General Neurology
Brain death/death by neurologic criteria
Nov. 09, 2024
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Fever: neurologic causes and complications …
- Updated 07.06.2024
- Released 01.20.2003
- Expires For CME 07.06.2027
Fever: neurologic causes and complications
Introduction
Overview
This article describes the pathophysiology of fever in the context of neurologic disorders. The human body's temperature is managed by a thermoregulatory mechanism, preventing extremes of body temperatures that can damage the nervous system. In fever, the hypothalamic thermostat setting increases. In hyperthermia, the thermostat setting remains normal, but there is abnormal exogenous heat exposure and endogenous production. Procalcitonin levels help distinguish central fever from infectious fever in brain injury patients, reducing unnecessary antibiotic use by identifying noninfectious causes of fever. Management of a patient with fever requires both the investigation of the cause as well as lowering of the temperature. A systematic review finds that fever therapy doesn't significantly reduce death or serious adverse events risk in febrile adults.
Key points
• Fever is probably the most common symptom observed by physicians. | |
• Thermoregulatory centers and pathways in the brain are involved in the control of body temperature. | |
• Several neurologic disorders, both infectious and noninfectious, have fever as a manifestation. | |
• Management of the patient with high fever depends on the cause. | |
• High fever may need to be lowered by use of antipyretics and cooling devices. |
Historical note and terminology
Fever is probably the most common symptom observed by neurologists and other physicians involved in patient care. Fever is defined as elevation of body temperature above normal limits of the central regulatory processes originating in the hypothalamus. The normal temperature is 37°C (98.6°F) based on Wunderlich's original observation (53). However, temperature readings are higher in healthy young individuals and lower in the elderly. There are circadian variations with lower temperatures in the morning and higher in the afternoon so that fever can be defined as morning temperature of greater than 37.2°C (98.9°F) and afternoon temperature greater than 37.7°C (99.9°F). Rectal temperatures are usually 0.6°C higher than those recorded from the skin. Elevations of 0.8°C (1.5°F) may occur during physical exercise. Measuring body temperature remains one of the basic procedures for assessing general health. A current study in the United States has determined that mean body temperature in men and women, after adjusting for age, height, and weight, has decreased monotonically by 0.03°C per birth decade during the past 150 years (41). An explanation of this is the development of treatments for infectious diseases over the last century, which has enabled marked reduction in inflammatory conditions that people had -- tuberculosis, syphilis, periodontal disease, nonhealing wounds, and dysentery -- with antibiotics and vaccines. Nonsteroidal antiinflammatory drugs enable us to live almost inflammation-free, which might have contributed to a steady decline in average body temperature as the body no longer needs to heat up to fight off disease.
Conditions other than fever may also cause rise of body temperature. For example, hyperthermia is due to excessive internal heat production or impairment of heat dissipation, such as in heat stroke, which results in a body temperature rise to above that set by the central regulatory processes. Although two different terms are used to describe rise of body temperature, the single term "hypothermia" is used for drop in body temperature, whether due to disturbance of central regulation, exposure to cold environment, or both acting simultaneously.
Along with pain, fever is one of the earliest symptoms recorded in medical antiquity. Historical aspects of fever are reviewed elsewhere (01; 08). Fever as a manifestation of infectious diseases was recognized before the discovery of microorganisms as causes of infections. Ancient physicians assessed fever merely by touch of the hand; Santorio Sanctorius and subsequently Herman Boerhaave and his pupils Gerard van Swieten and Anthonie de Haen emphasized the use of measurement of body temperature in the clinic, but its importance was not generally accepted until the late 19th century (27). Prior to the discovery of antibiotics, high fever due to severe infections was associated with high mortality. Sir William Osler called it the most terrible enemy of mankind. Fever is now recognized to be a symptom of noninfectious inflammatory conditions as well. Several substances were recognized as exogenous pyrogens (in Greek, pyro means fire) or fever producing. Immune challenges result in the production of endogenous pyrogens that act at the hypothalamic level.
Progress in neuroscience has enabled a better understanding of the neurobiological basis of fever. Fever associated with neurologic disorders is also referred to as neurogenic fever. Apart from being a symptom of neurologic disorders, high fever can also produce neurologic complications.
