Headache associated with intracranial infection …

Jong-Ling Fuh MD

Headache & Pain

Updated 03.31.2024
Released 09.20.1995
Expires For CME 03.31.2027

Headache associated with intracranial infection

Author: Jong-Ling Fuh MD

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Editor: Shuu-Jiun Wang MD

Headache associated with intracranial infection

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Introduction

Overview

Headache is usually the first and most frequently encountered symptom in intracranial infection, but it only accounts for less than 1% of acute headache presentations to the emergency department. Encephalitis is characterized by headache, fever, alteration of consciousness, focal neurologic deficit, and seizures (usually focal). Because the brain parenchyma has no sensory receptors, the headache of encephalitis and brain abscess may result from the meningeal inflammation that often accompanies these processes, including a nonspecific response to fever, increased intracranial pressure, or a mass-effect producing traction on pain-sensitive intracranial structures. The most common predisposing conditions of brain abscesses are otitis or mastoiditis. The prevalence of headache during the acute phase of COVID infection up to week 4 was about 50%, whereas persistent headache during the subacute phase was 31% in 1 month to 16% in 9 months. Physical signs of meningeal inflammation do not help clinicians rule in or rule out meningitis accurately. The headaches attributed to intracranial infection are further divided into four subtypes in the International Classification of Headache Disorders, 3rd edition. Headache remits with resolution of the infection in most cases, and headache might persist for more than three months after resolution of the causative infection in only a few patients. However, a longitudinal study showed that the 1-year prevalence of headache suffering was not higher amongst patients with prior intracranial infection than in the general population.

Key points

	• No physical sign of meningeal irritation could accurately distinguish those with and without meningitis.
	• Headache is the most common symptom of bacterial meningitis (87%), but bacterial meningitis is not a common etiology of acute headache presentation to the emergency room (< 1%).
	• The diagnosis of headache attributed to localized brain infection (code 9.1.4) included headache caused by brain abscess, subdural empyema, infectious granuloma, or other or other localized infective lesion, usually associated with fever, focal neurologic deficit(s), or altered mental state (including impaired vigilance).
	• The prevalence of headache during the acute phase of COVID infection up to week 4 was about 50%, whereas persistent headache during the subacute phase was 31% in 1 month to 16% in 9 months.

Historical note and terminology

Bacterial meningitis was first described by Vieusseaux after an outbreak in Switzerland in 1805 and was named "epidemic cerebrospinal fever." The meningococcus was first isolated from cerebrospinal fluid (CSF) by Weichselbaum in 1887. In 1932 the antimicrobial properties of sulfonamides were appreciated (55) as an effective treatment for meningococcal, pneumococcal, and haemophilus-related diseases. Survival from all three types of meningitis dramatically improved after penicillin was introduced in the 1940s (54).

In 1893 Sir William Macewen described surgical drainage as a successful treatment of brain abscess.

Quinke introduced the lumbar puncture in 1881 and originally described viral meningitis and encephalitis in 1896. In 1917, von Economo proposed the first pathologic correlates of presumed viral encephalitis during the epidemics of encephalitis lethargica. Aseptic meningitis, a term introduced by Wallgren in 1925, describes a benign and self-limited variant of meningitis usually caused by a viral infection, with headache a prominent feature of the illness.

Nathan Strong, a medical student, recognized meningismus as a diagnostic sign of meningitis in 1810. Vladimir Mihailovich Kernig described his maneuver for detecting meningeal irritation in 1882. In 1909 Jozef Brudzinski described at least five different meningeal signs in patients with meningitis.

Clinical manifestations

Presentation and course

	• The classical triad of symptoms of meningitis are fever, nuchal rigidity (neck stiffness), and change in mental status. Nevertheless, it occurs only in approximately 41% of patients with acute bacterial meningitis and is more common in patients older than 60 years of age.
	• Headache is the most common symptom of bacterial meningitis, yet it is not included in the classical triad.
	• Aseptic meningitis can be a cause of sudden-onset headache.
	• The prevalence of headache during the acute phase of COVID infection up to week 4 was about 50%, whereas persistent headache during the subacute phase was 31% in 1 month to 16% in 9 months.
	• Headache, mental status changes, focal neurologic deficit, and fever are hallmark symptoms of brain abscess.

The classification of headaches attributed to intracranial infection is covered in chapter nine (code 9.1) of the International Classification of Headache Disorders, 3rd edition (ICHD-III) (28). The headaches attributed to intracranial infection are further divided into four subtypes: 9.1.1 headache attributed to bacterial meningitis or meningoencephalitis, 9.1.2 headache attributed to viral meningitis or encephalitis, 9.1.3 intracranial fungal or other parasitic infection, and 9.1.4 headache attributed to localized brain infection.

Aseptic meningitis causes approximately 72% of meningitis cases, whereas bacterial and fungal meningitis cause approximately 8% each of the rest of cases (27). The classical triad of symptoms of meningitis are fever, nuchal rigidity (neck stiffness), and change in mental status. The classical triad was present approximately 41% of patients with acute bacterial meningitis (06) and is more common in patients older than 60 years (70). The diagnostic sensitivity was poor (73). Highly suggestive of bacterial meningitis are lethargy, stupor, and seizure activity. Changes in mental status are less common in viral meningitis than in bacterial meningitis (79). Patients with pneumococcal disease are more likely to have seizures, focal neurologic symptoms, and a reduced conscious level (74). The presence of petechiae strongly implicates Neisseria meningitidis (20).

