Fever and headache are frequent clinical manifestations. A systemic inflammatory reaction to an infection or other pathologic processes is reflected in fever.
While headaches may be brought on by physiological changes linked to fever, headaches and fever together raise the possibility of central nervous system (CNS) infections like encephalitis or meningitis.
Other inflammatory, endocrine, or vascular disorders, cancers, autoimmune or rheumatologic conditions, and systemic (non-CNS) infections should also be considered.
For proper treatment and a better prognosis, prompt and comprehensive evaluation to differentiate between these etiologies is crucial.
Diagnostic Approach for Infectious Disease Process in People with Fever and Headaches
It is necessary to establish whether the headache is primary or secondary. Secondary headaches—those brought on by another illness—are much less common than primary headaches, such as migraines and tension-type headaches.
Fever raises the possibility that a secondary process is taking place because fever is not usually present in primary headache disorders. Any past history that suggests one diagnostic entity is more likely than another must be considered once a secondary process and infection are suspected.
*Overlap exists, both may present with altered mental state
Fig. 1: General Diagnostic approach for patients with fever and headache
These include recent trauma, surgical procedures, exposure to drugs, foods, insects, animals, or sick contacts; immunosuppressive conditions or medications (keeping in mind that immunocompromised individuals are more susceptible to opportunistic infections and infection-associated oncogenesis due to lack of immune surveillance); and travel.
The timing is crucial: a process that has persisted for more than four weeks is regarded as chronic and may indicate a distinct group of infectious pathogens.
When evaluating some endemic infections (such as endemic mycoses or tuberculosis, both of which can reactivate during immunosuppression), knowledge of current and past geographic residence as well as recent travel are crucial factors. Other skin flora (such as Staphylococcus aureus) and nosocomial pathogens (such as Gram-negative bacilli) must be taken into consideration if a person exhibits a compromised skin barrier due to trauma, injection drug use, or surgery, especially involving the central nervous system.
Table 1:Differential diagnosis of headache with fever based on history
Anyone with altered mental status (AMS) should pursue neuroimaging, ideally magnetic resonance imaging (MRI), and this should be taken into consideration when a headache is accompanied by fever.
But most cases of bacterial meningitis might not show any abnormalities on neuroimaging.
If encephalitis or meningitis is suspected, lumbar punctures (LP) should be performed. Cell count, glucose CSF-to-blood ratio, protein and glucose concentrations, lactate level, CSF culture, and Gram stain should all be included in the analysis of cerebrospinal fluid (CSF). It is possible to request multiplex nucleic acid testing or repeat LP if bacterial meningitis is suspected but CSF cultures are negative, frequently in the context of prior antibiotic administration.
Cultures for the suspected organisms or specific stains (such as fungal stain and culture, cryptococcal antigen, acid-fast stain and culture for mycobacteria) should be requested if the index of suspicion is higher for an atypical etiology because of a history of immunocompromising conditions, HIV infection, or particular exposures.
Certain pathogens (such as spirochetes, arboviral illnesses, and different zoonoses) can also be identified using serology.
Instead of depending only on multiplex PCR panels, which may have lower sensitivity to detect HSV—the most frequent infectious cause of encephalitis—an HIV fourth-generation screening test and herpes simplex virus (HSV) polymerase chain reaction (PCR) on CSF should be requested if the presentation is more consistent with encephalitis.
Because of its increased sensitivity, MRI is advised if a brain abscess is suspected; LP should be avoided if a mass effect is noticeable.
Approach for Differential Diagnoses
Meningitis, encephalitis, and other (such as sinusitis or brain abscesses) are the three main categories into which infection-related headache and fever can be classified. Headache is a common symptom of other non-CNS infectious diseases like influenza and dengue fever, and pyrogenic cytokine release causes a correlation between headache and fever intensity.
(A)Meningitis
Immunosuppression and advanced age are the two main risk factors for infectious meningitis.
Meningitis usually manifests as nuchal rigidity and alerted mental state (AMS) with nausea.
