Neuroleptic Malignant Syndrome: A Clinical review

Neuroleptic Malignant Syndrome is a rare but serious idiosyncratic drug reaction to psychotropic medication and is potentially fatal if diagnosis and medical intervention are delayed. As stated in the ‘Royal college of Psychiatrists’ recent position statement on the syndrome (December 2014) all psychiatrists practising without immediate clinical supervision should be able to diagnose this medical emergency and refer to acute medical setting for the effective management of this condition. It can also develop upon withdrawal of some anti-parkinsonian medications (Harrison PA, McErlane KS, 2008).

NMS is an idiopathic condition that occurs in therapeutic doses in some patients, although its mechanism is still not fully understood. About 80% of cases of NMS develop within the first two weeks of antipsychotic use but can occur at any point during therapy. NMS is estimated to affect between 0.02% and 2.4% (Caroff SN, Mann SC, 1993). Some pooled data suggests the incidence of NMS is between 0.2%-3.23% (Pelonero AL, Levenson JL, 1998). Incidence is higher in those under 40 years old and in males (2:1 ratio). A previous episode of NMS significantly increases the risk of future similar reaction. NMS was known about as early as 1956, shortly after the introduction of the first phenothiazines. It was first described in 1960 by French clinicians who had been working on a study involving haloperidol. They characterised the condition that was associated with the side effects of haloperidol ‘syndrome malin des neuroleptiques” (Buckley PF, Hutchinson M, 1995). Reviews of NMS are provided by Caroff 1982 and Smego and Durack 1982 and Cope and Gregg 1983. It has been described sporadically since the 1960s; William Lishman, 2nd edition. In this paper we aim to present the challenges in diagnosing and managing the condition and discuss the pathophysiology of the syndrome, the variations in presentation and the prognosis in detail.


Two key theories have been proposed as the pathophysiological mechanisms by which neuroleptic malignant syndrome emerges. The evidence for the dopamine blockade theory comes from case reports of NMS in patients receiving neuroleptics and also in patients stopping their anti-parkinsonian medication.

1) The central blockade of dopamine receptors

Dopamine plays a vital role in mammalian core temperature regulation. (Cox et al J physio 1972) Henderson and Wooten reported a patient developing NMS after dopaminergic agonists were discontinued in a patient with Parkinson’s disease and remained on Haloperidol. Another patient with Huntington’s chorea on Tetrabenazine and Methyltyrosine also showed features of NMS. These two cases illustrated that either dopamine depletion or blockade could result in NMS.

2) A skeletal muscle pathology which predisposes to hyperthermia when exposed to neuroleptics (Caroff et al (Med Clin North Am 1993; 77:185.),)

This was based on observations that clinical features were common in NMS and malignant hyperthermia. The risk of developing malignant hyperthermia is tested by the in vitro Halothane-Caffeine test performed on the skeletal muscle fibres. The fibres from those at risk of developing malignant hyperthermia show increased senstivity by contracting at lower concentrations of halothane or caffeine added to bath solution than controls. However, studies conducted to test this hypothesis in NMS patients have yielded conflicting results. This could be explained by the differences in the diagnostic criteria, heterogeneity in clinical presentation as well as response to test drugs.

A direct toxic effect on the muscle structure has also been proposed as the mechanism behind the manifestation of NMS. In vitro experiments have demonstrated effects of Chlorpromazine on calcium ion transport across the sarcoplasmic reticulum.

3) Dysregulated sympathetic nervous system hyperactivity also implicated in the pathogenesis of NMS (Gurrera, (Am J Psychiatry 1999;). Sympathetic nervous system receives inhibitory input from higher centres including cortex, hypothalamus. Any disruption of this inhibitory input results in uncoordinated, excessive stimulation of the functional units of sympathetic nervous system’vasomotor, sudomotor, inotropic, thermogenic etc.

