Tuberculosis of the CNS …

Joseph R Berger MD

Infectious Disorders

Updated 12.27.2023
Released 12.18.1995
Expires For CME 12.27.2026

Tuberculosis of the CNS

Author: Joseph R Berger MD

See Contributor Disclosures

Editor: John E Greenlee MD

Tuberculosis of the CNS

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Introduction

Overview

The frightening appearance of multidrug-resistant tuberculosis has focused new attention on this ancient human scourge. Although tuberculosis remains a common infectious disorder in the underdeveloped and developing world, immigration has resulted in an increased frequency in developed countries. The author describes the large number of neurologic complications, particularly tuberculous meningitis, that occur with this microorganism. In developed countries, tuberculous infection is often unsuspected, and a high level of suspicion is required to establish the diagnosis. Cultures of CSF are time-consuming and, therefore, of little diagnostic value at the time of presentation. However, polymerase chain reaction for M tuberculosis is now widely employed to assist in early diagnosis. Corticosteroid therapy, although controversial, is increasingly employed as an adjunctive therapy to decrease the complications that attend tuberculous meningitis.

Key points

	• Although relatively rare in the developed world, neurologic disease resulting from tuberculosis remains a common problem in the developing world.
	• Meningitis is the most common neurologic complication and is often associated with cranial nerve palsies.
	• Cultures for M tuberculosis are time-consuming and frequently negative; CSF PCR has become a routine method for diagnosing tuberculous meningitis with sensitivities equal to or exceeding 90%. However, a negative PCR test does not exclude the diagnosis.
	• Treatment has been complicated by the increasing emergence of multidrug-resistant forms of the organism.

Historical note and terminology

Tuberculosis is the world's leading cause of death from a single infectious agent; neurologic complications of tuberculosis are not uncommon. Tuberculous meningitis remains a serious health threat in both developing and developed countries. Tuberculous meningitis is hardly a new health problem. The first descriptions of this disorder are often said to be those of Robert Whytt in his report in 1768 of hydrocephalus in children with a febrile illness. However, polymerase chain reaction technology has demonstrated Mycobacterium tuberculosis in human mummies, predating the writings of Hippocrates, Galen, and other early physicians who described the illness (110). Despite these and other early characterizations, the unequivocal association between tuberculosis and meningitis occurred with Koch’s discovery of the tubercle bacillus in 1882. Over 50 years later, in 1946, streptomycin was introduced as a treatment for tuberculosis and was demonstrated to be effective for pulmonary and meningeal disease. Shortly afterward, isoniazid and pyrazinamide were introduced. Although in 1900, the annual mortality rate in the United States was 200 per 100,000 individuals, by the initial years of the antibiotic era in 1953, that rate had fallen to 12.4 per 100,000 (110). Still widely prevalent in some countries, tuberculosis appeared close to being defeated by sanitation and chemotherapy in the second half of the 20th century, especially in developed countries. With the epidemic of the human immunodeficiency virus, however, a second epidemic of tuberculosis emerged worldwide. In the era of AIDS, not only has the evolution of multidrug-resistant strains of M tuberculosis become a problem of increasing concern, but there has also been an increasing recognition of central nervous system disease due to mycobacteria other than M tuberculosis.

Clinical manifestations

Presentation and course

	• Only a minority of adult patients with tuberculous meningitis have a prior history of tuberculous infection.
	• Fever may be absent in up to 20% of patients with tuberculous meningitis, and the absence of fever is particularly common in the elderly.
	• Cranial nerve abnormalities are observed in about 25% of affected patients.
	• Stroke from tuberculous vasculitis often affects deep nuclear structures and may result in various movement disorders.

Typically, tuberculous meningitis is preceded by a period of 2 to 8 weeks of nonspecific symptoms that include malaise, anorexia, fatigue, fever, myalgias, and headache. Initially intermittent, headaches eventually worsen and become continuous. In one large series, headaches were reported by 86% of patients (87). In infants prodromal symptoms include irritability, drowsiness, poor feeding, and abdominal pain. A low-grade fever is typically present, although some series report the absence of fever in up to 20% of patients with tuberculous meningitis. The frequent exception is the elderly patient, who may present simply with headache, confusion, or other neurologic disturbance in the absence of fever. Teoh and Humphries state that in their experience, fever is rarely in excess of 39°C when the tuberculous involvement is limited to the meninges alone (186). A prior history of tuberculosis is obtained in approximately one half of cases of childhood tuberculous meningitis and in approximately 10% of adult cases. Neck stiffness is reported by about one quarter of patients, and meningismus is detected in higher numbers (87). Infants often exhibit neck retraction and bulging fontanelles. With progression of infection, the patient develops increasing irritability, nausea, vomiting, confusion, and focal or generalized seizures. Psychosis has also been reported (29). A tuberculous encephalopathy in the absence of meningitis is a rare entity associated with diffuse white matter edema and extensive demyelination (89). Granulomas can be demonstrated in the brain, and the entity has been attributed to delayed hypersensitivity to tuberculoproteins (89).

Cranial nerve palsies are seen on admission in 15% to 30% of children and 15% to 40% of adults. The sixth cranial nerve is most commonly affected, followed in descending order of frequency by the third, fourth, seventh, second, eighth, tenth, eleventh, and twelfth (106; 191). Transitory cranial nerve dysfunction has been described (164). Papilledema is frequently observed and, on occasion, funduscopic examination may reveal choroidal tubercles; yellow lesions with indistinct borders present either singly or in clusters. Their presence is convincing evidence of the disease, but they appear in only about 10% of cases of tuberculous meningitis not associated with miliary tuberculosis. Causes of visual impairment other than tuberculous meningitis include opticochiasmatic arachnoiditis, tuberculomas compressing the optic nerves, and ethambutol toxicity in treated patients (186). Gaze palsies and internuclear ophthalmoplegia may also occur with parenchymal lesions due to vasculitic lesions and tuberculomas.

Among the neurologic signs observed are hemiparesis and hemiplegia, along with a wide variety of movement disorders that include chorea, hemiballismus, athetosis, cerebellar ataxia, tremor, and myoclonus (01). These abnormalities are usually the consequence of infarction due to tuberculous vasculitis but may occur as the result of mass lesions from tuberculomas or tuberculous abscesses. Strokes consequent to tuberculosis occur most frequently in the distribution of the anterior cerebral circulation but in rare cases have been observed in the vertebrobasilar distribution exclusively (157). A moyamoya pattern of vascular involvement has been reported with tuberculous meningitis in a 1-year-old child (95). Stroke-like manifestations consequent to cerebral venous thrombosis have also been observed with tuberculous meningitis (49). Involuntary movements may be observed in as many as 13% of cases, occur more commonly in children, and, in rare instances, may persist after treatment (193).

With identical pathophysiology to tuberculous meningitis, spinal meningitis occurs in between less than 1%; approximately 12% of cases and may manifest as radiculomyelopathy, transverse myelitis, or anterior spinal artery syndromes (19; 199; 169). In areas of high endemicity for tuberculosis, as many as one third of cases of myelitis may be the consequence of the infection (88). Tuberculous radiculomyelitis, characterized by subacute paraparesis, radicular pain, and bladder disturbance, typically develops after the onset of tuberculous meningitis and may even occur after sterilization of the CSF (64). Radiographic studies often show features of adhesive arachnoiditis (122). Intramedullary spinal cord abscesses and spinal infections with epidural abscess due to M tuberculosis may also result in myelopathy (62; 184). An intramedullary spinal tuberculoma can also mimic a conus tumor (183). In one study of 15 patients with spinal intramedullary tuberculosis, symptoms had been present on average 11 months at presentation (range 2 to 24 months) and the most common locations were cervical and cervicothoracic (148). Nerve root and spinal cord involvement may occur as a consequence of tuberculous spondylitis.

Tuberculous spondylitis usually involves the thoracolumbar spine, most commonly L1 (207). Spinal tuberculosis is the most common musculoskeletal manifestation of tuberculosis. Skeletal involvement occurs in approximately 10% of all patients with extrapulmonary tuberculosis, and in one half of these, the spinal column is affected (53). The association of paraplegia with tuberculous destruction of the anterior spinal column and progressive kyphosis was first described by Sir Percival Potts in 1779. The cancellous bone of the vertebral bodies is seeded by the microorganism hematogenously, typically from a pulmonary infection. The infection initially affects the anterior part of the vertebral body and subsequently spreads into the disc space and along the anterior and posterior longitudinal ligaments (52). Kyphosis results from vertebral collapse. Paradiscal destruction of the vertebral body results in kyphosis with disc preservation until late in the illness. Clinical manifestations include back pain, fever, and variable neurologic features from compression of nerve roots or the spinal cord. The onset is typically insidious, often progressing over 4 or more months before diagnosis (46). The associated spinal prominence, termed gibbus, follows collapse of the anterior vertebral column with kyphosis. Neurologic deficits accompany 23% to 76% of all cases of tuberculosis spinal disease (92). MR imaging is highly sensitive in detecting vertebral osteomyelitis, demonstrating hypointense lesions of the vertebral bodies on T1-weighted image and hyperintense T2-weighted signal in the disc space (52). Psoas abscess calcification is readily observed on CT imaging. Lumbosacral plexopathy may also occur as a consequence of tuberculosis (180). The diagnosis is confirmed by biopsy with tissue having a higher diagnostic yield than pus. However, the diagnosis is often difficult as spinal tuberculosis is paucibacterial and the yield of AFB staining has been reported to be 38% (46). Histopathological findings include caseating granuloma and giant cells, which strongly support the diagnosis. Histopathological examination has been reported to confirm the diagnosis in about 60% of patients (46).

