What are the signs and symptoms of Neuroleptic Malignant Syndrome (NMS) in a patient with a history of psychiatric illness taking neuroleptic medications?

Signs and Symptoms of Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome presents with four cardinal features: altered mental status, muscle rigidity (typically "lead pipe" rigidity), hyperthermia, and autonomic instability—with mental status changes or rigidity typically appearing first, followed by fever and autonomic dysfunction. 1, 2

Classic Tetrad of NMS

Mental Status Changes

• Delirium is the most common presentation, ranging from alert mutism to agitation to stupor to coma 1
• Altered consciousness is consistently present and represents one of the four cardinal features 2
• Mental status changes are among the initial manifestations in 82.3% of cases presenting with a single sign 3

Muscle Rigidity

• Lead pipe rigidity is the most common neurologic finding and a cardinal feature of NMS 1, 2
• Other muscle abnormalities include akinesia, dyskinesia, or waxy flexibility 1
• Rigidity, along with mental status changes, appears early—before hyperthermia and autonomic dysfunction in most cases 3
• The rigidity contributes directly to hyperthermia through sustained muscle contractility and heat production 2

Hyperthermia

• Fever is a key symptom that can progress to severe hyperthermia, with temperatures reaching 41°C (105.8°F) or higher 1, 2
• Hyperthermia results from dopamine D2 receptor blockade in the hypothalamus, which increases the temperature set point and impairs heat-dissipating mechanisms 2
• Fever typically develops after mental status changes and rigidity in the temporal progression of symptoms 3

Autonomic Instability

• Tachycardia and blood pressure fluctuations (both hypertension and labile blood pressure) are common autonomic dysfunction symptoms 1, 4
• Diaphoresis (excessive sweating) is a frequent autonomic symptom 1, 4
• Irregular pulse, cardiac dysrhythmias, and autonomic dysfunction typically appear later in the syndrome's progression 5, 6, 3
• Sialorrhea and dysphagia may also occur 1

Laboratory Abnormalities

Creatine Kinase Elevation

• Elevated creatine kinase (≥4 times upper limit of normal) is a key diagnostic criterion and results from muscle breakdown (rhabdomyolysis) due to sustained muscle contraction 1, 2
• CK elevation is assigned 10 points in the diagnostic scoring system for NMS 1
• Myoglobinuria may accompany severe CK elevation 5, 6

Other Laboratory Findings

• Leukocytosis with white blood cell count of 15,000-30,000 cells/mm³ is commonly present 1, 2
• Electrolyte abnormalities consistent with dehydration are frequently observed 1, 2
• Elevated liver enzymes may be present due to systemic stress response 1, 2
• Metabolic acidosis can develop as a complication 1

Temporal Progression Pattern

A critical clinical pearl: 70.5% of cases follow a predictable sequence—mental status changes, then rigidity, followed by hyperthermia, and finally autonomic dysfunction. 3 This temporal pattern is important for early recognition, as mental status changes or rigidity appear first in 82.3% of cases with a single presenting sign 3.

Key Diagnostic Considerations

Risk Factors to Assess

• History of antipsychotic use or withdrawal of dopaminergic agents 1
• Coadministration of multiple psychotropic agents 1
• Dehydration, physical exhaustion, or preexisting organic brain disease 1
• Use of long-acting depot antipsychotics 1
• Male gender (2:1 male predominance) 1

Critical Differential Diagnosis

• Serotonin syndrome features hyperreflexia, myoclonus, and clonus rather than lead-pipe rigidity, and involves recent serotonergic drug exposure 1, 2
• Malignant hyperthermia is triggered by anesthetic agents in the operating room, not antipsychotics 1, 2
• Anticholinergic toxicity should be excluded 1
• CNS infections (meningitis, encephalitis) must be ruled out 1

Clinical Pitfalls

NMS can present with variable and attenuated presentations, making early recognition challenging. 1 Not all patients will have all classic signs simultaneously—for example, a patient with mild NMS may be afebrile but have tachycardia and hypertension 7. The diagnosis is clinical, as there are no pathognomonic laboratory criteria 1. Symptoms may develop within days after starting or increasing antipsychotic medication 1.

Early recognition is crucial: mortality has decreased from 76% in the 1960s to less than 10-15% with prompt management. 1, 2