Encephalitis is characterized by headache, fever, alteration of consciousness, focal neurologic deficit, and seizures. Meningeal signs may be present as well. Thunderclap headache alone may be the initial manifestation of encephalitis (57).

Not all young children complain of headache. Infants and neonates can show symptoms of acute bacterial meningitis that are nonspecific, including lethargy, fussiness, sleepiness, jitteriness, anorexia, hypotonia, apnea, jaundice, diarrhea, and general weakness. Bulging anterior fontanels may develop, and parents may notice an enlarged swelling on top of the head. Neck stiffness is uncommon in infants (18). Children with acute bacterial meningitis are about 20% more likely to have seizures before they are admitted to the hospital.

Bacterial meningitis or meningoencephalitis. According to a Dutch study of 1268 adults with community-acquired bacterial meningitis, 83% suffered headaches, 74% had neck stiffness, 74% had fever, and 71% suffered impairment of consciousness. Headache is often the first symptom to appear and may be the only long-term complication of the illness. It is usually holocranial, acute, and shows a worsening trend; it is invariably accompanied by severe nuchal rigidity and photo- or phonophobia (45). A thunderclap headache that increases in severity in minutes may be the first symptom of acute bacterial meningitis. Postbacterial meningitis headache might occur, and it is classified as 9.1.1.3 Persistent headache attributed to past bacterial meningitis or meningoencephalitis in ICHD-III (28). The pain is described as diffuse and continuous, but the literature also contains descriptions of migraine-like headaches (45). Nevertheless, the Nord-Trøndelag Health Survey (HUNT3) showed that the 1-year prevalence of headache suffering was not higher among patients with prior intracranial infection than in the general population (41). It challenges the existence of chronic post-bacterial meningitis headache and does not indicate the presence of other long-term headaches induced by intracranial infection. A population-based retrospective cohort study in the United Kingdom showed that the relative risk of new-onset headache after encephalitis in the first year was 1.23 (24).

Headache incidence in patients with tuberculous meningitis ranges from 50% to 100% from prior studies (53; 65). The significant predictors of headache severity among the patients with tuberculous meningitis were seizure, CSF protein greater than 2.5 g/L, and basal exudates in neuroimaging study (38).

Viral meningitis or encephalitis. The most common symptoms of meningitis are fever, chills, abdominal pain, nausea, and headache. Short and fast breathing, loss of appetite, neck stiffness, and sensitivity to bright light are other symptoms (35). Aseptic meningitis could be list as a cause of sudden onset headache.

Herpes simplex virus type 2 (HSV-2) is a common cause of viral meningitis and severe headaches (96% to 100%); neck stiffness, nausea, vomiting, and photophobia are the most common symptoms (25). A rare disease, Mollaret meningitis, is characterized by recurrent episodes of aseptic lymphocytic meningitis followed by periods of symptomlessness. The symptoms include headache, stiff neck, fever, vomiting, and photophobia. Typically, meningitis is caused by herpes simplex virus type 2 (HSV-2) (52). One study showed that 22% patients with enterovirus meningitis reported a sudden onset of headache that led to the initial suspected diagnosis of subarachnoid hemorrhage (02).

Headache is very common in people infected by human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) and may be a part of the symptomatology of both acute and chronic HIV infection. Headache prevalence was 28% to 80% among HIV-infected adults in Africa (60; 40). Among them, 5% of all participants meeting criteria for migraine (60). In most cases, headache is dull and bilateral. Headache severity, frequency, and disability seem associated with severity of HIV infection as indicated by CD4 cell count, or viral load, or both, but not with the duration of HIV infection or the number of prescribed antiretroviral medications (34). A minority of patients with HIV have headache attributable to opportunistic infections. The most common intracranial infections associated with HIV infection and causing headache are toxoplasmosis and cryptococcal meningitis. The ICHD-III put this headache in the appendix A9.3 Headache attributed to human immunodeficiency virus (HIV) infection (28). The evidence of causation has to be demonstrated by at least two of the following: (1) headache has developed in temporal relation to the onset of HIV infection, (2) headache has developed or significantly worsened in temporal relation to worsening of HIV infection as indicated by CD4 cell count, or viral load, or both, (3) headache has significantly improved in parallel with improvement in HIV infection as indicated by CD4 cell count, or viral load, or both. The diagnosis needs to demonstrate the following: the development of headache in a temporal relation to the onset of HIV infection, worsening/improving with a decrease/increase in CD4 cell counts, or increase/decrease in viral load (28). A separate category is created for headaches caused by a specific infection or by the use of antiretroviral drugs (32). Antiretroviral drugs can also cause headache.

The prevalence of headache during the acute phase of SARS-CoV-2 infection up to week 4 was about 50%, whereas persistent headache during the subacute phase was 31% in 1 month to 16% in 9 months (15). Younger patients and those with a history of primary headache are more likely to experience acute headaches. Approximately half of them report headaches that are worse than their usual migraines. Persistent headaches in the subacute phase are more common among older patients and are not related to the primary headache (15). Persistent headaches are associated with mild COVID-19. Several pathophysiological mechanisms may be involved, including the trigeminovascular system. There are currently no specific evidence-based effective therapeutic options available. SARS-CoV-2 vaccinations are also associated with headache, whose pathophysiology is unknown (15).