HIV infection appears to increase the risk for extrapulmonary tuberculosis, including meningitis. There appears to be some controversy as to whether HIV infection increases the incidence of brain tuberculomas (134; 187); however, they must be considered as a cause of brain mass lesions in the patient with AIDS (16). In India, 12% of HIV-infected patients coming to autopsy have documented tuberculous meningitis (99). Most studies suggest that concomitant HIV infection does not appear to significantly alter the clinical manifestations or cerebrospinal fluid analysis (17; 13; 45). However, one study found that HIV seropositive individuals with tuberculous meningitis more commonly had cognitive abnormalities but lower rates of meningeal enhancement, communicating hydrocephalus, and inflammation (84). The commonest clinical manifestations include seizures, altered mental status, and fever with meningismus (17). Furthermore, based on small numbers, two studies have suggested that at least early response of tuberculous meningitis to chemotherapy appears similar among HIV-infected and non-HIV-infected individuals. The mortality rate in these two groups of patients is still controversial. Berenguer and colleagues showed an overall mortality of 33% among HIV-infected patients with tuberculous meningitis and 21% among non-HIV-infected individuals (13). Specifically, mortality rate directly attributable to tuberculous meningitis was 21% among HIV-infected and non-HIV-infected individuals; however, these data are questioned based on the differential loss to follow-up of 18% and 50%, respectively (13). CT characteristics are diverse and, in general, mirror those seen in tuberculous meningitis in the absence of HIV infection. However, a higher incidence of abnormal CT scans (intracranial tuberculomas characterized by ring-enhancing lesions in particular) has been reported in this population (17; 13; 45). Hydrocephalus and meningeal enhancement were observed on CT in approximately one half of all patients in one study in which intravenous drug abusers constituted more than 90% of the population (198). Mycobacterial spinal cord abscess has also been reported in AIDS (38).

Despite the frequency of M avium-intracellulare (MAI) in AIDS, few cases of meningitis due to nontuberculous mycobacteria have been reported. In a study from New York, MAI was cultured from the CSF in 15 of 16 cases with atypical mycobacterial meningitis complicating AIDS (73). The other case was due to M fortuitum. Ten of 15 patients with MAI died in the hospital, suggesting an especially poor prognosis. MAI may cause multiple ring-enhancing lesions (197). In rare instances, atypical mycobacteria may also result in neurologic disease in non-AIDS immunocompromise (192).

Prognosis and complications

Outcome in tuberculous meningitis is strongly associated with the stage of disease at presentation (32; 205). In 1948, the British Medical Research Council developed a method for staging the severity of the disease for purposes of classification in the initial trials of streptomycin in tuberculous meningitis (117). Stage I (early) is the presence of nonspecific symptoms and signs without alteration of consciousness. Stage II (intermediate) is disturbed consciousness without coma or delirium and minor focal neurologic signs. Stage III (advanced) is the presence of stupor or coma, severe neurologic deficits, seizures, or abnormal movements. Complete recovery or, occasionally, mild neurologic sequelae seems the rule in stage I cases, but severe neurologic sequelae and mortality as high as 30% are commonly reported in stage III cases (70; 87). In addition to the advanced stages, other factors associated with poor prognosis include extremes of age, coexistent miliary disease, extraordinarily high CSF protein levels with spinal block, and markedly reduced CSF glucose. A multivariate analysis of clinical, radiological, and neurophysiological abnormalities as predictors of outcome study suggested that focal weakness, Glasgow Coma Score, and abnormalities on somatosensory evoked potentials were the best predictors of 6-month outcome (120). The presence of abnormalities on head CT imaging may also predict a poorer outcome (67), particularly evidence of brain infarction (79).

In a Turkish study of more than 100 patients with tuberculous meningitis, 43.5% died, and neurologic sequelae occurred in 20%. Only 30.7% of patients experienced a complete recovery (67). A large review of tuberculous meningitis in children found an overall mortality rate of 23% (210). On clinical examination, the presence of spasticity and coma are poor prognostic features in children with tuberculous meningitis (82) as are high levels of CSF adenosine deaminase (75). Prior neonatal BCG vaccination appears to have little effect on the clinical findings and course of subsequent CNS tuberculosis (58). A retrospective cohort study of adult patients with tuberculous meningitis from California (2005-2010), Florida (2005-2012), and New York (2006-2012) found a cumulative rate of any complication or death of 55.4% (118). Stroke occurred in 8.4%; seizures in 18.8%; visual impairment in 21.6%; hearing impairment in 6.8%; and ventriculoperitoneal shunting was required in 8.4% (118).

In AIDS patients, a CD4 lymphocyte count of fewer than 22 cells/mm3 and illness lasting more than 14 days before hospital admission are poor prognostic signs (13). In the same study, the overall mortality was 33% in the HIV-infected population with tuberculous meningitis. The prognosis of tuberculous meningitis is considerably worse in the HIV-infected person when compared to immunologically competent persons. The degree of immunosuppression appears to be the greatest predictor of survival in HIV-infected persons (61). Survival is worse in the setting of negative tuberculin skin tests, prior opportunistic infection, and low CD4 counts (140; 144). One study comparing tuberculosis meningitis in HIV-infected and uninfected persons found that the hospital mortality was 63.3% in the former group, but only 17.5% in the latter (25). In children, although clinical features were not different between the HIV-infected and uninfected, abnormal neuroradiological findings were more common, and outcome was considerably worse in those infected with HIV (190).

Biological basis

Etiology and pathogenesis

	• Tuberculous meningitis follows hematogenous seeding of the meninges with establishment of Rich foci from which the organism is reactivated.
	• M tuberculosis is extremely fastidious. Cultures take a long time to incubate and may not be positive even in the face of established infection.

Mycobacterium tuberculosis is an aerobic, non-spore-forming, nonmotile bacillus measuring 0.5 µm × 4 µm. Its cell wall has a large fatty acid (mycolic acid) content that does not stain conventionally and resists acid de-coloration after staining with aniline dyes, thus, acquiring the term "acid-fast." The Ziehl-Neelsen and the Kinyoun stain effectively demonstrate the organism microscopically, whereas Lowenstein-Jensen is the classic medium for the organism inoculation and isolation. With a slow doubling time and the organism's generation time of 15 to 20 hours, 20 times longer than most bacterial pathogens, growth to demonstrable colonies takes between 3 and 8 weeks. The organism is an obligate parasite of humans but may infect other mammals, such as dogs and cats, that are in close contact with man. Man, however, is the only known reservoir of the organism. In addition to M tuberculosis, several other species of mycobacteria are variably pathogenic for man. Studies of archival isolates of M tuberculosis suggest the possibility that the development of CNS tuberculosis is strain-dependent (06).

M tuberculosis spreads from person to person through small, 1- to 10-micron airborne particles containing variable numbers of the organisms. These "droplet nuclei" are produced when a patient with active respiratory tract infection coughs, sings, or shouts, and they may subsequently be inhaled into the middle and lower portions of the lungs of anyone sharing the airspace with the infected individual. Despite ingestion of the bacilli by T-cell-activated macrophages, the organisms multiply locally and, from this site, disseminate lymphohematogenously to other organs, the apical sections of the lungs, the kidney, the vertebral bodies, and the central nervous system in particular. In the first 2 to 6 weeks after infection, sensitized lymphocytes and activated macrophages lead an intense inflammatory reaction against the foci of infection. These reactions organize into granulomas with a necrotic, caseous center. Some caseous foci continue to shelter viable bacilli, which will multiply in the presence of immunosuppression.

Intracranial tuberculoma: Prototype granuloma (1)

Non-contrast axial CT scan shows an area of low attenuation at left parieto-occipital region, mainly at subcortical white matter. (Contributed by Dr. Gurang Shah.)
Intracranial tuberculoma: Prototype granuloma (2)

Contrast-enhanced axial CT shows a solid rounded densely-enhancing lesion at the junction of grey and white matter with surrounding edema. (Contributed by Dr. Gurang Shah.)

The development of CNS tuberculosis follows previous hematogenous dissemination of M tuberculosis to the central nervous system, occurring either during the initial stages of the infection or later as a result of caseation at the primary site or other sites. The pathological studies of Rich and McCordock in 1933 dispelled the widely held belief that contemporaneous hematogenous dissemination was responsible for the development of tuberculous meningitis (151). They demonstrated that tuberculous meningitis may occur in the absence of miliary tuberculosis and that when miliary tuberculosis is present, the age of the lesions in the meninges may be different than that of lesions present elsewhere. In their study, they found that in 77 of 82 cases of tuberculous meningitis, a caseous tuberculous focus was found adjacent to CSF pathways. Also, in animal experiments, inoculation of the CSF with M tuberculosis results in tuberculous meningitis, whereas the intracarotid injection of the pathogen results in multiple intracerebral tuberculomata but not meningitis. As a result of these investigations, the development of CNS tuberculosis is now believed to be the consequence of growth and rupture of one or more small tuberculous, subpial lesions or Rich foci that had developed following an earlier hematogenous dissemination to the nervous system. Although immunological mechanisms are believed to play a role, the specific trigger for the growth and rupture of these lesions is not known. Growth of these lesions may be meningeal, parameningeal, or parenchymatous along any portion of the neuraxis. The symptoms and signs that eventuate depend on the site of the lesions and their rate of expansion.

The three main pathologic features in tuberculous meningitis are: (1) inflammatory meningeal exudate; (2) vasculitis of the arteries traversing the exudate, mainly small and medium-sized vessels; and (3) disturbance of the flow of the cerebrospinal fluid (169). Gross examination of the brain and meninges in tuberculous meningitis typically shows a diffuse opacification of the meninges overlying the convexities and a thick gray-green gelatinous exudate predominantly in the basal cisterns. The exudate not infrequently extends over the anterior pons, through the cisterna magna, and over the cervical spinal cord. Microscopically, lymphocytes, plasma cells, epithelioid cells, and fibrin predominate in the meningeal exudate. M tuberculosis is variably detected in the exudate but is often easily observed in meningeal tuberculomas. The degree of meningeal inflammation generally correlates with the duration of the infection; if observed early, the exudate and the inflammation may be greatest in the vicinity of the ruptured tuberculoma. Cranial epidural abscess, dural tuberculomas, focal tuberculous pachymeningitis, and tuberculous epidural empyema may also be observed and may occur in isolation (74).

