An Algorithmic Approach to Headache With Fever

Headache accompanied by fever is a common clinical presentation. Fever reflects a systemic inflammatory response to infection or other pathologic processes. Although physiologic changes associated with fever may cause headache, headache combined with fever raises concern for central nervous system (CNS) infection such as meningitis or encephalitis. Systemic (non-CNS) infections, malignancies, autoimmune or rheumatologic conditions, and other inflammatory, endocrine, or vascular disorders should also be considered. Prompt and thorough evaluation to distinguish among these etiologies is essential for appropriate management and improved prognosis.

Figure. A diagnostic algorithm for patients with fever and headache.
Abbreviations: CMV, cytomegalovirus; CNS, central nervous system; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; EEE, Eastern equine encephalitis virus; HHV-6, human herpesvirus 6; HSV-2, herpes simplex virus type 2; VP, ventriculoperitoneal.

Diagnostic Approach to Infectious Disease Processes in Individuals With Headache and Fever
Whether the presenting headache is primary or secondary must be determined. Primary headaches such as migraine and tension-type headache are far more common than secondary headaches—those caused by another condition. Fever is not typically present in primary headache disorders, and therefore fever increases the likelihood that a secondary process is occurring. Once a secondary process is considered and infection suspected, any historical clues that make one diagnostic entity more likely than another must be considered (Figure). These include 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) as well as recent trauma; surgical procedures; exposures to drugs, foods, insects, animals, or sick contacts; and travel. The timeline is key: a process that has lasted for ≥4 weeks is considered chronic and is suggestive of a different set of possible infectious pathogeneses (Table 1).

Knowledge of current and previous geographic residence as well as recent travel are important factors in considering certain endemic infections (eg, endemic mycoses or tuberculosis, both of which can reactivate during immunosuppression) (Figure and Table 1). If an individual presents with a disrupted skin barrier from trauma, injection drug use, or surgery—particularly involving the CNS—then other skin flora (eg, Staphylococcus aureus) and nosocomial pathogens (Gram-negative bacilli) must be considered.

Neuroimaging, preferably MRI, should be pursued in anyone with altered mental status (AMS) and should be considered when headache is accompanied by fever. However, a majority of bacterial meningitis cases may not reveal abnormal findings on neuroimaging.^1,2 Lumbar puncture (LP) should be pursued if meningitis or encephalitis is suspected.³ Cerebrospinal fluid (CSF) analysis should include cell count, glucose CSF-to-blood ratio, glucose and protein concentrations, lactate level, CSF culture, and Gram stain.^3,4 If bacterial meningitis is suspected but CSF cultures are negative, often in the setting of previous administration of antibiotics, multiplex nucleic acid testing can be requested, or LP repeated.⁵

If the index of suspicion is higher for an atypical etiology due to a history of immunocompromising conditions, human immunodeficiency virus (HIV) infection, or specific exposures, cultures for the suspected organisms or specific stains should be requested (eg, fungal stain and culture, cryptococcal antigen, acid-fast stain and culture for mycobacteria).3 Serology can also be used to identify specific pathogens (eg, spirochetes, arboviral diseases, various zoonoses).³ If the presentation is more consistent with encephalitis, an HIV fourth-generation screening test should be requested and herpes simplex virus (HSV) polymerase chain reaction (PCR) performed on CSF rather than relying solely on multiplex PCR panels, which may have inferior sensitivity to detect HSV—the most common infectious cause of encephalitis. If brain abscess is suspected, it is recommended to use MRI due to its improved sensitivity and avoid LP, which may be contraindicated if mass effect is apparent.³

Approach to Differential Diagnoses
The diagnosis of headache with fever caused by infection can be divided into 3 broad categories: meningitis, encephalitis, and other (eg, brain abscesses, sinusitis). Other non-CNS infectious entities such as influenza and dengue fever have headache as a prominent symptom, and fever intensity correlates with headache due to pyrogenic cytokine release. Discussion of the innumerable root causes of fever⁶ is beyond the scope of this article. 

