Tuberculous meningitis: Clinical manifestations and diagnosis

INTRODUCTION — Forms of central nervous system (CNS) infection due to Mycobacterium tuberculosis include meningitis, tuberculoma, and spinal arachnoiditis. An overview of CNS tuberculosis (TB) is presented separately. (See "Central nervous system tuberculosis: An overview".)

Issues related to clinical manifestations and diagnosis of tuberculous meningitis are be reviewed here. Issues related to management of tuberculous meningitis are discussed separately. (See "Central nervous system tuberculosis: Treatment and prognosis".)

Issues related to pulmonary TB and miliary TB are discussed separately. (See "Pulmonary tuberculosis: Clinical manifestations and complications" and "Diagnosis of pulmonary tuberculosis in adults" and "Epidemiology and pathology of miliary and extrapulmonary tuberculosis".)

Issues related to treatment of TB are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-resistant pulmonary tuberculosis in adults".)

Issues related to treatment of TB in patients with HIV infection are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of pulmonary tuberculosis in adults with HIV infection: Follow-up after initiation of therapy".)

EPIDEMIOLOGY — Tuberculous meningitis develops most commonly as a complication of progressive primary infection in infants and young children, and from chronic reactivation bacillemia in adults with immune deficiency caused by aging, alcoholism, malnutrition, malignancy, human immunodeficiency virus (HIV) infection, or drugs (such as tumor necrosis factor-alpha inhibitors).

In a 2022 meta-analysis including 52 studies and more than 12,000 patients from 28 countries, central nervous system tuberculosis (TB) constituted 13.9 percent of all cases of meningitis and 4.5 percent of all TB cases [1]. In the United States in 2018, tuberculous meningitis accounted for about 1 percent of TB cases and 4 percent of extrapulmonary TB disease [2].

CLINICAL MANIFESTATIONS

Signs and symptoms

Typical presentation — Patients with tuberculous meningitis commonly present with headache, fever, vomiting, and altered sensorium; these symptoms are also frequently observed with bacterial meningitis. Features that may help distinguish tuberculous meningitis from bacterial meningitis include:

●Subacute presentation; in one study including 160 patients with tuberculous meningitis, the time between the onset of symptoms and clinical presentation was less than one week in 7 percent of cases, one to three weeks in 57 percent, and more than three weeks in 36 percent. In contrast, bacterial meningitis typically presents within one week of symptoms; potential exceptions include meningitis due to listeriosis or brucellosis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

●Presence of neurologic symptoms; in the above study including 160 patients with tuberculous meningitis, altered consciousness, personality changes, and coma were observed in 59, 28, and 21 percent of cases, respectively [3]. Such symptoms are not typical of bacterial meningitis. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

●Presence of cranial nerve palsies (most frequently involving cranial nerve II and VI) are common; other cranial nerves are infrequently involved. In one study including 158 patients with tuberculous meningitis, cranial nerve palsies were observed in almost one-third of cases. Cranial nerve palsies are uncommon with bacterial meningitis, exceptions include meningitis due to listeriosis or meningitis associated with intracranial abscess [4].

Patients with tuberculous meningitis typically progress through three discernible phases [5-8]:

●The early prodromal phase, lasting one to three weeks, is characterized by the insidious onset of malaise, lassitude, headache, low-grade fever, and personality change.

●The meningitic phase follows with more pronounced neurologic features, such as meningismus, protracted headache, vomiting, lethargy, confusion, and varying degrees of cranial nerve and long-tract signs.

●The paralytic phase supervenes as the pace of illness accelerates rapidly; confusion gives way to stupor and coma, seizures, and often hemiparesis. For the majority of untreated patients, death ensues within five to eight weeks of the onset of illness.

Clinical presentation with central nervous system (CNS) manifestations in the absence of prior history of pulmonary symptoms is common; in one series including 61 patients with tuberculous meningitis, history of tuberculosis (TB) disease was elicited in only 10 percent of cases [9].

In children, headache is less common than in adults; irritability, restlessness, anorexia, and protracted vomiting are prominent symptoms. Seizures are more common in children and tend to occur early in illness [7].

Disease stages — Patients may be categorized by the stage of illness, based on mental status and neurologic signs [10,11]:

●Stage I – Alert and oriented with no focal neurologic signs.