The inflammation and exudate appear to predominate around meningeal vessels. Inflammation may affect the adventitia, media, and even intima. The lumen of these vessels may narrow, leading to occlusion of cerebral arteries and infarction of the underlying tissue. Fibrinoid necrosis and caseous necrosis may also occur in arteries, as may cerebral phlebitis. In tuberculous meningitis, the vessels at the base of the brain are most severely affected, particularly the internal carotid, proximal middle cerebral artery, and the perforating vessels to the basal ganglia, the medial striate, and thalamoperforating arteries (68). Consequently, cerebral infarctions are often seen at the base of the brain, around the lips of the Sylvian fissure, and in the basal ganglia. Vascular changes may predominate in CNS tuberculous infection (141); in some series, as many as 50% of patients are found to have cerebral infarction with tuberculous meningitis (80). Basal meningeal inflammation, hydrocephalus, focal neurologic deficits, and cranial nerve palsies are seen more often in the setting of cerebral infarction with tuberculous meningitis (163). Cerebral venous involvement with tuberculous meningitis is rare. Hydrocephalus may occur as a consequence of obstruction of the basal cisterns, the outflow of the fourth ventricle, or aqueductal occlusion (185).

As with other forms of bacterial meningitis, disruption of the blood-brain barrier is observed. Although the pathogenesis of the blood-brain barrier breakdown is likely multifactorial, mannan (antibody to a component of the mycobacterial cell wall) has been demonstrated to provoke blood-brain barrier breakdown in an experimental model (125). A wide array of cytokines can be observed in the CSF during tuberculous meningitis. However, no correlation could be detected between the stage of tuberculous meningitis or the clinical outcome of the disease and the presence of such cytokines in the CSF as tumor necrosis factor-alpha, interferon-gamma, interleukin-10 and interleukin-12 (116). The pathological findings may depend not only on the host response but also on the type and virulence of M tuberculosis (141).

The proinflammatory cytokine tumor necrosis factor (TNF) is critical for both the initial and the long-term host immune protection against tuberculosis. The administration of tumor necrosis factor-alpha blockers in treating rheumatological disorders, inflammatory bowel disease, psoriasis, and other conditions is attended by an increased risk of developing tuberculosis (201). Although neuron-derived TNF appears to have a limited role in protection against CNS tuberculosis, overall TNF production is important in preventing CNS tuberculosis (50). Microglial cells have also been demonstrated to be vital in determining the severity and clinical outcome of CNS tuberculosis (177). Host genetic factors (eg, polymorphisms of the CD43 gene) have been associated with susceptibility and disease severity to tuberculosis (22), as have other genes related to the innate immune system and genes related to CNS development (161).

Epidemiology

	• Most cases of tuberculosis in the United States are in foreign-born individuals.
	• Risk factors for tuberculosis include HIV infection, substance abuse, diabetes, severe kidney disease, low body weight, treatment with corticosteroids, homelessness, and incarceration.

Based on autopsy studies from the first half of this century in England and the United States, between 5% and 10% of patients with active tuberculosis were estimated to develop central nervous system involvement (152). In the United States in 1940, tuberculous meningitis was reported to be responsible for approximately 32% of all cases of bacterial meningitis; 25 years later, the figure had declined to less than 8% (02). This same year, in Bombay, India, 60% of the cases of meningitis in children ages 9 months through 5 years were caused by M tuberculosis (193). Autopsy studies indicate that tuberculous meningitis is three times more common in children, particularly between 6 months and 6 years of age, than in adults (152). A community-based study from New Mexico reported tuberculous meningitis in patients aged 4 months to 86 years (34). Historically, in up to 10% of reported cases, an acute infectious disease preceded the development of tuberculous meningitis in children. Other apparent risk factors for its occurrence evident in the New Mexico study included a history of alcoholism in 32% of adults, diabetes mellitus in 13%, malignancy in 8%, corticosteroid administration within the past 6 months in 8%, and AIDS in 4% (34). Additionally, intravenous drug use had been identified to be a risk factor for tuberculous meningitis before 1983 (132). Exposure to individuals with tuberculosis, homelessness, and incarceration increase the risk of tuberculosis.

Between 1985 and 1992, foreign-born cases accounted for 60% of the total increase of tuberculosis cases in the United States; however, human immunodeficiency virus infection has had the greatest impact on tuberculous morbidity among whites, blacks, males, and persons between 25 and 44 years of age (23). Coinciding with the AIDS epidemic, countries like Italy, Switzerland, and the United States have reported between a 20% and 30% increase in the number of tuberculosis cases since 1985 (128). Specifically, the number of cases in the United States between 1953 and 1985 was declining at an annual average rate of 5.8%, but from 1985 to 1990 the number of cases increased by 20% (23). In 1985, 5% of 4000 cases of extrapulmonary tuberculosis in the United States were meningitis (128). Between 1985 and 1990 extrapulmonary tuberculosis accounted for 29% of the total increase in the number of tuberculosis cases, and two thirds occurred in the 25- to 44-year-old age group (23). Interestingly, in the same time period the number of pulmonary cases increased only by 3% (09).

In the 1990s, the emergence of multidrug-resistant strains of M. tuberculosis (MDR-TB) was noticed. MDR-TB is resistant to both isoniazid and rifampicin, the cornerstones of TB therapy, with or without resistance to other drugs. It has been detected worldwide and, in the last World Health Organization survey conducted through 2002, had a median prevalence of 7.0% (209). Although observed more often in previously treated patients, it has been observed in as many as 3.2% of all new tuberculosis cases in China and India (167). Not unexpectedly, the incidence of MDR-TB meningitis is similarly increasing and presents significant challenges with respect to both diagnosis and treatment (21). Mortality with this organism is substantially higher, and it represents a serious threat in the HIV-infected population. Early detection of MDR-TB is of paramount importance when treating TB meningitis (133), but the initiation of appropriate treatment may be presumptive as rapid diagnostic methods may be insufficiently sensitive (24).

Estimates of the frequency with which mycobacterial infection of the CNS accompanies AIDS are dependent on the population studied, and until recently, they were limited by the lack of sensitive confirmatory diagnostic techniques. For instance, in an early review of AIDS patients with neurologic disease in San Francisco, none had mycobacterial CNS infection, whereas in Miami, which has the highest case rate of tuberculosis, and where 31% of all patients with tuberculosis are HIV-seropositive, 2.4% of HIV-infected patients with CNS disease had CNS tuberculosis (175; 14). Conversely, in a review of the neurologic disorders observed at autopsy of more than 900 patients with AIDS, 0.3% were found to have CNS tuberculosis (97). In a study from Spain, 455 (21%) of 2205 patients with tuberculosis had concomitant HIV infection, and 45 (10%) of those with tuberculosis and HIV had M tuberculosis isolated from the cerebrospinal fluid (13). Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, and other atypical mycobacteria infections frequently occur in AIDS and are often extrapulmonary in nature (145).

Prevention

The emphasis on the methods of controlling tuberculosis varies between developed and underdeveloped countries. Although in the former, most of the necessary mechanisms for case reporting and contact identification, means of early diagnosis, and availability of chemotherapeutic treatment are in place, many of these factors are scarce in third-world countries, where tuberculosis is likely to be prevalent. Social conditions that increase the risk of transmission, such as overcrowding and poor nutrition, need to be improved. The public should be educated about the mode of transmission of tuberculosis and the methods of control. Public health nursing and outreach services are critical for these tasks as well as for home supervision of patients to encourage treatment compliance and identification and treatment of contacts. Selective tuberculin testing should be done on groups at high risk of becoming infected, eg, care providers, immigrants from areas where tuberculosis is prevalent, homeless people, intravenous drug users, and prison inmates (12; 09; 23). The last three are of special interest given the high incidence of HIV and tuberculous infection among them (09). Individuals receiving tumor necrosis factor-alpha blockers are at increased risk for the development of tuberculosis; however, only one case of CNS tuberculosis in this group has been reported to date (109). Preventive treatment with isoniazid for 1 year has been shown to be effective in avoiding the progression of latent infection to clinical disease in more than 90% of immunocompetent and fully compliant individuals. Its efficacy in HIV-infected individuals is unknown (09).

In the United States, where most of the necessary methods of control are available, perhaps one of the most crucial aspects for the prevention of tuberculosis is to increase the awareness of physicians and other health providers to the increasing incidence of tuberculosis in this country in order to achieve an earlier recognition, diagnosis, and treatment of cases and their contacts. In particular, California, Florida, New Jersey, New York, and Texas accounted for more than 90% of the total increase in tuberculosis cases reported in the United States from 1985 through 1992 (23).

Strategies for disease prevention include bacillus of Calmette Guérin vaccination. BCG vaccination has an efficiency of approximately 80% in protecting young children from serious complications of tuberculosis, including miliary and meningeal disease (12; 128; 162). De March-Ayuela and colleagues suggest that BCG vaccination was not effective in protecting Spanish children under 5 years of age from tuberculous meningitis, and that the observed decline in its incidence was the consequence of improved treatment of tuberculous in adults (37). In contrast, Indian investigators found BCG most effective in preventing tuberculous meningitis in children ages 0 to 6 years, particularly, males in the upper strata socio-economic class (213).

Differential diagnosis

The differential diagnosis of central nervous system tuberculosis is broad. Given its nonspecific clinical manifestations, a variety of infectious, inflammatory, neoplastic, and vascular conditions need to be considered. The classical presentation of granulomatous meningitis, ie, fever, meningeal signs, encephalopathy, and CSF lymphocytic pleocytosis with low glucose and high protein, can also be caused by fungal infections, neurosyphilis, suppurative foci related to bacterial infection or abscesses, brucellosis, and neoplastic meningitis. In the patient with AIDS, distinguishing cryptococcal meningitis from tuberculous meningitis may be difficult. In this population, tuberculous meningitis was seen commonly in parenteral drug abusers, whereas cryptococcal meningitis was more common with advanced immunosuppression (154). Sarcoidosis and viral meningoencephalitis should also be considered if CSF glucose and protein are mildly to moderately elevated. Neurosarcoidosis is not infrequently associated with cranial involvement. Cerebrovascular accidents may be caused by the vasculitic process of tuberculous meningitis or mimicked by tuberculomas.

