Neuroleptic Malignant Syndrome – The Association of ...

Chapter 118

Neuroleptic Malignant Syndrome

Gautam Bhandari

INTRODUCTION is characterized by fever, muscular rigidity, altered mental status,
autonomic dysfunction and elevated creatine phos-phokinase.5
Neuroleptic malignant syndrome (NMS) is an infrequent, but
potentially life-threatening neurologic emergency associated with PATHOPHYSIOLOGY
the use of neuroleptic or antipsychotic drugs. It was first described
in association with the use of neuroleptic haloperidol in 1960 by Neuroleptic malignant syndrome is thought to be secondary to
Delay et al.1 Incidence rates for NMS ranges from 0.02% to 3% among decreased dopamine (DA) activity in central nervous system (CNS)
patients taking neuroleptic drugs.2,3 It is most often associated with either from:
typical high-potency neuroleptics (e.g. haloperidol, fluphenazine).4-6 • Blockade of dopamine type 2 receptors (D2 receptors)
However every class of neuroleptic has been implicated, including • Decreased availability of DA itself.
the low-potency neuroleptics (e.g. chlorpromazine) and newer However direct effect on peripheral skeletal muscles may play an
atypical antipsychotics (e.g. clozapine, risperidone, olanzapine) as additive role (Flow chart 1).
well as antiemetic drugs (e.g. metoclopramide, promethazine).7 There are three major central dopaminergic pathways: (1)
nigrostriatal, (2) mesolimbic/cortical and (3) hypothalamic. Acute
DEFINITION blockage of nigrostriatal and hypothalamic DA pathways are believed
to result in signs and symptoms of NMS (Figure 1).8
Neuroleptic malignant syndrome is a rare but life-threatening,
idiosyncratic reaction to neuroleptic/antipsychotic medication. It

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

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

Section 16 Chapter 118  Neuroleptic Malignant Syndrome

PATHOGENESIS OF NEUROLEPTIC MALIGNANT drugs and concomitant use of predisposing drugs (e.g. lithium,
SYNDROME AT CELLULAR LEVEL anticholinergic agents) offer higher risk of NMS.
Other risk factors are increased ambient temperature,
Neuroleptic malignant syndrome can occur as a result of changes in dehydration, history of organic brain syndrome or affective disorder,
pre- or postsynaptic DA signaling (Figure 2 and Table 1). There are genetics, young age and male gender, past history of NMS, trauma,
two mechanisms: infection, malnutrition, alcoholism, premenstrual phase in females
1. Reduced DA signaling resulting from sudden withdrawal of and thyrotoxicosis.

dopaminergic agents HISTORY AND CLINICAL FEATURES
2. Introduction of agents that block DA signaling (Table 2).
Neuroleptic malignant syndrome is more likely to develop following
RISK FACTORS initiation of neuroleptic therapy or an increase in the dose of drug.
The onset can be within hours, but on an average, it is 4–14 days after
Most consistent risk factors for developing NMS are prom­ inent initiation of therapy.
psychomotor agitation, higher doses of neuroleptics (mean and
maximum dose), greater neuroleptic dose increments over a TABLE 1 │ P athogenesis of neuroleptic malignant syndrome (NMS)
short period of time (increased dose within 5 days and parental (secondary to drugs), at cellular level
administration of drugs [especially depot intramuscular (IM)
preparations].8-10 Simultaneous use of two or more neuroleptic Presynaptic

Figure 1: Brain dopaminergic pathways: nigrostriatal, mesocortical/ Dopamine (DA) depletors Tetrabenazine reserpine
mesolimbic and tuberoinfundibular (hypothalamic pituitary)
Reduced DA precursor Cessation of the DA precursor,
Synaptic levodopa (L-DOPA)

Altered DA metabolism Cessation of COMT inhibitors
(e.g. tolcapone or entacapone)

