How do you differentiate serotonin syndrome from malignant hyperthermia (MH) in a patient with altered mental status, muscle rigidity, and autonomic instability, who is taking selective serotonin reuptake inhibitors (SSRIs) or monoamine oxidase inhibitors (MAOIs)?

Differentiating Serotonin Syndrome from Malignant Hyperthermia

The key distinguishing features are: serotonin syndrome presents with hyperreflexia and clonus (especially inducible and ocular clonus) in patients taking serotonergic medications (SSRIs, MAOIs), while malignant hyperthermia occurs after exposure to volatile anesthetics or succinylcholine with lead-pipe rigidity and is a genetically determined calcium dysregulation disorder. 1, 2, 3

Clinical Context and Timing

Medication History:

• Serotonin syndrome develops within 6-24 hours of starting, increasing, or combining serotonergic agents (SSRIs, MAOIs, tramadol, linezolid, triptans) 2, 4
• Malignant hyperthermia occurs during or within 24 hours after exposure to triggering anesthetic agents (halothane, succinylcholine), though onset can be delayed especially in patients on steroids 1

Neuromuscular Examination: The Critical Differentiator

Serotonin Syndrome Features:

• Hyperreflexia and clonus are highly diagnostic when occurring with serotonergic drug use 2, 4
• Spontaneous clonus, inducible clonus (especially with agitation or diaphoresis), or ocular clonus 2, 5
• Myoclonus present in 57% of cases 5
• Tremor and muscle rigidity that is more pronounced in lower extremities 3

Malignant Hyperthermia Features:

• Lead-pipe rigidity throughout, not hyperreflexia 1, 3
• Jaw rigidity (masseter spasm) is often an early sign 3
• Intense muscle contraction from calcium dysregulation in skeletal muscle 1
• Absence of clonus and hyperreflexia 3

Autonomic and Mental Status Features

Both conditions share:

• Hyperthermia (can exceed 41.1°C in severe cases) 4
• Tachycardia, hypertension, diaphoresis 4
• Altered mental status 4

Serotonin syndrome specific:

• Agitated delirium and confusion are prominent 4
• Mydriasis (dilated pupils) 4
• Blood pressure fluctuations (≥20 mm Hg diastolic or ≥25 mm Hg systolic within 24 hours) 4

Malignant hyperthermia specific:

• Hypercarbia is a prominent early feature 3
• Rapidly progressive course in surgical setting 3

Diagnostic Approach Using Hunter Criteria

For serotonin syndrome diagnosis, use the Hunter Criteria (84% sensitivity, 97% specificity): 4

Requires serotonergic agent exposure PLUS one of:

• Spontaneous clonus
• Inducible clonus with agitation or diaphoresis
• Ocular clonus with agitation or diaphoresis
• Tremor and hyperreflexia
• Hypertonia, temperature >38°C, and ocular or inducible clonus 2, 4

Laboratory Findings

Both conditions:

• Elevated creatine phosphokinase (CPK) from muscle breakdown 1
• Potential for rhabdomyolysis, metabolic acidosis, renal failure 4

Important caveat: There are no pathognomonic laboratory findings for serotonin syndrome 4

Pathophysiologic Mechanisms

Serotonin syndrome:

• Excessive stimulation of 5-HT1A and 5-HT2A receptors in the central nervous system 1
• Central origin of muscle contraction 1

Malignant hyperthermia:

• Genetically determined dysregulation of cytoplasmic calcium control in skeletal muscle 1
• Peripheral origin of muscle contraction 1

Common Pitfalls to Avoid

• Do not rely solely on fever and rigidity to make the diagnosis—the neuromuscular examination (clonus vs. lead-pipe rigidity) is the key differentiator 3
• Serotonin syndrome can be confused with neuroleptic malignant syndrome (which also has lead-pipe rigidity but occurs with antipsychotic use, not anesthetics) 1, 5
• Mild serotonin syndrome cases are easily missed due to variable presentation 4
• The Hunter Criteria should aid diagnosis but should not be used to rule out serotonin syndrome 6

Immediate Management Differences

Serotonin syndrome:

• Discontinue all serotonergic agents immediately 2, 5
• Benzodiazepines as first-line for agitation and neuromuscular symptoms 2, 5
• Cyproheptadine (12 mg initially, then 2 mg every 2 hours) for moderate-severe cases 2, 4
• External cooling measures 2, 5

Malignant hyperthermia:

• Discontinue triggering anesthetic agents 1
• Dantrolene is the specific treatment 3
• Aggressive supportive care 1

Critical distinction: If unable to differentiate between serotonin syndrome and neuroleptic malignant syndrome, benzodiazepines represent the safest therapeutic option while avoiding potentially harmful agents 3