Tuberculomas are typically identified on contrast neuroimaging as nodular-enhancing lesions in early stages followed by the development of ringlike enhancement.

Intracranial tuberculoma: Caseating granuloma (1)

Contrast-enhanced axial CT shows numerous conglomerate areas of dense ring-enhancements at grey-white matter junction of left fronto-parietal lobe. Extensive low-attenuating white matter edema is seen at left cerebral hemisphere. ...
Intracranial tuberculoma: Caseating granuloma (2)

T1-weighted axial MR image after three days of steroid therapy shows ill-defined low T1 signal at left parieto-occipital region due to persistent residual edema. The main lesion is isointense to brain parenchyma. (Contributed by D...
Intracranial tuberculoma: Caseating granuloma (3)

T2-weighted axial image shows lobulated low T2 signal lesion with specks of central high signal corresponding to central caseation. Surrounding high T2-signal edema is appreciated. (Contributed by Dr. Gurang Shah.)
Intracranial tuberculoma: Caseating granuloma (4)

T1-weighted axial imaging following intravenous Gadolinium contrast shows lobulated ring-enhancing lesions with central non-enhancing areas corresponding to Caseating necrosis. (Contributed by Dr. Gurang Shah.)

Solitary tuberculoma accounts for 80% of the cases of cerebral tuberculoma (44). These lesions are frequently misdiagnosed as neoplasms (11). At the pregranulomatous stage, its image is easily confused with a low-grade astrocytoma. Later, at the granulomatous stage, which exhibits uniform enhancement, lesions like sarcoid, mycotic granulomas, astrocytomas, and metastasis should be entertained. At the caseous stage, with its ring-enhancement appearance, pyogenic abscess, cystic astrocytoma, lymphoma, metastasis, toxoplasmosis, and cysticercosis should be considered. Tuberculous arachnoiditis or radiculomyelitis displays irregular diffuse thickening and enhancement of the meninges, relatively localized root thickening, and multiple nodules in the thecal sac and segmental enhancement of the spinal cord. In this situation, carcinomatous meningitis, lymphoma, and hypertrophic interstitial polyneuritis should be considered (94). In any event, the epidemiologic background of the patient and a detailed clinical history should be obtained to narrow down the differential diagnosis and increase the likelihood of correct diagnosis.

Diagnostic workup

	• CSF examination is key to diagnosing tuberculous meningitis.
	• CSF pressures are typically elevated.
	• CSF findings include a lymphocytic pleocytosis, an elevated protein, and low glucose.
	• CSF smears are positive in no more than 25% of instances, and neither culture nor PCR is 100% sensitive in detecting the organism.

Cerebrospinal fluid analysis is pivotal in diagnosing tuberculous meningitis. Opening pressure should be elevated, although not invariably so, with approximately half of both adult and pediatric patients having normal opening pressures in two studies (132; 103). The CSF may appear xanthochromic due to elevated protein concentrations and spinal block may result in Froin syndrome, clot formation of CSF after removal of any red blood cells due to the presence of high concentration of serum proteins, including fibrinogen. Reported median CSF white blood cell count ranges from 63 to 283 cells/mm3 (65; 191). On occasion, the CSF white cell count may be normal or exceed 4000 cells/mm3 (90; 132). In the early stages of infection, a significant number of polymorphonuclear cells may be observed, but over the course of several days to weeks, these are typically replaced by lymphocytes.

Changes in CSF parameters following the initiation of antituberculous therapy may be perplexing to the clinician. In a study of children with tuberculous meningitis in which weekly lumbar punctures were performed, only 37% had an uninterrupted decline in the CSF cell counts, and 21% had an upward course over 4 weeks (41). A paradoxical increase in polymorphonuclear cells or lymphocytes was observed in 20 of 61 patients following the initiation of antituberculous therapy (182). The persistent predominance of polymorphonuclear cells may result in mistaken diagnosis as may an increase in absolute numbers of CSF white blood cells (136; 121). In one study, 21.3% of patients with proven tuberculous meningitis had a CSF neutrophilic predominance (130). Rarely, large percentages of other cells, such as plasma cells and eosinophils, may be seen with tuberculous meningitis. However, their presence should suggest some other underlying process. An elevated CSF protein is the rule, with values usually in the 100 to 200 mg/dL range (87). Values may occasionally exceed 1 to 2 g/dL, which is suggestive of spinal block. In one large series of patients with AIDS and tuberculous meningitis, the CSF protein was reported to be normal in 43%, and, on occasion, the accompanying CSF white cell count may be normal or acellular, emphasizing the value of brain biopsy in establishing the diagnosis in some patients (17; 13; 98). Normal or acellular CSF appears to be more common in elderly patients (greater than 60 years of age), even in the absence of concomitant HIV infection (83). The CSF glucose is low, with values usually less than 50% of serum glucose and median values between 18 and 45 mg/dL (10; 36). In culture-proven cases, the CSF glucose tends to be lower than in presumptive tuberculous meningitis (191; 132). As with CSF cell counts, CSF protein and glucose values may also fluctuate in the first month following therapy (41). Failure of CSF polymorphonuclear cells to decline and glucose to increase following therapy should be considered atypical (138).

The hallmark of diagnosis of tuberculous meningitis is the demonstration of M tuberculosis in the CSF. Typically, no more than 25% of cases have identifiable M tuberculosis when acid-fast stains are performed on spun specimens of the CSF (181; 90). The percentages of positive smears improve with increased numbers of specimens; a positivity of 87% was obtained in a study examining four smears per patient (86). CSF cultures for M tuberculosis are not invariably positive either; positivity rates for clinically diagnosed cases range from 25% to 70% (03; 191). Additionally, mycobacterial cultures require several weeks before they are positive.

The limitations of these diagnostic tools have served as an impetus to the development of alternative diagnostic tests on the CSF that are based on the detection of the organism immunologically or by polymerase chain reaction detection of antibodies to M tuberculosis, together with the detection of substances in the CSF that are believed to be unique to M tuberculosis (30). Without a "gold standard" for diagnosing mycobacterial infection, the best diagnostic technique is polymerase chain reaction. With this technique, methods for extracting DNA and the amount of DNA in a sample size are crucial points for obtaining reliable sensitivity. In contrast to common viruses in which 10 to 100 or more copies may be present per cell, there may be only 10 to 100 bacilli per whole sample. The latter can be a particular problem in cerebrospinal samples in children, where small volumes of CSF may be submitted, and there may be few cells. On the other hand, proper selection of M tuberculosis-specific DNA and extreme care with respect to cross-contamination are crucial for obtaining good specificity results. It appears that MPB 64 protein-encoding gene is most specific for diagnosis of tuberculous meningitis (100). In some laboratories, the sensitivity of CSF polymerase chain reaction may not exceed 50% (93). The use of nested polymerase chain reaction can improve the sensitivity, enhancing it as much as 1000-fold (127; 107). With care for the above considerations, M tuberculosis was detected in cerebrospinal fluid with 90% sensitivity and 100% specificity in 21 patients with clinically suspected tuberculous meningitis (107). However, a review and meta-analysis of polymerase chain reaction for M tuberculosis found reported sensitivity rates of 56%, with a substantially higher specificity of 98% (135). Polymerase chain reaction is becoming increasingly available and may remain positive 4 or more weeks after the initiation of treatment (42). Naidu and Gogate report a specificity of 100% and a positivity of approximately 70% using a 1-step competitive enzyme-linked immunosorbent assay method with an antigen processed from an indigenously prepared soluble extract of M tuberculosis H37 Rv (124). Sensitivities of 98% and specificities of 100% have been seen with single-step PCR employing IS6110 PCR results that surpassed those of nested PCR (147). Results of clinical tests detecting M tuberculosis ribosomal RNA or DNA are available within 24 hours (61). However, some investigators have reported that commercial PCR assays for M tuberculosis are insensitive for the detection of the organism (202).

With respect to detection in the CSF of substances that are markers of M tuberculosis, measurement of the radiolabeled bromide partition ratio following the administration of oral or intravenous [84r] ammonium bromide was one of the earliest tests employed. It has been reported to have both a sensitivity and specificity on the order of 90% (113; 28). Tests of the CSF for the presence of tuberculostearic acid, a component of the mycobacteria cell wall, have been reported to have sensitivity and specificity in excess of 90%; those of CSF adenosine deaminase have been reported as 73% to 100% and 71% to 99%, respectively (113; 28; 51; 150). In a study of 157 patients, of whom 59 had confirmed tuberculous meningitis, adenosine deaminase levels of greater than 6 U/L were the best parameter to diagnose tuberculous meningitis (176), whereas others have suggested a level of 10 U/L (211). A cell-enzyme-linked immunosorbent assay method that determines antipurified protein derivative antibody production by cells derived from the CSF may have been proposed (08) but has gained little traction in the ensuing 2 decades. Antibodies directed to M tuberculosis can be detected immunologically with enzyme-linked immunosorbent assay with varying success (78; 205). Similarly, various immunological techniques have been employed to detect M tuberculosis antigen in the CSF, and high levels of sensitivity and specificity have been reported (77; 146). The combination of tests to detect mycobacterial immune complexes and M tuberculosis-specific DNA by polymerase chain reaction from the CSF had a sensitivity of 100% of culture-positive and 74% of culture-negative cases of tuberculous meningitis (119). Heat shock proteins (HSP), chiefly Hsp 25, Hsp 70, and Hsp 90, have been proposed as biomarkers in both pulmonary and extrapulmonary infection with M tuberculosis, including tuberculous meningitis (168). With the exception of the radiolabeled bromide partition ratio, the results of all these tests are available within hours, a distinct advantage over the long wait for mycobacterial cultures. CSF lactate has also been proposed as a biomarker for tuberculous meningitis, with a sensitivity of 69%, specificity of 90%, and negative predictive value of 98% (35). CSF adenosine deaminase (ADA) levels are typically elevated (greater than 5 U/L) in tuberculous meningitis, and very high levels of CSF adenosine deaminase are strongly suggestive of the diagnosis (171).