●Stage II – Conscious but with inattention, confusion, lethargy; they may have mild focal signs such as cranial nerve palsies or hemiparesis (Glasgow coma score 11 to 15) (table 1).

●Stage III – Advanced illness with delirium, stupor, coma, seizures, multiple cranial nerve palsies, and/or dense hemiplegia (Glasgow coma score ≤10) (table 1).

Atypical manifestations — Patients may present with atypical features that mimic other neurologic conditions. These include an acute, rapidly progressive meningitic syndrome suggesting pyogenic meningitis, or with slowly progressive dementia over months characterized by personality change, social withdrawal, loss of libido, and memory deficits. Less commonly, patients may present with an encephalitic course manifested by stupor, coma, and convulsions without overt signs of meningitis [12].

Uncommonly, tuberculous meningitis may present with concomitant tuberculoma or radiculomyelopathy. (See "Central nervous system tuberculosis: An overview", section on 'Tuberculoma' and "Central nervous system tuberculosis: An overview", section on 'Spinal arachnoiditis'.)

Patients with tuberculous meningitis may present with symptoms characteristic of complications, as discussed in the following section.

Complications — Complications of tuberculous meningitis include:

●Stroke − Stroke is a disabling complication of tuberculous meningitis. In one cohort including 559 patients with tuberculous meningitis, cerebral infarcts were observed in 26 percent of patients; these patients frequently present with dense hemiplegia [13].

●Seizures – Seizures among patients with tuberculous meningitis are generally focal; generalized seizures and status epilepticus also occur. Mechanisms include meningeal irritation, tuberculoma, infarction, and hyponatremia [14,15].

●Hydrocephalus – Hydrocephalus occurs in up to 80 percent of patients with tuberculous meningitis, and is often accompanied by signs of raised intracranial pressure. Hydrocephalus should be suspected when patient has features of elevated intracranial pressure, deteriorating vision, and/or deteriorating consciousness. In such cases, neuroimaging should be performed urgently [16].

Head computed tomography may demonstrate hydrocephalus, but magnetic resonance imaging is a more sensitive modality for detection of findings associated with tuberculous meningitis [17]. In addition, optic nerve sheath ultrasonography may be a useful tool for detection and monitoring of elevated intracranial pressure in patients with tuberculous meningitis [18]. (See "Normal pressure hydrocephalus" and "Evaluation and management of elevated intracranial pressure in adults" and "Hydrocephalus in children: Clinical features and diagnosis".)

●Hyponatremia − Hyponatremia is a potentially serious complication of tuberculous meningitis. Hyponatremia may develop at any point of time during course of tuberculous meningitis. In one study including 76 cases, hyponatremia was observed in approximately 45 percent of cases [19]. The onset and progression can be insidious with nonspecific symptoms (nausea, confusion, delirium, seizure) that may be mistakenly attributable to other pathologic features of the infection or its treatment. (See "Manifestations of hyponatremia and hypernatremia in adults" and "Diagnostic evaluation of adults with hyponatremia".)

Assessment of volume status is important to differentiate patients with the syndrome of inappropriate anti-diuretic hormone secretion (SIADH) from patients with central salt wasting; in general, patients with SIADH are euvolemic, while patients with central salt wasting are hypovolemic. (See "Diagnostic evaluation of adults with hyponatremia".)

●Vision loss – Vision loss, a severely disabling complication of tuberculous meningitis, occurs in approximately one-quarter of patients [20,21]. Mechanisms of vision loss include optochiasmatic arachnoiditis (encasement of optic nerves and optic chiasma by thick tuberculous exudates), compression of the optic chiasma by the dilated third ventricle from above, elevated intracranial pressure, endarteritis of vessels supplying the optic nerves and optic chiasma, and direct M. tuberculosis invasion of the optic nerves. Many survivors of tuberculous meningitis have permanent blindness. (See "Tuberculosis and the eye".)

●Transverse myelitis − Tuberculous myelitis is acute segmental spinal cord inflammation that may occur in the setting of tuberculosis disease; it may occur in the presence or absence of tuberculous meningitis. In one study including 114 patients with tuberculous meningitis in China, myelitis was observed in 17 percent of cases [22]. In another study including 52 patients with myelitis in India, tuberculous myelitis constituted 35 percent of cases [23]. (See "Central nervous system tuberculosis: An overview", section on 'Transverse myelitis' and "Central nervous system tuberculosis: Treatment and prognosis", section on 'Transverse myelitis'.)

