Chapter

118

Neuroleptic Malignant Syndrome

Gautam Bhandari

INTRODUCTION
Neuroleptic malignant syndrome (NMS) is an infrequent, but
potentially life-threatening neurologic emergency associated with
the use of neuroleptic or antipsychotic drugs. It was first described
in association with the use of neuroleptic haloperidol in 1960 by
Delay et al.1 Incidence rates for NMS ranges from 0.02% to 3% among
patients taking neuroleptic drugs.2,3 It is most often associated with
typical high-potency neuroleptics (e.g. haloperidol, fluphenazine).4-6
However every class of neuroleptic has been implicated, including
the low-potency neuroleptics (e.g. chlorpromazine) and newer
atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) as
well as antiemetic drugs (e.g. metoclopramide, promethazine).7

DEFINITION
Neuroleptic malignant syndrome is a rare but life-threatening,
idiosyncratic reaction to neuroleptic/antipsychotic medication. It

is characterized by fever, muscular rigidity, altered mental status,

autonomic dysfunction and elevated creatine phos-phokinase.5

PATHOPHYSIOLOGY
Neuroleptic malignant syndrome is thought to be secondary to
decreased dopamine (DA) activity in central nervous system (CNS)
either from:
Blockade of dopamine type 2 receptors (D2 receptors)
Decreased availability of DA itself.
However direct effect on peripheral skeletal muscles may play an
additive role (Flow chart 1).
There are three major central dopaminergic pathways: (1)
nigrostriatal, (2) mesolimbic/cortical and (3) hypothalamic. Acute
blockage of nigrostriatal and hypothalamic DA pathways are believed
to result in signs and symptoms of NMS (Figure 1).8

Flow chart 1: Pathophysiology of neuroleptic malignant syndrome (NMS)

Abbreviations: ANS, Autonomic nervous system; BP, Blood pressure

Section 16
PATHOGENESIS OF NEUROLEPTIC MALIGNANT
SYNDROME AT CELLULAR LEVEL
Neuroleptic malignant syndrome can occur as a result of changes in
pre- or postsynaptic DA signaling (Figure 2 and Table 1). There are
two mechanisms:
1. Reduced DA signaling resulting from sudden withdrawal of
dopaminergic agents
2. Introduction of agents that block DA signaling (Table 2).

RISK FACTORS
Most consistent risk factors for developing NMS are prominent
psychomotor agitation, higher doses of neuroleptics (mean and
maximum dose), greater neuroleptic dose increments over a
short period of time (increased dose within 5 days and parental
administration of drugs [especially depot intramuscular (IM)
preparations].8-10 Simultaneous use of two or more neuroleptic

Chapter 118 Neuroleptic Malignant Syndrome

drugs and concomitant use of predisposing drugs (e.g. lithium,
anticholinergic agents) offer higher risk of NMS.
Other risk factors are increased ambient temperature,
dehydration, history of organic brain syndrome or affective disorder,
genetics, young age and male gender, past history of NMS, trauma,
infection, malnutrition, alcoholism, premenstrual phase in females
and thyrotoxicosis.

HISTORY AND CLINICAL FEATURES

Neuroleptic malignant syndrome is more likely to develop following
initiation of neuroleptic therapy or an increase in the dose of drug.
The onset can be within hours, but on an average, it is 414 days after
initiation of therapy.

TABLE 1Pathogenesis of neuroleptic malignant syndrome (NMS)

(secondary to drugs), at cellular level
Presynaptic
Dopamine (DA) depletors

Tetrabenazine reserpine

Reduced DA precursor

Cessation of the DA precursor,

levodopa (L-DOPA)

Synaptic
Altered DA metabolism

Cessation of COMT inhibitors

(e.g. tolcapone or entacapone)

Altered DA reuptake

Amphetamines, cocaine

Postsynaptic

Figure 1: Brain dopaminergic pathways: nigrostriatal, mesocortical/

mesolimbic and tuberoinfundibular (hypothalamic pituitary)

D2 receptor blockade

Antipsychotics antiemetics
(e.g. metoclopramide, droperidol)

