What is Neuroleptic Malignant Syndrome (NMS), its causes, symptoms, and treatment options, particularly in younger adults with a history of psychiatric disorders or neurological conditions?

Neuroleptic Malignant Syndrome (NMS)

Neuroleptic Malignant Syndrome is a rare but potentially fatal neurological emergency caused by dopamine receptor blockade from antipsychotic medications, characterized by the clinical tetrad of hyperthermia, muscle rigidity, altered mental status, and autonomic instability—requiring immediate discontinuation of the offending agent and aggressive supportive care. 1, 2

Definition and Pathophysiology

NMS results from dopamine D2 receptor blockade in the hypothalamus, which increases the temperature set point and impairs heat-dissipating mechanisms, while the same blockade in nigrostriatal pathways produces muscle rigidity via extrapyramidal pathways 3. This leads to increased calcium release from the sarcoplasmic reticulum, causing sustained muscle contractility that generates both rigidity and heat production 3. The sustained muscle contraction results in rhabdomyolysis, releasing creatine kinase into the bloodstream 3.

Clinical Presentation

The Classic Tetrad

The four cardinal features typically progress in a specific temporal sequence 2, 4:

• Mental status changes (alert mutism, delirium, agitation, stupor, or coma) appear first in 82.3% of cases 2, 4
• Muscle rigidity ("lead pipe" rigidity) develops early, often as the initial or second manifestation 2, 4
• Hyperthermia (>100.4°F, can reach 41°C or higher) progresses after mental status changes and rigidity 2, 3
• Autonomic instability (tachycardia, blood pressure fluctuations, diaphoresis, cardiac dysrhythmias) typically appears last 2, 4

Additional Clinical Features

• Sialorrhea and dysphagia may occur 2
• Other muscle abnormalities include akinesia, dyskinesia, or waxy flexibility 2
• Diaphoresis (excessive sweating) is frequent 2

Laboratory Findings

Order these tests immediately when NMS is suspected 3:

• Creatine kinase (CK): The single most important marker, typically elevated ≥4 times upper limit of normal, often 1000-10,000 U/L 3
• Complete blood count: Leukocytosis of 15,000-30,000 cells/mm³ is common 2, 3
• Comprehensive metabolic panel: Electrolyte abnormalities consistent with dehydration, elevated liver enzymes (AST, ALT often 45-55 IU/L or higher) 2, 3
• Arterial blood gas: Check for metabolic acidosis, which indicates poor prognosis 3
• Urinalysis: Assess for myoglobinuria from rhabdomyolysis 1
• Coagulation studies: If disseminated intravascular coagulation is suspected 3

Diagnostic Criteria

Use this point-based system where ≥76 points indicates probable NMS 2:

• Dopamine antagonist exposure or dopamine agonist withdrawal within 3 days: 20 points 2
• Hyperthermia (>100.4°F oral on ≥2 occasions): 18 points 2
• Rigidity: 17 points 2
• Mental status alteration: 13 points 2
• CK elevation (≥4 times upper limit of normal): 10 points 2
• Sympathetic nervous system lability: 10 points 2
• Negative workup for infectious, toxic, metabolic, or neurologic causes: 7 points 2
• Hypermetabolism: 5 points 2

Differential Diagnosis

Distinguish NMS from these conditions 2, 3:

• Serotonin syndrome: Features hyperreflexia, myoclonus, and clonus (not lead-pipe rigidity), recent serotonergic drug exposure, typically lower CK levels 2, 3
• Malignant hyperthermia: Triggered by anesthetic agents in the operating room, not antipsychotics 2, 5
• Anticholinergic toxicity: Lacks severe rigidity and extreme CK elevation 2
• CNS infections (meningitis, encephalitis): Excluded by appropriate workup 2
• Acute catatonia: Can be difficult to distinguish but lacks the same degree of autonomic instability 2

Risk Factors

Identify these high-risk scenarios 2:

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

Causative Agents

All antipsychotics can cause NMS 6, 5, 7:

• First-generation (typical) antipsychotics: Haloperidol is frequently implicated 5, 8
• Second-generation (atypical) antipsychotics: Risperidone, quetiapine, and others can cause NMS 6, 8, 9
• NMS can occur with atypical antipsychotics despite lower D2 receptor affinity 8

Treatment

Immediate Management (Do Not Wait for Lab Results)

The cornerstone of treatment is immediate discontinuation of all antipsychotic medications plus aggressive supportive care 1, 2, 3:

1. Stop the offending agent immediately—this is the first and most critical step 1
2. If NMS was triggered by abrupt withdrawal of an anti-Parkinson drug, consider reintroducing it 2

Supportive Care Measures

• Benzodiazepines for agitation (first-line agent) 1, 2
• External cooling measures for hyperthermia 1, 2
• IV fluids aggressively for dehydration and to prevent renal failure from rhabdomyolysis 1, 2
• Normalize vital signs with appropriate agents for autonomic instability 1

Pharmacologic Interventions for Severe Cases

• Dopaminergic agents (bromocriptine) to address dopamine deficiency 1
• Muscle relaxants (dantrolene sodium) to reduce muscle rigidity and hyperthermia 1

Advanced Interventions

• Emergency sedation, neuromuscular paralysis, and intubation for extreme hyperthermia (>41.1°C) 1, 2
• ICU admission necessary for approximately 25% of patients 1
• Electroconvulsive therapy (ECT) as second-line treatment for severe and persistent NMS, particularly if concurrent psychiatric condition would benefit from ECT 1
• Hemodialysis if renal failure occurs 2
• Plasmapheresis may have a role in severe NMS with organ dysfunction 9

Monitoring for Complications

Watch closely for these life-threatening complications 1, 2:

• Rhabdomyolysis with markedly elevated CK 1, 2
• Metabolic acidosis 1, 3
• Acute renal failure 1, 2
• Seizures 1
• Disseminated intravascular coagulation 1
• Hepatotoxicity 2
• Pulmonary edema 2
• Aspiration pneumonia (especially with vocal cord dysfunction) 9

Critical Pitfalls to Avoid

• Never use physical restraints—they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis, thereby increasing mortality 1
• Avoid pro re nata (p.r.n.) chemical restraints, which are prohibited 1
• Do not wait for all lab results before initiating treatment—begin supportive care immediately upon clinical suspicion 3
• Do not confuse with serotonin syndrome—NMS shows much higher CK levels (often >1000 U/L), more pronounced leukocytosis, and lead-pipe rigidity rather than hyperreflexia 3

Prognosis and Outcomes

• Mortality has decreased dramatically from 76% in the 1960s to less than 10-15% with prompt recognition and management 1, 2, 3
• Early recognition and immediate intervention are crucial for improving outcomes 1, 2
• Most patients recover promptly with appropriate treatment 8
• If antipsychotic treatment is required after recovery, carefully consider reintroduction and monitor closely, as recurrences have been reported 6, 5

Special Considerations in Younger Adults

• NMS can occur in adolescents and young adults with psychiatric disorders 9
• Polypharmacy (multiple psychotropic agents) increases risk significantly 2, 9
• Overdose situations may present with overlapping features of multiple syndromes, complicating diagnosis 9
• Low BMI and malnutrition may be additional risk factors 9