Management of complications is discussed separately. (See "Central nervous system tuberculosis: Treatment and prognosis", section on 'Management of complications'.)

Patients with HIV infection — HIV infection is an important risk factor for tuberculous meningitis. Among patients with HIV infection, the presentation of tuberculous meningitis is the same as in patients without HIV infection; however, concurrent TB outside the CNS and lung occurs more commonly. In addition, initiation of antiretroviral therapy in patients with HIV infection and no prior CNS symptoms may precipitate onset of new symptoms, reflecting progression of underlying TB infection as a manifestation of immune reconstitution inflammatory syndrome. (See "Immune reconstitution inflammatory syndrome".)

Routine test findings — Routine blood counts and chemistries are relatively nonspecific; mild anemia is common. Hyponatremia may be observed in the context of inappropriate antidiuretic hormone or cerebral salt wasting [19,24]. Central diabetes insipidus resulting in hypernatremia has also been described [25].

Chest radiograph abnormalities may be seen in up to half of patients with CNS TB, ranging from focal lesions to a miliary pattern [10,25]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Radiographic imaging' and "Pulmonary tuberculosis: Clinical manifestations and complications" and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis", section on 'Radiographic imaging'.)

CT of the chest is an important diagnostic modality to evaluate for concomitant pulmonary tuberculosis (image 1). In one study including 81 patients with tuberculous meningitis, chest CT thorax abnormalities were observed in two-thirds of patients; centrilobular nodules were the most common lung parenchyma abnormality, and asymptomatic miliary lung lesions were observed in 10 percent of tuberculous meningitis cases [26].

The tuberculin skin test (TST) or an interferon-gamma release assay (IGRA) is frequently positive [5,6]; however, a negative result does not exclude TB. In one report including 118 European children, TST had a sensitivity of 62 percent (95% CI 51-72 percent) at the 5 mm cutoff and 50 percent (95% CI 40-60 percent) at the 10 mm cutoff [27]. The sensitivities of QuantiFERON-TB and T-SPOT.TB assays were 72 percent (95% CI 58-82 percent) and 83 percent (95% CI 58-95 percent), respectively. In a subset of children who underwent TST, IGRA, as well as CSF culture and CSF nucleic acid amplification testing, 84 percent (95% CI 68-94 percent) had at least one positive test result. (See "Tuberculosis infection (latent tuberculosis) in children" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

DIAGNOSIS

Overview of clinical approach — The diagnosis of tuberculous meningitis should be suspected in patients with relevant clinical manifestations (subacute presentation of stiff neck, headache, fever, and vomiting) and relevant epidemiologic factors (history of prior tuberculosis [TB] infection or disease, known or possible TB exposure, and/or past or present residence in or travel to an area where TB is endemic). Patients with suspected concomitant pulmonary TB who pose a public health risk for transmission should be admitted and isolated with airborne precautions. (See "Tuberculosis transmission and control in health care settings", section on 'Clinical triaging'.)

The diagnosis may be definitively established in the setting of cerebrospinal fluid (CSF) with positive smear for acid-fast bacilli (AFB), CSF culture positive for M. tuberculosis, or CSF with positive nucleic acid amplification test (NAAT) [28]. However, definitive diagnosis can be challenging, given suboptimal sensitivity and specificity of diagnostic tests [27,29]. A presumptive diagnosis of tuberculous meningitis may be made in the setting of relevant clinical and epidemiologic factors and typical CSF findings (lymphocytic pleocytosis, elevated protein concentration, and low glucose concentration).

Diagnostic tools for patients with suspected tuberculous meningitis include CSF examination and radiographic imaging [30]:

●CSF examination – At the time of lumbar puncture (LP), the opening pressure should be measured. CSF should be sent for total cell count with white blood cell differential, protein concentration, and glucose concentration (with serum level for comparison), NAAT, and AFB smear and culture; in patients with HIV infection, CSF testing should also include cryptococcal antigen. Additional fluid should be saved in case additional studies are warranted.

The diagnostic yield may be increased by submitting multiple CSF specimens (at least three) from repeated LPs and greater volumes (at least 5 mL); however, empiric antituberculous therapy should not be delayed while obtaining serial CSF specimens [31]. The sensitivity of AFB smear and culture is maintained for a few days after starting treatment, and the sensitivity of CSF NAAT is maintained for up to one month after starting treatment [24,32]. (See 'Spinal fluid examination' below.)

