How do you differentiate between central fever, drug fever, and paroxysmal sympathetic hyperactivity in a patient with a high fever and suspected brain injury or infection?

Differentiating Central Fever, Drug Fever, and Paroxysmal Sympathetic Hyperactivity

In patients with suspected brain injury, use procalcitonin levels (<0.5 ng/mL excludes infection), temporal relationship to medications (drug fever appears after mean 21 days), and the PSH-Assessment Measure tool (for episodic sympathetic hyperactivity with dystonia) to distinguish these three entities, while always treating as infectious fever first in unstable patients. 1, 2, 3

Immediate Diagnostic Algorithm

Step 1: Obtain procalcitonin level and blood cultures immediately before any intervention, regardless of clinical suspicion. 1

Step 2: Assess hemodynamic stability and clinical trajectory:

• If procalcitonin >0.5 ng/mL OR patient clinically deteriorating → Treat as infectious fever with empirical antimicrobials within 1 hour 1
• If procalcitonin <0.5 ng/mL AND patient stable → Proceed to differentiate between central fever, drug fever, and PSH 1, 4

Central Fever (Neurogenic Fever)

Clinical Presentation:

• Core temperature >37.5°C driven by neurological dysregulation in the absence of sepsis or clinically significant inflammatory process 5
• Occurs in approximately 25% of neurocritical care patients, with almost half being noninfectious in etiology 5
• Well-tolerated fever despite high temperatures, without clinical toxicity 1
• Associated with severe traumatic brain injury, particularly with impending herniation or obliterated basal cisterns 5

Diagnostic Features:

• Procalcitonin remains <0.5 ng/mL 1, 4
• No temporal relationship to medication administration 1
• Absence of episodic paroxysmal symptoms (no cyclic pattern with dystonia) 2, 3
• CSF analysis shows ≤5 white blood cells/µL, normal opening pressure, and normal protein concentration (essentially excludes meningitis in immunologically normal hosts) 5

Management:

• Controlled normothermia targeting 36.0–37.5°C using automated feedback-controlled temperature management devices 5
• Propranolol 20-30 mg every 6 hours reduces temperature by at least 1.5°C within 48 hours 6
• Continue propranolol until all signs of autonomic dysfunction abate 6

Drug Fever

Clinical Presentation:

• Fever appears after mean of 21 days (median 8 days) following drug initiation, though highly variable 1
• Well-tolerated fever without hemodynamic instability or organ dysfunction 1
• Rash and eosinophilia occur in only a small fraction of cases—do not rely on these findings 1

Diagnostic Features:

• Procalcitonin <0.5 ng/mL (drug fever does not elevate procalcitonin) 1, 4
• Clear temporal relationship to medication administration within past 21 days 1
• Fever resolution within 1-3 days after stopping offending agent (may take up to 7 days) 1
• Fever persists despite discontinuation of antimicrobials if infection was misdiagnosed 1

Management:

• Discontinue suspected medication if temporal relationship exists and patient is stable 1
• Avoid rechallenge with suspected drug unless absolutely essential, as more severe reactions may occur 1
• Monitor temperature for 1-7 days after discontinuation to confirm defervescence 1

Paroxysmal Sympathetic Hyperactivity (PSH)

Clinical Presentation:

• Episodic, cyclic, and simultaneous fever with tachycardia, hypertension, tachypnea, excessive diaphoresis, and dystonia (increased muscle tone or posturing) 2, 3
• Occurs in 1.5% of survivors with acquired brain injury 3
• More commonly observed in patients with stroke, with tachycardia and hypertension as main manifestations 2
• Associated with decorticate/decerebrate posturing and profuse sweating 6

Diagnostic Features:

• Procalcitonin <0.5 ng/mL (helps differentiate from sepsis) 4
• PSH-Assessment Measure (PSH-AM) tool is optimal for early identification and severity stratification 2, 3
• PSH-AM consists of: (1) diagnosis likelihood tool from clinical characteristics, and (2) clinical feature scale for severity of each sympathetic hyperactivity 3
• Paroxysmal pattern: episodic symptoms rather than continuous fever 2, 3
• Specific posturing (dystonia) distinguishes PSH from other fever causes 2, 3

Management Strategy (Three-Point Approach):

1. Reduction of stimulation: Minimize environmental triggers 7

2. Reduction of sympathetic excitatory afferents:

   • Morphine for symptom-abortive treatment of discrete breakthrough episodes 7
   • Short-acting benzodiazepines for acute episodes 7

3. Inhibition of sympathetic hyperactivity effects on target organs:

   • Long-acting benzodiazepines for prevention 7
   • Nonselective β-blockers (propranolol 20-30 mg every 6 hours) 7, 6
   • α2 agonists for refractory cases 7
   • Opioids and GABA agonists as adjuncts 7
   • Combination therapy from different classes is most effective 7

Serial monitoring of procalcitonin helps differentiate PSH fever from sepsis and guides rational antibiotic use. 4

Critical Pitfalls to Avoid

• Never delay empirical antimicrobial therapy in unstable patients while pursuing alternative diagnoses—delay increases mortality from sepsis 1
• In critically ill patients, assume infectious etiology until proven otherwise, particularly when procalcitonin is elevated or patient shows clinical deterioration 1
• Do not rely on CSF cell count alone in immunocompromised patients—maintain high suspicion for infection regardless of cell count until cultures are final 5, 8
• Lumbar puncture should be performed in any patient with new fever and unexplained altered consciousness or focal neurologic signs, unless contraindicated 5
• Obtain imaging study before lumbar puncture if focal neurologic findings suggest disease above foramen magnum to exclude mass lesions or obstructive hydrocephalus 5
• Do not assume normal initial CSF excludes infection—5-10% of HSV encephalitis cases have completely normal initial CSF findings; consider repeat lumbar puncture at 24-48 hours 8