Intracranial fungal or other parasitic infection. In the United States, the most common clinical features of acute Lyme neuroborreliosis are lymphocytic meningitis with episodic headaches and mild neck stiffness, cranial neuropathy (particularly facial palsy), or motor or sensory radiculoneuritis (63). Nevertheless, in Europe, Borreliosis garinii infection causes a type of neurologic involvement (Bannwarth syndrome or tick-borne meningopolyneuritis), which presents with painful radiculoneuritis that is associated with lymphocytic meningitis, often without headache, and can be followed by cranial neuropathy or pareses of the extremities (49).

The subacute aseptic meningitis syndrome can be due to a fungal infection, most frequently Cryptococcus neoformans. In general, over 75% of patients present with headache and fever, which typically develop insidiously over 2 to 4 weeks (75). Headache and fever are also the most common clinical manifestations of patients who have coccidioidomycosis meningitis, the clinical symptoms of which are highly variable and can range from acute to chronic (67).

Localized brain infection. Headache, mental status changes, focal neurologic deficit, and fever are hallmark symptoms of brain abscess. According to a nationwide and population-based cohort study conducted in Denmark, 66% of patients reported headaches, 54% had fever, 46% had cognitive impairment, 38% had nausea and vomiting, 25% had seizures, 24% had cerebral nerve palsy, 42% had other motor and sensory nerve deficits, and 82% had neurologic deficits (08). A classic triad of headache, fever, and neurologic deficit was observed in 20% of cases only. Clinical manifestations are dependent on the location and size of the brain abscess, the host immune status, and the virulence of the causative microorganism. Children and adolescents with intravenous or nasal substance use have an increased risk for brain abscess in case of patent foramen ovale (09).

Prognosis and complications

In most of cases, headache remits with resolution of the infection. However, the infection may remain active for months, leading to chronic headache. In a minority of cases, headache persists for more than three months after resolution of the causative infection (28).

A 10-year retrospective study showed only 6.3% of fetal headache was due to meningitis (43). Bacterial meningitis is associated with significant morbidity and mortality (27). The mortality of bacterial meningitis varies geographically and by the patient's age and the infectious agent. The mortality in adults varies from 6% in Germany to 54% in Malawi, and in neonates, from 10% in developed countries to 58% in developing countries (27). Early complications of bacterial meningitis are cerebral edema, obstructive hydrocephalus, septic shock, and seizures. Long-term sequelae include focal neurologic deficits, hearing loss, cognitive impairment, and epilepsy (42). Several factors contribute to adverse clinical outcomes, including older age, hypotension, seizures, lack of antibiotics prior to hospitalization, concomitant pneumonia, purpuric rash, tachycardia, lower Glasgow Coma Scale scores, focal neurologic deficits, a low white blood cell count in CSF, a positive blood culture result, and high serum C-reactive protein levels (27).

The prognosis of viral meningitis is excellent. Patients generally make a complete recovery in several weeks. However, some develop persistent neurologic signs or symptoms. In contrast, encephalitis has significant mortality and morbidity. The prognosis of other viral encephalitis varies with the infectious agent. Prior studies found mortality rates between 5% and 20% for HSV encephalitis (01). Mortality and morbidity were most commonly associated with age, preexisting illness, fever on admission, and fever duration after treatment, as well as lower Glasgow Coma Scores or higher acute physiology and chronic health evaluation (APACHE) scores on admission (01).

The overall mortality for brain abscesses has drastically decreased following the development of effective antimicrobials, highly sensitive imaging procedures, and improved surgical techniques. The Danish nationwide cohort study revealed that in-hospital mortality of brain abscess was 6% but that at 6 months after discharge, the death rate increased to 12%. After discharge for 6 months, favorable outcomes increased from 24% to 57% (08).

Clinical vignette

Case 1. A 44-year-old male was admitted to a hospital with persistent pain over bilateral occipital and temporal regions for about four days. The nonthrobbing headaches were not associated with nausea, vomiting, photophobia, and phonophobia. In the beginning, the intensity of pain was bearable, and he could still go to work. He took ibuprofen, but the pain was persistent. He visited the emergency room because the pain became excruciating. He had a temperature 38.6°C. There was no history of recent trauma or symptoms of upper respiratory infection, sore throat, rashes, or mucosal lesions.

On examination, he had a temperature of 36.9°C, but his vital signs were otherwise normal. He was moaning and refused to sit upright. He had no skin or genital lesions. He held his neck in flexion but had no evidence of meningismus. The neurologic examination was normal.

Routine laboratory studies were normal except for an elevated C reactive protein 2.18 mg/dL. CSF contained 432 white blood cell count per mm3 (97% lymphocytes, 1% monocytes), seven erythrocytes per mm3, glucose 49 mg/dL, and protein 156.7 mg/dL. Cultures of CSF for bacteria, fungi, and viruses were negative. Herpes varicella zoster was positive by polymerase chain reaction (PCR). MRI with and without contrast showed no focal lesions, but there was diffuse meningeal enhancement.

