What is central fever and how is it diagnosed in patients with brain injury or neurological conditions?

Central Fever: Definition and Diagnosis

Central fever (also called neurogenic fever) is defined as a core body temperature >37.5°C caused by neurological dysregulation of hypothalamic temperature control mechanisms, occurring without evidence of sepsis or clinically significant inflammatory processes, and is fundamentally a diagnosis of exclusion that can only be made after ruling out infectious and other non-infectious causes. 1

Definition and Key Characteristics

Central fever results from direct damage to the hypothalamus and its thermoregulatory pathways, distinguishing it from fever driven by infectious or inflammatory processes. 1 The condition is more common than historically recognized, occurring in 4-37% of traumatic brain injury (TBI) survivors. 1, 2

Key distinguishing features include:

• Core temperature persistently >37.5°C without cyclic patterns typical of infectious fever 1
• Earlier onset compared to infectious fever (median day 2 versus day 6 for infectious causes) 3
• Absence of elevated inflammatory markers (C-reactive protein, procalcitonin, leukocyte count remain relatively normal) 3
• Strong association with specific lesion locations, particularly left midbrain and hypothalamic regions 3

Diagnostic Approach: A Systematic Algorithm

Central fever diagnosis requires methodical exclusion of all other causes before attribution to neurological dysregulation. 1, 4

Step 1: Initial Infectious Workup (Mandatory)

All patients with fever in the setting of CNS injury must undergo comprehensive infectious evaluation:

• Obtain chest radiograph for all ICU patients with new fever 1, 5
• Collect at least two sets of blood cultures (60 mL total) 1, 5
• If central venous catheter present, obtain simultaneous central and peripheral blood cultures 1
• Consider CT imaging for patients with recent thoracic, abdominal, or pelvic surgery 1, 5
• Perform lumbar puncture for patients with neurological symptoms if not contraindicated 1, 5

Step 2: Clinical Pattern Recognition

Evaluate timing and characteristics that favor central versus infectious etiology:

• Early onset (days 1-3) strongly suggests central fever, with onset on day 2 being most typical 3
• Late onset (days 4-9) more consistent with infectious causes 3
• Persistent elevation without diurnal variation favors central fever 1
• Associated with higher NIHSS scores and worse neurological status 3

Step 3: Neuroanatomical Assessment

Identify lesion locations associated with central fever:

• Left hypothalamic region involvement (odds ratio 9.7 for central fever) 3
• Left midbrain lesions 3
• Subarachnoid hemorrhage, particularly with intraventricular extension 4
• Pontine hemorrhage 5
• Traumatic brain injury affecting temperature-regulating regions 1, 6

Step 4: Laboratory Differentiation

Infectious parameters help distinguish fever etiology:

• Normal or minimally elevated inflammatory markers (CRP, procalcitonin, WBC) suggest central fever 3
• Significantly elevated inflammatory markers indicate infectious or inflammatory causes 3
• This distinction is critical but not absolute—some overlap exists 4

Temperature Monitoring Requirements

Accurate temperature measurement is essential for diagnosis and management:

• Use central temperature monitoring methods: pulmonary artery catheters, bladder catheters, or esophageal thermistors 1, 5
• When central monitoring unavailable, use oral or rectal temperatures over axillary or tympanic measurements 1, 5
• Continuous monitoring is preferable to intermittent measurements 6, 5
• Brain temperature can be up to 2°C higher than systemic temperature and may vary independently 6

Critical Diagnostic Pitfalls

Common errors that lead to misdiagnosis or delayed treatment:

• Premature attribution to central fever without adequate infectious workup is the most dangerous error, as it delays treatment of potentially life-threatening infections 1, 4
• Relying on blunted fever responses in elderly or immunosuppressed patients, who may have serious infections without significant temperature elevation 1
• Failing to recognize that TBI patients are immunocompromised and predisposed to sepsis 2
• Using unreliable temperature measurement sites (axillary, tympanic) that underestimate true core temperature 1, 5
• Delaying treatment while pursuing diagnosis—fever itself causes secondary brain injury regardless of etiology 6, 5, 7

Clinical Significance and Urgency

Central fever causes secondary brain injury through multiple mechanisms:

• Increased metabolic demands on already-injured brain tissue 1, 7
• Enhanced release of excitatory neurotransmitters 1, 7
• Increased free radical production 1, 7
• Elevated intracranial pressure 1, 6
• Worsened histopathological and behavioral outcomes even with small temperature elevations 7

The diagnosis must be pursued urgently because uncontrolled fever precipitates secondary brain injury regardless of whether the source is infectious or neurogenic. 1, 6 Treatment should not be delayed while establishing the specific etiology. 5