. 311 (16): 1670–83. doi:10.1001/jama.2014.3654. PMID 24756517.
  33. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry. 1985;142(10):1137-1145. doi:10.1176/ajp.142.10.1137
  34. Berardi D, Amore M, Keck PE, Troia M, Dell’Atti M. Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study. Biol Psychiatry. 1998;44(8): 748-754.
  35. Keck PE, Pope HG, Cohen BM, McElroy SL, Nierenberg AA. Risk-factors for neuroleptic malignant syndrome—a casecontrol study. Arch Gen Psychiatry. 1989;46(6):914-918.
  36. Kuno S, Mizuta E, Yamasaki S. Neuroleptic malignant syndrome in parkinsonian patients: Risk factors. Eur Neurol. 1997; 38(2):56-59.

Template:Diseases of the nervous system

Template:WikiDoc Sources