Acyclovir was administered intravenously for 5 days from admission and shifted to Valaciclovir treatment because of phlebitis and because his headaches had improved significantly after treatment; there was no recurrence of severe headache.

Comment. Neurologic complications such as meningitis due to varicella zoster virus (VZV) reactivation are not uncommon as previously thought. Herpes varicella zoster virus (VZV) is the third most frequent causal agent of viral meningitis, with a frequency ranging from 5% to 29% (36; 21). A common cause of sporadic encephalitis is herpes simplex virus (HSV) type 1. In contrast to HSV encephalitis, which is almost exclusively due to HSV-1, viral meningitis in immunocompetent adults is generally caused by HSV-2.

The patient’s headache had developed in temporal relation to the onset of the varicella zoster virus encephalitis and had significantly improved in parallel with improvement of the infection. For diagnosis, PCR analysis of viral particles in the CSF is crucial when aseptic meningitis is suspected. The optimal therapy for meningitis with varicella zoster infection has not been determined yet. However, the guidelines issued by the Infectious Diseases Society of America recommend the administration of intravenous acyclovir at 10 to 15 mg/kg every 8 hours for varicella zoster virus encephalitis (68). Intravenous acyclovir 10 mg/kg three times daily was suggested by the Association of British Neurologists and British Infection Association National Guidelines (61).

Case 2. A 12-year-old boy presented in the Emergency Department with a complaint of headache and fever. The headache had been present for several weeks and a temperature elevation was noted a day prior to the examination. The headache was holocranial, dull, and achy. The patient had nausea, vomiting, photophobia, and phonophobia. His temperature was 38°C, pulse 100. His fundi were normal. He had slight neck resistance. Kernig and Brudzinski signs were negative. Neurologic examination was normal.

Laboratory studies revealed a white blood cell count of 12,000/mm with a normal differential. CSF opening pressure was 18 cm of H2O, and closing pressure was 16 cm of H2O. There were 12 WBC/mm3 (83% monocytes and 17% polymorphonuclear). Glucose was 60 mg/dl and protein 60 mg/dl. The Gram stain was negative. A diagnosis of viral meningitis was made.

The fever and headache persisted. The following day, CSF revealed a white blood cell count of 80/mm3. Protein was 70/ml. The other laboratory results were the same as they had been previously. The patient was hospitalized and treated with antibiotics. There was no improvement, and a CT scan three days later showed a brain abscess in the frontal region. Sinus films demonstrated an osteomyelitis of the frontal sinus. The patient underwent surgery for this and was given a course of antibiotic treatment. He was discharged without sequelae.

Comment. The classic brain abscess triad of headache, fever, and focal neurologic deficit may be found in as few as 20% of patients. The duration of the patient's headache, which should have prompted a brain imaging study, was the clue to diagnosing the brain abscess. The duration of symptoms of enteroviral disease is typically brief.

Biological basis

	• Streptococcus pneumoniae is the commonest cause of bacterial meningitis.
	• Herpes simplex virus is the most common cause of aseptic meningitis.
	• The most common causative microorganisms of brain abscess were the Streptococcus and Staphylococcus species.
	• Headache attributed to intracranial infection may result from the meningeal inflammation, increased intracranial pressure, or a mass effect producing traction on pain-sensitive intracranial structures.

Etiology and pathogenesis

Streptococcus pneumoniae causes about 72% of cases of bacterial meningitis, and Neisseria meningitidis causes about 11%, in people older than 16 years old. About 35% of cases of early-onset neonatal meningitis are caused by E coli and Streptococcus agalactiae (27). Mycobacterium tuberculosis causes both subacute and chronic meningitis, whereas cryptococcus, nocardia, candida, histoplasma, and coccidiomycosis are common causes of chronic meningitis.

About 20% to 50% of aseptic meningitis was attributed to viruses (69). Herpes simplex virus accounts for 50% to 75% of identified viral cases, with varicella zoster virus, enteroviruses, and arboviruses accounting for the majority of the remainder (69).

Brain abscesses may be caused by aerobic or anaerobic bacteria and often contain multiple organisms that come from the source of the infection (62). The most common predisposing conditions were contiguous foci of infection: otitis or mastoiditis (33%), sinusitis (10%), meningitis (6%), and odontogenic foci (5%) (10). The most common causative microorganisms were Streptococcus and Staphylococcus species (10).

Septic venous thrombosis of the cerebral dural sinuses and cortical veins may occur as a complication of bacterial meningitis, subdural empyema, or epidural abscess; it may also develop as a complication of an infection in the skin of the face, paranasal sinuses, middle ear, or mastoid. In cavernous sinus thrombosis, headache is usually located in the frontal and retro-orbital regions.

The headache of meningitis may be caused by increased intracranial pressure from cerebral edema and hydrocephalus or may mediate through sensory nerve fibers that originate from the trigeminal nerve and innervate the meninges. In addition to their ability to mediate pain, sensory nerve fibers can release vasoactive factors, including the proinflammatory neuropeptides substance P and calcitonin gene-related peptide. Apart from their role in afferent nociception, trigeminal nerve fibers participate in the vasomotor innervation of meningeal blood vessels, forming the so-called trigeminovascular system. Unmyelinated sensory C-fibers release vasoactive neuropeptides from perivascular terminals in response to nociceptive stimuli, including the presence of an inflammatory environment.