●Radiographic imaging – Radiographic tools for evaluation of patients with suspected CNS TB include computed tomography (CT) and magnetic resonance imaging (MRI). (See 'Radiographic imaging' below.)

For settings in which radiographic imaging is readily available, patients with suspected tuberculous meningitis should have head CT prior to LP. Neuroimaging prior to LP is especially important in the setting of papilledema or other signs that may be indicative of elevated intracranial pressure (ICP; such as altered mental status, new-onset seizure, or focal neurologic deficits). For patients with mild-to-moderate hydrocephalus in the absence of signs of elevated ICP, LP may be pursued. For patients with contraindications to immediate LP in the setting of characteristic clinical, epidemiologic, and radiographic features of CNS TB, empiric therapy should be initiated promptly (and not be deferred pending LP).

Patients with suspected TB should undergo chest radiography; in the setting of relevant signs or symptoms, diagnostic evaluation for pulmonary TB should be pursued. In addition, for patients with signs and symptoms of suggestive of TB at other sites, diagnostic evaluation should be pursued accordingly (such as lymph node biopsy, bone marrow biopsy); such interventions may be safer and more accessible than CNS-based diagnosis [32]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Radiographic imaging' and "Tuberculous lymphadenitis" and "Clinical manifestations, diagnosis, and treatment of miliary tuberculosis".)

Patients with suspected or proven tuberculous meningitis should always be tested for HIV infection. (See "Screening and diagnostic testing for HIV infection".)

Bedside evaluation — Among patients with suspected CNS TB, a careful neurologic examination should be undertaken, including assessment of mental status, cranial nerves, sensory and motor examination, cerebellar function, and reflexes. (See "The detailed neurologic examination in adults".)

In addition, patients should be evaluated for other systemic manifestations of TB. Signs of active TB outside the CNS are of diagnostic importance if present. Patients should be assessed for fever, weight loss, jaundice, lymphadenopathy, hepatomegaly, splenomegaly, bone and joint lesions, and dermatologic findings. In patients with miliary TB, careful funduscopic examination often demonstrates choroidal tubercles; these are multiple ill-defined raised yellow-white nodules of varying size near the optic disk (picture 1). (See "Tuberculosis and the eye".)

Spinal fluid examination

Routine studies — The opening pressure is usually moderately elevated (180 to 300 mm H₂O) [25]. Typical CSF findings in tuberculous meningitis include lymphocytic pleocytosis, elevated protein concentration, and low glucose concentration (table 2).

●The CSF white blood cell count is typically between 100 and 500 cells/microL, with lymphocyte predominance. Early in the course of illness, a lower cell count and/or neutrophilic predominance may be observed. In addition, neutrophilic predominance may be observed in the setting of spinal block and/or paradoxical worsening.

●The CSF protein concentration is typically 100 to 500 mg/dL. However, in patients with subarachnoid block, the CSF protein concentration may be as high as 2 g/dL [24,25]

●The CSF glucose concentration is <45 mg/dL in most cases.

Acid-fast bacilli smear and culture — The sensitivity of acid-fast staining for diagnosis of tuberculous meningitis is 30 to 60 percent [31,33]. The diagnostic yield is increased with volume of CSF (up to 10 to 15 mL) and number of CSF specimens (up to four) [6,31]. AFB smears and cultures may be positive even days after treatment has been initiated.

Organisms can be demonstrated most readily in a smear of the clot or sediment. If no clot forms, addition of 2 mL of 95% alcohol induces a heavy protein precipitate that carries bacilli to the bottom of the tube upon centrifugation. The centrifuged deposit should be applied to a glass slide (20 mcL in an area not exceeding one centimeter in diameter) and stained by the standard Kinyoun or Ziehl-Neelsen method. Under light microscopy, between 200 and 500 high-powered fields should be examined (approximately 30 minutes), preferably by more than one observer [6,31]. Some labs screen with fluorescence staining (image 2) and, when necessary, use light microscopy (image 3) to confirm the findings.

In one series including 52 patients, 37 percent of cases were diagnosed on the basis of an initial positive AFB smear; the diagnostic yield increased to 87 percent when up to four serial specimens were examined, and in some cases antituberculous therapy had been administered before a positive smear was obtained [6]. In another study including 132 adults with suspected tuberculous meningitis, AFB smear was positive in 58 percent of cases [31].