Areas of brain known to have a role in the pathogenesis of neuroleptics malignant syndrome are

1) Basal ganglia- motor control and movement
2) Limbic system- primitive behavioural responses, emotions, feeding behaviours and biological rhythms

3) Hypothalamus- behavioural drive centres endocrine functions, body temp control, autonomic nervous system control

Figure 1:

FIGURE 2. Pathophysiology Cascade in Neuroleptic Malignant Syndrome. (Gurrera Am J Psychiatry 1999; 156:169’180)

Clinical presentation and diagnosis

Although Neuroleptic malignant syndrome (NMS) had been first recognised in 1960s following the discovery of neuroleptics, it has remained a diagnostic challenge due to the variations in presentation and similarities to other common side effects to these drugs such as extra pyramidal signs.

Severe muscle rigidity and high temperature following recent administration of antipsychotic medication along with autonomic instability and fluctuating mental state are characteristic features of neuroleptic malignant syndrome.

According to Caroff et al (Med Clin North Am 1993; 77:185.), 16% of NMS cases develop within 24 hours of exposure and about two thirds within the first week and all within 30 days. It is very unlikely for NMS to develop after a month of commencing treatment unless there was a dose increase or addition of another antipsychotic.

NMS is self limiting in most cases, if the drug is discontinued and about 63% of patients recover within 1 week and nearly all within a month.
But symptoms may be prolonged in those who had long acting depot antipsychotics.

Despite development of diagnostic criteria and rating scales to assess severity, some cases with neuroleptic malignant syndrome can present with milder symptoms and signs leading to a delay in diagnosis and treatment.

Levenson’s criteria have been widely used in studies and consist of the following

After exposure to antipsychotics,

3 Major signs

1) Muscle rigidity
2) Elevated Temperature
3) Elevated Serum Creatine Kinase (> 1000IU/L)
6 Minor signs

1) Tachycardia
2) Diaphoresis ( excessive sweating)
3) Abnormal blood pressure
4) Tachypnoea
5) Leucocytosis
6) Altered consciousness
For a diagnosis of NMS, all 3 major signs or 2 major signs plus 4 minor signs must be present following exposure to neuroleptic medication

Nierenberg and colleagues criteria describe the signs more specifically as

1) Exposure to an antipsychotic or dopaminergic agent or recent discontinuation of dopamine agonist

5 major signs

1) Elevated temperature > 38 degree C
2) Elevated Serum Creatine Kinase >3 times normal
3) Muscular lead-pipe rigidity
4) Autonomic instability (2 or more of sweating, tachycardia, increased or decreased blood pressure
5) Altered consciousness 4 minor signs

1) Autonomic instability incontinence, arrhythmias
2) Respiratory distress (dyspnea, tachypnea, hypoxia or respiratory failure)
3) Leukocytosis (>12.0 �� 109/L)
4) EPS (tremor, cogwheeling, dystonia or choreiform movements

Using the Nierenberg’s criteria, NMS can be diagnosed if 4 major signs or 3 major signs plus 3 minor signs are present.

There are various case reports describing other clinical signs including opisthotonus, oculogyric crisis, internuclear opthalmoplegias, grand mal seizures, Babinski’s signs, chorea and trismus.

Laboratory abnormalities including mild alterations in liver enzymes, metabolic acidosis, decreased serum iron concentrations, elevated catecholamines have been described in some cases. Neuroimaging studies are done to exclude mainly other diagnose and are generally within normal limits. There may be generalized slowing in Electroencephalography indicating metabolic encephalopathy. (Caroff SN)


0.02 to 3% among patients with neuroleptic drugs. Risk factors vary among population and although age is not a risk factor it is more common in younger adults and incidence rate is more in men than women 2:1 and more in Inpatients than outpatients.
Risk is associated more commonly with older generation typical antipsychotic drugs compared to atypical antipsychotic drugs. It also seen in other drugs such as antiemetics e.g.: metachlopramide, promethazine. Interestingly abrupt discontinuation of medication for Parkinson’s disease e.g.: L-dopa, Amantaditne, Carbidopa have been reported to cause NMS.

Risk factors

Among the various risk factors studied, the most consistent ones have been agitation, dehydration and exhaustion.( Cohen BM, et al. Cohen BM, et al.) Genetic studies have been conducted to identify specific gene polymorphisms as there is a familial predisposition to develop neuromalignant syndrome. Though three genes were studied, the A1 allele of the dopamine D2 receptor gene (DRD2) appeared at a higher frequency re consistently found risk factors by Suzuki et al(American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 117B:57’60 (2003). however about 60% of patients without NMS also had the A1 allele at a higher frequency.