Encephalitis can be caused by direct infection of neurons and glia with inflammation of cortical vessels. The disease is typically due to viruses.

Because the brain parenchyma has no sensory receptors, the headache of encephalitis and brain abscess may result from the meningeal inflammation, increased intracranial pressure, or a mass-effect producing traction on pain-sensitive intracranial structures.

Differential diagnosis

A headache may be the symptom of a significant organic disease if it (1) is a new headache (ie, a recent-onset headache or a change in headache pattern); (2) is late onset in life (typically over 50 years of age); (3) is an effort-induced headache or positional headache; (4) is thunderclap headache; (5) is posttraumatic headache (6) presents with meningismus or fever; (7) is positive for focal neurologic signs; or (8) presents with significant comorbidities (22).

The pattern of evolution and the associated features are extremely important in the differential diagnosis of headache. The patient who presents with a thunderclap headache should be assumed to have an acute neurologic disorder. Headache onset related to exertion may suggest a ruptured aneurysm, although aneurysms can rupture independent of exertion and a benign headache disorder may have an exertional onset. Changes in awareness or cognition suggest an intracranial process; however, these changes sometimes occur in migraine. One can be less concerned about a new process if a patient's current headache is typical of prior headaches except for the intensity of pain. However, acute CNS events can trigger an otherwise typical migraine. The first headache in an individual's life is less likely to be migraine in an older patient than in a younger one (22).

The first or worst attack of migraine may be difficult to differentiate from meningitis, encephalitis, or a subarachnoid hemorrhage, particularly if the headache is of the thunderclap variety. The classic presentation of an aneurysmal subarachnoid hemorrhage is severe, acute-onset headache associated with a stiff neck, photophobia, nausea, vomiting, and perhaps obtundation or coma; it is easily differentiated from migraine. This catastrophic presentation is often preceded by a minor hemorrhage that can signal the likelihood of a major rupture within hours, days, or weeks, but may be more difficult to diagnose. In most series of patients with minor leaks related to subarachnoid hemorrhage, headache, nausea, or vomiting are common; loss of consciousness is less common (71). Reversible cerebral vasoconstriction syndromes are characterized by “recurrent thunderclap headaches” and “reversible cerebral vasoconstrictions”; they are more common than previously thought and should be differentiated from aneurismal subarachnoid hemorrhage (16). The potential complications of reversible cerebral vasoconstriction syndromes include posterior reversible encephalopathy syndromes, ischemic strokes over watershed zones, cortical subarachnoid hemorrhage, and intracerebral hemorrhage. Any patient who presents with a severe, sudden-onset headache should be evaluated with neuroimaging and lumbar puncture (80).

The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL), also known as pseudomigraine with neurologic symptoms and lymphocytic pleocytosis syndrome, is a rare, self-limited, benign disorder (03). Patients had episodes of migraine associated with lymphocytic pleocytosis. Onset was between the ages of 14 and 39 years and was more frequent in men. One quarter of the patients had a prodromal, viral-like illness. The clinical picture consisted of at least one neurologic deficit lasting more than four hours, including hemiparesthesia, dysphagia, or hemiparalysis accompanied by mild to moderate bilateral throbbing headache and, occasionally, fever. Lymphocytic pleocytosis (> 15 cells/uL) associated with increased CSF protein was found. CT and MRI were normal, but EEG often showed focal slowing. The etiopathogenesis of HaNDL is poorly understood. Studies have failed to provide a definite viral association. Postinfectious or inflammatory mechanisms in which autoantibodies are directed against neuronal or vascular antigens have been proposed (03).

Spontaneous intracranial hypotension might mimic aseptic meningitis. Orthostatic headache charter and typical diffuse pachymeningeal enhancement in contrast MRI findings are characteristic and clearly contribute to the differential diagnosis between viral meningitis and spontaneous intracranial hypotension (04).

Viral encephalitis is caused by the neurotropic viruses and can be mimicked by a brain abscess, a brain tumor, postinfectious encephalomyelitis, and toxic encephalopathy. Clues that can aid in distinguishing among these entities are the speed of onset of symptoms, a history of a prodrome, an infectious exposure, a travel history, suspected or known toxic ingestion (including prescribed and over-the-counter medications), and a history of medical illnesses. A new headache that is present for days or weeks may represent a primary neurologic disorder and demands a complete neurologic evaluation.

Drug-induced aseptic meningitis should be noticed. In a study, most patients presented with headache, fever, meningismus, and mental status changes (47). Four groups of drugs, including nonsteroidal anti-inflammatory drugs, antibiotics, immunosuppressive-immunomodulatory drugs, and antiepileptic drugs, were associated with drug-induced aseptic meningitis in 26% to 35% of cases. The interval between exposure and meningitis ranged from minutes to five months. Underlying systemic disorders were often present, particularly systemic lupus erythematosus. The CSF showed pleocytosis with neutrophilic predominance, normal-to-low glucose values, and increased proteins. Neuroimaging results were normal in most patients. Complete recovery in several days after drug discontinuation was the rule.