Studies to detect antibodies against M tuberculosis in the CSF have also been employed as diagnostic measures for detection of early disease. The sensitivity of antibody testing is 0.75 (95% confidence interval 0.66-0.82) and the specificity is 0.98 (95% confidence interval 0.96-0.99) (69). The antibodies that appear to have the greatest sensitivity and specificity are anti-M37Ra, anti-antigen5, and anti-M37Rv (69).

Routine laboratory studies provide few clues to the diagnosis of tuberculous meningitis. Hyponatremia may indicate the presence of the syndrome of inappropriate antidiuretic hormone. In the presence of miliary dissemination, cultures of extraneural sites, such as the bone marrow and lung, may be positive. The chest x-ray in adult patients reveals abnormalities consistent with pulmonary tuberculosis (eg, apical scarring, hilar adenopathy, Ghon complex, or miliary disease) in 25% to 50% of patients but is more frequently revealing in children, where radiographic changes have been noted in 50% to 90% (106; 173; 181; 179; 27). More common in the era before effective antituberculous therapy, miliary disease is observed in 25% to 50% of adults and 15% to 25% of children with tuberculosis meningitis (212; 173; 60; 36; 179; 132). Positivity of skin testing for delayed hypersensitivity to tuberculosis with purified protein derivative has been reported in 40% to 65% of adults with tuberculosis meningitis and in 85% to 90% of children (178; 181; 72; 60; 27; 132). Therefore, both the chest x-ray and the purified protein derivative may be negative in the face of tuberculous meningitis, and a high index of suspicion for the diagnosis must be held for the prompt initiation of therapy. The presence of tuberculosis can be highly suspected based on newer serological studies that can rapidly detect tuberculosis antigens or using immunologic assays that measure the production of interferon-gamma by tuberculosis-specific T lymphocytes exposed to M. tuberculosis antigens (QuantiFERON and T-SPOT TB tests) (04). However, these tests are not diagnostic of tuberculous meningitis and may lack sensitivity.

Although the diagnosis of tuberculous meningitis is based primarily on the clinical presentation, CT or MRI of the head may reveal thickening and enhancement of the meninges (particularly the basilar meninges), hydrocephalus, infarction, edema often located periventricularly, and mass lesion due to associated tuberculoma or tuberculous abscess (20; 208; 165; 207).

Dural-based abscess (CT)

CT demonstrates a dural-based abscess with surrounding parenchymal edema. (Contributed by Dr. Sherman Stein.)

These findings are useful in aiding the initial diagnosis and assessing clinical deterioration during treatment course. Hydrocephalus appears to be the single most common abnormality seen by CT scan in tuberculous meningitis, which was reported in 52% to 80% of patients and detected in 100% of 30 children with CNS tuberculosis in one study (200; 131; 34). The degree of hydrocephalus correlates with the duration of the disease (15). Enhancement of the meninges is seen in approximately 60%, and infarctions, the third most common CT finding, are seen in 28% (131). Lesions of the meninges may be localized or diffuse (56). The focal lesions are typically en plaque, homogeneous, uniformly enhancing, and dural-based (56). Tuberculous pachymeningitis should also be considered in the differential diagnosis of "idiopathic" cranial hypertrophic pachymeningitis (137). In children, the presence of high density within the basal cisterns on noncontrast CT scans has been reported to be a specific sign for tuberculous meningitis (05). Basal ganglia infarction is the chief cause of permanent neurologic disability in children and, in one study from South Africa, was observed unilaterally in 21% and bilaterally in 10% of 198 children with tuberculous meningitis undergoing CT scan. It occurred in an additional 22% of children during treatment (159). Tuberculomas, typically presenting in younger patients and generally solitary (80%), may appear early as isodense or hypodense areas with uniform enhancement, and they later show a ringlike enhancement (44). Chronic tuberculomas calcify. Davis found tuberculomas in 16% of patients with culture positive for presumptive tuberculous meningitis (34). Treatment failure may be incorrectly interpreted at times due to the occasional paradoxical expansion of intracranial tuberculomas with chemotherapy (149). Radiographic imaging of the diffuse infiltration of the brain parenchyma by small granulomas (less than 5 mm) in the course of miliary tuberculosis may reveal multiple small, contrast-enhancing intraparenchymal lesions (54; 47). CNS tuberculosis should be considered in the differential diagnosis of densely enhancing choroid plexi with unilateral or bilateral lateral ventricle enlargement accompanying leptomeningitis (26). Isolated CNS tubercular ventriculitis has been reported (96). Angiography is characterized by a hydrocephalic pattern of the vessels, narrowing of the vessels at the base of the brain, and narrowed or occluded small and medium-sized vessels with few collaterals (102). Spinal arachnoiditis, which may complicate tuberculous meningitis, can be visualized with myelography by the irregularity of the thecal sac, nodularity and thickening of nerve roots, clumping of nerve roots, and presence of CSF block (94). MRI with gadolinium enhancement may show thickened enhancing meninges, tuberculous nodules, loculation and obliteration of the subarachnoid space, linear intradural enhancement, and intrinsic spinal cord abnormalities (94; 64).

Thickening meninges (CT)

CT demonstrates contrast enhancement of thickening meninges and multiple intraparenchymal enhancing lesions. (Contributed by Dr. Sherman Stein.)

FLAIR abnormalities along the cerebellar folia or hydrocephalus may be suggestive of tuberculous meningitis (71). Ruptured intracranial tuberculous aneurysms may be seen on rare occasions (112).

Neuroradiological findings can help distinguish tuberculous meningitis from other opportunistic infections or neoplastic processes in patients with AIDS presenting with neurologic manifestations. The presence of multiloculated abscesses, cisternal enhancement, basal ganglia infarction, and communicating hydrocephalus are observed with tuberculous meningitis but are not commonly encountered in toxoplasma encephalitis or CNS lymphoma (206). The application of MRS may enable the diagnosis of tuberculous granulomas by "fingerprinting" specific biochemical components of the mycobacteria (59). The presence of lipids detected in brain lesions by MRS may prove helpful in establishing the diagnosis of CNS tuberculosis (76). Thallium-201 single photon emission computed tomography can be helpful in distinguishing intracranial mass lesions complicating HIV infection due to tuberculosis or toxoplasmosis from those due to primary CNS lymphoma (108). Patients with intracranial infections, eg, tuberculosis, Cryptococcus, and bacterial abscess, typically have thallium-negative scans but positive gallium scans (101).

Management

	• The recommendations for the best regimen for managing tuberculous meningitis continue to evolve.
	• Combination therapy for months is required for cases with a low probability of drug resistance and longer courses for drug resistant strains.
	• The co-administration of corticosteroids has been controversial, though the consensus is that it should be routinely administered to patients without HIV infection.

Tuberculous meningitis should be considered a medical emergency. When the disease is strongly suspected, treatment should be started empirically even before confirmation by microbiological or molecular diagnostic techniques. In spite of the indisputable achievement in reducing morbidity and mortality from central nervous system infection by mycobacteria, the optimal treatment regimen remains undefined and largely empirical.

The antimicrobials used in the treatment of tuberculous meningitis historically have been divided into first- and second-line agents based on efficacy, including blood-brain barrier penetrance and toxicity (Table 1). Although three drug regimens have been employed successfully, the high morbidity and mortality of the disorder, coupled with the increasing frequency of multidrug-resistant organisms, may warrant more aggressive regimens. Aggressive intracranial spread of the infection has been observed during inadequate therapy of multidrug-resistant intracranial tuberculosis (91). There are currently at least 18 new drugs in clinical development for tuberculosis from the preclinical stage to phase II-III studies and beyond (31). The British Infection Society recommends that treatment of all forms of CNS tuberculosis should consist of four drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) for 2 months followed by two drugs (isoniazid and rifampicin) for at least 10 months (189).

Although isoniazid, pyrazinamide, and ethionamide penetrate readily into cerebrospinal fluid, rifampin, ethambutol, and streptomycin do so poorly, especially in noninflamed meninges (48). First-line drugs include isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin. Bactericidal against both intracellular and extracellular bacilli, peak levels of isoniazid following oral administration exceed levels needed to inhibit most strains of M tuberculosis in vitro (0.025 µL to 0.05 µg/mL) by 100-fold (111). Penetration through inflamed meninges is excellent, with CSF concentration 90% that of serum; however, in the absence of inflammation, the penetration is about 20% of serum levels. Levels of isoniazid in the CSF are lower in "fast acetylators" of the drug (40). Drug toxicity with isoniazid includes hepatotoxicity, peripheral neuropathy when pyridoxine is not co-administered, seizures, alterations in mental state, and potentiates phenytoin toxicity. Rifampin, a bactericidal against intracellular and extracellular bacilli, achieves high serum levels after oral administration. Cerebrospinal fluid levels are approximately 20% or less of serum levels in the presence of meningeal inflammation. The main adverse reactions include hypotoxicity, interstitial nephritis, hemolysis, eosinophilia, and induction of p450 liver enzymes. Pyrazinamide has a bacteriostatic effect on intracellular rather than extracellular organisms and penetrates the CSF well. Some have shown cerebrospinal concentrations of 100% of the serum concentration. Hepatotoxicity is its chief toxicity. Ethambutol achieves CSF concentrations of 10% to 50% of serum levels in the presence of meningeal inflammation. The chief toxicity of this tuberculostatic drug is retrobulbar neuritis, which develops in as many as 1% of persons on the currently recommended dose. Careful attention to visual acuity and color perception is required while the patient is on this drug. Streptomycin penetration into cerebrospinal fluid requires meningeal inflammation for levels to approximate one quarter of that of the serum. It appears to have a bacteriostatic effect in vivo. Streptomycin must be given parenterally, and renal failure and ototoxicity are its chief adverse effects. The second-line agents for treating tuberculous include para-aminosalicylic acid, ethionamide, cycloserine, amikacin, kanamycin, rifabutin, viomycin, and capreomycin.