Altered DA reuptake Amphetamines, cocaine
Postsynaptic

D2 receptor blockade Antipsychotics antiemetics
(e.g. metoclopramide, droperidol)

Reduced postsynaptic Cessation of postsynaptic DA agonists
stimulation 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

539

Neurology Section 16

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

Withdrawal of: Introduction of:
Levodopa (L-DOPA) Neuroleptics: Phenothiazines, butyrophenones, thiothixanes

Tolcapone/entacapone “Atypical” antipsychotics: clozapine, olanzapine, risperidone, quetiapine metoclopramide, droperidol,
Dopamine agonists (e.g. bromocriptine) 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: TABLE 3 │ T he Diagnostic and Statistical Manual of Mental
1. Motor symptoms Disorders, fourth edition (DSM-IV) criteria for diagnosis
2. Altered mental status of neuroleptic malignant syndrome (NMS)
3. Hyperthermia
4. Autonomic instability. •  The development of severe muscle rigidity and elevated
temperature associated with the use of antipsychotic medication.
Motor Symptoms
•  Two or more of the following:
Because of basal ganglia dopaminergic involvement, the primary – Diaphoresis
motor feature is rigidity or the so-called “lead-pipe rigidity”. Other –  Elevated or labile blood pressure (BP)
motor abnormalities include akinesia/bradykinesia, dystonia, – Tachycardia
mutism, chorea, dysarthria and tremors.2 – Incontinence
– Dysphagia
Altered Mental Status – Mutism
– Tremor
Changes in the mental status ranging from confusion, delirium and – Changes in the level of consciousness ranging from confusion
stupor to coma are common in NMS.11 to coma
– Leukocytosis
Hyperthermia – Laboratory evidence of muscle injury [e.g. elevated creatine
kinase (CK)]
Fever more than 38°C is commonly seen and sometimes it exceeds – Diaphoresis
41°C.12 –  Elevated BP
– Tachycardia
Autonomic Instability
• The symptoms in Criteria A and B are not due to another substance
Autonomic dysfunction manifests with respiratory irregul-arities, (e.g. phencyclidine), neurological or other medical conditions (e.g.
cardiac arrhythmias, varying blood pressure (BP), incontinence and viral encephalitis).
diaphoresis.2,13
• The symptoms in Criteria A and B are not better accounted for by a
DIAGNOSTIC CRITERIA mental disorder (e.g. mood disorder with catatonic features).

Diagnostic criteria include: Source: Data from Diagnostic and Statistical Manual of Mental Disorders, fourth
• The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Washington, DC: American Psychiatry Association; 1994

edition (DSM-IV) criteria (Table 3) TABLE 4 │ L evenson’s clinical criteria for diagnosis of neuroleptic
• Levenson’s clinical criteria (Table 4). malignant syndrome (NMS)
All the three major or two major and four minor, criteria suggest a
high probability of NMS, if supported by clinical history. Category Manifestations

INVESTIGATIONS Major Fever, rigidity, elevated creatinine phosphokinase
concentration

Minor Tachycardia, abnormal arterial pressure, tachycardia,
altered consciousness, diaphoresis, leukocytosis

540 Laboratory Studies abnormalities like hypocalcemia, hypomagnesemia, hypo- or
hypernatremia, hyperkalemia and metabolic acidosis are frequently
Laboratory studies include: observed. Myoglobinuric acute renal failure can result from
• Elevated serum creatine kinase (CK) rhabdomyolysis. A low serum iron concentration (mean 5.71 µmol/L,
• Other laboratory abnormalities. normal 11–32 µmol/L) is commonly seen in NMS, and is sensitive
but not specific marker for NMS among acutely ill.
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 Other Investigations
reflect rhabdomyolysis secondary to muscular rigidity. The degree of
CK elevation seems to correlate directly with disease severity and In severe NMS cases, coma and stupor may be present. In these
higher levels are consistent with a worse prognosis.2 circumstances, imaging studies and spinal tap cerebrospinal fluid
(CSF) may be performed to evaluate for an alternative cause or
Other laboratory abnormalities: Other most consistent finding is determine if there is an accompanying cerebral edema from ongoing
leukocytosis with a white blood cells (WBC) count 10,000–40,000.2,13 metabolic derangements. A brain computed tomography (CT)
A left shift may be present. scan/magnetic resonance imaging (MRI) and CSF may be normal.
Mild elevation of lactate dehydrogenase (LDH), alkaline
phosphatase and liver transaminases are common. Electrolyte