Fever was also induced for therapeutic purposes, due to the belief that fever is a protective reaction of the body and high temperatures can destroy pathogenic organisms. In the earlier part of the 20th century fever was induced by inoculation with tertian malaria to cure general paresis, a form of neurosyphilis (12). This approach became obsolete after the introduction of penicillin.
Management of a feverish patient in the pre-pharmacological era included use of herbs and application of cooling, such as by baths. Aspirin, introduced in 1897, was recognized to reduce pain and fever, but its mechanism of action was not known at that time. The action is now believed to be mediated at the CNS level.
Clinical manifestations
Presentation and course
|
• Fever may be sustained, intermittent, remittent, or relapsing. | |
|
• Fever is accompanied by other symptoms such as malaise, rigors, seizures, and impairment of consciousness. | |
|
• Prognosis of the patient depends on the cause of the fever. |
The classical patterns of fever are listed below, but these may change due to treatment.
|
• Sustained implies that the temperature elevation is persistent. | |
|
• Intermittent pattern has wide fluctuations in temperature, indicating a deep-seated septic focus, malignancy, or drug fever. | |
|
• Remittent fever is one where the temperature falls every day but not to normal level and fever recurs. It is typical of some diseases such as tuberculosis. | |
|
• In relapsing fevers, febrile episodes are separated by intervals of normal temperature, which may stretch into days. |
Fever is accompanied by several other changes in body function and symptoms, such as back pain, generalized myalgias, and anorexia. The patient complains of malaise and fatigue. Shivering is common as the temperature is rising. Rigors (episodes of profound chill with piloerection) may occur with septicemia. Sweating may be accompanied by drop of high temperature due to cooling effect of evaporation of perspiration. Fever reduces mental acuity and may cause delirium and stupor. In infants and children under the age of five years, fever is associated with febrile seizures, particularly if there is a previous history of seizure disorder. Elderly patients with dementia and hepatic or renal failure are also susceptible to febrile seizures. Dehydration and loss of weight occurs with prolonged fever. Cardiovascular collapse and cardiac arrest may occur with extremely high temperatures.
The pulse rate is faster in fever, and bradycardia indicated cardiac conduction disturbances may occur in acute rheumatic fever and Lyme disease.
Prognosis and complications
The prognosis of a patient with fever depends on the cause of fever and associated illness. Some patients may recover spontaneously. High fever can produce neurologic complications under certain conditions, particularly in susceptible individuals. Neurologic manifestations of hyperthermia in the acute stage may be reversible if temperature is reduced but prolonged hyperthermia may lead to permanent deficits. The magnitude of hyperthermia as well as genotypic differences in the physiological response to hyperthermia may also determine an individual’s risk of developing neurologic deficits.
The development of fever in a patient with severe head injury is associated with a worse prognosis. High fever in children following admission to hospital with traumatic brain injury is associated with a poor hospital discharge Glasgow Coma Score (48). The association between hyperthermia and early neurologic deterioration, increased morbidity, and mortality in acute ischemic stroke is well known. The highest body temperature recorded during the first 72 hours after admission is a significant predictor of mortality in acute cerebral infarct patients. The deleterious effect of hyperthermia has also been shown in patients with subarachnoid hemorrhage as well as in diffuse cerebral hypoxia after cardiopulmonary resuscitation. Fever is consistently associated with worse outcomes across multiple outcome measures in patients with stroke and other brain injuries. Some of the complications of fever involving the nervous system include the following:
Febrile convulsions. These are described in a separate clinical article in MedLink Neurology. Factors operating at the molecular, cellular, and systems level in fever-related epileptiform syndromes include carbon dioxide chemosensitivity as well as mechanisms of acid-base regulation, pointing to susceptibility genes coding pH-sensitive target proteins.
Febrile seizures are mostly self-limiting with no sequelae in later life but may be complex in a minority of cases with other underlying factors and may herald the onset of epilepsy syndromes of which febrile seizures are part of the manifestations (10).
Febrile infection-related epilepsy syndrome (FIRES) and non-FIRES new onset refractory status epilepticus (NORSE) were compared in 34 and 30 patients, respectively (20). FIRES patients were younger (median age 28 vs. 48 years, p = .048) and more likely cryptogenic (odds ratio = 6.89). FIRES had more respiratory and gastrointestinal prodromes and higher levels of cerebrospinal fluid interleukin 6, cerebrospinal fluid macrophage inflammatory protein-1 alpha, and serum chemokine ligand 2. Despite these differences, status epilepticus subtype, clinical features, neuroimaging findings, and outcomes were similar after adjusting for age or etiology (20).