The sensitivity of CSF AFB culture for diagnosis of tuberculous meningitis is often <50 percent, although some studies report positive culture rates of up to 85 percent [6,31].

Issues related to mycobacterial culture techniques are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Mycobacterial culture'.)

Nucleic acid amplification tests — NAATs on CSF are an important diagnostic tool due to rapid turnaround time and high specificity. In one meta-analysis including 63 studies comprising more than 1300 patients with tuberculous meningitis (confirmed by culture), the specificity and sensitivity of NAATs were 99 percent (95% CI 98-99) and 82 percent (95% CI 75-87 percent), respectively [34].

NAATs may be used in combination with (but not as a substitute for) AFB smear and culture. NAAT on CSF has not been approved by the US Food and Drug Administration in the United States; however, some laboratories offer laboratory-developed and validated NAATs. A negative NAAT result should not be used to exclude tuberculous meningitis, given variable sensitivity [29]. Mycobacterial deoxyribonucleic acid (DNA) may remain detectable in CSF for up to a month after initiation of treatment [32].

In high prevalence settings, patients with suspected tuberculous meningitis should have CSF sent for NAAT if feasible; this tool is particularly useful in the setting of negative AFB smear [35-42]. We are in agreement with the World Health Organization (WHO), which issued recommendations in 2017 favoring use of the Xpert MTB/RIF Ultra assay as an initial diagnostic test for tuberculous meningitis [43]. This approach is supported by a prospective study including 129 adults in Uganda with HIV infection and suspected tuberculous meningitis (22 with confirmed tuberculous meningitis) in which the sensitivity of Xpert Ultra was 95 percent and the negative predictive value of Xpert Ultra was >90 percent; the sensitivity for Xpert or culture was 45 percent [44]. However, in a subsequent randomized trial including 205 patients tuberculous meningitis, Xpert Ultra was not superior to Xpert MTB/RIF for diagnosis of tuberculous meningitis in adults with or without HIV infection [45], and some have cautioned against use of Xpert Ultra to ‘rule out’ tuberculous meningitis [46].

In low-prevalence settings, the Xpert MTB/RIF assay may be used as diagnostic tool if the assay has been validated by the laboratory for this indication [47]. In one systematic review and meta-analysis including 18 studies, the sensitivity and specificity for this assay in CSF (compared with culture) were 81 and 98 percent, respectively [41]. In addition, the positive predictive value of NAATs is limited in low-prevalence settings [42]. Quantitative NAAT results may be a useful prognostic tool; a high bacterial load correlates with cycle threshold (Ct) <16, medium load with Ct 16 to 22, low load with Ct 22 to 28, and very low load with Ct >28. A high CSF M. tuberculosis bacterial load prior to treatment (measured using the Xpert MTB/RIF assay) has been associated with higher disease severity and higher likelihood of new neurologic events after initiation of therapy [48].

Metagenomic next-generation sequencing (NGS) is emerging as an additional diagnostic tool. Preliminary studies suggest that NGS is capable of identifying M. tuberculosis in CSF and distinguishing tuberculous meningitis from other conditions [49,50].

Issues related to NAATs for diagnosis of pulmonary TB are discussed further separately. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'NAA (probe-based) testing'.)

Antigen testing — Urine-based detection of mycobacterial cell wall glycolipid lipoarabinomannan (urine LAM test) has been recommended by the WHO for diagnosis of tuberculosis in patients with HIV infection; it may also be useful as a CSF assay for diagnosis of tuberculous meningitis. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Patients with HIV infection'.)

In one cohort study including 101 patients in Uganda with suspected tuberculous meningitis (of whom 95 had HIV infection), the sensitivity of Fujifilm SILVAMP tuberculosis LAM (FujiLAM) on CSF was comparable to that of Xpert MTB/RIF Ultra (52 and 55 percent, respectively) [51].

Adenosine deaminase — Measurement of the CSF adenosine deaminase (ADA) level may be a useful adjunctive test for diagnosis of tuberculous meningitis [30,52]. However, elevated CSF ADA level may also be observed in the setting of bacterial infections and neurobrucellosis [52,53], and there is no clear threshold to distinguish tuberculous meningitis from meningitis caused by other infectious agents.

