What is the difference between neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) in terms of triggers, symptoms, and management?

Difference Between Neuroleptic Malignant Syndrome and Malignant Hyperthermia

Neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) are distinct life-threatening hypermetabolic emergencies that differ fundamentally in their triggers, underlying mechanisms, and clinical contexts, though both present with hyperthermia, rigidity, and autonomic instability.

Triggers and Causative Agents

Malignant Hyperthermia

• MH is triggered exclusively by volatile inhalational anesthetic agents and succinylcholine during general anesthesia 1
• The triggering agents include all volatile (inhalation) anesthetic agents and the depolarizing neuromuscular blocker succinylcholine 1
• MH represents an intrinsic abnormality of skeletal muscle tissue where triggering agents produce changes within the muscle cell resulting in elevated myoplasmic calcium 2

Neuroleptic Malignant Syndrome

• NMS is triggered by antipsychotic medications (dopamine antagonists) or abrupt withdrawal of dopaminergic agents 3, 4
• Causative agents include thioxanthenes, phenothiazines, butyrophenones, and newer atypical antipsychotics 5, 6
• NMS can occur days after starting or increasing antipsychotic medication, and has been associated with virtually all neuroleptics 3, 5

Underlying Pathophysiology

Malignant Hyperthermia

• MH is a primary muscle cell disorder where excessive calcium release from the sarcoplasmic reticulum causes hypermetabolism 2
• The mechanism involves direct muscle cell dysfunction with elevated myoplasmic calcium activating acute cellular catabolic processes 2
• MH has autosomal-dominant inheritance with prevalence estimated at 1:3000 1

Neuroleptic Malignant Syndrome

• NMS is a central nervous system disorder caused by dopamine receptor blockade or dopamine depletion 3, 5
• The postulated mechanisms affect the CNS rather than the muscle cell itself 6
• NMS shows male predominance (2:1 ratio) and is associated with risk factors including dehydration, physical exhaustion, multiple psychotropic agents, and preexisting organic brain disease 3

Clinical Presentation and Timing

Malignant Hyperthermia

• The earliest sign of MH is unexplained increase in end-tidal CO₂ despite increased minute ventilation, often before temperature elevation 1, 7
• Increased carbon dioxide production and heart rate occur early, with temperature potentially still normal when diagnosis is made 1
• Masseter spasm after succinylcholine administration is a characteristic early sign 1
• Generalized muscle rigidity may occur even in the presence of non-depolarizing neuromuscular blockade 1

Neuroleptic Malignant Syndrome

• NMS typically presents with mental status changes or lead-pipe rigidity as the initial manifestations (82.3% of cases), followed by hyperthermia and autonomic dysfunction 3, 8
• The classic tetrad includes delirium (ranging from alert mutism to coma), lead-pipe rigidity, fever progressing to hyperthermia, and autonomic instability with tachycardia and blood pressure fluctuations 3
• Symptoms develop over days rather than minutes to hours as in MH 3, 5
• Diaphoresis, sialorrhea, and dysphagia are common 3

Diagnostic Features

Malignant Hyperthermia

• Diagnosis is based on pattern recognition during anesthesia: unexplained hypercarbia, tachycardia, and muscle rigidity in the presence of triggering agents 1
• Temperature may rise rapidly if untreated but is not always the first sign 7
• Suspected cases should undergo in vitro contracture testing (IVCT) at specialized MH laboratories 1

Neuroleptic Malignant Syndrome

• NMS diagnosis uses a point-based system where ≥76 points indicates probable NMS, including dopamine antagonist exposure (20 points), hyperthermia >100.4°F (18 points), rigidity (17 points), mental status alteration (13 points), and CK elevation ≥4× normal (10 points) 3
• Laboratory findings include leukocytosis (15,000-30,000 cells/mm³), elevated CK and liver enzymes, and electrolyte abnormalities consistent with dehydration 3
• The diagnosis is clinical with no pathognomonic laboratory criteria 3

Key Distinguishing Features from Similar Conditions

Differentiating NMS from Serotonin Syndrome

• NMS presents with lead-pipe rigidity, while serotonin syndrome features hyperreflexia, clonus, and myoclonus 3, 4
• Serotonin syndrome involves recent serotonergic drug exposure rather than antipsychotics 3

Management Approaches

Malignant Hyperthermia Treatment

• Immediately stop all trigger agents, turn off and remove vaporizer, hyperventilate with 100% oxygen at 2-3× normal minute volume, and insert activated charcoal filters on inspiratory and expiratory limbs 1, 7
• Administer dantrolene 2 mg/kg IV immediately, repeating until cardiac and respiratory systems stabilize; maximum dose (10 mg/kg) may need to be exceeded 1
• Active body cooling with chilled (4°C) saline 2000-3000 mL IV, cold sheets, fans, and ice packs to axillae and groin 1
• Do not waste time changing the circuit or anesthetic machine 1
• Delay in treatment is associated with increased mortality 1

Neuroleptic Malignant Syndrome Treatment

• Immediately discontinue all antipsychotic medications and provide aggressive supportive care including benzodiazepines for agitation, external cooling for hyperthermia, and IV fluids for dehydration 3, 4
• Consider reintroducing anti-Parkinsonism drugs if NMS was triggered by abrupt withdrawal 4
• For severe NMS, consider dopaminergic agents (bromocriptine) and dantrolene sodium after initiating supportive care 4
• Emergency sedation, neuromuscular paralysis, and intubation may be necessary for extreme hyperthermia >41.1°C 4
• Avoid physical restraints as they exacerbate isometric muscle contractions, worsening hyperthermia and lactic acidosis 4
• Avoid anticholinergics for routine prevention of extrapyramidal symptoms as they may worsen autonomic instability 4

Mortality and Prognosis

Malignant Hyperthermia

• Survival is highly dependent on early recognition and prompt action with dantrolene administration 1
• Early treatment has dramatically improved outcomes 1

Neuroleptic Malignant Syndrome

• Mortality has decreased from 76% in the 1960s to <10-15% with prompt management and early recognition 3, 4
• Life-threatening complications include rhabdomyolysis, metabolic acidosis, renal failure, seizures, disseminated intravascular coagulation, hepatotoxicity, and pulmonary edema 4
• Approximately 25% of patients require ICU admission 4

Critical Clinical Pitfalls

For MH: Do not delay treatment while awaiting temperature elevation—unexplained hypercarbia is sufficient to initiate treatment 1, 7. Ensure adequate dantrolene supply (36-50 ampoules may be needed for an adult) 1.

For NMS: Do not confuse lead-pipe rigidity with the hyperreflexia of serotonin syndrome 3. Monitor CK levels during follow-up as they can indicate recurrence 9. Wait at least 2 weeks following resolution before attempting antipsychotic rechallenge 10.