Reduced postsynaptic
stimulation

Cessation of postsynaptic DA agonists

such as pergolide, bromocriptine

Abbreviations: COMT, Catechol-O-methyltransferase; D2 Receptor, dopamine

type 2 receptor

Figure 2: Drugs acting at presynaptic, synaptic and postsynaptic levels in a dopamine neuron may cause neuroleptic malignant syndrome (NMS)
Abbreviations: DA, Dopamine; D2 Receptors, Dopamine type 2 receptors; COMT, Catechol-O-methyltransferase; 3-MT, 3-methoxytyramine; HVA,
Homovanillic acid; MAO, Monoamine oxidase

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Section 16

TABLE 2Pharmacologic agents associated with neuroleptic malignant syndrome (NMS)

Withdrawal of:

Introduction of:

Levodopa (L-DOPA)

Neuroleptics: Phenothiazines, butyrophenones, thiothixanes

Tolcapone/entacapone
Dopamine agonists (e.g. bromocriptine)

Atypical antipsychotics: clozapine, olanzapine, risperidone, quetiapine metoclopramide, droperidol,

prochlorperazine, promethazine

Amantadine

Rare cases seen with tricyclic antidepressants overdose, citalopram overdose, amphetamines,
cocaine, loxapine, diatrizoate, lithium

The four defining features that characterize NMS are:

1. Motor symptoms
2. Altered mental status
3. Hyperthermia
4. Autonomic instability.

Motor Symptoms
Because of basal ganglia dopaminergic involvement, the primary
motor feature is rigidity or the so-called lead-pipe rigidity. Other
motor abnormalities include akinesia/bradykinesia, dystonia,
mutism, chorea, dysarthria and tremors.2

Altered Mental Status

Changes in the mental status ranging from confusion, delirium and
stupor to coma are common in NMS.11

Hyperthermia
Fever more than 38C is commonly seen and sometimes it exceeds
41C.12

Autonomic Instability
Autonomic dysfunction manifests with respiratory irregul-arities,
cardiac arrhythmias, varying blood pressure (BP), incontinence and
diaphoresis.2,13

TABLE 3The Diagnostic and Statistical Manual of Mental

Disorders, fourth edition (DSM-IV) criteria for diagnosis
of neuroleptic malignant syndrome (NMS)
T
 he development of severe muscle rigidity and elevated
temperature associated with the use of antipsychotic medication.
Two or more of the following:
Diaphoresis
Elevated or labile blood pressure (BP)
Tachycardia
Incontinence
Dysphagia
Mutism
Tremor
Changes in the level of consciousness ranging from confusion
to coma
Leukocytosis
Laboratory evidence of muscle injury [e.g. elevated creatine
kinase (CK)]
Diaphoresis
Elevated BP
Tachycardia
The symptoms in Criteria A and B are not due to another substance
(e.g. phencyclidine), neurological or other medical conditions (e.g.
viral encephalitis).
The symptoms in Criteria A and B are not better accounted for by a
mental disorder (e.g. mood disorder with catatonic features).
Source: Data from Diagnostic and Statistical Manual of Mental Disorders, fourth
edition (DSM-IV). Washington, DC: American Psychiatry Association; 1994

DIAGNOSTIC CRITERIA
Diagnostic criteria include:
The Diagnostic and Statistical Manual of Mental Disorders, fourth
edition (DSM-IV) criteria (Table 3)
Levensons clinical criteria (Table 4).
All the three major or two major and four minor, criteria suggest a
high probability of NMS, if supported by clinical history.

INVESTIGATIONS
Laboratory Studies
Laboratory studies include:
Elevated serum creatine kinase (CK)
Other laboratory abnormalities.
Elevated serum creatine kinase: In NMS, CK is typically more than
1,000 IU/L and can be as high as 100,000 IU/L.2,3,14 Elevated CK levels
reflect rhabdomyolysis secondary to muscular rigidity. The degree of
CK elevation seems to correlate directly with disease severity and
higher levels are consistent with a worse prognosis.2

540

Other laboratory abnormalities: Other most consistent finding is

leukocytosis with a white blood cells (WBC) count 10,00040,000.2,13
A left shift may be present.
Mild elevation of lactate dehydrogenase (LDH), alkaline
phosphatase and liver transaminases are common. Electrolyte

TABLE 4Levensons clinical criteria for diagnosis of neuroleptic

malignant syndrome (NMS)
Category

Manifestations

Major

Fever, rigidity, elevated creatinine phosphokinase

concentration

Minor

Tachycardia, abnormal arterial pressure, tachycardia,

altered consciousness, diaphoresis, leukocytosis

abnormalities like hypocalcemia, hypomagnesemia, hypo- or

hypernatremia, hyperkalemia and metabolic acidosis are frequently
observed. Myoglobinuric acute renal failure can result from
rhabdomyolysis. A low serum iron concentration (mean 5.71 mol/L,
normal 1132 mol/L) is commonly seen in NMS, and is sensitive
but not specific marker for NMS among acutely ill.