Brain damage. Extremely high temperature, ie, a core temperature of 40°C or above, is required to produce irreversible damage to the brain, which is consistent with the cellular changes and cell death occurring above this temperature. This occurs in conditions such as heat stroke. Temperature of the brain has an important influence on the extent of brain injury that follows intervals of hypoxia-ischemia and hyperthermia exacerbate ischemic brain injury in stroke patients. Even structures not primarily affected by ischemia may be damaged by hyperthermia. Upregulation of neurotransmitters, release of free oxygen radicals, aggravation of blood-brain barrier disruption, increase of potentially damaging ischemic depolarization in the focal ischemic penumbra, enhanced inhibition of protein kinases, and deterioration of cytoskeletal proteolysis are all mechanisms incriminated in worsening neuronal damage in the case of hyperthermia following brain injury.
Following traumatic brain injury, hyperthermia increases hemoglobin extravasation whereas hypothermia reduces hemoglobin levels, compared with normothermia.
Neurocognitive effects of hyperthermia may persist after the acute insult, whereas cerebellar damage predominates in long-term cases due to sensitivity of the Purkinje cells to thermal damage (52). Ataxia, dysarthria, and nystagmus are some of the manifestations. Recovery may be incomplete or may not occur.
Neural tube defects with fever in the first trimester. Women who experience fever of 38.9°C or higher for extended periods of time in the first month of pregnancy should be considered at increased risk for neural tube defects. Several developmental defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. Association between high fever during the second trimester of pregnancy and the subsequent development of schizophrenia in the child has been postulated to be due to the damage to the developing amygdalohippocampal complex (14).
Increased intracranial pressure. Increases in brain temperature are closely associated with intracranial pressure.
Biological basis
|
• 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. |
An experimental study aimed to understand the neural circuits responsible for fever induced by interleukin-1β (IL-1β), independent of cyclooxygenase (COX). Researchers found that COX inhibitor indomethacin did not prevent fever responses in rats, such as brown adipose tissue (BAT) thermogenesis and cutaneous vasoconstriction (CVC), suggesting COX-independent fever mechanisms. Neural pathways in the rostral raphe pallidus area (rRPa) and dorsomedial hypothalamus (DMH) were found crucial for these responses. Activation of glutamate receptors in the DMH is required for COX-independent, IL-1β-induced BAT thermogenesis. These findings build a foundation for understanding COX-independent, IL-1β-induced fevers and their neural control (29).
Anatomic localization
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 (54).
Pathophysiology
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 one 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 (44). 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 (23). 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 (50). 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 (36).
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 (46).
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 (17).
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 (34).
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 (33).
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 (47). 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
|
Infections | |||
|
Bacterial | |||
|
• Brain abscess | |||
|
- Tuberculosis | |||
|
Fungal | |||
|
• COVID-19 with involvement of the brain | |||
|
Viral hemorrhagic fevers | |||
|
• Lassa fever, Marburg virus, Ebola virus | |||
|
Rickettsial infection | |||
|
• Amebic meningoencephalitis | |||
|
Postoperative neurosurgical infections | |||
|
Autoimmune disorders | |||
|
Systemic lupus erythematosus | |||
|
Neuroinflammatory disorders | |||
|
CNS tumors | |||
|
Carcinomatous meningitis | |||
|
Neurogenic fever | |||
|
Cerebrovascular disease; stroke | |||
|
Traumatic brain injury | |||
|
Cerebral edema | |||
|
Drug-induced and treatment-related disorders | |||
|
Drug-induced aseptic meningitis | |||
|
Heat stroke | |||
|
Drug-induced disturbance of temperature control in hot weather | |||
|
Acute mountain sickness (Hyperthermia indicated by *) | |||
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 (37).
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 (32). 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 (35).
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 (13).
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 (22).
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 (28).
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 (42).
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 (16). 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 one of the four most common complications (the other three 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 (30). 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 (43). 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 (39). 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.