The differential diagnosis of infectious encephalitis and autoimmune encephalitis is notoriously difficult, particularly at an early stage after symptom onset. The two groups differed significantly for the presence of headache, fever, epileptic seizures, and CSF cell-count at presentation. Nevertheless, application of the clinical algorithm resulted in a low sensitivity (58%) and very low specificity (8%) for the diagnosis of possible autoimmune encephalitis (72). Headache is less common in autoimmune encephalitis.

Diagnostic workup

	• Kernig sign and Brudzinski sign should not be relied on for diagnosis.
	• Polymerase chain reaction testing has a high sensitivity and specificity and can currently be used to more accurately define infection.
	• Lumbar puncture is contraindicated in patients with a brain abscess.

For more than 100 years, clinicians have used three physical signs (nick stiffness, Kernig and Brudzinski signs) to help diagnose meningitis at bedside. A stiff neck is a sign of meningeal irritation and is present when the neck resists passive flexion. A Brudzinski sign is characterized by spontaneous hip flexion during passive neck flexion. The Kernig sign is presented as the inability or reluctance of full extension of the knee when the hip is flexed 90 degrees while the patient is in the supine position. Nevertheless, the diagnostic accuracy of these signs is low, with sensitivities ranging from 5% for both Kernig and Brudzinski signs to 30% for nuchal rigidity (27). Jolt accentuation of headache (exacerbation of a baseline headache with horizontal rotation of the neck) might be a useful tool for distinguishing acute aseptic meningitis from other diseases. A Cochrane review of nine studies (1161 participants) showed pooled sensitivity of 65.3% and pooled specificity of 70.4% (30). Jolt accentuation for headache may exclude diagnoses of meningitis in emergency settings, but high-quality evidence to support the use of this test is lacking.

The meningitis guidelines from American, British, and European infection societies all recommend immediate lumbar puncture without delay for CT or MRI in immunocompetent adults with suspected bacterial meningitis who have a stable Glasgow Coma Scale score of 12 out of 15 or more, without seizures (73). As a general rule, Gram stain and CSF culture obtained 24 hours after the initiation of antimicrobial therapy should be negative if the organism is sensitive to the antibiotic. The diagnosis of bacterial meningitis is then made on the basis of the abnormalities in CSF white blood cell count (usually more than 1000/μL, neutrophilic pleocytosis), glucose (hypoglycorrhachia [< 30 mg/dL]) and protein concentrations (elevated protein [usually > 100 mg/dL]), and the latex particle agglutination technique (70). CSF lactate, if taken before antibiotic treatment, has a sensitivity of 0.93 (95% CI 0.89-0.96) and specificity of 0.96 (0.93-0.98) in differentiating bacterial from viral meningitis, and it may have advantages over glucose in that it is unaffected by the serum concentration (46). The latex particle agglutination test is a rapid diagnostic test for identification of bacterial antigens in CSF. Its specificity and sensitivity vary in different species and studies (33). All adults and children with meningitis should undergo Gram staining and culture, regardless of CSF white blood cell count (27). The sensitivity of CSF Gram stain for bacterial meningitis is about 50% to 90% (27).

Three quarters of patients with Listeria meningitis have a CSF pleocytosis, with a predominance of neutrophils, frequently mixed with lymphocytes or monocytes. Lymphocytes or monocytes predominate in the remaining cases. Protein elevations in the CSF exceed 199 mg/dL. Glucose levels are in the normal range. CSF cultures are positive in at least 80% of cases of meningitis and meningoencephalitis (05).

In viral meningitis, the CSF shows a mild pleocytosis (usually less than 1000 cells/mm3) (79). Early in the course there may be a predominance of polymorphonuclear cells, but this rapidly shifts to lymphocytic pleocytosis. The CSF pressure is normal or slightly elevated, the CSF protein is normal or slightly elevated, and the glucose is either normal or slightly reduced. If the diagnosis is still in doubt, antibiotics should be started and the lumbar puncture repeated after 12 hours to document the shift from polymorphonuclear cells to mononuclear cells. The CSF should be analyzed for viral antigens and incubated for viral culture (79). Acute and convalescent serum viral titers will provide clues to the etiology of the disease. The peripheral white blood count may be normal or elevated with a normal differential cell count. Virus can be isolated from other sites, such as the throat and stool (79). The CSF cell count was normal in 15% of the adult patients with enteroviral central venous infection (02).

Polymerase chain reaction (PCR) assays have been particularly useful in the diagnosis of viral meningitis (79). The sensitivity and specificity of polymerase chain reaction for both bacterial (N meningitidis, S pneumoniae, and H influenzae) and viral (herpes simplex viruses, varicella-zoster virus, and enteroviruses) meningitis exceed 90% (79). Polymerase chain reaction sensitivity is less than 50% if the test is performed one week after the onset of the symptoms. This causes false negatives. One study showed aseptic meningitis has unknown etiologies in 81% of patients, and it might be due to underutilization of polymerase chain reaction (56). In patients with a high index of clinical suspicion of bacterial meningitis but negative PCR tests, direct next-generation sequencing and metagenomics of CSF have been proposed to detect pathogens (76).

