2/10/2016 NeurolepticMalignantSyndrome

DrugInducedMovementDisorders
NEUROLEPTICMALIGNANTSYNDROME
Clinical
Neurolepticmalignantsyndromeistherarestoftheneurolepticinducedmovementdisorders.Itis
themostseriousandrepresentsaneurologicemergencyinmostcases.Ithasnowbeenreported
tooccurwithalldrugsthateffectthecentraldopaminergicsystem(includingdopamineagonists
and levodopa). There's an isolated report of neuroleptic malignant syndrome in a patient on a
trycyclicmedication.Itislikelyanidiosyncraticreactionandpatientscan,ifneeded,begiven
thesameagentagainwithoutrecurrence.

Itisestimatedthat0.51%ofpatientsexposedtoneurolepticswilldevelopthissyndrome.Most
patients will develop it shortly after initial exposure and 90% within two weeks of startingthe
neuroleptic. It can occur with all the neuroleptics but haldol and trifluperazine are the most
common.Ithasalsobeenseenwithclozapineandmetoclopramide.

The classic triad involves the autonomic nervous system (fever in 100%), the extrapyramidal
system(rigidity),andcognitivechanges.Thetwocharacteristiclaboratoryfindingsreportedin
75% of cases are a high CPK and leukocytosis. 95% of patients are iron deficient. The CSF is
usually normal. The EEG can show diffuse slowing. Other features include tachypnea (78%),
diaphoresis (60%), and labile blood pressure (54%). The temperature does not usually exceed
41C and often peaks before the motor systems become prominent. The most frequent
extrapyramidalfindingsincluderigidity(90%)andtremor(56%).Dystoniaandchoreahavealso
been reported. Mental status changes occur in 75% of patients. This starts as drowsiness and
confusionbutcanprogresstostuporandcoma.Othersymptomscanincludeseizures,pyramidal
tractfindings,ocularflutter,cardiacarrhythmias.

Physical exhaustion, dehydration, hyponatremia, young male gender, affective disorders,

thyrotoxicosis, or prior brain pathology all increase the rate of this syndrome developing. An
increasedriskoccursinpatientscombininghaldolwithlithium.

Oncesymptomsdevelopprogressionisquiterapidandreachespeakintensityinabout72hours.
This can very from 45 minutes to as long as 65 days. Some cases remain mild and clear up
withoutintervention.Thedurationofthesymptomscanlastfrom8hoursto40days(longerwith
parental medication). With early recognition and aggressive treatment there is only a 5%
mortality rate (much improved in the last 20 years). Most patients who survive make a full
recovery.Someareleftwithpermanentparkinsonism,ataxia,anddementia.Reoccurrenceshave
beendescribedfollowingexposuretothesameneurolepticbutthisisnotcommon.

Pathophysiology
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Thepathophysiologyisnotcompletelyunderstoodbutisthoughttoinvolve3systems.

Theseincludeabnormalitiesinthe:

1.Centraldopaminesystem.
2.Musclemembranedysfunction.
3.Sympatheticnervoussystem.Evidenceforthecentraldopaminemechanismcomesfrom
thefactthatasimilarsyndromeisseeninParkinson'sdiseasewithabruptwithdrawalof
levodopaoranticholinergics.Additionally95%ofpatientswiththissyndromedevelop
parkinsoniansymptoms.Muscleabnormalitieshavebeeninvokedbecauseoftheclinical
similaritytomalignanthyperthermia.Abnormalitiesinthesympatheticsystemare
supportedbychangesintheurineandplasmacatecholaminelevels.

Treatment
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Earlyrecognitionisextremelyimportanttoreducemortality.Withouttherapythissyndromewill
resolveonitsownoverseveralweeksbutwithactivetreatmentimprovementwilloccurwithin
4872hours.

The first phase of treatment is supportive therapy with adequate hydration and metabolite
(electrolyte) stabilization with cooling blankets to reduce hyperthermia. Ventilatory assistance
mayberequiredandoccasionallydialysisisnecessaryforrenaldysfunction.

Drug therapy starts with discontinuing the neuroleptic. There are a variety of other effective
medications that can be used but the two most frequent ones include Dantrolene sodium and
bromocriptine (individually or combined). These drugs reduce the mortality and shorten the
courseofthesyndrome.Dantrolenecanbegivenintravenouslyororallystartingwith23mgper
kgdosesdividedTIDuptoatotalof10mg/kg/day.BromocriptinecanbegivenorallyorbyNG
tubestartingwith2.5mgTIDandincreasingevery24hoursby2.5mgTIDuntilaresponseis
seenoruntilamaximumdoseof60mgisachieved.

It is reasonable to start both drugs at the same time with intravenous Dantrolene and oral
bromocriptine. Once symptoms start to resolve the Dantrolene can be discontinued and the
bromocriptine can be maintained. The duration of treatment should be at least for ten days for
oralneuroleptics,andtwotothreeweeksforparentaldrugs.Othertreatmentsthatcanbeused
includelevodopa,pergolide,benzodiazepines,andrarelyECT.

IfthissyndromeoccursinthesettingofParkinson'sdiseasethetreatmentisbasicallythesame
excepttheparkinsonianmedicationshouldbereinstitutedasquicklyaspossible.Becauseofthe
riskofthissyndromedrugholidaysarenolongerroutinelyrecommendedforParkinson'sdisease.

If the neuroleptic is to be reintroduced a waiting period of two weeks should be used for oral
medication at least six weeks for parental medication. It would be prudent to use a different
neurolepticthantheonethatoriginallycausedthesyndrome.

TardiveResources

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