What are the clinical characteristics of central fever in patients with brain injury or neurological conditions?

Clinical Characteristics of Central Fever

Central fever (neurogenic fever) is defined as core temperature >37.5°C driven by neurological dysregulation in the absence of sepsis or clinically significant inflammatory processes, and is fundamentally a diagnosis of exclusion that requires ruling out infectious and other non-infectious causes first. 1, 2

Defining Features

Temperature Pattern

• Persistent temperature elevations without cyclic patterns distinguish central fever from other fever syndromes 2, 3
• Core temperature exceeds 37.5°C (100.4°F) 1
• Unlike Adult-Onset Still's Disease (quotidian evening spikes) or Familial Mediterranean Fever (self-limited 1-3 day episodes), central fever maintains continuous elevation 3

Epidemiology and Context

• Occurs in 4-37% of traumatic brain injury survivors, making it more common than historically recognized 4
• Fever develops in approximately 70-90% of neurological ICU patients overall, though not all are central in origin 5
• Most strongly associated with subarachnoid hemorrhage, cerebral trauma, and ischemic or hemorrhagic stroke 6

Pathophysiological Mechanism

Central fever results from direct damage to the hypothalamus and its thermoregulatory pathways, causing dysregulation of temperature control mechanisms rather than the cytokine-mediated response seen in infectious fever. 2

Key Mechanistic Differences

• Neurological dysregulation occurs without the inflammatory mediators (cytokines, prostaglandins) that characterize infectious fever 1, 2
• Brain temperature may exceed core body temperature in acute severe TBI, though the clinical significance remains uncertain 4
• The mechanism differs fundamentally from peripheral muscle dysfunction seen in malignant hyperthermia or neuroleptic malignant syndrome 2

Clinical Consequences

Secondary Brain Injury Mechanisms

Uncontrolled central fever precipitates secondary brain injury through multiple pathways that worsen outcomes regardless of whether fever originates from infection or thermoregulatory dysfunction. 1

• Increased brain metabolic rate of oxygen consumption 1
• Enhanced release of excitatory neurotransmitters 2
• Increased free radical production and oxidative stress 2, 7
• Elevated intracranial pressure (ICP) 1, 2
• Impaired brain tissue oxygenation (PbtO2) 1
• Aggravated excitotoxicity, inflammation, and apoptosis 7

Outcome Associations

• Associated with increased risk of complications and unfavorable neurological outcomes 1
• Linked to higher mortality rates in acute brain injury patients 5
• Correlates with early neurological deterioration 5
• In subarachnoid hemorrhage specifically, associated with delayed cerebral ischemia 5

Diagnostic Approach

Critical Distinction: Diagnosis of Exclusion

The most important clinical characteristic is that central fever can only be diagnosed after systematically excluding infectious and other non-infectious causes, as premature diagnosis while missing infection significantly worsens outcomes. 2, 6, 4

Required Workup Before Diagnosis

• Chest radiograph for all ICU patients with new fever 1, 2, 8
• At least two sets of blood cultures (60 mL total), with simultaneous central and peripheral collection if central venous catheter present 1, 2
• CT imaging for patients with recent thoracic, abdominal, or pelvic surgery 1, 2
• Lumbar puncture if altered consciousness or focal neurologic signs are unexplained and not contraindicated 1, 8

Differentiating from Infectious Fever

Correctly differentiating central fever from infectious fever is both challenging and clinically critical due to the impact of failing to identify treatable infection, consequences of antibiotic overuse, and detrimental effects of hyperthermia on brain-injured patients. 1

• Absence of sepsis markers or clinically significant inflammatory processes 1, 2
• No identifiable infectious source after thorough investigation 2, 6
• Patients with TBI are immunocompromised and predisposed to sepsis, making infection the primary concern in comatose patients 4

Distinguishing from Other Hyperthermic Syndromes

• Neuroleptic malignant syndrome presents with muscle rigidity, elevated creatine phosphokinase, and association with antipsychotic medications—features absent in central fever 2
• Malignant hyperthermia involves peripheral muscle dysfunction with calcium dysregulation, whereas central fever originates from central thermoregulatory failure 2

Common Pitfalls

Premature Diagnosis

• Central fever remains a diagnosis of exclusion; premature treatment while missing infection worsens outcomes 2
• Approximately half of febrile episodes in neurological ICU patients have infectious etiology 1, 6

Undertreatment Despite Guidelines

• Studies demonstrate persistent undertreatment of fever in TBI patients by critical care staff despite knowledge of negative effects 9
• Only 31% of documented fever events received any nursing intervention in one study 9
• Patients were more likely to have temperatures exceeding 40°C (13%) than normothermic temperatures (5%) 9

Monitoring Limitations

• Neurologic examination has inherent limitations in critically ill patients, potentially masking focal findings 1
• Certain populations (elderly, immunosuppressed) may have blunted fever responses 2
• Dissociations between brain and body temperature frequently occur in head-injured patients 7

Management Implications

Regardless of fever etiology, acute management of temperature is essential because deleterious effects and secondary injury risk occur whether temperature elevation stems from infection or impaired thermoregulation. 1

• Controlled normothermia targeting 36.0-37.5°C is recommended for neurogenic fever in comatose patients with acute traumatic encephalopathies 1
• Uncontrolled fever requires urgent management in the acute phase when patients remain at significant risk of secondary brain injury 1
• Antipyretics (acetaminophen, NSAIDs) have limited efficacy in controlling fever and minimizing temperature variability in severe TBI 1
• Automated feedback-controlled temperature management devices are recommended for optimal control 1