Section 16 Chapter 118  Neuroleptic Malignant Syndrome

A nonspecific increase in CSF protein has been reported in 37% Intensive monitoring and supportive treatment need admission
cases.11 Presence of accompanying metabolic encephalopathy may to the intensive care unit (ICU). The following supportive treatment
show generalized slow-wave activity on electroencephalography should be provided:
(EEG). • Discontinue neuroleptic agent or precipitating drug
• Maintain cardiorespiratory stability. Mechanical ventilation,
DIFFERENTIAL DIAGNOSIS OF NEUROLEPTIC
MALIGNANT SYNDROME antiarrhythmic agents or pacemakers may be required.15
• Maintain euvolemic state using intravenous (IV) fluids. Insensible
Differential diagnosis of neuroleptic malignant syndrome can be
broadly, divided into two categories: fluid loss from fever and diaphoresis should also be considered.16 If
1. Conditions related to NMS CK is very elevated, high volume IV fluids and urine alkalinization
2. Conditions unrelated to NMS. wfaiitluhrIeVfrsoomdiruhmabbdiocamrbyoolnyasties.1[7Na(HCO3)] may help to prevent renal
• Lower the temperature using cooling blankets, ice cold water,
Conditions Related to Neuroleptic gastric lavage and ice packets in axilla and cold sponging.
Malignant Syndrome Antipyretics may be used.
• Lower BP, if markedly elevated. Clonidine is effective in this
• Serotonin syndrome setting.
• Malignant hyperthermia • Prescribe heparin or low-molecular-weight heparin (LMWH) for
• Malignant catatonia DVT prevention
• Acute lethal catatonia (ALC) • Use benzodiazepines (e.g. clonazepam or lorazepam 0.5–1 mg)
• Central cholinergic syndrome to control agitation if necessary.
• Metabolic encephalopathy/encephalitis.
Specific Pharmacotherapy
Conditions Unrelated to Neuroleptic
Malignant Syndrome Commonly used agents are dantrolene, bromocriptine and
amantadine. Other drugs used are levodopa (L-DOPA) and
• Central nervous system infection (meningitis/encephalitis) carbidopa, apomorphine subcutaneously (SC), IV clonidine and
• Heat stroke benzodiazepines (Table 5).
• Delirium tremens Clinical preferences seem to determine the use of bromocriptine
• Parkinsonism and/or dantrolene. Since bromocriptine is not available in injection
• Seizures form, it can be given only orally or through a nasogastric tube. It is
• Acute porphyria usually well tolerated in psychotic patients. It can be combined with
• Septic shock supportive care in mild to moderate NMS patients.
• Tetanus In patients who have severe rigidity, rhabdomyolysis and extreme
• Strychnine toxicity hyperthermia, IV dantrolene may be preferred with or without
• Pheochromocytoma. bromocriptine. Alternatively, initial management may include IV
dantrolene followed by oral bromocriptine. Treatment is continued
TREATMENT for at least 10 days after resolution of the episode, as neuroleptics
are cleared slowly from the body systems. Early withdrawal of
Neuroleptic malignant syndrome is a medical emergency, and the treatment can precipitate recurrence of NMS. With depot
can lead to death if untreated. The first step is prompt recognition of neuroleptics, treatment should be continued up to 2–3 weeks beyond
NMS and immediate withdrawal of the neurol­eptic agents, and also clinical recovery. After resolution and stabilization of symptoms,
excluding other medical conditions. Supportive medical care, specific treatment of NMS should be tapered off gradually with serial follow-
pharmacotherapy and electroconvulsive therapy (ECT) are useful in up of CK and myoglobulin levels. Sudden withdrawal of treatment
complete treatment. inspite of recovery is discouraged.18

