| || |
• Ventromedial preoptic area of the anterior hypothalamus is the thermostat of the body.
| || |
• Molecular components of pathways for generation of fever are targets for antipyretic drugs.
| || |
• Cytokines are critical for the induction of fever.
| || |
• Prostaglandin E2 is the most important link between the peripheral immune system and the brain and mediates acute phase of fever induced as an immune response in bacterial infection.
| || |
• Various neurologic disorders have fever as a symptom.
The region of the brain involved in control of temperature in the ventromedial preoptic area of the anterior hypothalamus, which is referred to as the "fibrogenic center" or "thermostat" of the body. The ventral part of the lateral preoptic nucleus and the dorsomedial hypothalamus (DMD) neural pathways reduce core body temperature in response to a thermal challenge, and the outputs from the dorsomedial hypothalamus are responsible for activity-induced fever (44).
The main feature of pathophysiology of fever is the increase in hypothalamic temperature set point by action of exogenous and endogenous pyrogens. Arginine vasopressin, an endogenous antipyretic, attenuates fever by influencing the thermoregulatory neurons in the preoptic region and anterior hypothalamus and may enhance the efficacy of nonsteroidal antipyretic drugs. Studies of molecular components of fever-generation pathways represent targets for antipyretic drugs (04).
The manifestation of the pathological response is stereotyped and independent of the causative agent. Exogenous pyrogens such as lipopolysaccharides and endotoxins are released from gram-negative bacteria during infection. Exogenous pyrogens act both directly on the thermoregulatory center and stimulate the release of cytokines from macrophages.
Role of cytokines. Endogenous pyrogens are mostly cytokines such as interleukin-1beta, interleukin-6, tumor necrosis factor, and interferon-gamma. The primary sources of cytokines are phagocytic monocytes and macrophages. In addition to their role in the pathogenesis of diseases such as multiple sclerosis and Alzheimer disease, cytokines are also critical in the induction of fever. This explains why antibodies targeting cytokines have been used as therapy for individuals with unusual and persistent febrile reactions that are not responsive to common antipyretics.
Role of prostaglandins. These large proteins are excluded by the blood-brain barrier, although they can enter the organum vasculosum of the lamina terminalis through fenestrated capillaries and act on perivascular cells, which have a high concentration of prostaglandin receptors, to produce prostaglandins. The prostaglandins activate the preoptic area, which sends axonal processes to the hypothalamus, and orchestrate the febrile response. This mechanism is supported by the fact that prostaglandin inhibitors such as aspirin effectively block the febrile response. Nonsteroidal antiinflammatory drugs normalize the action of the thermoregulatory center in the hypothalamus by decreasing production of prostaglandins through inhibition of cyclooxygenase enzymes. Sickness syndrome, a brain-mediated response with fever as 1 of the symptoms that occurs in infectious and inflammatory diseases, is mediated by prostaglandins acting on the brain and can be prevented by aspirin or ibuprofen (35). The paraventricular nucleus of the hypothalamus produces autonomic and endocrine responses involved in elevation of body temperature. The pathway connecting the preoptic area and the paraventricular nucleus involves a double inhibitory relay through temperature-sensitive GABAergic neurons in the hypothalamus. This pathway would essentially "turn up the thermostat" during a fever, causing an increase in body temperature via normal thermoregulatory pathways. Selective genetic deletion of the EP3 receptors in the median preoptic nucleus of mice eliminates febrile response, indicating that EP3 receptor-bearing neurons in the median preoptic nucleus are required for fever responses (18). Prostaglandin E2 is considered to decrease the preoptic gene expression of GABAA subunits via an EP3-dependent pathway, leading to the hypothesis that a rapid decrease in preoptic GABAA expression may be involved in prostaglandin E2-induced fever (41). The prostaglandin-dependent inflammatory pathway for fever induction is distinct from the pathway of hypothalamopituitary axis activation because fever, but not circulating cortisol, is attenuated by an inhibition of prostaglandin formation. Prostaglandin E2 is considered the most important link between the peripheral immune system and the brain, and mediates different components of the acute phase reaction in fever induced as an immune response in bacterial infection. The important role of prostaglandin E2 synthases in disorders of the nervous system and fever is the basis for ongoing development of inhibitors of these enzymes (28).
Role of nitric oxide. Nitric oxide modulates fever in the brain, but the site where it exerts this action is not quite clear. Locus coeruleus neurons express nitric oxide synthase and soluble guanylyl cyclase. Febrile response to endotoxins is accompanied by stimulation of the nitric oxide-cyclic guanosine monophosphate pathway in the locus coeruleus (37).
Nitric oxide synthase inhibitors that block nitric oxide production from endothelial nitric oxide synthase in the brain eliminate the lowering of the thermoregulatory set point, which supports the role of nitric oxide in temperature regulation by inhibiting neuronal activity of the paraventricular nucleus of the hypothalamus and interleukin-1 beta gene expression during immune stress. Free radical formation is increased in fever but antioxidants generally do not have any effect on temperature regulation.