Other Investigations
In severe NMS cases, coma and stupor may be present. In these
circumstances, imaging studies and spinal tap cerebrospinal fluid
(CSF) may be performed to evaluate for an alternative cause or
determine if there is an accompanying cerebral edema from ongoing
metabolic derangements. A brain computed tomography (CT)
scan/magnetic resonance imaging (MRI) and CSF may be normal.

Section 16
A nonspecific increase in CSF protein has been reported in 37%
cases.11 Presence of accompanying metabolic encephalopathy may
show generalized slow-wave activity on electroencephalography
(EEG).

DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC

MALIGNANT SYNDROME
Differential diagnosis of neuroleptic malignant syndrome can be
broadly, divided into two categories:
1. Conditions related to NMS
2. Conditions unrelated to NMS.

Conditions Related to Neuroleptic

Malignant Syndrome

Serotonin syndrome
Malignant hyperthermia
Malignant catatonia
Acute lethal catatonia (ALC)
Central cholinergic syndrome
Metabolic encephalopathy/encephalitis.

Conditions Unrelated to Neuroleptic

Malignant Syndrome

Central nervous system infection (meningitis/encephalitis)

Heat stroke
Delirium tremens
Parkinsonism
Seizures
Acute porphyria
Septic shock
Tetanus
Strychnine toxicity
Pheochromocytoma.

TREATMENT
Neuroleptic malignant syndrome is a medical emergency, and
can lead to death if untreated. The first step is prompt recognition of
NMS and immediate withdrawal of the neuroleptic agents, and also
excluding other medical conditions. Supportive medical care, specific
pharmacotherapy and electroconvulsive therapy (ECT) are useful in
complete treatment.

Supportive Care
Aggressive therapy is needed in NMS. However, supportive care in
NMS is absolutely essential. Complications are common and severe,
even fatal. These include:
Dehydration
Electrolyte imbalances
Acute renal failure associated with rhabdomyolysis
Cardiac arrhythmias including torsade de pointes and cardiac
arrest
Myocardial infarction
Cardiomyopathy
Respiratory failure from chest wall rigidity, aspiration pneumonia,
pulmonary embolism
Deep vein thrombosis (DVT)
Thrombocytopenia
Disseminated intravascular coagulation (DIC)
Seizures from hyperthermia and metabolic derangements
Hepatic failure
Sepsis.

Chapter 118 Neuroleptic Malignant Syndrome

Intensive monitoring and supportive treatment need admission
to the intensive care unit (ICU). The following supportive treatment
should be provided:
Discontinue neuroleptic agent or precipitating drug
Maintain cardiorespiratory stability. Mechanical ventilation,
antiarrhythmic agents or pacemakers may be required.15
Maintain euvolemic state using intravenous (IV) fluids. Insensible
fluid loss from fever and diaphoresis should also be considered.16 If
CK is very elevated, high volume IV fluids and urine alkalinization
with IV sodium bicarbonate [Na(HCO3)] may help to prevent renal
failure from rhabdomyolysis.17
Lower the temperature using cooling blankets, ice cold water,
gastric lavage and ice packets in axilla and cold sponging.
Antipyretics may be used.
Lower BP, if markedly elevated. Clonidine is effective in this
setting.
Prescribe heparin or low-molecular-weight heparin (LMWH) for
DVT prevention
Use benzodiazepines (e.g. clonazepam or lorazepam 0.51 mg)
to control agitation if necessary.