Traumatic spinal cord injury. A study monitored 86 patients with acute severe traumatic spinal cord injuries to assess the effects of neurogenic, inflammatory, and infective fevers on spinal cord physiology and metabolism (51). High fever, occurring in 76.7% of patients, was linked to various metabolic disturbances and inflammation. Neurogenic fever was more common with injuries above T4. Differentiating fever types using clinical characteristics helped accurately diagnose neurogenic fever, potentially reducing unnecessary septic screens and antibiotic use. Infective fever was the most damaging (51).
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 three weeks, and for which at least two 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 two 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 (31).
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 (49).
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.
Epidemiology
Fever is a symptom of many diseases and epidemiology is described along with neurologic disorders where fever is a prominent symptom.
Differential diagnosis
Confusing conditions
The differential diagnosis of fever in a neurologic patient is based on clinical neurologic manifestations. In fever the hypothalamic thermostat setting rises. Hyperpyrexia refers to an extremely high fever, going beyond 106.7°F (41.5°C). In hyperthermia, the hypothalamic thermostat setting remains normal and body temperature increases due to increased endogenous heat production or exogenous heat exposure. Fever is a nonspecific response and is of limited value in the neurologic diagnosis. Fever associated with infections is usually higher and fluctuates more than chronic low-grade fever associated with autoimmune disorders. A distinction should be made between fever and hyperthermia as defined in the introduction. Various conditions with hyperthermia under the categories of heat stroke and drug-induced disorders are described in other clinical summaries in MedLink Neurology.
Q fever, caused by Coxiella burnetii, should be included in the differential diagnosis of acute neurologic disease in a patient with fever. Patients with acute Q fever infection have frequent neurologic symptoms, varying from a severe headache in most of the patients to confusion, but rarely meningitis.
Familial Mediterranean fever, characterized by recurrent episodes of fever and painful polyserositis, is caused by mutations of the Mediterranean fever gene (26). Neurologic manifestations include demyelinating lesions, pseudotumor cerebri, and stroke due to brain stem infarction resulting from central nervous system vasculitis. In another study on 104 patients with familial Mediterranean fever, 22 had neurologic findings that included headache, epilepsy, and tremor (07). The most common gene mutation was homozygous M694V.
Serological testing should be performed in cases of meningoencephalitis, lymphocytic meningitis, and peripheral neuropathy, including Guillain-Barré syndrome and myelitis.
Differential diagnosis of fever of unknown origin is probably the most challenging in medicine because more than 200 disorders may present with this symptom. There is no standard diagnostic strategy, and diagnosis is guided by clues from the history, physical examination, and routine laboratory tests. The diagnostic approach should be clue-driven to narrow diagnostic possibilities to avoid excessive non-clue–directed testing (11). In a retrospective study of hospitalized patients, PET/CT studies were considered clinically helpful in determining the cause of fever of unknown origin in 66.5% of cases; they were of positive contributory value in 46%, and they helped to exclude suspected causes in 20.5% (15). Disorders relevant to the nervous system that can present as fever of unknown origin include hypothalamic lesions such as tumors and infectious granulomas, adult-onset Still disease, chronic fatigue syndrome, anticonvulsant hypersensitivity syndrome, and Gaucher disease. Noninfectious diseases are the most frequent cause of fever of unknown origin in the elderly and temporal arteritis the most frequent specific cause.
Diagnostic workup
|
• Measurement of the core body temperature | |
|
• Basic laboratory tests: blood counts and chemistry | |
|
• Biomarkers of inflammation/infection or malignant disease | |
|
• Brain imaging |
The first step is accurate recording of core body temperature. A rectal thermometer is more reliable than skin surface or buccal recordings. The temperature is monitored constantly in an intensive care setting.
Basic laboratory investigations include blood counts, serum electrolytes, blood urea nitrogen, creatine, and liver function tests. Further investigations of the cause depend on the clinical features and suspected pathology. The predominant causes are infections. Gene expression profiles of blood leukocytes in febrile children can help to discriminate viral from bacterial causes of fever without an apparent source (19).
Several biomarkers have been used to differentiate infections from inflammatory or malignant causes of fever, but commonly used biomarkers, such as C reactive protein, do not have enough sensitivity or specificity to guide treatment decisions, and procalcitonin is the most helpful laboratory biomarker for this purpose (24). Cerebrospinal fluid is examined and cultured if meningitis is considered as a clinical diagnosis.