One meta-analysis included 10 studies and more than 350 with tuberculous meningitis (most of which defined an elevated ADA as 9 or 10 U/L) estimated the sensitivity and specificity of ADA for diagnosis of tuberculous meningitis to be 79 and 91 percent, respectively [54]. Another meta-analysis including 13 studies and more than 1000 patients with tuberculous meningitis noted the sensitivity and specificity of ADA for diagnosis of tuberculous meningitis depended on the definition of an elevated ADA level [55]. For ADA threshold of 4 U/L, the sensitivity and specificity were >93 and <80 percent, respectively; for ADA threshold of 8 U/L, the sensitivity and specificity were <59 and >96 percent, respectively.

Radiographic imaging — Radiographic modalities for evaluation of patients with suspected CNS TB include brain CT or brain MRI [56,57]. Brain MRI is superior to CT in defining lesions of the basal ganglia, midbrain, and brainstem [58,59].

In patients with tuberculous meningitis, classical neuroimaging findings include hydrocephalus, basilar exudates, periventricular infarcts, and cerebral parenchymal tuberculomas (image 4 and image 5 and image 6 and image 7 and image 8) [25,29]. Presence of basilar meningeal enhancement along with presence of hydrocephalus is strongly suggestive of tuberculous meningitis (image 8) [60-63]. In the setting of stage I disease, the CT scan is normal in approximately 30 percent of cases. In the setting of stage III disease, CT findings may include hydrocephalus as well as basilar enhancement. Marked basilar enhancement has been correlated with presence of vasculitis and risk for basal ganglia infarction.

In two large community-based series, hydrocephalus was observed in approximately 75 percent of cases, basilar meningeal enhancement in 38 percent, cerebral infarcts in 15 to 30 percent, and tuberculomas in 5 to 10 percent [60,61]. In a case series from Hong Kong including 31 patients with tuberculous meningitis, hydrocephalus was observed on presentation in 9 cases; among 22 patients without initial hydrocephalus, hydrocephalus developed after the start of antituberculous therapy in 1 patient [62].

Optochiasmatic arachnoiditis, an important cause of vision loss, is characterized radiographically by presence of tuberculous exudates in the region of interpeduncular, suprasellar, perimesencephalic, and Sylvian cisterns [64].

Periventricular brain infarcts are seen in up to half of patients and are common in advanced disease. Most infarcts are observed in the basal ganglia. In many patients, infarcts are asymptomatic and not associated with focal neurologic deficits [13,65].

Radiographic manifestations of tuberculoma and spinal arachnoiditis, which may occur in patients with tuberculous meningitis, are described separately. (See "Central nervous system tuberculosis: An overview", section on 'Tuberculoma' and "Central nervous system tuberculosis: An overview", section on 'Spinal arachnoiditis'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of tuberculous meningitis (subacute or chronic meningitis syndrome with cerebrospinal fluid [CSF] characterized by a lymphocytic pleocytosis, lowered glucose concentration, and elevated protein concentration) includes:

●Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis) – As with tuberculous meningitis, fungal meningitis often presents subacutely and may be associated with cranial neuropathies. Immunosuppression (due to HIV infection or other causes) is an important risk factor. In patients with cryptococcal meningitis, the CSF profile classically demonstrates elevated opening pressure, low white blood cell count with a mononuclear predominance, slightly elevated protein concentration, and low glucose concentration. Definitive diagnosis is made by CSF culture; a positive cryptococcal antigen in the CSF or serum strongly suggests the presence of infection. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV".)

●Neurobrucellosis – Brucellosis typically presents with insidious onset of fever, malaise, night sweats, and arthralgias. It may be complicated by neurobrucellosis; manifestations include meningitis, encephalitis, brain abscess, myelitis, radiculitis, and/or neuritis (with involvement of cranial or peripheral nerves). CSF findings include a pleocytosis (10 to 200 white blood cells, predominantly mononuclear cells), mild to moderately elevated protein levels, hypoglycorrhachia, and elevated adenosine deaminase. The diagnosis may be established via antibody or agglutination testing of spinal fluid; uncommonly, the organism may be recovered in CSF culture. (See "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Neurosyphilis – Meningitis and meningovascular disease are manifestations of early neurosyphilis. Clinical manifestations of syphilitic meningitis include headache, confusion, nausea, vomiting, and stiff neck; in addition, cranial neuropathies may occur. Visual acuity may be impaired if there is concomitant uveitis, vitreitis, retinitis, or optic neuropathy. In addition, an infectious arteritis affecting the vasculature of the subarachnoid space may occur, result in thrombosis, ischemia, and stroke involving the brain or spinal cord. Diagnostic testing includes serum treponemal and nontreponemal tests and spinal fluid examination to assess for presence of pleocytosis, elevated protein concentration, and CSF Venereal Disease Research Laboratory tests. (See "Neurosyphilis".)

