Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), although rare, is a potentially life-threatening side effect of neuroleptic agents. NMS is considered an idiosyncratic reaction that may occur at any time during the course of treatment or when dopamine antagonistic therapy is discontinued. Incidence of NMS is not believed to be dose-related.

Incidence

• Among patients treated with neuroleptics, 0.02-3.23% are diagnosed with neuroleptic malignant syndrome. This wide discrepancy is due to many factors including lack of agreement on diagnostic criteria and difficulty estimating the size of the population at risk.
• The mortality rate associated with NMS is approximately 11.6%. Patients receiving various pharmacological interventions including dantrolene, bromocriptine, and amantadine have displayed lower mortality rates than those treated only with supportive measures.
• There are two peak age groups for the incidence of NMS, including individuals younger than 40 and over 70. The majority of cases, 80%, affect people under the age of 40. Patients displaying NMS in the younger group are commonly people taking neuroleptics for psychotic disorders, while those in the older group commonly develop NMS after discontinuation of dopaminergic agents.
• NMS is approximately twice as common in men.

Clinical Presentations>

Onset of NMS

• The onset of NMS generally occurs 3-9 days after the initiation of neuroleptic treatment or the addition of a second medication. However, NMS may occur after a single dose or prolonged treatment.

  Table: Risk factors associated with NMS

  Male gender Parenteral administration of neuroleptics Withdrawal of anti-parkinsonian medication Prolonged use of restraints Dehydration Agitation Alcoholism

• The symptoms of NMS typically develop over the course of 1-3 days.
• The types of drugs most commonly associated with NMS are neuroleptic agents such as phenothiazines, butyrophenones, and thioxanthenes. Higher potency neuroleptics may be more likely to cause this syndrome.
• Newer atypical antipsychotics have been implicated in causing NMS in rare cases. A 2002 review cited isolated reports of NMS associated with clozapine, risperidone, olanzapine and possibly quetiapine, but indicated that these agents carry a lower risk for NMS than traditional neuroleptics.
• NMS may also occur when individuals cease taking dopaminergic agents such as L-dopa and carbidopa, which are used to treat Parkinson's disease.

Diagnosis of NMS

• NMS presents with a relatively consistent clinical picture.
  • Autonomic dysfunction is often the earliest clinical finding in NMS. Common manifestations of autonomic instability include massive peripheral hyperadrenergic state, hypertension, postural hypotension, violence, tachycardia, tachypnea, hypoventilation, pallor, flushing, vasoconstriction, incontinence, excessive perspiration and diaphoresis.
  • Hyperthermia, generally in the range of 39-42°C (in rare cases fever is not present) is believed to be a result of excessive heat production (from muscle contraction) when heat dissipating mechanisms are overwhelmed (from vasoconstriction).
  • Altered mental status is standard and ranges from mild confusion, agitation, and lethargy to stupor and coma.
  • Rigidity of the musculature may range from mild hypertonicity to lead-pipe rigidity.
    • Other extrapyramidal symptoms that are common in NMS patients include tremors, cogwheeling, masked face, dystonia, dyskinesia, opisthotonos, dysphagia, sialorrhea, choreiform movements, trismus, opsoclonus, oculogyric process, retrocollis, festinating gait, and flexor-extensor posturing.
• Though no single laboratory test can produce a definitive diagnosis of NMS, certain laboratory abnormalities are commonly associated with this syndrome.
  • Above normal levels of creatinine phosphokinase (CPK), (>1000 units/L) are commonly present. Levels as high as 100,000 units/L have been reported.
  • Another indicator of NMS is elevated WBC counts in the range of 10,000-40,000/ mm.
  • Elevated CPK and WBC levels are the result of prolonged muscle contraction and hyperthermia.
  • Toxicological screening should be performed to determine the presence of any causative or exacerbating substances, such as MDMA (ecstasy) or cocaine.
  • Other complications related to NMS that may be detectable in lab tests include: myoglobinuria, metabolic acidosis, renal insufficiencies, and elevated hepatic transaminases.
• The differential diagnosis of NMS is relatively straightforward. Infectious, metabolic, environmental, and toxicological etiologies should be ruled out first.
  • CNS infections mimicking NMS can generally be distinguished by lumbar puncture and encephalogram. NMS lacks changes in glucose, white cells, and protein expected in central nervous system infections. Encephalitis and sepsis are two problems that may be mistaken for NMS.
  • Metabolic problems that can resemble NMS include hyperthyroidism, hypothyroidism, and hypomagnesemic tetany.
  • People taking neuroleptics may be increasingly susceptible to heat stroke, as these agents are believed to suppress central heat loss mechanisms. However, presentation with neuroleptic-induced heat stroke is associated with hot, dry skin rather than the diaphoresis associated with NMS. Furthermore, unlike those with NMS, patients who had neuroleptic-induced heat strokes may present with seizures, absence of EPS, absence of sweating, and history of exposure to high temperature.
  • Allergic drug reactions may produce fever and autonomic instability, but not rigidity. Furthermore, neuroleptics may produce extrapyramidal symptoms in the absence of fever, leukocytosis, and autonomic disturbances. Serotonin syndrome and atropinism (overdose with anticholinergic drugs) may also be confused with NMS. Intoxication with MDMA (ecstasy) or cocaine may mimic the symptoms of NMS.
• Otherwise only a few disorders are similar in appearance to NMS. Two diseases commonly mistaken for NMS are malignant hyperthermia and lethal catatonia, both of which present with fever and muscle rigidity.
  • Malignant hyperthermia describes a genetically determined defect in calcium transport which manifests as an abnormal contraction response of muscle tissue. This condition can lead to lethal hyperthermia and its onset is most frequently associated with exposure to anesthetics. This can be diagnosed by exposing biopsied muscle tissue to caffeine or halothane in vitro which results in a hypercontractile response when compared with normal muscle.
  • Lethal catatonia is a syndrome characterized by mutism, motor hyperactivity, altered consciousness, and fever that may progress to severe autonomic disturbances, coma, and death. Unlike NMS, this disease can present with severe anxiety and agitation as well as choreiform stereotypy.