In patients with traumatic brain injury, fever may be associated with rise in intracranial pressure; monitoring of intracranial pressure may be combined with brain temperature recordings.
Brain imaging studies may reveal the primary pathology. In patients with core body temperature of 40°C, loss of distinction between gray and white matter may be observed on CT scan.
Central fever, characterized by elevated body temperature without infection or drug reaction, lacks definitive diagnostic criteria. A retrospective study of 70 patients with neurologic insults found that procalcitonin levels were significantly lower in those with central fever (0.09 nanograms per deciliter) compared to those with infections (1.4 nanograms per deciliter, p < 0.001) (21). Although C-reactive protein and erythrocyte sedimentation rate were also lower in central fever, the differences were not statistically significant. Procalcitonin may be a useful biomarker to differentiate infectious from noninfectious fever in brain injury patients, potentially reducing unnecessary antibiotic use.
Management
|
• Measures to lower temperature | |
|
• Treatment of the cause of fever | |
|
• Maintenance of the fluid and electrolyte balance | |
|
• Treatment of complications of fever such as febrile convulsions |
Temperature control is crucial in managing severe acute brain injury such as traumatic brain injury, acute ischemic stroke, and others. Hypothermic temperature control reduces cerebral metabolic demand and inflammation, but its effectiveness varies across conditions. Although fever prevention is universally beneficial, the impact of hypothermic temperature control remains inconsistent in severe acute brain injury (25).
Management of the febrile neurologic patient is focused on the cause of fever. However, reduction of high fever is important. There is little evidence that temperatures between 37.5°C to 39.0°C are harmful except in infants, the elderly, or those with impairment of cardiac, pulmonary, or cerebral function as well as pregnant women. Efforts should be made to lower the temperature in these risk groups. Various methods for reducing temperature start with simple measures such as administration of drugs such as aspirin, acetaminophen, and ibuprofen. Acetaminophen and ibuprofen are both safe and effective medications for quickly reducing fever in young people, but only one of these drugs should be given at a time because there is no evidence that simultaneous use of both is more effective (09). The use of aspirin in children with viral infections should be avoided for possible risk of developing Reye syndrome. Simple procedures such as cold sponges and cooling with a fan might suffice, but for high fever with temperature over 40°C, combination of antipyretics with cooling devices is indicated. Glucocorticoids are potent antipyretics but their use may mask the inflammatory features of infections. However, early adjunctive treatment with dexamethasone improves the outcome in adults with acute bacterial meningitis.
Most patients with traumatic brain injury admitted to an intensive care unit environment develop a fever. It is an accepted practice to lower body temperature in patients with acute brain injury who develop fever, and several treatment options for controlling temperature are available. Although fever is one of the factors associated with poor outcome after ischemic brain injury and intracerebral hemorrhage, there are currently no prospective randomized trials demonstrating the benefit of fever control in these patients (03; 05).
Seriously ill patients are externally cooled and sedated or given drugs that suppress shivering so that fever and energy expenditure are more rapidly reduced than if treated with antipyretic drugs alone. For emergency situations with high fever, hypothermic devices may be required for rapid cooling. Hypothermia blankets are not practical for this purpose. Air-circulating cooling blankets do not effectively reduce body temperature in febrile neurointensive care unit patients. Intravascular cooling devices are more effective in prophylactically controlling the body temperature of neurologic intensive care patients with severe intracranial disease. The CoolGard/Cool Line catheter system has been demonstrated to be a safe and useful adjunct in the management of fever in critically ill neurologic patients. CoolGard has been shown to effectively lower body temperature to the target values for neurointensive care patients with fever after neurosurgical procedures that were resistant to pharmacotherapy (40).
Antipyretic medications, surface cooling, and intravascular cooling may all reduce temperatures in patients with subarachnoid hemorrhage, but benefits from cooling may be offset by shivering, which tends to raise body temperature (45). Fever following acute brain injury often predicts poor outcomes. Standard treatment methods like medication (paracetamol or nonsteroidal anti-inflammatory drugs) often fail, requiring physical interventions such as cooling devices are effective in achieving normal body temperature. Though data are not conclusive on normothermia benefits versus standard care tolerating mild fever (06).