A combination of isoniazid (15 to 20 mg/kg), rifampin (20 mg/kg), pyrazinamide (40 mg/kg), and ethionamide (20 mg/kg), all given throughout 6 months of treatment resulted in an overall mortality of 3.8% among 184 children, of whom 80% had British Medical Research Council classification of stage 2 or 3 tuberculous meningitis (196). A study in adults with tuberculous meningitis, nearly half of whom were HIV-infected, failed to reveal any significant improvement in survival when a standard 9-month antituberculosis regimen, which included rifampin at 10 mg/kg, was compared to an intensified regimen that included higher-dose rifampin (15 mg/kg) and levofloxacin (20 mg/kg) daily for the first 8 weeks of treatment (63).

Table 1. Chemotherapeutic Regimens for Tuberculous Meningitis

Low probability of drug resistance:
Drug		Usual daily dose	Maximum dose		Duration
Isoniazid Rifampin Pyrazinamide -or- Isoniazid Rifampin Ethambutol -or- Streptomycin Isoniazid Rifampin		5 to10 mg/kg 10 to 20 mg/kg 15 to 30 mg/kg 5 to 10 mg/kg 10 to 20 mg/kg 15 to 25 mg/kg 15 mg/kg 5 to 10 mg/kg 15 mg/kg* 10 to 20 mg/kg 10 to 20 mg/kg*	300 mg 600 mg 2500 mg 300 mg 600 mg 1000 mg 300 mg 900 mg 600 mg 600 mg		6 months 6 months 2 months 9 months 9 months 2 months 2 months 2 months 8 months 1 month 8 months
High probability of drug resistance:
(A)	Isoniazid Rifampin Pyrazinamide Ethambutol -or- Streptomycin			5 to 10 mg/kg 25 mg/kg 15 to 30 mg/kg 25 mg/kg 15 mg/kg		1 year 1 year 2 months 2 months 2 months
(B)	In cases of documented drug resistance, chemotherapy must be tailored to the demonstrated sensitivities.
* Twice weekly

Optimal regimens in treating CNS disease due to atypical mycobacteria, such as Mycobacterium avium-intracellulare, have not been precisely defined. A 4-drug regimen is needed to treat Mycobacterium avium-intracellulare (85). Recommendations include using azithromycin (500 to 1000 mg/day) and clarithromycin (500 to 1000 mg/day) in combination with ethambutol or clofazimine (100 mg/day). Alternative regimens include the use of ciprofloxacin and rifampicin. Further study will be required to determine the best regimen. Some investigators have reported a significant increase in the frequency of adverse reactions to antituberculous therapy in patients with AIDS, necessitating an alteration of therapy in as many as 18% (172). These adverse reactions are most frequent in the first month of therapy. Other investigators have failed to find a significantly different rate of adverse reactions to therapy in the HIV-infected population as compared to a non-HIV-infected population (13). The coexistence of a second infection should always be considered in AIDS patients not responding to antituberculous therapy despite proven disease (129).

Though corticosteroid therapy had been initially controversial, it is increasingly being adopted in the treatment of tuberculous meningitis, and the British Infection Society also recommends that adjunctive corticosteroids (either dexamethasone or prednisolone) should be given to all patients with tuberculous meningitis regardless of disease severity (189). Similarly, the Cochrane Database concluded that corticosteroids should be routinely used in HIV-negative people with tuberculous meningitis; however, there was insufficient evidence to support their routine use in the HIV-infected population (143). Consensus exists that steroids are likely beneficial in brain edema and spinal block (132). One of the major concerns against the widespread adoption of corticosteroid administration in tuberculous meningitis is the possibility that the consequent reduction in meningeal inflammation may decrease the CSF penetration of the antituberculous drugs. Nonetheless, this was not the case in one study measuring concentration of isoniazid, rifampin, pyrazinamide, and streptomycin in cerebrospinal fluid obtained weekly, 3 hours after oral administration, for over 6 weeks (81). In one large study of children, corticosteroids seemed to reduce the number of deaths during the acute phase of the illness but increased the risk of relapse and did not statistically affect overall mortality (203). A review by Horne eloquently supports their use in patients with British Medical Research Council stage III disease (66). In addition, a Chinese study supports this application, as only 30% of steroid-treated, stage III patients died in comparison to 61% of those not on steroids (166). Interestingly, survival in the stage II group was also better, 5% versus 12% (126). Similarly, a study from Egypt of 280 children with tuberculous meningitis showed that dexamethasone not only improved overall survival but also reduced the number of permanent sequelae (55). A South African study found that corticosteroids improved both survival rate and intellectual outcome in children with tuberculous meningitis but had no effect on intracranial pressure, hydrocephalus, or basal ganglia infarcts (160). Other potential indications for corticosteroids include (1) tuberculous encephalopathy in children; (2) raised intracranial pressure, particularly when associated with intractable headache; (3) signs of spinal arachnoiditis; and (4) evidence of cerebral vasculitis. Corticosteroids have also been used empirically in the treatment of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) (139).

Despite the above, many authorities reserve the use of corticosteroids for desperate situations. The clinical benefit of adjunctive corticosteroids does not appear to attenuate the immunological mediators in the subarachnoid space nor suppress peripheral T cell responses to mycobacterial antigens (170)--though dexamethasone has been demonstrated to reduce matrix metalloproteinases in the CSF, which correlated with a concomitant reduction in CSF neutrophils (57). The definite value of corticosteroids in tuberculous meningitis still requires further study. Similarly, thalidomide has been studied in a small, open-labeled clinical trial in children with tuberculous meningitis for its anti-inflammatory effects (158). However, its application must await further study (195).

Long-term careful follow-up of patients treated for tuberculous meningitis is essential as late complications are not infrequently observed. In one study, 14 of 22 patients developed symptomatic tuberculomas during the course of antituberculous therapy, and in five of them, it occurred after more than 6 weeks of therapy (194).

Surgical intervention is required in the management of obstructive hydrocephalus, although in the absence of obstruction hydrocephalus may be managed medically. When reducing elevated intracranial pressure in the latter instance, the use of furosemide and acetazolamide was significantly more effective than antituberculous drugs alone (155). Although a ventricular drain is helpful in the acute stages, ventriculoperitoneal and ventriculoatrial shunts are effective and should not be delayed until the infection is eradicated. Surgery may also be necessary in the face of tuberculomas or tuberculous abscesses developing in tandem with tuberculous meningitis. However, tuberculomas often resolve with adequate therapy, and unless there is impending cerebral herniation or compromise of the anterior visual pathways, the procedure may prove unnecessary. Similarly, when the response to antituberculous therapy is unsatisfactory in the setting of intramedullary spinal tuberculoma, surgery is warranted (105). Surgery is also mandated when the diagnosis of a CNS tuberculoma is in doubt. Some investigators recommend medical trials of antituberculous medication for a duration of at least 2 months before resorting to surgical exploration in suspected cases (07).

Paradoxical progression of CNS tuberculosis with the appearance of new lesions on radiographic imaging may occur immediately after the institution of appropriate treatment (153). Sometimes, following an initial period of 2 to 8 weeks of clinical stability or improvement after initiation of chemotherapy, it is not unusual to observe transient worsening in clinical and CSF parameters. This situation is thought to represent an uncommon hypersensitivity reaction to a massive release of tuberculoproteins, and corticosteroids are useful in this therapeutic paradox (132; 204). Similarly, 2 to 18 months after the initiation of adequate antituberculous therapy, enlarging intracranial tuberculomas may result in clinical deterioration. Teoh and Humphries found that the organisms isolated from these enlarging tuberculomas were sensitive to the antibiotic employed and suggested that their appearance was an immunological phenomenon (186). Surgery can usually be avoided with the administration of corticosteroids and continued antituberculous therapy. Resolution of the fever may require weeks. CSF glucose levels return to normal within 2 months in 50% of patients and within 6 months in almost all, whereas CSF pleocytosis requires more than 6 months to resolve in 25%, and the CSF protein remains elevated in 40% at this time (104; 10). Additionally, the continued alteration in level of consciousness in the early stages of the disease may be the result of concomitant hydrocephalus or hyponatremia.

In the setting of HIV infection, the initial clinical manifestations of tuberculous CNS disease or a paradoxical worsening established disease may attend the development of the immune reconstitution inflammatory syndrome (IRIS). In this disorder, immune recovery following the initiation of highly active antiretroviral therapy (HAART) results in an inflammatory reaction. These patients are typically severely immunosuppressed at the time of initiation of HAART; in one study, CD4 cell counts averaged 36 cells/cu mm (114) but have been associated with considerable short-term morbidity (139). The disorder frequently results in confusing clinical manifestations (18). Radiological manifestations of neurologic TB-IRIS were associated with a high prevalence of low-density lesions on non-contrast-enhanced CT scans as well as with multiple intraparenchymal lesions and perilesional edema (115).

Despite the prompt initiation of effective antituberculous therapy for CNS tuberculosis, survival is poor in some populations. A study of tuberculous meningitis in inner-city Atlanta revealed a mortality rate of 41.2% despite the initiation of appropriate therapy within 3 days of hospital admission (142). Although almost 50% of this population was HIV-infected, survival did not correlate with seropositive status, stage at presentation, or treatment regimen (142). This experience has not been universal. A large study from Vietnam reported that survival of tuberculous meningitis is substantially worse in the HIV-infected population (188). Whereas the clinical manifestations were not different between the HIV-infected and non-infected groups, mortality at 9 months was 64.6% in the former and 28.2% in the latter (188). The rate of sequelae among survivors varies in different series. In children, neurologic sequelae are seen in approximately 25% of survivors, although higher rates have been observed. In adults, the rates of these neurologic sequelae approximate those in children. The sequelae include cognitive disturbances, seizures, hemiparesis, ataxia, visual impairment accompanying optic atrophy, and other persistent cranial nerve palsies (123; 174; 43; 132). A study of children who have recovered from tuberculous meningitis reveals that they often suffer a marked generalized impairment of cognitive and motor development that does not appear to be remedial to early intervention (156).

