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Medicines Q&As
Q&A 309.3
What is Neuroleptic Malignant Syndrome?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 3rd February 2014
Background
Neuroleptic Malignant Syndrome (NMS) is a serious and unpredictable idiosyncratic drug reaction. It
is characterised by four groups of symptoms; altered mental state, fever, extrapyramidal symptoms,
and autonomic instability (1). The exact cause of NMS is as yet unknown, but it is postulated that
dopamine blockade or depletion can lead to abnormal regulation of body temperature and
Parkinsonian-like symptoms (2,3). The majority of cases are caused by antipsychotic agents but other
drugs with a dopaminergic action may also be implicated. For more detailed information on drugs
which may cause NMS, please refer to Medicines Q&A number 324 ‘Which drugs can cause
Neuroleptic Malignant Syndrome?’
Answer
NMS is a rare but serious idiosyncratic drug reaction which is potentially severe, unpredictable, and
may lead to significant adverse effects for the patient (1). NMS generally develops within the first two
weeks of an antipsychotic drug being initiated or after a change of dose (1). Incidence rates have
decreased from 3% since it was first described in 1960 to around 0.01-0.02% in patients treated with
antipsychotics (4). It is thought this decrease is due to increased awareness of the syndrome amongst
clinicians leading to earlier diagnosis and a shift to prescribe atypical rather than typical antipsychotics
(4).
Diagnosis
There are many proposed diagnostic criteria available describing NMS, but there is currently no
consensus on which set to use (2,5). Generally, either International Classification of Disease (ICD) or
Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are accepted for definitions of
mental and neurological diseases. However, although NMS is listed in the DSM, this criteria has not
been universally adopted as it has been suggested that if patients present with atypical symptoms,
NMS may be missed using this diagnostic tool (5). Diagnosis is therefore symptom-based, and relies
on considering and excluding differential diagnoses, which include the following:
 Serotonin Syndrome (see Medicines Q&A no. 219)
 Malignant hyperthermia
 Drug-induced catatonia
 Infection
 Heat stroke
 Toxicity/overdose of other drugs (monoamine oxidase inhibitors, lithium)
 Drugs of abuse (cocaine, amphetamines, and CNS stimulants)
 Alcohol or sedative withdrawal(2,3)
A 61 year old patient who died due to suspected NMS was found to have high levels of dopamine and
its metabolites in her urine. This prompted the authors of a case report to consider whether levels of
urinary catecholamines would be helpful to distinguish NMS from serotonin syndrome, although
further investigation is required. This approach may be particularly useful in patients who present with
an atypical syndrome (6).
A number of risk factors have been identified which may predispose patients to developing NMS.
These include male sex, mental retardation, iron deficiency, high ambient temperature, depot
antipsychotic injections, alcoholism, exhaustion, and dehydration (1, 2). However, NMS is
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Medicines Q&As
unpredictable and should be considered in any patients in whom symptoms arise, especially since
manifestations of agitation or delirium may be difficult to differentiate from escalation of psychosis (7).
Symptoms
Onset is abrupt and symptoms generally progress rapidly over 24- 72 hours (2). The symptom groups
and their main signs are summarised in table 1. Following withdrawal of the causative drug, most
patients recover within 7 to 10 days, and virtually all patients recover within 30 days, but symptoms
may be prolonged when long-acting depot injections are implicated (3,4). A significant minority of
patients may suffer long-term sequelae, including neurological impairment, muscle contraction, and
cognitive deficits (1)
Table 1: Groups of symptoms and signs of Neuroleptic Malignant Syndrome (2, 3, 8)
Altered
Hyperthermia
Autonomic Instability
Muscle Rigidity
consciousness
Drowsiness
Temperature of
Fluctuating Blood
Creatinine kinase
>38.5°C
Pressure
markedly raised
Confusion
Tachycardia
Extrapyramidal symptoms
Stupor
Diaphoresis
Parkinson-like symptoms
Coma
Incontinence
Trismus (jaw contraction)
Delirium
Tachypnoea
‘Lead pipe’ rigidity
Grand mal
High arterial pressure
Rhabdomyolysis
seizures
Opisthotonus (spinal
contraction)
Babinski’s sign (abnormal
flexion of the toes)
Chorea
Laboratory findings
Creatinine kinase is markedly increased, usually between 1,000IU/ml and 100,000IU/L (3).
Leukocytosis is present in up to 75% of cases (3). Impaired liver function tests, ECG abnormalities,
and electrolyte disturbances may also be present (1). Cerebral CT scans and lumbar punctures are
usually normal (2).
