Neuroleptic malignant syndrome
Keywords and synonyms: NMS

# Overview
The neuroleptic malignant syndrome is an uncommon adverse reaction to medications with dopamine receptor-antagonist properties or the rapid withdrawal of dopaminergic medications. The syndrome is characterized by severe rigidity, fever, tremor, autonomic dysfunction, altered mental status, and elevated serum creatinine phosphokinase. This is a life-threatening condition, with difficulties in diagnosis and treatment. This syndrome can further complicates psychiatric treatment.

# Historical Perspective
The first reported case of NMS appeared in 1956, shortly after the introduction of the antipsychotic drug chlorpromazine (Thorazine). Additional case reports quickly followed, and in a 1960 study French clinicians gave the syndrome its current name when they reported on the adverse effects of the newly introduced neuroleptic haloperidol and characterized a syndrome malin des neuroleptiques.2 Pooled data from 1966 to 1997 suggested the incidence of NMS ranges from 0.2% to 3.2% of psychiatric inpatients receiving neuroleptics; however, as physicians have become increasingly aware of the syndrome and with the advent of new neuroleptic medications, the incidence has decreased to around 0.01% to 0,02%.

# Classification
There is no established system for the classification of NMS.

# Pathophysiology
The pathophysiologic mechanisms of NMS are complex and still under debate among physicians But the majority of physicians agree that sudden and significant reduction in central dopaminergic activity within the mesolimbic/cortical, the nigrostriatal, and hypothalamic pathways help explain the clinical features of the neuroleptic malignant syndrome. This theory is supported by the observation that the use of antipsychotic drugs that specifically block D 2 receptors primarily cause NMS and that the syndrome can also be induced by abrupt dopamine withdrawal.
Additionally, this theory is supported by the dopamine receptorimaging study of NMS patients in the acute phase which demonstrated a complete lack of D2 receptor binding. Another study demonstrated low levels of dopamine metabolite in the CSF of patients with NMS in the acute phase. However D2 receptor antagonism does not explain all the presenting signs] and symptoms of NMS, nor does it explain its occurrence with antipsychotic medications with lower D2 activity and medications without known antidopaminergic activity. Abnormalities in the sympathetic system are supported by the frequent presence of autonomic symptoms in NMS as well as demonstrated changes in the urine and plasma catecholamine levels in patients with NMS. Some have hypothesized that NMS shares pathophysiological similarities with malignant hyperthermia and that a defect in calcium regulatory proteins within sympathetic neurons may be the essential factor that brings about the onset of NMS. Another system that also appears to play a role in the signs and symptoms of NMS is the peripheral skeletal muscle system. The release of calcium is increased from the sarcoplasmic reticulum of muscle cells with antipsychotic usage, possibly leading to increased muscle contractility and rigidity, breakdown of muscle, and hyperthermia. However, these theories are unable to explain why only a small fraction of patients develop NMS after exposure to neuroleptics.  Furthermore, it remains unknown why patients who develop NMS are usually able to continue being treated with similar medications and, at times, even the same offending agent.

# Causes
Potent typical neuroleptics such as fluphenazine, haloperidol, trifluoperazine, chlorpromazine, and prochlorperazine have been most frequently associated with NMS and thought to confer the greatest risk. Although atypical neuroleptics appear to have reduced the risk of developing NMS compared to typical neuroleptics. But a significant number of cases have been reported with most atypical neuroleptics including clozapine, risperidone, olanzapine, quetiapine, aripiprazole, olanzapine aripiprazole, and ziprasidone. The neuroleptic malignant syndrome has also been associated with nonneuroleptic agents with antidopaminergic activity such as diatrizoate, droperidol, tetrabenazine, and metoclopramide. The rapid switching from one type of dopamine receptor agonist to another in such patients has also been associated with NMS, and there may be some risk of NMS associated with the abrupt withdrawal of Parkinson medications that are not known to have direct dopaminergic activity such as amantadine and tolcapone. 

# Differential Diagnosis
- Infection (sepsis, SIRS)
- Serotonin syndrome
- Delirium tremens
- Heat Stroke
- Malignant hyperthermia

## NMS and Serotonin Syndrome
The clinical features of NMS and serotonergic syndrome are very similar.  This can make differentiating them very difficult.
Features, classically present in NMS, that are useful for differentiating the two syndromes are:
- Fever
- Muscle rigidity
- Laboratory values (WBC and CK)
One the basis of stiffness and fever it can be differentiated from:
- Tetanus
- Stiff man syndrome
- Meningitis
- Tardive dyskinesia
- Parkinsonism

# Epidemiology and Demographics
The incidence of neuroleptic malignant syndrome is 0.02 % to 3% among patients taking antipsychotic medications. This wide range in the incidence probably reflects differences among population samples and differences in the surveillance methods used.
The majority of the patients is of adult populations but this rare disorder has been documented in all age groups from 0.9 to 78 years.Age is not a risk factor. In most studies, men outnumber women twofold.