Most cases of fungal meningitis have a mononuclear pleocytosis in the range of 20 to 500 cells/mm3. However, Aspergillus, Zygomycetes, Pseudoallescheria, and Blastomyces fungal meningitis, are characterized by a predominance of polymorphonuclear cells (23). When eosinophils are detected in the cell count and differential, C immitis needs to be considered as the cause of the meningitis. CSF protein levels are generally elevated and glucose concentrations are variable but commonly depressed in fungal meningitis. Fungal meningitis is a condition that causes hypoglycorrhachia (23). Positive cultures are the "gold standard" for diagnosis of fungal meningitis, but they may be negative or slow in growth. To increase the yield of fungal cultures, a large volume of CSF (10 to 30 mL) is needed. Series of CSF serologic tests for fungal antigens or antibodies should be obtained. CSF lactic acid concentrations are generally elevated during fungal meningitis (23). The galactomannan antigen can be detected in biological fluids (serum, bronchoalveolar washing liquid, or CSF) in patients with aspergillosis (59), and serum 1,3-β-D-glucan may be diagnostically helpful for other systemic fungal infections (50). The India ink test enables staining of the capsule of Cryptococcus (51). Cryptococcal antigen testing is considered the gold standard test for CSF detection of Cryptococci (58). It can be detected in CSF or peripheral blood samples via latex agglutination, enzyme immunoassay, or lateral flow assay detection and demonstrates a 97% sensitivity in CSF and 86% to 100% specificity (19).

The combination of a CSF glucose concentration between 45 and 35 mg/dL, and a lymphocytic pleocytosis, an unrelenting headache, stiff neck, fatigue, night sweats, and fever, is highly suspicious for tuberculous meningitis (44). Positive smears for acid-fast bacilli are reported in only 10% to 40% of cases of tuberculous meningitis in adults. It takes four to eight weeks to identify the organism by CSF culture, which is positive in approximately 50% of adults (44). The GeneXpert MTB/RIF (Cepheid, Sunnyvale, California, USA) is a commercial, cartridge-based nucleic acid amplification test that detects DNA sequences specific for M tuberculosis and rifampicin resistance in clinical specimens in around two hours. It has been endorsed by the World Health Organization for use in resource-limited, tuberculosis-endemic countries since 2010 (48). The sensitivity was very high, but the specificity was only 60% (44). If mycoplasma tuberculosis is suspected, the initiation of chemotherapy should not await the results of CSF cultures and should not depend on the results of acid-fast bacilli smears. In a patient with compatible clinical features, the combination of meningeal enhancement and any degree of hydrocephalus is strongly suggestive of tuberculous meningitis (39).

In the guidelines of the European Society of Clinical Microbiology and Infectious Diseases, brain MRI, including DWI/ADC and T1-weighted imaging with and without gadolinium, are strongly recommended for patients with suspected brain abscesses. Contrast-enhanced CT is recommended when MRI is not available (07).

CSF analysis demonstrates normal or only nonspecific abnormalities. In general, lumbar puncture is contraindicated in patients with a brain abscess because of the risk of herniation (15% to 30%), unless the information is crucial (31). Routine blood tests are rarely helpful in diagnosing brain abscess. Blood cultures should be drawn if endocarditis is suspected. Sedimentation rate is often elevated.

Management

	• In bacterial meningitis treatment, no difference in outcome was observed when comparing corticosteroids that were given before or after antibiotics, and a slight improvement in hearing loss was observed in the studies that gave steroids post-antibiotics.
	• In the absence of convincing clinical data of harm related to adjunctive corticosteroid treatment, European Society of Clinical Microbiology and Infectious Diseases guidelines strongly recommend the use of corticosteroids in patients with brain abscesses who have severe symptoms because of perifocal edema or impending herniation.

The treatment of bacterial meningitis consists of supportive care, prompt antibiotic administration, and measures to lower intracranial pressure. Antibiotics should cover a broad range of organisms initially, but the regimen may be simplified when the culture results are available. For treatment recommendations regarding antibiotic regimens, the reader is referred to excellent reviews of this topic (66).

In the 2015 Cochrane review of the use of corticosteroids in acute bacterial meningitis, corticosteroids were not associated with a reduction in mortality. However, corticosteroids significantly reduced hearing loss and neurologic sequelae (11). Adjunctive corticosteroid therapy has been shown to reduce morbidity and mortality in all but late-stage disease for patients with tuberculosis meningitis (39).

Clinicians should prescribe amoxicillin, cefuroxime, or doxycycline as first-line agents for the treatment of erythema migrans in Lyme disease (37). Although most studies have used parenteral regimens for neuroborreliosis, several European studies support the use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis, reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neurologic symptomatology, or failure to respond to oral regimens. Viral meningitis and encephalitis are treated primarily with support, including measures to lower intracranial pressure. Empirical acyclovir treatment is recommended when herpes simplex virus encephalitis is suspected (64).