Meningitis
The most important risk factors for infectious meningitis are advanced age and immunosuppression.⁷ Meningitis typically presents with nuchal rigidity and AMS accompanied by nausea.^7,8 Headache, fever, neck stiffness, and AMS have the best positive predictive value for diagnosis.⁸ Positive Kernig and Brudzinski signs may be noted, although these lack sensitivity.⁹

Acute meningitis is typically viral or bacterial.¹ Viruses—particularly enteroviruses, HSV, and West Nile virus (WNV)—are the most common causes of acute aseptic meningitis (Table 1).¹⁰ Herpesviruses account for ~5% of viral meningitis cases with HSV-2 being more commonly associated than HSV-1. HSV-2 meningitis often occurs in the setting of genital herpes.¹ Nonpolio enteroviral meningitis accounts for ~85% of cases, typically following gastrointestinal illness and presenting in the summer months. WNV is the most common cause of viral meningitis epidemics during the summer in the United States.^1,11 Immunocompromised individuals are at greater risk. HIV can also cause meningitis, primarily around the time of seroconversion, but a diagnosis of HIV alone does not indicate it is the primary etiology.

Bacterial meningitis may result in severe neurologic deficits and disability including memory, sensory, or functional impairment.^7,12 Risk of severe disability or mortality increases with symptom number or severity and infection with Streptococcus pneumoniae.⁸ The most common bacterial pathogenic culprits (all vaccine-preventable) are S pneumoniae (~70% of cases) and Neisseria meningitidis (~10% of cases), particularly in teenagers and adults.^7,13 All encapsulated organisms pose an increased risk in those with functional or anatomic asplenia or terminal complement deficiency. Less common causes include Haemophilus influenzae and Listeria monocytogenes (~5% of bacterial meningitis cases). The H influenzae vaccine has reduced the prevalence of H influenzae meningitis; however, the organism still poses a risk to immunocompromised individuals, particularly those with asplenia or who are unvaccinated. Listeria tends to follow food exposures. A number of outbreaks have been reported.^1,10,13-15

Acute meningitis can be caused by other bacteria, fungi, or parasites (Table 1). Certain organisms are more likely to lead to chronic meningitis (>1 month of symptoms), which is more often bacterial or fungal in nature.¹ Tuberculosis, spirochetal diseases (eg, Lyme disease [Borrelia burgdorferi], syphilis [Treponema pallidum]), and L monocytogenes are more likely to progress to chronic meningitis than other bacterial species, with tuberculosis highest on the differential. Endemic mycoses (eg, coccidioidomycosis, histoplasmosis) should be considered when there is a history of travel to or residence in endemic areas, and Cryptococcus neoformans should be considered in people with HIV with CD4⁺ T-lymphocyte counts <100 cells/mm.^1,9

Encephalitis
Encephalitis is an inflammatory disorder of the CNS manifesting as encephalopathy. Encephalopathy is defined as AMS or abnormal behavior for >24 hours. CNS inflammation is indicated by at least 2 of the following: fever, positive neuroimaging, CSF pleocytosis, seizure, focal neurologic deficits, or positive EEG findings.¹⁶ Encephalitis does not always present with nuchal signs or photophobia, which in combination with altered mentation should raise the possibility of meningoencephalitis.¹⁷

Infectious encephalitis, in contrast to meningitis, is characterized by inflammation of the brain parenchyma rather than the meninges. The presentation of encephalitis is marked by neurologic symptoms, which may manifest as altered mental status, confusion, behavioral changes, motor and sensory deficits, and seizures.¹⁸ Encephalitis has high morbidity and mortality rates, with up to 62% of adults experiencing encephalitis sequelae including epilepsy, memory problems, fatigue, sleep disturbances, cognitive changes, personality changes, or chronic pain.¹⁸

Viral etiologies, particularly HSV and enteroviruses, are among the most common causes of encephalitis implicated in nearly 60% of cases. Arboviruses also cause a substantial number of encephalitis cases.¹⁸ The prevalence of certain arboviruses is highly regionally dependent. Japanese encephalitis virus contributes to a substantial number of cases in Asia, whereas WNV causes sporadic outbreaks in most of the United States, with variable incidence by region and year. Several other mosquito-borne viral encephalitides should be considered depending on geographic context (Table 1), including Eastern and Western equine encephalitis viruses and St. Louis encephalitis virus.