Antipyretics are ineffective in lowering body temperature during episodes of hyperthermia. The primary focus of treating hyperthermia is to swiftly reduce body temperature through physical methods. Additionally, it is essential to identify the root cause of the hyperthermia, as the management approach varies depending on the underlying condition. A retrospective study investigated the effect of bromocriptine, a central dopamine receptor agonist, on body temperature in patients with acute brain injury and suspected central fever (38). Thirty three patients in a neurologic-intensive care unit were included. After adjusting for confounders, a significant temperature decline was noted following bromocriptine administration: -0.3°C at 24 hours, -0.5°C at 48 hours, and -0.7°C at 72 hours. This suggests that bromocriptine may have an antipyretic effect in this patient population and may hold promise for the future (38).
General management includes maintenance of the fluid and electrolyte balance, which is likely to be disturbed with prolonged fever. Other complications are managed as required. For example, febrile convulsions require use of anticonvulsant medications.
Outcomes
A systematic review and meta-analysis examined the effects of fever therapy on febrile adults. Forty-two randomized clinical trials involving 5140 participants were analyzed, which included the use of antipyretic drugs, physical cooling, and a combination of both. The study found that fever therapy does not significantly reduce the risk of death or serious adverse events, with high certainty evidence supporting these conclusions. The impact of fever therapy on nonserious adverse events was unclear due to very low certainty evidence. Therefore, the effectiveness of fever therapy in improving patient outcomes remains uncertain (18).
References
- 01
- Atkins E. Fever: historical aspects. In: Bomford R, Henerson B, editors. Interleukin-1, inflammation and disease. New York: Elsevier Science Publishers, 1989:3-15.
- 02
- Azar J, Elinav H, Safadi R, Soliman M. Malignant deep brain stimulator withdrawal syndrome. BMJ Case Rep 2019;12(5).** PMID 31092485
- 03
- Badjatia N. Fever control in the neuro-ICU: why, who, and when. Curr Opin Crit Care 2009;15(2):79-82. PMID 19578318
- 04
- Bartfai T, Conti B. Fever. ScientificWorldJournal 2010;10:490-503. PMID 20305990
- 05
- Bohman LE, Levine JM. Fever and therapeutic normothermia in severe brain injury: an update. Curr Opin Crit Care 2014;20(2):182-8. PMID 24553340
- 06
- Bogossian EG, Taccone FS. Fever management in acute brain injury. Curr Opin Crit Care 2022;28(2):130-7. PMID 35058405
- 07
- Canpolat M, Gumus H, Gunduz Z, et al. Neurological manifestations in familial Mediterranean fever: results of 22 children from a reference center in Kayseri, an urban area in Central Anatolia, Turkey. Neuropediatrics 2017;48(2):79-85. PMID 27656843
- 08
- Cooper KE. Some historical perspectives on thermoregulation. J Appl Physiol 2002;92:1717-24. PMID 11896042
- 09
- Crook J. Fever management: evaluating the use of ibuprofen and paracetamol. Paediatr Nurs 2010;22(3):22-6. PMID 20426354
- 10
- Cross JH. Fever and fever-related epilepsies. Epilepsia 2012;53 Suppl 4:3-8. PMID 22946716
- 11
- Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: a clinical approach. Am J Med 2015;128(10):1138.e1-15. PMID 26093175
- 12
- Daey Ouwens IM, Lens CE, Fiolet ATL, et al. Malaria fever therapy for general paralysis of the insane: a historical cohort study. Eur Neurol 2017;78(1-2):56-62. PMID 28633136
- 13
- De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908-19. PMID 29768139
- 14
- Edwards MJ. Hyperthermia in utero due to maternal influenza is an environmental risk factor for schizophrenia. Congenit Anom (Kyoto) 2007;47(3):84-9. PMID 17688466
- 15
- Gafter-Gvili A, Raibman S, Grossman A, et al. [18F]FDG-PET/CT for the diagnosis of patients with fever of unknown origin. QJM 2015;108(4):289-98. PMID 25208896
- 16