Individual risk of NMS with typical and atypical drugs

Differential Diagnosis

In order to make a clear diagnosis of NMS, it is very important to rule out other causes of clinical picture like NMS that includes hyperthermia, muscle rigidity, autonomic dysfunction. It is also important to discontinue patient’s psychotropic medication until the confirmation of NMS.

Other conditions which mimic clinical symptoms of NMS are
1. Rhabdomyolysis from other causes
2. CNS infections
3. Cerebral tumours
4. Tetanus and Lithium Toxicity
5. Heat stroke from neuroleptic drugs
6. Catatonia
7. Drug interactions with MAO-inhibitors
8. Central Anticholinergic syndrome
9. Malignant hyperthermia induced by anaesthetic agents
10. Serotonin syndrome

Clinicians should carry out a comprehensive history, physical examination, appropriate investigations including FBC (particularly white blood cell count), CPK (creatine phosphokinase), CT scan, Lumbar Puncture etc.

History of exposure to hot and humid whether, exercise without adequate fluid intake among patients on neuroleptic drugs can induce a hyperthermia resulting in heat stroke. Sudden onset associated with seizures, absence of EPSE and sweating helps to differentiate from NMS
Heat stroke usually responds well to quick and adequate fluid replacement, cooling methods.

Although acute lethal catatonia is rare, the prodromal symptorms of schizophrenia are usually present 2-3 weeks before the onset of catatonia.

MAO-inhibitors when used along with TCA, Narcotic drugs can result NMS like symptoms.

Central anticholinergic syndrome result from atropine toxicity and clinical symptoms includes dry mouth, dry skin, dilated pupil and urinary retention and associated with confusion. Symptoms usually respond to physostigmine.


Treatment of neuroleptic malignant syndrome includes stopping the suspected medication with immediate effect and supportive measures to prevent complications. It is imperative that the patient is transferred to intensive care to receive the appropriate treatment and prevention of complications leading to increased mortality. Airway protection and supportive measures to correct body temperature and restoring systemic perfusion by correcting fluid imbalance is vital in the initial stages.

Cooling blankets, gastric or colonic lavage and alcohol baths are methods used to treat hyperthermia. Non depolarising muscle relaxants can be used by anaesthetists to reduce body temperature by abolishing heat generating muscle contractions in resistant hyperthermia. Benztrophin and paracetamol are not helpful in reducing temperature in neuroleptics malignant syndrome as their mechanism of controlling the temperature is via the prostaglandin synthesis

Dantrolene is used to reduce muscle contractions thereby decreasing the temperature and oxygen consumption within 48 hours. It is used at an IV dose of 2-3mg/kg or oral dose of 100 to 400mg/d in divided doses. According to Sakkas et al, Dantrolene reduces the mortality rates from 21% to 8.6%. Restoring dopaminergic activity in the CNS with Bromocriptine at a dose of 7.5 to 60mg /d has shown to reduce mortality from 21% to 8% and Amantadine at a dose of 100-400mg/d orally or via nasogastric tube from 21% to 6%. (Sakkas et al)
Cardio-respiratory failure, renal failure and thromboembolism are the common causes of mortality in neuroleptic malignant syndrome

Patients carry better prognosis if NMS diagnosed early and treated quickly. Over the last 20 years due to awareness of symptoms and improved medical management, the NMS mortality rates have dropped by 10%.

Risk factors for recurrence

High potency neuroleptics dose dependant manner
Reintroduction before recovery from initial episode of NMS
Bipolar disorder and concomitant use of Lithium
In children and adolescents
The duration of NMS spanned from 1 to 119 days. Nine percent of patients died and 20% resolved with serious sequelae. Patients receiving low-potency neuroleptics had
a poorer outcome (p = .01). Fever was related to longer duration of illness (p = .03). Anticholinergics and bromocriptine were effective and without fatalities, but dantrolene was not useful in this sample of children and adolescents.


Sources and selection criteria
We searched Embase, Medline with the terms ‘Neuroleptic malignant Syndrome’, NMS with atypical antipsychotics, malignant hyperthermia. We included data from case reports, case series, clinical reviews focusing on neuroleptic malignant syndrome.

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