Of the bacterial causes, encephalitis can manifest as a complication of meningitis such as with pneumococcus and Mycobacterium tuberculosis, or can be secondary to an atypical infection such as borreliosis, brucellosis, or scrub typhus.^19-21 Molds can rarely disseminate in immunocomproimsed hosts.²² Protozoa can travel through the blood and lymph to reach the brain. Amoebae can travel through the blood or the sinuses to reach the brain, resulting in primary amebic meningoencephalitis or granulomatous amoebic encephalitis, both of which are nearly always fatal.^23-25

Certain agents have tropism for particular portions of the brain. HSV-1 tends to demonstrate hyperintense signal of the temporal lobes on MRI.²⁶ Japanese encephalitis virus may result in hyperintense lesions of the thalamus, basal ganglia, and brainstem.²⁷ Rabies primarily involves the basal ganglia, thalamus, midbrain, and pons on MRI.²⁸ Powassan virus may show changes in the superficial and deep white matter.²⁹ HIV encephalitis may present with hyperintensities in the periventricular regions and centrum semiovale, which differs from CD8 encephalitis—primarily a histopathologic diagnosis—and progressive multifocal leukoencephalopathy (which shows multifocal and confluent white matter lesions, typically >3 mm).^30-32 Infections in the brain caused by organisms of the Cryptococcus and Toxoplasma genuses are generally characterized by ring-enhancing lesions.^33,34 Individuals infected with organisms such as HSV, WNV, enterovirus 71, and L monocytogenes can present with a rhombencephalitis manifesting with cranial nerve, sensory, and motor deficits.²⁶

After the infectious phase, some individuals develop an autoimmune or postinfectious encephalitis. HSV-1 is implicated in anti–NMDA receptor encephalitis in an estimated 7% to 25% of cases.³⁵ Acute disseminated encephalomyelitis typically follows a febrile infectious or vaccine administration and is associated with several bacterial, viral, and protozoal postinfectious courses (Table 1).³⁶ Tuberculous encephalopathy occurs in the setting of infection with tuberculosis, but without the presence of organisms in the brain; the mechanism is thought to be a hypersensitivity reaction.³⁷

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%)³⁸ or fungal (eg, 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.³⁹

Brain abscess is a serious complication of an initial inflammatory focus in the brain parenchyma, and abscesses are often polymicrobial.⁸ The greatest risk factors are neurosurgery, solid cancers, ear infections, and immunomodulating treatments.⁴⁰ Abscesses may follow meningitis and encephalitis; however, more common sources are trauma, surgery, hematogenous spread, or craniofacial infection such as sinusitis.⁴⁰ The site of infection can determine where an abscess is most likely to form, and specific neurologic deficits can reflect localized mass effect (Figure and Table 2).⁴⁰

Diagnostic Approach to Noninfectious Disease Processes in the Individual With Headache and Fever 
Once a secondary process is considered and a noninfectious cause is suspected, historical clues that make one diagnostic entity more likely than another must be considered (Table 3). These include certain systemic or associated symptoms as well as occupational, environmental, and drug exposures.

Occupational and Environmental Exposure
Occupational and environmental exposures can cause toxic, inflammatory, or immune-mediated effects, particularly in military or industrial settings.^74-78 A focused history should include job duties; deployment locations; exposure to combustion products, solvents, metals, pesticides, or radiation; and use of protective equipment (Table 3).^74-78

Exposures (eg, burn pits, particulate matter, or industrial and toxic chemicals) may cause low-grade systemic inflammation presenting with headache, fatigue, myalgia, and arthralgias.^74,76-78 Laboratory findings, including mild inflammatory marker elevations or organ involvement, are often nonspecific.^75,77