Specific Pharmacotherapy
Commonly used agents are dantrolene, bromocriptine and
amantadine. Other drugs used are levodopa (L-DOPA) and
carbidopa, apomorphine subcutaneously (SC), IV clonidine and
benzodiazepines (Table 5).
Clinical preferences seem to determine the use of bromocriptine
and/or dantrolene. Since bromocriptine is not available in injection
form, it can be given only orally or through a nasogastric tube. It is
usually well tolerated in psychotic patients. It can be combined with
supportive care in mild to moderate NMS patients.
In patients who have severe rigidity, rhabdomyolysis and extreme
hyperthermia, IV dantrolene may be preferred with or without
bromocriptine. Alternatively, initial management may include IV
dantrolene followed by oral bromocriptine. Treatment is continued
for at least 10 days after resolution of the episode, as neuroleptics
are cleared slowly from the body systems. Early withdrawal of
the treatment can precipitate recurrence of NMS. With depot
neuroleptics, treatment should be continued up to 23 weeks beyond
clinical recovery. After resolution and stabilization of symptoms,
treatment of NMS should be tapered off gradually with serial followup of CK and myoglobulin levels. Sudden withdrawal of treatment
inspite of recovery is discouraged.18

Electroconvulsive Therapy
Electroconvulsive therapy improves some of the components of the
syndrome like fever, sweating and the level of consciousness. It is
speculated that it works by facilitating brain DA activity.19 Indications
of ECT are severe NMS, refractory to medical therapy (> 48 hours)
and when it is not possible to differentiate a diagnosis of NMS from
ALC.18

PREGNANCY AND NEUROLEPTIC

MALIGNANT SYNDROME
Hyperthermia associated with NMS during first trimester
of pregnancy may cause birth defects such as anencephaly.
Bromocriptine is relatively safe for treating NMS during pregnancy.

PROGNOSIS
Most episodes of NMS resolve within 2 weeks and reported mean
recovery times are 711 days.4,7 Cases persisting for 6 months with
residual catatonia and motor signs are reported. Risk factors for
a prolonged course are depot antipsychotic use and concomitant

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Section 16

TABLE 5Specific pharmacotherapy: Commonly used agents and drugs

Category

Bromocriptine

Dantrolene

Amantadine

Levodopa and
carbidopa

Mechanism of action

Central dopamine (DA) agonist

Skeletal muscle relaxation via

inhibition of calcium release
from sarcoplasmic reticulum

Release DA from
dopaminergic terminals
and other central sites

Dopamine agonist

100300 mg bd

25250 mg tds or qid

Hepatotoxicity,
uncontrolled psychosis,
seizures

MI, arrhythmia, asthma,

peptic ulcer, dyskinesia

Secondary to muscle
relaxation; it may decrease
body temperature, oxygen
consumption, heart rate and
respiratory rate
Dose

Oral: 2.510 mg/d four times

a day with increments of 2.5
mg tid every 24 hours until a
response is seen or up to 60
mg/d

Oral: 50200 mg/d

Intravenous: 23 mg/kg/d up to
a dose of 10 mg/kg/d
Adverse effects

Dose-limiting hypotension,
psychosis, nausea and so forth

Hepatotoxicity (especially with

doses > 10 mg/kg/d)

Abbreviations: tid, Ter in die (Three times a day); bd, Bis in die (Twice a day); tds, Ter die sumendus (Three times a day); qid, Quater in die (Four times each day);
MI, Myocardial infarction

structural brain disease. Most patients recover without neurologic

sequelae, except where there is severe hypoxia or grossly elevated
temperatures for a long duration.
Reported mortality rates for NMS are 520%. Disease severity and
the occurrence of medical complications are the strongest predictors
of mortality.

Restarting Neuroleptics
Patient restarted on neuroleptic agents may or may not have
recurrent NMS episode. Early resumption of neuroleptic therapy, use
of high-potency drugs, parental neuroleptics and concomitant use of
lithium, appear to be high-risk factors for recurrence of NMS.
If neuroleptic medication is required, the following guidelines
may minimize the risk of NMS recurrence.3,13 However, none of these
guarantee either success or failure:
Wait for at least 2 weeks before restarting therapy
Use low-potency rather than high-potency drugs
Start with low doses and titrate upward slowly
Avoid concomitant lithium
Avoid dehydration
Carefully monitor for symptoms of NMS.

CONCLUSION
Neuroleptic malignant syndrome is a rare, but life-threatening
medical emergency following usage of neuroleptics. Early
recognition and prompt treatment has shown encouraging outcome
(reduced mortality).

ACKNOWLEDGMENT
The Author is thankful to Dr JC Maloo, DM (Neuro) Medical Director
and Senior Consultant Neurologist, Manidhari Hospital, Jodhpur, for
his kind guidance.

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542

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