- Gillow SJ, Ouyang B, Lee VH, John S. Factors associated with fever in intracerebral hemorrhage. J Stroke Cerebrovasc Dis 2017;26(6):1204-8. PMID 28187992
- 17
- Gupta A, Cooper ZA, Tulapurkar ME, et al. Toll-like receptor agonists and febrile-range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release. J Biol Chem 2013;288(4):2756-66. PMID 23212905
- 18
- Holgersson J, Ceric A, Sethi N, Nielsen N, Jakobsen JC. Fever therapy in febrile adults: systematic review with meta-analyses and trial sequential analyses. BMJ 2022;378:e069620. PMID 35820685
- 19
- Hu X, Yu J, Crosby SD, Storch GA. Gene expression profiles in febrile children with defined viral and bacterial infection. Proc Natl Acad Sci U S A 2013;110(31):12792-7. PMID 23858444
- 20
- Jimenez AD, Gopaul M, Asbell H, et al. Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis. Epilepsia 2024;65(6):e87-e96. PMID 38625055
- 21
- Khanum I, Shoaib MS, Awan S. A comparative study on the use of procalcitonin to distinguish between central fever and infectious causes of fever. Pan Afr Med J 2024;47:43. PMID 38681106
- 22
- Kiyatkin EA, Sharma HS. Acute methamphetamine intoxication brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities. Int Rev Neurobiol 2009;88:65-100. PMID 19897075
- 23
- Lazarus M, Yoshida K, Coppari R, et al. EP3 prostaglandin receptors in the median preoptic nucleus are critical for fever responses. Nat Neurosci 2007;10:1131-3. PMID 17676060
- 24
- Limper M, de Kruif MD, Duits AJ, Brandjes DP, van Gorp EC. The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non-infectious fever. J Infect 2010;60(6):409-16. PMID 20347867
- 25
- Lin V, Tian C, Wahlster S, Castillo-Pinto C, Mainali S, Johnson NJ. Temperature control in acute brain injury: an update. Semin Neurol 2024;44(3):308-23. PMID 38593854
- 26
- Luger S, Harter PN, Mittelbronn M, Wagner M, Foerch C. Brain stem infarction associated with familial Mediterranean fever and central nervous system vasculitis. Clin Exp Rheumatol 2013;31(3 Suppl 77):93-5. PMID 23710607
- 27
- MacKenzie MA, van Heteren GM, van der Meer JW. Klinische thermometrie. I. Historische ontwikkelingen [Clinical thermometry. I. Historical developments]. Ned Tijdschr Geneeskd 1997;141(19):954-6. PMID 9340543
- 28
- Meier K, Lee K. Neurogenic fever. J Intensive Care Med 2017;32(2):124-9.** PMID 26772198
- 29
- Mota CMD, Madden CJ. Neural circuits mediating circulating interleukin-1β-evoked fever in the absence of prostaglandin E2 production. Brain Behav Immun 2022;103:109-21. PMID 35429606
- 30
- Muehlschlegel S, Carandang R, Ouillette C, Hall W, Anderson F, Goldberg R. Frequency and impact of intensive care unit complications on moderate-severe traumatic brain injury: early results of the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study. Neurocrit Care 2013;18(3):318-31. PMID 23377884
- 31
- Mulders-Manders CM, Pietersz G, Simon A, Bleeker-Rovers CP. Referral of patients with fever of unknown origin to an expertise center has high diagnostic and therapeutic value. QJM 2017. PMID 29036369
- 32
- Najjar S, Najjar A, Chong DJ, et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation 2020;17(1):231.** PMID 32758257
- 33
- Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol 2011;301(5):R1207-28. PMID 21900642
- 34
- Nakamura K, Matsumura K, Kobayashi S, Kaneko T. Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci Res 2005;51(1):1-8. PMID 15596234
- 35
- Niazkar HR, Zibaee B, Nasimi A, Bahri N. The neurological manifestations of COVID-19: a review article. Neurol Sci 2020;41(7):1667-71.** PMID 32483687
- 36
- O'Banion MK. Prostaglandin E2 synthases in neurologic homeostasis and disease. Prostaglandins Other Lipid Mediat 2010;91(3-4):113-7. PMID 19393332
- 37
- Park SY, Kwon JS, Kim JY, et al. Severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis. Clin Microbiol Infect 2018;24(4):432. PMID 28899841
- 38
- Perez V, McCreary M, Sheperd L, Nelson T, Sharma K. Antipyretic efficacy of bromocriptine in central fever: an exploratory analysis. Neurocrit Care 2023;39(2):499-504. PMID 36964441