Treatment

• Patients believed to have NMS should be transferred to an intensive care unit.
• Discontinuation of the offending neuroleptic agent is the first priority in the treatment of NMS. If prescribed, lithium should be discontinued as should anticholinergic drugs, in the case of severe extrapyramidal symptoms. Alternatively, if NMS was caused by discontinuation of dopamine agonists, these agents should be reinstated.
• The foundation of NMS treatment generally includes rapid cooling, fluid and electrolyte repletion, critical care monitoring, and supportive antipyretics.
• The pharmacologic treatment of NMS is based on dopamine agonists.
  • Bromocriptine is regarded as the drug of choice, with most patients responding within one day. Bromocriptine should be started at a dose of 2.5 mg orally, 2-3 times/day, and can be increased by 2.5-7.5 mg daily to a maximum dose of 30-45 mg/day.
  • Amantadine, an indirect dopamine agonist, can be given orally at a dose of 100-200 mg twice daily.
  • Levodopa alone, or in combination with carbidopa (a dopadecarboxylase inhibitor), may be effective for treating patients who are dopamine depleted.
• Dantrolene, a nonspecific skeletal muscle relaxer, can be used when muscle rigidity is severe and body temperature is difficult to control. Dantrolene is given orally in daily dosages of 50-600 mg or intravenously at doses of 1-10 mg/kg every 6 h. Dantrolene can produce a rare but fatal hepatocellular injury and should not be used in patients with preexisting liver disease.
• Otherwise, the treatment of NMS is based on symptomatology. Depending on the nature and severity of the patient's condition, other interventions include short-term antihypertensives (such as nifedipine), vasodilators (such as minoxidil or nitroprusside), heparin (to prevent deep venous thrombosis and pulmonary embolism), oxygen, and intubation.
• Most patients recover from the acute complications of NMS within 2-14 days without any cognitive impairment. In some instances a residual catatonic state persists for weeks or months after acute hyperthermic symptoms subside. Prolonged dysfunction is usually related to high fever, hypoxia, or other complications. Some complications that may be associated with NMS include renal failure, electrolyte abnormalities, dysrhythmias, aspiration pneumonia, sepsis, and pulmonary embolism secondary to the formation of deep vein thromboses. NMS caused by depot injections also tends to take longer to resolve.
• If treatment is deemed successful, a minimum of 2 wk should be allowed before the reintroduction of neuroleptics. Approximately, one-third of patients in whom neuroleptics are rechallenged experience recurrence of symptoms.
• In some cases death results from NMS or associated life-threatening complications. Mortality among NMS patients is usually attributed to respiratory failure resulting from thromboembolism or pneumonia.