Role of interleukins. IL-6, an endogenous pyrogen, is a key regulator of temperature. The neuroprotective action of IL-6 counteracts its pyretic effect, which has an adverse effect on the outcome of stroke.
IL-1beta is released at the periphery during infection and acts on IL-1 receptors in the brain to induce fever and neuroendocrine activation. In brain structures lacking IL-1beta receptor, activation of extracellular signal-regulated protein kinase 1 and 2 is likely to occur in response to both direct and indirect action of IL-1beta on its target cells.
Role of heat shock proteins. Heat shock proteins have been identified in all cells, prokaryotic and eukaryotic, to protect the cells from harmful insults and stress. Increased heat shock protein synthesis can occur during normal cellular functions and respond to exposure from environmental stress and infection. Although the molecular mechanisms responsible for heat shock protein cellular protection are still not fully understood, their expression is critical for cellular survival. The heat-inducible 70 kDa heat shock protein (Hsp70) has been associated with protection of leukocytes against the cytotoxicity of inflammatory mediators and with improved survival of severe infections. Thus, a systemic increase of body temperature as triggered by fever stimulates Hsp70 expression in peripheral leukocytes, especially in monocytes. Expression of Hsp70, induced by fever, may protect monocytes when confronted with cytotoxic inflammatory mediators, thereby improving the course of the disease. Hsp70 has been shown to be elevated in serum of patients with sepsis and may exert endotoxin-like effects through toll-like receptors (TLRs). Enhanced Hsp70 release in patients concurrently exposed to fever and TLR agonists may contribute to the pathogenesis of sepsis (15).
Role of the sympathetic nervous system. Excitatory premotor neurons that control the thermoregulatory effector organs have been identified with expression of vesicular glutamate transporter and mediate thermoregulation including fever induction (26).
Metabolic impact of fever. Fever increases the metabolic demand on the body. Each degree of rise of temperature increases oxygen consumption by 13% and increases caloric and fluid requirements. The central thermoregulatory mechanism for temperature control also functions for metabolic regulation and stress-induced hyperthermia (25).
Space fever. There is a sustained increase in astronauts' core body of approximately 1°C, which develops gradually over 2.5 months under resting conditions and is associated with decreased evaporation of sweat and elevation of interleukin-1 receptor antagonist, a key antiinflammatory protein (38). During exercise, the astronauts' body temperature often exceeds 40°C (104°F) and combined with extremely high regional neuronal activity in motor areas, further increases cerebral metabolic rate with aggravation of the heat strain on the brain. There is a concern that excessive fluctuations in core body temperature can impair both physical and cognitive performance and can even be life-threatening.
Neurologic disorders with fever. Various disorders with fever as a symptom and neurologic manifestations are shown in Table 1. These are described in other MedLink Neurology clinical summaries. A few that are not covered in other summaries are described briefly in the text following.
Table 1. Fever Associated with Neurologic Disorders
| || |
| || |
• Brain abscess
• Q fever
| || |
- Whipple disease
| || |
• COVID-19 with involvement of the brain
• Severe fever with thrombocytopenia syndrome (SFTS) virus
• Viral meningitis
• West Nile virus infection
• Zika virus infection with fever
Viral hemorrhagic fevers
| || |
• Lassa fever, Marburg virus, Ebola virus
• Dengue fever
• Crimean-Congo hemorrhagic fever
| || |
• Amebic meningoencephalitis
• Cerebral malaria
• Sleeping sickness due to Trypanosoma brucei
Postoperative neurosurgical infections
Infections in neurologically disabled persons, eg, paraplegia
| || |
Systemic lupus erythematosus
| || |
Primary central nervous system lymphoma
Rupture of intracranial dermoid cysts with chemical meningitis
| || |
Cerebrovascular disease; stroke
Traumatic brain injury
| || |
Drug-induced and treatment-related disorders
| || |
Drug-induced aseptic meningitis
Neuroleptic malignant syndrome
| || |
Drug-induced disturbance of temperature control in hot weather
Exposure to extreme heat
Strenuous sports in hot weather
Acute mountain sickness
Genetic disorders: hereditary periodic fever, familial Mediterranean fever
Fever of unknown origin
Severe fever with thrombocytopenia syndrome virus. Severe fever with thrombocytopenia syndrome (SFTS) has several neurologic manifestations, and one of the common manifestations is encephalitis due to direct invasion of the CNS by SFTS virus with elevated levels of cytokines, such as IL-8 in the CSF (29).
COVID-19 with involvement of the nervous system. COVID-19 is a highly infectious pandemic caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It frequently presents with unremitting fever, hypoxemic respiratory failure, and involvement of other organs, eg, encephalopathy (24). These patients may present with fever and pulmonary symptoms but nervous system involvement is frequent manifested by loss of smell, headache, dizziness, impaired consciousness, acute cerebrovascular disease, and convulsions (27).