The best positive predictive value for diagnosis is found in headache, fever, neck stiffness, and AMS. Despite their lack of sensitivity, positive Kernig and Brudzinski signs may be observed.
Most cases of acute meningitis are caused by bacteria or viruses. The most frequent causes of acute aseptic meningitis are viruses, especially enteroviruses, HSV, and West Nile virus (WNV).
About 5% of cases of viral meningitis are caused by herpesviruses, with HSV-2 being more frequently linked than HSV-1. Genital herpes frequently coexists with HSV-2 meningitis.
About 85% of cases are nonpolio enteroviral meningitis, which usually manifests in the summer after a gastrointestinal ailment.
The most frequent cause of viral meningitis outbreaks in the world during the summer and early fall months is enterovirus. They are responsible for more than 90% of all viral meningitis cases where a pathogen is identified. People with weakened immune systems are more vulnerable.
Meningitis can also be brought on by HIV, especially during the period of seroconversion, but an HIV diagnosis by itself does not prove that this is the main cause.
Severe neurologic impairments, such as memory loss, sensory impairment, or functional impairment, can be caused by bacterial meningitis.
The number or severity of symptoms and Streptococcus pneumoniae infection raise the risk of severe disability or death.
Neisseria meningitidis (~10% of cases) and S pneumoniae (~70% of cases) are the most frequent bacterial pathogenic culprits (all vaccine-preventable), especially in teenagers and adults.
Those with terminal complement deficiency or functional or anatomic asplenia are more vulnerable to all encapsulated organisms.
Hemophilus influenzae and Listeria monocytogenes (~5% of bacterial meningitis cases) are less frequent causes. Although the H influenzae vaccine has decreased the incidence of H influenzae meningitis, immunocompromised people are still at risk from the organism, especially those who are unvaccinated or have asplenia. Listeria usually follows exposure to food. Numerous outbreaks have been documented.
Other bacteria, fungi, or parasites can cause acute meningitis. Certain organisms are more likely to cause chronic meningitis (symptoms lasting more than one month), which is typically caused by bacteria or fungi.
Compared to other bacterial species, tuberculosis, spirochetal diseases (such as Lyme disease [Borrelia burgdorferi], syphilis [Treponema pallidum], and L monocytogenes are more likely to cause chronic meningitis.
Cryptococcus neoformans should be taken into consideration in individuals with HIV whose CD4+ T-lymphocyte counts are less than 100 cells/mm, and endemic mycoses (such as coccidioidomycosis and histoplasmosis) should be taken into consideration when there is a history of travel to or residency in endemic areas.
(B)Encephalitis
Encephalitis is a CNS inflammatory disease that presents as encephalopathy. AMS or abnormal behavior lasting longer than twenty-four hours is referred to as encephalopathy.
Fever, positive neuroimaging, CSF pleocytosis, seizures, focal neurologic deficits, or positive EEG results are all signs of CNS inflammation. Nuchal symptoms and photophobia are not always indicative of encephalitis, but they should raise the possibility of meningoencephalitis when combined with altered mentation.
Unlike meningitis, infectious encephalitis is characterized by inflammation of the brain parenchyma instead of the meninges.
Neurologic symptoms, such as altered mental status, confusion, behavioral changes, motor and sensory deficits, and seizures, are indicative of encephalitis. With up to 62% of adults experiencing encephalitis sequelae, such as epilepsy, memory issues, exhaustion, sleep disturbances, cognitive changes, personality changes, or chronic pain, encephalitis has high rates of morbidity and mortality.
Nearly 60% of cases of encephalitis are caused by viruses, especially HSV and enteroviruses. A significant portion of encephalitis cases are also brought on by arboviruses. Certain arboviruses have very regional variations in their prevalence. Japanese encephalitis virus contributes to a significant number of cases in Asia. Depending on the geographic setting, a number of additional mosquito-borne viral encephalitides, such as St. Louis encephalitis virus and Eastern and Western equine encephalitis viruses, should be taken into consideration.