- 39
- Picetti E, Oddo M, Prisco L, Helbok R, Taccone FS. A survey on fever monitoring and management in patients with acute brain injury: the SUMMA study. J Neurosurg Anesthesiol 2019;31(4):399-405.** PMID 30273201
- 40
- Popugaev KA, Savin IA, Goriachev AS, et al. First experience of using CoolGard system in intensive care patients after neurosurgical interventions: series of 10 observations [Article in Russian]. Anesteziol Reanimatol 2011;(2):42-9. PMID 21688659
- 41
- Protsiv M, Ley C, Lankester J, Hastie T, Parsonnet J. Decreasing human body temperature in the United States since the industrial revolution. Elife 2020;9:e49555. PMID 31908267
- 42
- Rincon F, Hunter K, Schorr C, Dellinger RP, Zanotti-Cavazzoni S. The epidemiology of spontaneous fever and hypothermia on admission of brain injury patients to intensive care units: a multicenter cohort study. J Neurosurg 2014;121(4):950-60.** PMID 25105701
- 43
- Rincon F, Patel U, Schorr C, et al. Brain injury as a risk factor for fever upon admission to the intensive care unit and association with in-hospital case fatality: a matched cohort study. J Intensive Care Med 2015;30(2):107-14. PMID 24132129
- 44
- Saper CB, Romanovsky AA, Scammell TE. Neural circuitry engaged by prostaglandins during the sickness syndrome. Nat Neurosci 2012;15(8):1088-95. PMID 22837039
- 45
- Scaravilli V, Tinchero G, Citerio G; Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Fever Management in SAH. Neurocrit Care 2011;15(2):287-94. PMID 21755388
- 46
- Soriano RN, Ravanelli MI, Batalhao ME, Carnio EC, Branco LG. Propyretic role of the locus coeruleus nitric oxide pathway. Exp Physiol 2010;95(6):669-77. PMID 20176679
- 47
- Stahn AC, Werner A, Opatz O, et al. Increased core body temperature in astronauts during long-duration space missions. Sci Rep 2017;7(1):16180.** PMID 29170507
- 48
- Suz P, Vavilala MS, Souter M, Muangman S, Lam AM. Clinical features of fever associated with poor outcome in severe pediatric traumatic brain injury. J Neurosurg Anesthesiol 2006;18:5-10. PMID 16369134
- 49
- Takakazu O. Psychogenic fever: how psychological stress affects body temperature in the clinical population. Temperature 2015;2(3):368-78.** PMID 27227051
- 50
- Tsuchiya H, Oka T, Nakamura K, et al. Prostaglandin E2 attenuates preoptic expression of GABAA receptors via EP3 receptors. J Biol Chem 2008;283(16):11064-71. PMID 18292084
- 51
- Visagan R, Kearney S, Blex C, et al. Adverse effect of neurogenic, infective, and inflammatory fever on acutely injured human spinal cord. J Neurotrauma 2023;40(23-24):2680-93. PMID 37476968
- 52
- Walter EJ, Carraretto M. The neurological and cognitive consequences of hyperthermia. Crit Care 2016;20(1):199.** PMID 27411704
- 53
- Wunderlich CA. On temperature in diseases. Translated by WB Woodman. London: Sydenham Society, 1871.
- 54
- Zhao ZD, Yang WZ, Gao C, et al. A hypothalamic circuit that controls body temperature. Proc Natl Acad Sci U S A 2017;114;(8)2042-7. PMID 28053227
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Ravindra Kumar Garg DM FRCP
Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.
See Profile
Editor
-
Peter J Koehler MD PhD
Dr. Koehler of Maastricht University has no relevant financial relationships to disclose.
See Profile
Former Authors
- K K Jain MD†
Patient Profile
- Age range of presentation
-
- 0 months to 65+ years
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
General Neurology
Bowel dysfunction in neurologic disorders
Oct. 10, 2024
-
General Neurology
Coma due to primary brainstem and diencephalic lesions
Oct. 05, 2024
-
Neuro-Ophthalmology & Neuro-Otology
Transient visual loss
Sep. 25, 2024
-
General Neurology
Sports activities: neurologic complications
Sep. 09, 2024
-
General Neurology
Hyperventilation syndrome
Sep. 03, 2024
-
General Neurology
Whiplash injuries
Sep. 03, 2024
-
Neurobehavioral & Cognitive Disorders
Apraxia
Aug. 28, 2024