Supportive Care Electroconvulsive Therapy

Aggressive therapy is needed in NMS. However, supportive care in Electroconvulsive therapy improves some of the components of the
NMS is absolutely essential. Complications are common and severe, syndrome like fever, sweating and the level of consciousness. It is
even fatal. These include: speculated that it works by facilitating brain DA activity.19 Indications
• Dehydration of ECT are severe NMS, refractory to medical therapy (> 48 hours)
• Electrolyte imbalances and when it is not possible to differentiate a diagnosis of NMS from
• Acute renal failure associated with rhabdomyolysis ALC.18
• Cardiac arrhythmias including torsade de pointes and cardiac
PREGNANCY AND NEUROLEPTIC
arrest MALIGNANT SYNDROME
• Myocardial infarction
• Cardiomyopathy Hyperthermia associated with NMS during first trimester
• Respiratory failure from chest wall rigidity, aspiration pneumonia, of pregnancy may cause birth defects such as anencephaly.
Bromocriptine is relatively safe for treating NMS during pregnancy.
pulmonary embolism
• Deep vein thrombosis (DVT) PROGNOSIS
• Thrombocytopenia
• Disseminated intravascular coagulation (DIC) Most episodes of NMS resolve within 2 weeks and reported mean
• Seizures from hyperthermia and metabolic derangements recovery times are 7–11 days.4,7 Cases persisting for 6 months with
• Hepatic failure residual catatonia and motor signs are reported. Risk factors for
• Sepsis. a prolonged course are depot antipsychotic use and concomitant

541

Neurology Section 16

TABLE 5 │ Specific pharmacotherapy: Commonly used agents and drugs

Category Bromocriptine Dantrolene Amantadine Levodopa and
carbidopa

Mechanism of action Central dopamine (DA) agonist Skeletal muscle relaxation via Release DA from Dopamine agonist
inhibition of calcium release dopaminergic terminals
from sarcoplasmic reticulum and other central sites

Dose Oral: 2.5–10 mg/d four times Secondary to muscle 100–300 mg bd 25–250 mg tds or qid
a day with increments of 2.5 relaxation; it may decrease
mg tid every 24 hours until a body temperature, oxygen
response is seen or up to 60 consumption, heart rate and
mg/d respiratory rate

Oral: 50–200 mg/d

Intravenous: 2–3 mg/kg/d up to
a dose of 10 mg/kg/d

Adverse effects Dose-limiting hypotension, Hepatotoxicity (especially with Hepatotoxicity, MI, arrhythmia, asthma,
uncontrolled psychosis, peptic ulcer, dyskinesia
psychosis, nausea and so forth doses > 10 mg/kg/d) seizures

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 2. Levenson JL. Neuroleptic malignant syndrome. Am J Psychiatry.
sequelae, except where there is severe hypoxia or grossly elevated 1985;142(10):1137-45.
temperatures for a long duration.
Reported mortality rates for NMS are 5–20%. Disease severity and 3. Velamoor VR. Neuroleptic malignant syndrome. Recognition,
the occurrence of medical complications are the strongest predictors prevention and management. Drug Saf. 1998;19(1):73-82.
of mortality.
4. Chandran GJ, Mikler JR, Keegan DL. Neuroleptic malignant syndrome:
Restarting Neuroleptics care report and discussion. CMAJ. 2003;169(5):439-42.