Among the bacterial causes, encephalitis can be secondary to an atypical infection like borreliosis, brucellosis, or scrub typhus, or it can appear as a complication of meningitis like with pneumococcus and Mycobacterium tuberculosis.
In immunocompetence hosts, mold can rarely disseminate. Protozoa can enter the brain through the lymphatic and circulatory systems. Amoebae can enter the brain through the sinuses or blood and cause granulomatous amoebic encephalitis or primary amoebic meningoencephalitis, both of which are almost always fatal.
Some micro-organisms prefer specific areas of the brain. On MRI, HSV-1 frequently exhibits a hyperintense temporal lobe signal. The brainstem, basal ganglia, and thalamus may develop hyperintense lesions as a result of the Japanese encephalitis virus. On MRI, the basal ganglia, thalamus, midbrain, and pons are the main areas affected by rabies. The Powassan virus may cause alterations in both deep and superficial white matter.
In contrast to CD8 encephalitis, which is primarily a histopathologic diagnosis, HIV encephalitis can manifest as progressive multifocal leukoencephalopathy (which exhibits multifocal and confluent white matter lesions, usually >3 mm) and hyperintensities in the periventricular regions and centrum semiovale.
Ring enhancing lesions are a common feature of brain infections brought on by organisms belonging to the Toxoplasma and Cryptococcus genera.
People who are infected with pathogens like HSV, WNV, enterovirus, and L monocytogenes may exhibit cranial nerve, sensory, and motor deficits as well as rhombencephalitis.
Some people experience autoimmune or postinfectious encephalitis following the infectious phase. An estimated 7% to 25% of cases of anti-NMDA receptor encephalitis are linked to HSV-1. Acute disseminated encephalomyelitis is linked to multiple bacterial, viral, and protozoal postinfectious courses and usually follows a febrile infectious or vaccine administration. A hypersensitivity reaction is thought to be the mechanism behind tuberculous encephalopathy, which happens when there is a tuberculosis infection but no organisms in the brain.
Table 2: Regional prevalence of infectious etiology of encephalitis
(C)Brain Abscess and Sinusitis
Sinusitis, a common cause of headache and fever, is often due to viral infection without abscess formation; it can also be bacterial (<2%)or fungal (e.g., Aspergillus, Mucorales in certain types of immunocompromise), increasing the risk of progression to abscess.
Fungal etiologies should be considered in the setting of immunosuppression or poorly controlled diabetes and may also present as invasive fungal rhinosinusitis rather than an abscess.
A brain abscess, which is frequently polymicrobial, is a dangerous consequence of an initial inflammatory focus in the brain parenchyma. Neurosurgery, ear infections, solid cancers, and immunomodulating therapies are the biggest risk factors.
Although meningitis and encephalitis can cause abscesses; trauma, surgery, hematogenous spread, and craniofacial infections like sinusitis are more frequent causes.
An abscess is most likely to form depends on the site of infection, and certain neurologic deficits may indicate a localized mass effect.
Table 3: Sources of Brain abscess, common sites and associated symptoms
Diagnostic Approach to Noninfectious Disease Processes in the Individual With Headache and Fever
Historical indicators that make one diagnostic entity more likely than another must be considered after a secondary process is suspected and a noninfectious cause is suspected. These include exposure to drugs, the environment, and the workplace, as well as specific systemic or related symptoms.
(A)Environmental and Occupational Exposure
Toxic, inflammatory, or immune-mediated effects can result from occupational and environmental exposures, especially in military or industrial settings.
Job responsibilities, deployment sites, exposure to radiation, solvents, metals, pesticides, or combustion products, and use of protective gear should all be included in a focused history.
Burn pits, particulate matter, and industrial and toxic chemicals are examples of exposures that can result in low-grade systemic inflammation, which manifests as headache, fatigue, myalgia, and arthralgias. Laboratory results are frequently nonspecific and include organ involvement or mild elevations of inflammatory markers.
(B)Autoimmune, Vascular, and Rheumatologic Disorders
Important noninfectious causes of headache with fever include rheumatologic, vascular, and autoimmune diseases.