A brain abscess requires either surgical drainage or excision and antibiotic therapy. Stereotactic aspiration of the purulent center is recommended for the purposes of diagnosis and decompression unless it is contraindicated because of the suspected organism type or the patient’s clinical condition (12). Commonly accepted treatment guidelines include aspiration or excision of all lesions that are larger than 2.5 cm in diameter or are causing a mass effect. Aspirating the abscess allows confirmation of the diagnosis and isolation of the bacterial etiology, obvious aids in antibiotic selection. If immediate surgery is planned, preoperative antibiotics should be withheld so as not to sterilize culture. When the patient is not immunosuppressed, a combination of vancomycin, metronidazole, and cefotaxime may be used empirically while awaiting the results of microbiological testing of the aspirated material (14). When an immunosuppressed patient has a brain abscess, empirical treatment must take into account the patient's specific immune defect. Because it is not always practical to drain the abscess, open excision is often employed initially or following unsuccessful aspiration (13). Indications for nonsurgical treatment include multiple abscesses, abscesses smaller than 2 cm in diameter, abscesses in surgically inaccessible regions or in the cerebritis stage, and a normal level of consciousness without clinical deterioration (13). Measures to lower intracranial pressure may be required. In the absence of convincing clinical data of harm related to adjunctive corticosteroid treatment, European Society of Clinical Microbiology and Infectious Diseases guidelines strongly recommend the use of corticosteroids in patients with brain abscesses who have severe symptoms because of perifocal edema or impending herniation. For aspirated or conservatively treated brain abscesses, the European Society of Clinical Microbiology and Infectious Diseases guidelines recommend intravenous antimicrobial treatment for 6 to 8 weeks. Expert opinion may suggest a shorter duration (eg, 4 weeks) for patients undergoing brain abscess excision (07).

The headache associated with intracranial infections should resolve with treatment of the underlying condition. Until the infection has cleared, the headache can be treated with nonopioid analgesics or (if it is severe) with opioids, bearing in mind that the use of opioids may obscure certain aspects of the neurologic examination (eg, level of consciousness, pupillary size). If the headache persists long after the infection and its complications have resolved, the patient may require evaluation and treatment of a chronic type of headache. The evaluation includes neuroimaging to rule out the sequelae of intracranial infections, such as obstructive or communicating hydrocephalus, residual cerebral edema, or mass effect. Once these entities have been excluded, a lumbar puncture may be necessary to rule out increased intracranial pressure, even in the absence of papilledema. Treatment of the residual headache is described in the chapter on intractable chronic daily headache.

Wiwanitkit proposed a hypothesis that vasodilatation secondary to nitrite production by bacteria can result in vasodilatation in the blood vessels and stimulation of nociceptive nerve endings in the meningeal vessel wall (77). In a rat model of pneumococcal meningitis, it was also found that zolmitriptan and naratriptan reduced the influx of leukocytes into the cerebrospinal fluid, reduced intracranial pressure, reduced brain water content, and attenuated the increase of regional cerebral blood flow (29). Therefore, triptan might be useful to control the headache in the patients with bacterial meningitis; however, it needs further study to prove its efficacy.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Jong-Ling Fuh MD

Dr. Fuh of Taipei Veterans General Hospital and National Yang-Ming University School of Medicine has no relevant financial relationships to disclose.
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Editor

Shuu-Jiun Wang MD

Dr. Wang of the Brain Research Center, National Yang-Ming University, and the Neurological Institute, Taipei Veterans General Hospital, has no relevant financial relationships to disclose.
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Former Authors

Stephen D Silberstein MD
Debra Ann Pollack MD
Paula M Mendes MD
Madhavi Gupta MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Encephalitis: 323

Intracranial abscess: 324.0

Non-arthropod-borne viral disease of CNS: 049.9

Meningitis, unspecified: 322.9

Viral meningitis, unspecified: 047.9
ICD-10: Encephalitis: G05

Intracranial abscess: G06.0

Non-arthropod-borne viral disease of CNS: A89

Meningitis, unspecified: G03.9

Viral meningitis, unspecified: A87.9

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Headache associated with intracranial infection

Associated Disorders

Bacterial meningitis
Lyme disease

Differential Diagnosis

migraine
thunderclap headache
ruptured aneurysm
aneurysmal subarachnoid hemorrhage
nonbacterial meningitis
- meningoencephalitis
- lymphocytic pleocytosis
- acute purulent sinusitis
- CNS lymphoma
- neurotropic viruses
- lupus
- sarcoidosis
- carcinomatous meningitis
- subdural empyema
- epidural abscess
- cerebral neoplasm
- cerebrovascular accident
- encephalitis
- brain tumor
- postinfectious encephalomyelitis
- toxic encephalopathy
- drug-induced aseptic meningitis
- cerebral infarction
- subdural hematoma

Also Relevant

Arboviral encephalitis
Brain abscess
Cryptococcal meningitis
Gram-negative bacillary meningitis
Headache associated with HIV and AIDS
- Herpes simplex encephalitis
- Molecular diagnosis of CNS infections
- Recurrent meningitis
- Viral meningitis

Clinical Categories

Headache & Pain

Headache associated with intracranial infection …

Headache associated with intracranial infection

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Headache associated with intracranial neoplasms

Acupuncture

Migraine in childhood

Headache attributed to head trauma

Migraine: pathogenesis and pathophysiology

Tension-type headache

Benign paroxysmal vertigo

Vagal nerve stimulation for headaches

Headache associated with intracranial infection

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Headache associated with intracranial neoplasms

Acupuncture

Migraine in childhood

Headache attributed to head trauma

Migraine: pathogenesis and pathophysiology

Tension-type headache

Benign paroxysmal vertigo

Vagal nerve stimulation for headaches

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