Temperatures above 104°F (40°C) or renal failure secondary to rhabdomyolysis are indicators of
severe NMS and are associated with a poorer prognosis. Further complications can include seizures,
disseminated intravascular coagulation, respiratory failure, and aspiration pneumonia (3, 9).
Much controversy remains in the literature regarding the causes, diagnosis, and treatment of NMS,
and clinical practice appears to vary widely. More research in this field is needed to resolve some of
the remaining disparities in understanding of the condition (10).
Summary

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Neuroleptic Malignant Syndrome is a rare but serious idiosyncratic drug reaction.
An awareness of the risk factors, causative agents, and symptoms is essential as NMS is a
potentially fatal condition.
Early recognition of the syndrome may improve management and decrease mortality, so
clinicians should be aware of which drugs can cause NMS and how diagnosis is made
Symptoms include hyperthermia, autonomic instability, altered consciousness, and muscle
rigidity.
Laboratory findings include elevated creatinine kinase, leukocytosis and impaired liver function
tests
NMS is a diagnosis of exclusion, so differential diagnoses must be ruled out.
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Limitations
This Q&A provides only a quick reference guide to the diagnosis and symptoms of neuroleptic
malignant syndrome. It does not detail treatment or causative agents. NMS in children is not
considered. Both reviews and case reports were used in compiling this Q&A. Further details regarding
differential diagnoses were not within the scope of this document.
Quality Assurance
Prepared by
Hayley Johnson, Regional Drug & Therapeutics Centre
Date Prepared
3rd February 2014
Checked by
Sarah Smith, Regional Drug & Therapeutics Centre
Date of check
12th February 2014
Search strategy
EMBASE: Neuroleptic Malignant Syndrome + Antipsychotics
Neuroleptic Malignant Syndrome + [Amantadine OR Bromocriptine OR levodopa] +
Parkinson’s Disease
Neuroleptic Malignant Syndrome + Neuroleptic Agents. Limit to 2012-Current
MEDLINE: Neuroleptic Malignant Syndrome + Antipsychotics
Neuroleptic Malignant Syndrome + [Amantadine OR Bromocriptine OR levodopa] +
Parkinson Disease
Neuroleptic Malignant Syndrome + Antipsychotics. Limit to 2012-Current
Neuroleptic Malignant Syndrome Information Service. www.nmsis.org
In-house resources
References
1. Troller JN, Chen X, and Sachdev PS. Neuroleptic Malignant Syndrome Associated with
Atypical Antipsychotic Drugs. CNS Drugs 2009; 23(6): 477-492.
2. Adnet P, Lestavel P, and Krivosic-Horber R. Neuroleptic Malignant Syndrome. British Journal
of Anaesthesia 2000; 85(1): 129-135.
3. Maule E. Management of Neuroleptic Malignant Syndrome. Clinical Pharmacy 2009; 1(7):
203-205.
4. Strawn J, Keck P, and Caroff S. Neuroleptic Malignant Syndrome. The American Journal of
Psychiatry 2007; 164(4): 870-876.
5. Pandya M and Pozuelo L. A Malignant Neuroleptic Spectrum: Review of Diagnostic Criteria
and treatment implications in three case reports. International Journal of Psychiatry In
Medicine 2004; 34(3): 277-28
6. Sokoro AA. Zivot J, and Ariano RE. Neuroleptic malignant syndrome versus serotonin
syndrome: the search for a diagnostic tool. Annals of Pharmacotherapy 2011; 45(9): e50
7. Seitz DP and Gill SS. Neuroleptic Malignant Syndrome Complicating Antipsychotic Treatment
of Delirium or Agitation in Medical and Surgical Patients: Case Reports and a Review of the
Literature. Psychosomatics 2009; 50(1): 8-15.
8. Lader M. Lethal Complications of Antipsychotic Drugs. Clinical Risk 2006; 12(3): 113-117
9. Caroff S. Neuroleptic Malignant Syndrome: Still a Risk, but Which Patients May Still Be in
Danger? Neuroleptic Malignant Syndrome Information Service. www.nmsis.org Accessed
03/02/2014.
10. Margetic B, Aukst-Margetic B. Neuroleptic malignant syndrome and its controversies.
Pharmacoepidemiology and Drug Safety 2010; 19(5): 429-435.
Available through NICE Evidence Search at www.evidence.nhs.uk
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