Unintended weight loss could be a sign of endocrine disorders, cancer, or giant cell arteritis (GCA).
Rheumatologic or collagen vascular diseases are frequently accompanied by myalgias and arthralgias.
In adults over 50 with new headaches and fever, scalp tenderness and jaw claudication strongly suggest GCA.
Visual loss, diplopia, eye pain, or uveitis are examples of ocular symptoms that can indicate Behçet disease, sarcoidosis, GCA, or vasculitis.
Systemic lupus erythematosus or Still disease may be indicated by a rash (such as malar, photosensitive, or evanescent); recurrent oral or genital ulcers may indicate Behçet disease.
Exposures at work and in the environment may be important factors to consider when assessing potential sarcoidosis.
Giant cell arteritis patients may experience proximal muscle stiffness, diminished or nodular temporal pulses, and temporal artery or scalp tenderness.
People with other rheumatologic, vascular, and autoimmune disorders may have livedo reticularis or purpura, salmon-colored rashes, uveitis, or mucosal ulcers.
Elevated erythrocyte sedimentation rate or C-reactive protein levels are frequently found in laboratory studies of people with autoimmune, vascular, and rheumatologic disorders.
Depending on the condition, further testing may identify antinuclear antibodies, anti-double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies, low complement, hyperferritinemia, or elevated angiotensin converting enzyme levels.
Vascular imaging may reveal stenoses or beading of the afflicted vessels; neuroimaging may show parenchymal or meningeal enhancement in neurosarcoidosis or vasculitic lesions.
Tissue biopsies are frequently required for diagnosis, such as temporal artery biopsies for suspected GCA or biopsies of lymph nodes or other affected organs.
(C) Endocrine Disorders
One of the main noninfectious causes of headache with fever is endocrine disorders, especially thyroid dysfunction.
Thyrotoxicosis can cause headache and fever, which can be more severe during a thyroid storm. The most common causes of thyrotoxicosis are subacute thyroiditis, toxic multinodular goiter, and Graves’ disease. Thyroid storm, a potentially fatal situation in which severe, uncontrolled hyperthyroidism results in the failure of several organs, is indicated by severe hormone excess combined with organ dysfunction.
New or worsening headaches, tachycardia, weight loss, conjunctival injection, and diaphoresis are historical indicators of thyrotoxicosis. Goiter, tremor, or hair loss may be found during examination. Thyroid stimulating hormone (TSH), T3, free T4, and Graves antibodies are all part of the initial laboratory assessment. Imaging may include a nuclear medicine thyroid scan.
(D)Oncologic and Hematologic Disorders
Two significant non-infectious causes of headache with fever are hematologic and oncologic disorders.
Acute myeloid leukemia, acute lymphoblastic leukemia, primary CNS lymphoma, and Burkitt lymphoma have all been linked to headache and fever.
Weight loss, exhaustion, and excessive perspiration are examples of historical characteristics. Lymphadenopathy may be discovered during examination.
Peripheral blood smears, coagulation tests, and complete blood counts are all part of the laboratory evaluation.
Bone marrow analysis, CSF testing, and brain and spinal MRI are examples of imaging and specialized tests.
(E)Etiologies Associated with Drugs
Antibiotics, immunosuppressants, antiepileptics, and nonsteroidal anti-inflammatory drugs are frequently linked to headache and fever in patients with drug-induced aseptic meningitis.
These symptoms can also be brought on by serotonergic medications, mimicking serotonin syndrome.
Recent modifications to prescriptions, dosages, or the introduction of new medications are examples of historical features. When the cause of headache and fever is unknown, a comprehensive medication review is crucial.
Table 4: Diagnostic consideration to noninfectious diseases
In conclusion
Careful, focused, and thorough questioning and examination are necessary when someone presents with a fever and headache.
Potential causes are numerous, and symptoms are erratic and prone to change.
Improving results requires prompt identification of the underlying pathology using an algorithmic, multidisciplinary approach.
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Author Information
Thar Thar Oo
MBBS, MD, MPH, FAAN
Senior Consultant Neurologist