# Risk Factors
Following are the major risk factors for the development of NMS.
- Initiation or dose escalation of neuroleptioc medication
- Use of high dose, high potency intramuscular neuroleptics
- Concurrent use of multiple neuroleptics
- physical exhaustion
- Heat stroke
- Dehydration
- hyponatremia
- thyrotoxicosis
- psychoactive substances
- presence of a structural or functional brain disorder such as encephalitis, tumor, delirium, or dementia

# Screening
There is insufficient evidence to recommend routine screening for NMS.

# Natural History, Complication and Prognosis
Most cases of neuroleptic malignant syndrome resolve within two weeks. The reported mean recovery time is 7 to 11 days. Depot antipsychotic use with concomitant structural brain disease is a risk factor for prolonged illness. Most patients recover without neurologic sequela if there is no prolonged hypoxic brain damage.
The mortality rate of NMS varies from 5 to 20%. Delay in diagnosis or treatment can prolong the recovery time that may result in parkinsonism or an increase in morbidity secondary to cardiopulmonary or renal complications.  When a death occurs in NMS patients that are due to DIC, arrhythmias, or cardiovascular complications.

# Diagnosis

## Diagnostic Study of Choice

## History and Symptoms
The tetrad of neuroleptic malignant symptoms usually evolves in one to three days. About 97-100% of the patients have the following features.
- Almost 82% of the patients present with mental status change
- Generalized muscle rigidity that is often extreme
- Hyperthermia, almost 87% of patients have a temperature of more than 38C a but even higher temperatures, greater than 40C, is present in 40%
- Autonomic instability typically takes the form of tachycardia (88%), labile or high blood pressure (61-77 %), and tachypnea (73%). Dysrhythmias may occur. Diaphoresis is often profuse.

## Physical Examination
- Altered mental status
- Muscle rigidity
- Hyperthermia
- Diaphoresis
- Tachycardia
- Tachypnea
- Increased or labile blood pressure
- Dystonia
- Dyskinesia
- Resting tremor

## Laboratory Findings
- Elevated serum CK
- Leukocytosis
- Mild elevations of LDH, ALP, and liver transaminases are common
- Electrolyte abnormalities: Hypocalcemia, metabolic acidosis, hypo or hypernatremia are common.
- Elevated creatinine may result from rhabdomyolysis

## Electrocardiogram
Electrolyte imbalances can cause cardiac arrhythmias that can cause cardiac arrest if not treated in a timely fashion. Both classes of antipsychotic drugs can cause serious cardiac side effects regardless of the electrolyte imbalances. One of the adverse side effects of antipsychotics is a prolongation of the QT interval that can convert into torsades de pontes causing sudden cardiac death.

## X-ray
There are no x-ray findings associated with NMS.

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with NMS.

## CT scan
Imaging studies with scans do not provide any diagnostic information for NMS. However, the CT brain may be helpful to rule out other conditions.

## MRI
MRI brain does not provide any diagnostic information for NMS but can be used to rule out other conditions.

## Other Imaging Findings
There are no other imaging findings associated with NMS.

## Other Diagnostic Studies
There are no other diagnostic studies associated with NMS.

# Treatment

## Medical Therapy
The management of patients with NMS should be based upon a hierarchy of clinical severity and diagnostic certainty. When manifestations are severe, intensive care unit monitoring and treatment are required.

### Stop causative agent
The single most important step in the treatment of NMS is removal os causative agents. If possible, other potential contributing psychotropic agents should also be stopped. When the precipitant is the discontinuation of dopaminergic therapy, it should be reinstituted.
Supportive care
Complications of the NMS are often fatal and following supportive treatment is required in the intensive care unit.
- Discontinue any precipitating antipsychotic medication
- Maintain cardiorespiratory stability. Mechanical ventilation and cardio consultation may be required.
- Maintain euvolemic state through the administration of intravenous fluids,
- If CK is elevated then urine alkalinization with high volume fluid should be done to prevent renal failure from rhabdomyolysis
- Cooling blankets should be used to lower fever, more aggressive measures such as ice water gastric lavagemay be required.
- Lower blood pressure if markedly elevated. clonidinemay be used.
- Prescribe heparin or LMWH to prevent deep venous thrombosis
- If needed, use benzodiazepines (eg, lorazepam 0.5 to 1 mg) to control agitation

### Pharmacotherapy
Recommendations for the treatment of NMS are based on clinical experience and case reports and randomized control trials were never done.  Dantrolene, amantadine, and bromocriptine are commonly used medications.  These agents are used in more severe cases and the dose is escalated if the patient gets worse.  A reasonable approach is to start with benzodiazepines (lorazepam or diazepam) along with dantrolene in moderate or severe cases, followed by the addition of bromocriptine or amantadine.

## Surgery
Surgical intervention is not recommended for the management of NMS.

## Primary Prevention
Prevention is the most important aspect of treatment. This includes reducing the risk factors, early recognization of the disease, and prompt discontinuation of the causative agent.

## Secondary Prevention
There are no established measures for the secondary prevention of NMS.