Outcomes

Paradoxical worsening, defined as clinical deterioration or the development of any new neurologic signs and symptoms with either worsening of preexisting CNS lesions or the appearance of new lesions on imaging studies 4 or more weeks after the initiation of therapy, has been described in 7.3% to 56% of HIV-negative patients with tuberculous meningitis and is associated with a higher mortality (39).

Six months after successful treatment of tuberculous meningitis, a decline in global cognitive performance has been demonstrated in patients with concomitant HIV infection. However, this decline did not impact functional abilities (33).

Media

References

01: Alarcon F, Duenas G, Ceballos N, Lees AJ. Movement disorders in 30 patients with tuberculous meningitis. Mov Disord 2000;15:561-9. PMID 10830424
02: Allison MJ, Dalton HP. Etiology of meningitis at the Medical College of Virginia. Va Med Mon 1967;94:317-9. PMID 6040280
03: Alvarez S, McCabe WR. Extrapulmonary tuberculosis revisited: a review of experience at Boston City and other hospitals [review]. Medicine 1984;63:25-55. PMID 6419006
04: Al-Zamel FA. Detection and diagnosis of Mycobacterium tuberculosis. Expert Rev Anti Infect Ther 2009;7:1099-108. PMID 19883330
05: Andronikou S, Smith B, Hatherhill M, Douis H, Wilmshurst J. Definitive neuroradiological diagnostic features of tuberculous meningitis in children. Pediatr Radiol 2004;34:876-85. PMID 15378213
06: Arvanitakis Z, Long RL, Hershfield ES, et al. M. tuberculosis molecular variation in CNS infection: evidence for strain-dependent neurovirulence. Neurology 1998;50:1827-32. PMID 9633735
07: Awada A, Daif AK, Pirani M, Khan MY, Memish Z, Al Rajeh S. Evolution of brain tuberculomas under standard antituberculous treatment. J Neurol Sci 1998;156:47-52. PMID 9559986
08: Baig SM. Anti-purified protein derivative cell-enzyme-linked immunosorbent assay, a sensitive method for early diagnosis of tuberculous meningitis. J Clin Microbiol 1995;33:3040-1. PMID 8576371
09: Barnes PF, Bloch AB, Davidson PT, Snider DE. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991;324:1644-50. PMID 2030721
10: Barrett-Connor E. Tuberculous meningitis in adults. South Med J 1967;60:1061-7. PMID 6061905
11: Bayindir C, Mete O, Bilgic C. Retrospective study of 23 pathologically proven cases of central nervous system tuberculomas. Clin Neurol Neurosurg 2006;108:353-7. PMID 16644403
12: Benenson AN. Tuberculosis. In: Benenson AN, editor. Control of communicable diseases in man. Springfield: Byrd PrePress, 1985.
13: Berenguer J, Moreno S, Laguna F, et al. Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 1992;326:668-72. PMID 1346547
14: Berger JR, Moskowitz L, Fischl M, Kelley RE. Neurologic disease as the presenting manifestation of acquired immunodeficiency syndrome. South Med J 1987;80:683-6. PMID 3473692
15: Bhargava S, Gupta AK, Tandon PN. Tuberculous meningitis--a CT study. Br J Radiol 1982;55:189-96. PMID 7066619
16: Bhigjee AI, Naidoo K, Patel VB, Govender D. Intracranial mass lesions in HIV-positive patients - the KwaZulu experience. S Afr J Med 1999;89:1284-18. PMID 3729203
17: Bishburg E, Sunderam G, Reichman LB, Kapila R. Central nervous system tuberculosis with the acquired immunodeficiency syndrome and its related complex. Ann Intern Med 1986;105:210-3. PMID 3729203
18: Blaivas AJ, Lardizabal A, Macdonald R. Two unusual sequelae of tuberculous meningitis despite treatment. South Med J 2005;98(10):1028-30. PMID 16295818
19: Brooks WD, Fletcher AP, Wilson RR. Spinal cord complications of tuberculous meningitis. Q J Med 1954;23:275-90. PMID 13194846
20: Bullock MR, Welchman JM. Diagnostic and prognostic features of tuberculous meningitis on CT scanning. J Neurol Neurosurg Psychiatry 1982;45:1098-101. PMID 6984460
21: Byrd TF, Davis LF. Multidrug-resistant tuberculous meningitis. Curr Neurol Neurosci Rep 2007;7:470-5. PMID 17999892
22: Campo M, Randhawa AK, Dunstan S, et al. Common polymorphisms in the CD43 gene region are associated with tuberculosis disease and mortality. Am J Respir Cell Mol Biol 2015;52(3):342-8. PMID 25078322
23: Cantwell M, Snider DE, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994;272:535-9. PMID 8046808
24: Caws M, Thwaites GE, Duy PM, et al. Molecular analysis of Mycobacterium tuberculosis causing multidrug-resistant tuberculosis meningitis. Int J Tuberc Lung Dis 2007;11:202-8. PMID 17263292
25: Cecchini D, Ambrosioni J, Brezzo C, et al. Tuberculous meningitis in HIV-infected and non-infected patients: comparison of cerebrospinal fluid findings. Int J Tuberc Lung Dis 2009;13:269-71. PMID 19146759
26: Cho IC, Chang KH, Kim YH, Kim SH, Han MH. MRI features of choroid plexitis. Neuroradiology 1998;40:303-7. PMID 9638671
27: Clark WC, Metcalf JC Jr, Muhlbauer MS, Dohan FC Jr, Robertson JH. Mycobacterium tuberculosis meningitis: a report of twelve cases and a literature review. Neurosurgery 1986;18:604-10. PMID 3086768
28: Coovadia YM, Dawood A, Ellis ME, Coovadia HM, Daniel TM. Evaluation of adenosine deaminase activity and antibody to Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid and the radioactive bromide partition test for the early diagnosis of tuberculosis meningitis. Arch Dis Child 1986;61:428-35. PMID 3087296
29: Daif A, Obeid T, Yaqub B, AbdulJabbar M. Unusual presentation of tuberculous meningitis. Clin Neurol Neurosurg 1992;94:1-5. PMID 1321691
30: Daniel TM. New approaches to the rapid diagnosis of tuberculosis meningitis. J Infect Dis 1987;599-602. PMID 3102626
31: Dartois VA, Rubin EJ. Anti-tuberculosis treatment strategies and drug development: challenges and priorities. Nature Rev Microbiol 2022;20:685-702. PMID 35478222
32: Dastur DK, Udani PM. The pathology and pathogenesis of tuberculous encephalopathy. Acta Neuropathol 1966;6:311-26. PMID 5297864
33: Davis AG, Dreyer AJ, Albertyn C, et al. Cognitive impairment in tuberculous meningitis. Clin Infect Dis 2022;ciac831. PMID 36262054
34: Davis LE, Rastogi KR, Lambert LC, Skipper BJ. Tuberculous meningitis in the southwest United States: a community-based study. Neurology 1993;43:1775-8. PMID 8414030
35: de Almeida SM, Kussen GB, Cogo LL, Nogueira K. Cerebrospinal fluid lactate as a predictive biomarker for tuberculous meningitis diagnosis. Diagnosis 2022. [Epub ahead of print] PMID 36476307
36: Delage G, Dusseault M. Tuberculous meningitis in children: a retrospective study of 79 patients, with an analysis of prognostic factors. Can Med Assoc J 1979;120:305-9. PMID 427668
37: de March-Ayuela P. Trend in tuberculous meningitis in Barcelona in children aged 0-4 years: correlation with the annual risk of tuberculous infection. Tuber Lung Dis 1994;75:423-8. PMID 7718830
38: Doll DC, Yarbro JW, Phillips K, Klott C. Mycobacteria spinal cord abscess with an ascending polyneuropathy [letter]. Ann Intern Med 1987;106:333-4. PMID 3800203
39: Dominguez-Moreno R, Garcia-Grimshaw M, Medina-Julio, D, et al. Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review. Neurol Sci 2022;43(4):2699-708. PMID 34705128
40: Donald PR, Gent WL, Seifart HI, Lamprecht JH, Parkin DP. Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status. Pediatrics 1992;89:247-50. PMID 1734391
41: Donald PR, Schoeman JF, Cotton MF, van Zyl LE. Cerebrospinal fluid investigations in tuberculous meningitis. Ann Trop Paediatr 1991;11(3):241-6. PMID 1719923
42: Donald PR, Victor TC, Jordaan AM, Schoeman JF, van Helden PD. Polymerase chain reaction in the diagnosis of tuberculous meningitis. Scand J Infect Dis 1993;25:613-7. PMID 8284646
43: Donner M, Wasz-Hockert O. Late neurologic sequelae of tuberculous meningitis. Acta Pediatr 1962;51(Suppl 141):34-422.
44: Draouat S, Abdenabi B, Ghanem M, Bourjat P. Computed tomography of cerebral tuberculoma. J Comput Assist Tomogr 1987;11:594-7. PMID 3597881
45: Dube MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992;93:520-4. PMID 1442854
46: Dunn RN, Ben Husien M. Spinal tuberculosis. Bone Joint J 2018;100-B(4):425-31. PMID 29629596
47: Eide FF, Gean AD, So YT. Clinical and radiographic findings in disseminated tuberculosis of the brain. J Neurol 1993;43:1427-9. PMID 8018121
48: Ellard GA, Humphries MJ, Allen BW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Am Rev Resp Dis 1993;148:650-5. PMID 8368635
49: Fiorot Junior JA, Felicio AC, Fukujima MM, et al. Tuberculosis: an uncommon cause of cerebral venous thrombosis. Arq Neuropsiquiatr 2005;63:852-4. PMID 16258669
50: Francisco NM, Hus NJ, Keeton R, et al. TNF-dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. J Neuroinflammation 2015;12:125. PMID 26112704