Patient restarted on neuroleptic agents may or may not have 5. Strawn JR, Keck PE, Caroff SN. Neuroleptic malignant syndrome. Am J
recurrent NMS episode. Early resumption of neuroleptic therapy, use Psychiatry. 2007;164(6):870-6.
of high-potency drugs, parental neuroleptics and concomitant use of
lithium, appear to be high-risk factors for recurrence of NMS. 6. Seitz DP, Gill SS. Neuroleptic malignant syndrome complicating
If neuroleptic medication is required, the following guidelines antipsychotic treatment of delirium or agitation in medical and surgical
may minimize the risk of NMS recurrence.3,13 However, none of these patients: case reports and a review of the literature. Psychosomatics.
guarantee either success or failure: 2009;50(1):8-15.
• Wait for at least 2 weeks before restarting therapy
• Use low-potency rather than high-potency drugs 7. Kogoj A, Velikonja I. Olanzapine induced neuroleptic malignant
• Start with low doses and titrate upward slowly syndrome—a case review. Hum Psychopharmacol. 2003;18(4):301-9.
• Avoid concomitant lithium
• Avoid dehydration 8. Heiman-Patterson TD. Neuroleptic malignant syndrome and malignant
• Carefully monitor for symptoms of NMS. hyperthermia. Important issue for the medical consultant. Med Clin
North Am. 1993;77(2):477-92.
CONCLUSION
9. Berardi D, Amore M, Keck PE, et al. Clinical and pharmacologic risk
Neuroleptic malignant syndrome is a rare, but life-threatening factors for neuroleptic malignant syndrome: a case-control study. Biol
medical emergency following usage of neuroleptics. Early Psychiatry. 1998;44(8):748-54.
recognition and prompt treatment has shown encouraging outcome
(reduced mortality). 10. Keck PE, Pope HG, Cohen BM, et al. Risk factors for neuroleptic
malignant syndrome. A case-control study. Arch Gen Psychiatry.
ACKNOWLEDGMENT 1989;46(10):914-8.

The Author is thankful to Dr JC Maloo, DM (Neuro) Medical Director 11. Koch M, Chandragiri S, Rizvi S, et al. Catatonic signs in neuroleptic
and Senior Consultant Neurologist, Manidhari Hospital, Jodhpur, for malignant syndrome. Compr. Psychiatry. 2000;41(1):73-5.
his kind guidance.
12. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North
REFERENCES Am. 1993;77(1):185-202.

1. Delay J, Pichot P, Lemperiere T, et al. A non-phenothiazine and non- 13. Rosebush P, Stewart T. A prospective analysis of 24 episodes of
reserpine major neuroleptic, haloperidol, in the treatment of psychoses. neuroleptic malignant syndrome. Am J Psychiatry. 1989;146(6):717-25.
Ann Med Psychol (Paris). 1960;118(1):145-52.
14. Hermesh H, Manor I, Shiloh R, et al. High serum creatinine kinase
level: possible risk factor for neuroleptic malignant syndrome. J Clin
Psychopharmacol. 2002;22(3):252-6.

15. Parry AK, Ormerod LP, Hamlin GW, et al. Recurrent sinus arrest in
association with neuroleptic malignant syndrome. Br J Psychiatry.
1994;164(5):689-91.

16. Guzé BH, Baxter LR. Current concepts. Neuroleptic malignant
syndrome. N Engl J Med. 1985;313(3):163-6.

17. Lappa A, Podestà M, Capelli O, et al. Successful treatment of a
complicated case of neuroleptic malignant syndrome. Intensive Care
Med. 2002;28(7):976-7. Epub 2002.

18. Caroff SN, Mann SC, Keck PE. Specific treatment of the neuroleptic
malignant syndrome. Biol Psychiatry. 1998;44(6):378-81.

19. Hermesh H, Aizenberg D, Weizman A, et al. A successful
electroconvulsive treatment of neuroleptic malignant syndrome. Acta
Psychiatr Scand. 1987;75(3):237-9.

542