Neuroleptic Malignant Syndrome: a rare but potentially fatal phenomenon

Neuroleptic malignant syndrome (NMS) is a rare and life-threatening neurological emergency. This syndrome is reported to occur in 0.02% to 3% of people taking neuroleptic medications. While NMS is predominantly associated with typical high-potency neuroleptic agents (e.g. haloperidol, fluphenazine), every class of neuroleptic drug has been implicated including low-potency neuroleptics (e.g. chlorpromazine), atypical antipsychotic agents (e.g. clozapine, risperidone, olanzapine), and some antiemetic medications (e.g. metoclopramide, promethazine).

NMS is characterised by a myriad of clinical features including hyperthermia, muscle rigidity, autonomic instability, and altered mental status. In 90% of cases, symptoms develop within two weeks of initiating neuroleptic therapy. However, symptoms can occur after a single dose or after many years of treatment with the same agent. The emergence of NMS is associated with the use of high doses and agents with a prolonged duration of effect. Other commonly listed risk factors include concomitant use of lithium or other psychotropic drugs, higher potency agents, depot formulations, and comorbid substance abuse, neurologic disease, or acute medical illness. Abrupt withdrawal of anti-Parkinson medication may also be a potential precipitant. While age and gender are not considered to be risk factors, many NMS case reports relate to young men. This distribution is thought to be a reflection of the higher use of neuroleptic agents in this population.

Early identification of NMS is crucial so that appropriate treatment may commence. If left untreated, the course of the disease is unpredictable and can result in severe systemic complications. Death may occur early in the course of the disease as a result of respiratory failure or cardiovascular arrest, or as the disease progresses due to renal failure, refractory acidosis, or multiorgan failure. Since the 1960’s, reported mortality rates have declined from 76% to an estimated 10% to 20%. These improved statistics may be attributed to greater awareness of the disease, earlier diagnosis, and more aggressive intervention.

Pathophysiology

The cause of NMS is unknown and current theories are limited in their ability to explain all clinical features with supporting data. Pivotal to most theories is the specific dopamine receptor blocking action of the individual neuroleptic agent. Central dopamine blockade in the hypothalamus may cause hyperthermia and other signs of autonomic dysfunction. Interference with dopamine pathways may also lead to Parkinson’s-type symptoms such as rigidity and tremor.

Another theory suggests that the rigidity and muscle damage seen in NMS represents a primary effect on the peripheral skeletal muscle system. It is proposed that neuroleptic use directly changes mitochondrial function in muscle tissue. This may denote a direct toxic effect of these agents on the skeletal muscle that manifests as increased muscle contractility, muscle breakdown, and hyperthermia in susceptible individuals. This theory may also help to explain the disrupted modulation of the sympathetic nervous system that results in increased muscle tone and metabolism, and unregulated sudomotor and vasomotor activity. These effects lead to ineffective heat dissipation, and labile blood pressure and heart rate.

Familial clusters of NMS may also suggest a genetic predisposition to the disorder. Genetic studies identified an overrepresentation of a specific allele of the dopamine D₂ receptor gene in NMS patients. This allele is associated with reduced function of dopamine receptors.

Clinical Features

Typical symptoms evolve over one to three days and may include the following:

• Mental status change is an initial symptom in 82% of patients and presents as agitated delirium with confusion rather than psychosis. The significance of this symptom is often underappreciated in this population and may be mistaken for treatment failure or patient noncompliance. Progression to stupor or coma may occur.
• Muscular rigidity is generalised and often extreme. Symptoms are usually described as increased tone resembling that of a “lead pipe” or stable resistance through all ranges of movement. Other motor abnormalities include tremor (affecting 45% to 92% of patients) and less commonly, dystonia and other dyskinesias.
• Hyperthermia is the defining symptom according to many diagnostic criteria. A temperature of more than 38°C is typical and presents in approximately 87% of patients. However, temperatures more than 40°C may occur in 40% of patients.
• Autonomic instability typically presents in the form of tachycardia (88%) or labile blood pressure (61% to 77%). Dysrhythmias may also occur.

Unfortunately, due to the idiosyncratic nature of the syndrome and substantial variability in presentation, no consistent diagnostic criterion has been developed. Analysis of reported cases demonstrate that the typical course (developed in around 70% of patients) consists firstly of altered mental status, followed by rigidity, then hyperthermia and autonomic dysfunction. However, a greater than 24-hour delay in the presentation of fever has led to initial diagnostic confusion in some cases.