Rheumatologic, Vascular, and Autoimmune Conditions
Rheumatologic, vascular, and autoimmune disorders are important noninfectious causes of headache with fever (Table 3).^79-87 Unintentional weight loss may indicate malignancy, giant cell arteritis (GCA), or endocrine disease.^80,82,83,88 Myalgias and arthralgias commonly accompany rheumatologic or collagen vascular disease.^79,81,83,85 Scalp tenderness and jaw claudication strongly suggest GCA in adults aged >50 years with new headaches and fever.^{82,83,85,87-91} Ocular symptoms—including visual loss, diplopia, eye pain, or uveitis—may reflect vasculitis, GCA, sarcoidosis, or Behçet disease.^79,82,84,86 Rash (eg, malar, photosensitive, evanescent) can indicate systemic lupus erythematosus or Still disease; recurrent oral or genital ulcers point to Behçet disease.^79-81,84,86 Occupational and environmental exposures may be relevant when evaluating possible sarcoidosis.^78,79

Temporal artery or scalp tenderness, diminished or nodular temporal pulses and proximal muscle stiffness may be present in people with giant cell arteritis.^82,83 Livedo reticularis or purpura, a salmon colored rashe, uveitis, or mucosal ulcers may be present in people with other rheumatologic, vascular and autoimmune conditions.^79,81,84,85 Laboratory studies often show elevated erythrocyte sedimentation rate or C-reactive protein levels in those with rheumatologic, vascular, and autoimmune conditions.^79-83 Additional testing may reveal antinuclear antibodies, anti–double-stranded DNA antibodies, antineutrophil cytoplasmic antibodies, low complement, hyperferritinemia, or elevated angiotensin-converting enzyme levels depending on the disorder.^79-81 Neuroimaging may demonstrate parenchymal or meningeal enhancement in neurosarcoidosis or vasculitic lesions; vascular imaging may show stenoses or beading of affected vessels.^79-81,84,86 Tissue biopsy—such as temporal artery biopsy for suspected GCA or biopsy of lymph nodes or other involved organs—is often necessary for diagnosis.^{79,82,83,87,90,91}

Endocrine Disorders
Endocrine disorders, particularly thyroid dysfunction, are key noninfectious causes of headache with fever. Headache and fever may occur in thyrotoxicosis and can be pronounced in thyroid storm.^92-98 Thyrotoxicosis most often results from Graves disease, toxic multinodular goiter, or subacute thyroiditis.⁹⁴ Severe hormone excess with organ dysfunction indicates thyroid storm (ie, life-threatening emergency where severe, uncontrolled hyperthyroidism causes multiple organs to fail).^95-98

Historical clues to thyrotoxicosis include new or worsening headache, tachycardia, weight loss, conjunctival injection, and diaphoresis.^99,100 Examination may reveal goiter, tremor, or hair loss.^94,99 Initial laboratory evaluation includes thyroid-stimulating hormone, T3, free T4, and Graves antibodies. Imaging may include a nuclear medicine thyroid scan.^92,95

Hematologic and Oncologic Processes
Hematologic and oncologic disorders are important noninfectious causes of headache with fever. Headache and fever have been reported in people with acute myeloid leukemia, acute lymphoblastic leukemia, primary CNS lymphoma, and Burkitt lymphoma.^101,106

Historical features may include weight loss, fatigue, and abnormal sweating.⁸⁵ Examination may reveal lymphadenopathy.¹⁰⁷ Laboratory evaluation includes complete blood count, coagulation studies, and peripheral blood smear.¹⁰⁷ Imaging and special tests may include brain and spinal MRI, bone marrow analysis, and CSF testing.^103,107

Drug-Related Etiologies
Headache and fever can occur in people with drug-induced aseptic meningitis and are commonly associated with antibiotics, immunosuppressants, antiepileptics, and nonsteroidal anti-inflammatory drugs.^108-112 Serotonergic medications may also produce these symptoms, as in serotonin syndrome.¹¹³

Historical features include recent changes in medications, dosages, or the addition of new drugs. A thorough medication review is essential when the cause of headache and fever is unclear.

Conclusion
Individuals presenting with fever and headache require careful, directed, and detailed questioning and examination. Manifestations are variable and subject to change, and potential etiologies are myriad. Timely determination of the underlying pathology using an algorithmic, multidisciplinary approach is key to improving outcomes.