What are the symptoms of Neuroleptic Malignant Syndrome (NMS) in a patient with a history of psychiatric illness taking neuroleptic medications such as haloperidol (antipsychotic) or risperidone (atypical antipsychotic)?

Symptoms of Neuroleptic Malignant Syndrome (NMS)

NMS presents with a classic tetrad of symptoms: altered mental status, muscle rigidity, hyperthermia, and autonomic dysfunction—all of which must be evaluated immediately in any patient taking antipsychotic medications. 1

Cardinal Clinical Features

Mental Status Changes

• Delirium is the most common presentation, ranging from alert mutism to agitation, stupor, or coma 1
• Altered consciousness including confusion, agitation, aggression, or catatonic states 2, 3
• Mental status alterations are assigned 13 points in the diagnostic scoring system 1

Muscle Rigidity

• Lead pipe rigidity is the most common neurologic finding and the hallmark of NMS 1
• Other muscle abnormalities include akinesia, dyskinesia, or waxy flexibility 1
• Muscle rigidity is often associated with myonecrosis, myoglobinuria, and elevated serum CPK 3
• Rigidity is assigned 17 points in the diagnostic scoring system 1
• This distinguishes NMS from serotonin syndrome, which presents with hyperreflexia, clonus, and myoclonus rather than lead-pipe rigidity 1

Hyperthermia

• Fever progressing to hyperthermia is a key symptom, with diagnostic criteria requiring temperature >100.4°F oral on ≥2 occasions 1
• Hyperpyrexia is a defining feature 4, 2
• Hyperthermia is assigned 18 points in the diagnostic scoring system 1

Autonomic Dysfunction

• Tachycardia and blood pressure fluctuations are common autonomic symptoms, often preceding other manifestations 1
• Irregular pulse or blood pressure, cardiac dysrhythmias 4, 2
• Diaphoresis (excessive sweating) is frequent 1
• Tachypnea 3
• Sympathetic nervous system lability is assigned 10 points diagnostically 1

Additional Clinical Manifestations

Early Symptoms

• Sialorrhea (excessive salivation) and dysphagia may occur 1
• Urine incontinence 3
• Pallor and dehydration 3

Laboratory Abnormalities

• Creatine kinase elevation ≥4 times upper limit of normal (assigned 10 points diagnostically) 1
• Leukocytosis with white blood cell count of 15,000-30,000 cells/mm³ 1, 3
• Electrolyte abnormalities consistent with dehydration 1
• Elevated liver enzymes 1
• Myoglobinuria from rhabdomyolysis 2, 3

Critical Diagnostic Considerations

Timing and Context

• Symptoms typically develop within days after starting or increasing antipsychotic medication 1
• Dopamine antagonist exposure or dopamine agonist withdrawal within 3 days is assigned 20 points diagnostically 1
• NMS can occur with all neuroleptics, both typical (like haloperidol) and atypical (like risperidone), most often during the first week of treatment or after dose increases 4, 2, 5

Variable Presentations

• Not all patients will have all classic signs and symptoms—presentations can be variable and attenuated 6, 5
• Minor muscular rigidity may occur in atypical presentations, making diagnosis more challenging 5
• Long-acting depot antipsychotics can complicate diagnosis, as symptoms may persist for weeks due to prolonged drug release 5

Differential Diagnosis Features

The diagnosis is clinical with no pathognomonic laboratory criteria, requiring exclusion of: 1

• Serotonin syndrome (distinguished by hyperreflexia, clonus, myoclonus, and recent serotonergic drug exposure rather than lead-pipe rigidity)
• Malignant hyperthermia (triggered by anesthetics, not antipsychotics)
• Anticholinergic toxicity
• CNS infections (meningitis, encephalitis)
• Acute catatonia

Clinical Urgency

Early recognition is crucial: mortality has decreased from 76% in the 1960s to <10-15% with prompt management 1, 7, but life-threatening complications remain common, including rhabdomyolysis, metabolic acidosis, renal failure, seizures, disseminated intravascular coagulation, hepatotoxicity, and pulmonary edema 1.