●Bacterial meningitis – Bacterial meningitis presents acutely with fever, nuchal rigidity, and altered mental status. Typical CSF findings include white blood cell count of 1000 to 5000/microL (neutrophil predominance), protein concentration 100 to 500 mg/dL, and glucose concentration <40 mg/dL. The diagnosis may be established via isolation of a bacterial pathogen from CSF or blood cultures. In patients with partially treated meningitis, there is usually minimal effect on the CSF chemistry and cytology findings, but the yield of Gram stain and culture may be diminished. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

●Focal parameningeal infection (brain abscess, spinal epidural abscess, sphenoid sinusitis) – Clinical manifestations of parameningeal infection may be subacute and nonspecific. Initial evaluation should consist of radiographic imaging (of the brain and/or spinal cord). LP is contraindicated in patients with papilledema or focal symptoms or signs; if it is feasible to obtain CSF, findings may demonstrate elevated protein concentration, low glucose concentration, and pleocytosis. A microbiologic diagnosis may be established culture of material obtained via stereotactic-guided aspiration or surgery. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess" and "Spinal epidural abscess" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

●Viral meningitis (herpes simplex, mumps) – Viral CNS infection usually presents acutely, in contrast to tuberculous meningitis, which is typically subacute. In the setting of viral meningitis, the CSF also typically demonstrates a lymphocytic pleocytosis, elevated protein but normal glucose, and negative Gram stain and culture. Definitive diagnosis of viral meningitis is established via CSF polymerase chain reaction. (See "Aseptic meningitis in adults".)

●Neoplastic meningitis – Leptomeningeal metastases (LM) are diagnosed in approximately 5 percent of patients with advanced cancer; the most common primary tumors associated with development of LM are breast, lung, and melanoma. Clinical manifestations include headache, nausea and vomiting, leg weakness, ataxia, altered mental status, diplopia, and facial weakness. Typical MRI findings include linear and nodular leptomeningeal enhancement; thickening and enhancement of cranial nerves or nerve roots, including the cauda equina, and hydrocephalus. CSF findings include elevated opening pressure, mild pleocytosis, elevated protein and decreased glucose concentrations. The diagnosis of LM is definitively established via identification of malignant cells in the CSF. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)

Issues related to CNS disease in patients with HIV infection are discussed further separately. (See "Approach to the patient with HIV and central nervous system lesions".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of tuberculosis".)

SUMMARY

●Patients with tuberculous meningitis commonly present with stiff neck, headache, fever, and vomiting; these symptoms are also frequently observed with bacterial meningitis. Features that may help distinguish tuberculous meningitis from bacterial meningitis include subacute presentation, presence of neurologic symptoms, and presence of cranial nerve palsies. (See 'Clinical manifestations' above.)

●Tuberculous meningitis should be suspected in patients with relevant clinical manifestations and epidemiologic factors (history of prior tuberculosis [TB] infection or disease, known or possible TB exposure, and/or past or present residence in or travel to an area where TB is endemic). (See 'Overview of clinical approach' above.)

●The diagnosis of tuberculous meningitis may be definitively established in the setting of cerebrospinal fluid (CSF) with positive smear for acid-fast bacilli, CSF culture positive for Mycobacterium tuberculosis, or CSF with positive nucleic acid amplification test. However, definitive diagnosis can be challenging, given suboptimal sensitivity and specificity of diagnostic tests. A presumptive diagnosis of tuberculous meningitis may be made in the setting of relevant clinical and epidemiologic factors and typical CSF findings (lymphocytic pleocytosis, elevated protein concentration, and low glucose concentration) (table 2). (See 'Overview of clinical approach' above.)

●Radiographic modalities for evaluation of patients with suspected tuberculous meningitis include brain computed tomography (CT) or magnetic resonance imaging (MRI). Brain MRI is superior to CT in defining lesions of the basal ganglia, midbrain, and brainstem. (See 'Radiographic imaging' above.)