Treatment

Successful treatment of NMS depends on early clinical recognition and prompt withdrawal of offending agents. Additionally, other potentially contributing psychotropic agents (lithium, anticholinergic agents, serotonergic agents) should be reviewed and ceased if possible. As neuroleptics cannot be removed via dialysis and concentrations in the bloodstream decrease slowly, general symptomatic treatment is essential. It is also vital that secondary complications be identified and managed effectively. Potential complications that require management include:

• Rhabdomyolysis from sustained muscle rigidity
• Dehydration
• Electrolyte imbalance
• Acute renal failure associated with rhabdomyolysis
• Cardiac arrhythmias including torsades de pointes
• Cardiac arrest
• Myocardial infarction
• Respiratory failure from chest wall rigidity, aspiration pneumonia, pulmonary embolism
• Deep vein thrombosis
• Thrombocytopenia
• Seizures from hyperthermia
• Hepatic failure
• Sepsis

Due to the serious nature of the syndrome, swift admission to an intensive care unit where regular monitoring and administration of supportive therapy can be provided is necessary. Some parameters may require the addition of adjunct treatment and monitoring. The following measures should be provided:

• Maintenance of cardiorespiratory stability – mechanical ventilation or antiarrhythmic agents may be needed.
• Fluid loss from fever and excessive sweating should also be considered. If creatine kinase is significantly elevated, high volume intravenous fluids with urine alkalinisation may help prevent or treat renal failure from rhabdomyolysis.
• Lowering fever using cooling blankets can help. More aggressive physical measures may be employed such as ice water gastric lavage and ice packs in the underarm region. Use of paracetamol or aspirin may have a role in reducing temperature, although evidence to support their use is lacking.
• Lowering blood pressure if marked hypertension occurs. Although there is no preference for any specific agent, there is significant evidence to support the effectiveness of clonidine in this situation. An infusion of nitroprusside may be advantageous in facilitating cooling through cutaneous vasodilation.
• Heparin or low molecular weight heparin may be prescribed for the prevention of DVT in immobilised patients.
• Benzodiazepines (e.g. clonazepam, lorazepam) may be used to control agitation, if necessary.

Recommendations for specific medical treatments in NMS are based upon case reports and clinical experience and not upon data from controlled clinical trials. Dantrolene, bromocriptine, or amantadine are commonly prescribed to alleviate some of the initial symptoms.

Dantrolene is a direct-acting skeletal muscle relaxant and is effective in treating malignant hyperthermia. Its purpose is to reduce the production of heat as well as rigidity. Effects are reported within minutes of administration. Doses of 1-2.5mg/kg IV are typically given in adults and can be repeated to a maximum of 10mg/kg per day.

Bromocriptine, a dopamine agonist, is prescribed to restore lost dopaminergic tone. Doses of 2.5mg every six to eight hours can be titrated up to a maximum dose of 40mg per day. It is generally continued for ten days after NMS is controlled, then tapered slowly. However, longer courses of treatment may be required for patients who have received parenteral neuroleptics.

Amantadine has dopaminergic and anticholinergic effects and may beadministered as an alternative to bromocriptine.

Most patients recover within two weeks without any long-term adverse effects. However, more protracted cases have been reported. Risk factors for a more prolonged course include the use of depot injections and pre-existing structural brain disease. Residual neurologic effects normally only occur in patients who experience severe hypoxia or prolonged or extreme hyperthermia.

Restarting Neuroleptics

Patients may or may not experience a recurrence of NMS with subsequent neuroleptic therapy. The risk of recurrence is difficult to quantify from the available data. Hence, caution is recommended when reinstating these agents. If neuroleptic medication is required, the following guidelines may minimise the risk.

• Recommencement after at least two weeks has elapsed since the resolution of symptoms, or six weeks if parenteral neuroleptics have been used
• Start with low doses and titrate upward slowly
• Avoid concomitant lithium
• Prevent dehydration
• Monitor for symptoms of NMS

Most patients who experience NMS have schizophrenia. For these patients, continued use of neuroleptic agents is often necessary. While there is a dearth of evidence on this rare condition, patients may be able to receive the offending agent again without recurrence of symptoms. However, it would be reasonable to consider reinitiating neuroleptic therapy with a lower potency neuroleptic from a different chemical class.