Hereditary periodic fever syndromes. Hereditary periodic fever syndromes are defined by recurrent attacks of generalized inflammation for which no infectious or autoimmune cause can be identified. These are rare genetic disorders with involvement of various body systems including the nervous system. Investigation has revealed impaired cytokine recognition and defective signaling molecules in recurrent attacks of fever. Disorders of interleukin-1 processing might be involved in the pathogenesis of these disorders.
Familial Mediterranean fever. It is an inherited inflammatory disorder characterized by attacks of fever. Neurologic manifestations include headaches, seizures, and tremor. In a clinical trial, canakinumab, a monoclonal antibody, was found to be effective for controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever (11).
Drug-induced neurologic disorders. Fever is an adverse effect of several drugs used therapeutically. Drug abuse, particularly involving methamphetamine, may produce fever. Acute methamphetamine intoxication induces a dose-dependent body and brain hyperthermia, which induces leakage of the blood-brain barrier, structural damage, and cerebral edema (17).
Parkinsonism-hyperpyrexia syndrome. This is a systemic inflammatory response syndrome, which presents acutely as aggravation of muscular rigidity, autonomic instability, fever, confusion, and diaphoresis and can mimic neuroleptic malignant syndrome. The most common trigger for onset of this syndrome is reduction or withdrawal of anti-Parkinson medications, particularly levodopa.
A rare cause of Parkinsonism-hyperpyrexia syndrome is malfunction of a deep brain stimulator due to depletion of battery and can be treated by administration of dopamine agonists and replacing the battery (02).
Neurogenic fever. Neurologic illness is a risk factor for neurogenic fever, which primarily occurs in subarachnoid hemorrhage and traumatic brain injury, with hypothalamic injury and paroxysmal sympathetic hyperactivity as the proposed mechanisms (21).
Stroke. Fever is extremely frequent during acute cerebral damage, and brain temperature is significantly higher than core body temperature and may be underestimated. Results of a multicenter retrospective cohort study in critically ill adult patients with neurologic injuries, including acute ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage, showed that fever was common and significantly associated with increased mortality (33).
Intracerebral hemorrhage. Fever is common in patients with intracerebral hemorrhage and is not associated with infection in most of the cases. Patients with fever have higher mortality, but survivors have shorter length of stay in the hospital (14). Theories for the mechanism of neurogenic fever in these patients include decrease of blood supply to the lower midbrain causing disinhibition of thermogenesis, stimulation of prostaglandin production, and direct hemotoxic damage to thermoregulatory centers in the preoptic region.
Traumatic brain injury. Fever in patients with acute brain injury is associated with aggravation of secondary brain injury. Diffuse axonal injury and frontal lobe injury of any type are independent predictors of an increased risk of development of neurogenic fever following severe traumatic brain injury. Fever is 1 of the 4 most common complications (the other 3 are hyperglycemia, systemic inflammatory response syndrome, and hypotension) of traumatic brain injury in the intensive care unit that have an impact on short-term outcomes (22). Fever should be considered in the prognosis of high-risk traumatic brain injury patients. A retrospective matched cohort study has shown that fever is a frequent occurrence after brain injury and that it is independently associated with in-hospital case fatality (34). A study based on questionnaire about first-line management of fever in head injury showed that the main thresholds for antipyretic therapy were 37.5°C and 38.0°C, with ice packs as the most frequently used physical method, an external nonautomated system as the most frequent utilized device, and paracetamol as the most used drug (30). Neurogenic fever in the patient with traumatic brain injury may be due to raised intracranial pressure as a result of cerebral edema and if untreated, can cause further damage to the brain.
Surgical procedures on the brain. During neurosurgical procedures, brain temperature is the highest body temperature measured, either in normothermia or in fever.
Fever of unknown origin. This is the term used for a persisting fever with temperature higher than 38.3°C on several occasions over more than 3 weeks, and for which at least 2 weeks' laboratory investigations do not reveal any clue. In some of these cases the cause is eventually diagnosed or the fever resolves. Recurrent fever of unknown origin is uncommon and is defined as recurrence of episodes of prolonged fever separated by at least 2 weeks of fever-free intervals. Nearly half of patients with fever of unknown origin remain undiagnosed despite extensive evaluation. However, an additional yield of 10.9% in determining cause of fever in undiagnosed patients in a nonexpertise center has been reported following referral to a tertiary center (23).
Psychogenic fever. This stress-induced fever is also referred to as “emotional fever” or “functional hyperthermia.” Psychogenic fever is not relieved by antipyretic drugs, but by anxiolytic drugs or by use of other approaches to resolve stress (40).
Factitious fever. Also referred to as “fraudulent fever,” high temperature is created by manipulation of the thermometer or raising of body temperature by self-induced means. Fever may be the only symptom, with the patient looking inappropriately well, or it may be part of a complex factitious disorder. The sufferers are usually young women with a history of personality disorder and multiple hospital admissions for obscure disorders.