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Difficulty: MediumFormulating a Differential Diagnosis

A 42-year-old man is brought to the emergency department by his wife due to confusion, agitation, and shivering that began earlier today. He has a history of major depressive disorder, for which he takes fluoxetine. Three days ago, he was evaluated at an urgent care clinic for a purulent right lower leg wound and was prescribed an oral antibiotic for presumed methicillin-resistant *Staphylococcus aureus* (MRSA) cellulitis. On presentation, his temperature is 39.1°C (102.4°F), blood pressure is 158/94 mm Hg, heart rate is 122/min, and respiratory rate is 22/min. Physical examination reveals an agitated and diaphoretic man. The right lower extremity shows resolving erythema and induration without fluctuance. Neurologic examination is notable for generalized muscle rigidity, brisk deep tendon reflexes (3+ bilaterally), and reproducible bilateral ankle clonus. Bowel sounds are hyperactive. Laboratory studies show a leukocyte count of 11,500/mm311,500/\text{mm}^3 and a creatine kinase level of 850 U/L850 \text{ U/L}. Which of the following is the most likely diagnosis?

  1. Serotonin syndromeAnswer
  2. B
    Neuroleptic malignant syndrome
  3. C
    Anticholinergic toxicity
  4. D
    Malignant hyperthermia
  5. E
    Sepsis-associated encephalopathy

Answer

Serotonin syndrome
The correct diagnosis is serotonin syndrome. This patient's presentation of altered mental status, autonomic instability (fever, tachycardia, hypertension, diaphoresis), and neuromuscular hyperactivity (hyperreflexia, reproducible clonus, and rigidity) is highly characteristic of this toxidrome. He has a history of depression treated with fluoxetine, a selective serotonin reuptake inhibitor (SSRI). Furthermore, the recent prescription for an oral antibiotic targeting MRSA cellulitis strongly suggests he was given linezolid. Linezolid is an oxazolidinone antibiotic that also possesses reversible, non-selective monoamine oxidase inhibitor (MAOI) properties. The concurrent use of linezolid and an SSRI is a well-documented precipitant of life-threatening serotonin syndrome due to synergistically impaired serotonin metabolism and inhibited reuptake.

Step-by-Step Solution

1
Identify the patient's key clinical triad from the physical examination.
The patient exhibits altered mental status (agitation, confusion), autonomic instability (fever, tachycardia, diaphoresis), and neuromuscular hyperactivity (hyperreflexia, clonus, rigidity).
Categorizing the specific signs of a toxidrome is the first crucial step in formulating a differential diagnosis for acute toxic or metabolic encephalopathy.
2
Review the patient's medication history for potential pharmacologic triggers.
The patient takes fluoxetine (an SSRI) and recently started an oral antibiotic for an MRSA infection, which is highly likely to be linezolid.
Identifying recent medication additions or potential drug-drug interactions is necessary to establish the etiology of the toxidrome.
3
Synthesize the clinical and pharmacologic data to select the most likely diagnosis.
The combination of an SSRI with linezolid (which possesses MAOI activity) classically precipitates serotonin syndrome, which perfectly matches the patient's neuromuscular findings and autonomic instability.
Matching the pathophysiologic mechanism of the drug interaction with the patient's distinct physical exam findings confirms the diagnosis and successfully excludes overlapping differentials.

Key Concept

Differentiating toxic encephalopathies by identifying the classic neuromuscular findings of serotonin syndrome (hyperreflexia, clonus) and recognizing the drug-drug interaction between SSRIs and linezolid.
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Formulating a Differential Diagnosis

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