51: French GL, Teoh R, Chan CY, Humphries MJ, Cheung SW, O'Mahony G. Diagnosis of tuberculous meningitis by detection of tuberculostearic acid in cerebrospinal fluid. Lancet 1987;2:117-9. PMID 2885596
52: Garcia-Monco JC. Central nervous system tuberculosis. Neurol Clin 1999;17:737-59. PMID 10517926
53: Gautam MP, Karki P, Rijal S, Singh R. Pott’s spine and paraplegia. J Nepal Med Assoc 2005;44(159):106-15. PMID 16570378
54: Gee GT, Bazan C 3d, Jinkins JR. Miliary tuberculosis involving the brain: MR findings. AJR Am J Roentgenol 1992;159:1075-6. PMID 1414778
55: Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991;10:179-83. PMID 2041662
56: Goyal M, Sharma MC, Gaikwad SB, Mishra NK, Sharma A. Imaging appearance of pachymeningeal tuberculosis. AJR Am J Roentgenol 1997;169:1421-4. PMID 9353472
57: Green JA, Tran CT, Farrar JJ, et al. Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis. PLoS One 2009;4(9):e7277. PMID 19789647
58: Guler N, Ones U, Somer A, Salman N, Yalcin I. The effect of prior BCG vaccination on the clinical and radiographic presentation of tuberculosis meningitis in children in Istanbul, Turkey. Int J Tuberc Lung Dis 1998;2:885-90. PMID 9848608
59: Gupta RK, Roy R, Dev R, et al. Finger printing of Mycobacterium tuberculosis in patients with intracranial tuberculomas by using in vivo, ex vivo, and in vitro magnetic resonance spectroscopy. Magn Reson Med 1996;36:829-33. PMID 8946348
60: Haas EJ, Madhavan T, Quinn EL, Cox F, Fisher E, Burch K. Tuberculous meningitis in an urban general hospital. Arch Intern Med 1977;137:1518-21. PMID 921437
61: Havlir DV, Barnes PF. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1999;340:367-73. PMID 9929528
62: Heary RF, Hunt CD, Krieger AJ, Vaid C. HIV status does not affect microbiologic spectrum or neurologic outcome in spinal infections. Surg Neurol 1994;42:417-23. PMID 7974148
63: Heemskerk AD, Bang ND, Mai NT, et al. Intensified antituberculosis therapy in adults with tuberculous meningitis. N Engl J Med 2016;374(2):124-34. PMID 26760084
64: Hernandez-Albujar S, Arribas JR, Royo A, Gonzalez-Garcia JJ, Pena JM, Vazquez JJ. Tuberculous radiculomyelitis complicating tuberculous meningitis: case report and review. Clin Infect Dis 2000;30:915-21. PMID 10854362
65: Hinman AR. Tuberculous meningitis at Cleveland Metropolitan General Hospital 1959 to 1963. Am Rev Resp Dis 1967;95:670-3. PMID 6021129
66: Horne NW. A critical evaluation of corticosteroids in tuberculosis. Adv Tuberc Res 1966;15:1-54. PMID 5326273
67: Hosoglu S, Ayaz C, Geyik MF, Kokoglu OF, Ceviz A. Tuberculous meningitis in adults: an eleven-year review. Int J Tuberc Lung Dis 1998;2:553-7. PMID 9661821
68: Hsieh FY, Chia LG, Shen WC. Locations of cerebral infarctions in tuberculous meningitis. Neuroradiology 1992;34:197-9. PMID 1630608
69: Huang TY, Zhang XX, Wu QL, et al. Antibody detection tests for early diagnosis in tuberculous meningitis. Int J Infect Dis 2016;48:64-9. PMID 27173078
70: Humphries MJ, Teoh R, Lau J, Gabriel M. Factors of prognostic significance in Chinese children with tuberculous meningitis. Tubercle 1990;71:161-8. PMID 2238120
71: Hwang JH, Lee KM, Park JE, et al. Atypical cerebral manifestations of disseminated Mycobacterium tuberculosis. Front Neurol 2017;8:462. PMID 29033887
72: Idriss ZH, Sinno AA, Kronfol NM. Tuberculous meningitis in childhood. Am J Dis Child 1976;130:364-7. PMID 1266821
73: Jacob CN, Henein SS, Heurich AE, Kamholz S. Nontuberculous mycobacterial infection of the central nervous system in patients with AIDS. South Med J 1993;86:638-40. PMID 8506483
74: Jacques C, Boukobza M, Polivka M, Ferrario A, George B, Merland JJ. Cranial epidural tuberculoma. A case report. Acta Radiol 2000;41:367-70. PMID 10937760
75: Jakka S, Veena S, Rao AR, Eisenhut M. Cerebrospinal fluid adenosine deaminase levels and adverse neurological outcome in pediatric tuberculous meningitis. Infection 2005;33:264-6. PMID 16091897
76: Jayasundar R, Singh VP, Raghunathan P, Jain K, Banerji AK. Inflammatory granulomas: evaluation with proton MRS. NMR Biomed 1999;12:139-44. PMID 10414948
77: Kadival GV, Samuel AM, Mazarelo TB, Chaparas SD. Radioimmunoassay for detecting Mycobacterium tuberculosis antigen in cerebrospinal fluids of patients with tuberculous meningitis. J Infect Dis 1987;155:608-11. PMID 3102628
78: Kalish SB, Radin RC, Levitz D, Zeiss CR, Phair JP. The enzyme-linked immunosorbent assay method for IgG antibody to purified protein derivative in cerebrospinal fluid of patients with tuberculous meningitis. Ann Intern Med 1983;99:630-3. PMID 6638721
79: Kalita J, Misra UK. Outcome of tuberculous meningitis at 6 and 12 months: a multiple regression analysis. Int J Tuberc Lung Dis 1999;3:261-5. PMID 10094329
80: Kalita J, Singh RK, Misra UK, Kumar S. Evaluation of cerebral arterial and venous system in tuberculous meningitis. J Neuroradiol 2018;45(2):130-5. PMID 28970078
81: Kaojarern S, Supmonchai K, Phuapradit P, Mokkhavesa C, Krittiyanunt S. Effect of steroids on cerebrospinal fluid penetration of antituberculous drugs in tuberculous meningitis. Clin Pharmacol Ther 1991;49:6-12. PMID 1988241
82: Karande S, Gupta V, Kulkarni M, Joshi A. Prognostic clinical variables in childhood tuberculous meningitis: an experience from Mumbai, India. Neurol India 2005;53(3):375-6. PMID 16010058
83: Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH. Tuberculous meningitis in South African urban adults. QJM 1998;91:743-7. PMID 10024937
84: Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD. The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 2000;181:118-26. PMID 11099721
85: Kemper CA, Tze-Chiang M, Nussbaum J, et al. Treatment of Mycobacterium avium complex bacteremia in AIDS with a four-drug regimen: rifampin, ethambutol, clofazimine, and ciprofloxacin. Ann Intern Med 1992;116:466-72. PMID 1739237
86: Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979;241:264-8. PMID 102806
87: Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. Tuberculous meningitis: a 30-year review. Clin Infect Dis 1993;17:987-94. PMID 8110957
88: Khan MI, Garg RK, Rizvi I, et al. Tuberculous myelitis: a prospective follow-up study. Neurol Sci 2022;43(9):5614-24. PMID 35739331
89: Kim HJ, Shim K-W, Lee M-K, et al. Tuberculous encephalopathy without meningitis: pathology and brain MRI findings. Eur Neurol 2011;65(3):156-9. PMID 21372574
90: Klein NC, Damsker B, Hirschman SZ. Mycobacterial meningitis: retrospective analysis from 1970-1983. Am J Med 1985;79:29-34. PMID 4014303
91: Kohli A, Khan NI, Choudhury OP, Lodhari JR. Tryst and treatment of an unusual case of MDR CNS tuberculosis. BMJ Case Rep 2011;2011. PMID 22679323
92: Kotil K, Alan MS, Bilge T. Medical management of Pott disease in the thoracic and lumbar spine: a prospective clinical study. J Neurosurg Spine 2007;6(3):222-8. PMID 17355021
93: Kox LF, Kuijper S, Kolk AH. Early diagnosis of tuberculous meningitis by polymerase chain reaction. Neurology 1995;45:2228-32. PMID 8848198
94: Kumar A, Montanera W, Willinsky R, TerBrugge KG, Aggarwal S. MR features of tuberculous arachnoiditis. J Comput Assist Tomogr 1993;17:127-30. PMID 8419420
95: Kumar MR, Saini L, Kaushik JS, Chakrabarty B, Kumar A, Gulati S. A combination of moyamoya pattern and cerebral venous sinus thrombosis: a case of tubercular vasculopathy. J Trop Pediatr 2015;61(5):393-6. PMID 26136258
96: Kumar S, Kumar R, Radotra BD, Singh M. Tubercular ventriculitis: an uncommon entity. Indian J Pediatr 2014;81(6):608-10. PMID 23625471
97: Kure K, Llena JF, Lyman WD, et al. Human immunodeficiency virus-1 infection of the nervous system: an autopsy study of 268 adults, pediatric and fetal brains. Hum Pathol 1991;22:700-10. PMID 2071114
98: Laguna F, Adrados M, Ortega A, Gonzalez-Lahoz JM. Tuberculous meningitis with acellular cerebrospinal fluid in AIDS patients. AIDS 1992;6:1165-7. PMID 1466848
99: Lanjewar DN, Shetty CR, Jain PP. Profile of central nervous system pathology in patients with AIDS: an autopsy study from India. AIDS 1998;12:309-13. PMID 9517994
100: Lee BW, Tan JA, Wong SC, et al. DNA amplification by the polymerase chain reaction for the rapid diagnosis of tuberculous meningitis. Comparison of protocols involving three mycobacterial DNA sequences, IS6110, 65 kDa antigen, and MPB64. J Neurol Sci 1994;123:173-9. PMID 8064310
101: Lee VW, Antonacci B, Tilak S, Fuller JD, Cooley TP. Intracranial mass lesions: sequential thallium and gallium scintigraphy in patients with AIDS. Radiology 1999;211:507-12. PMID 10228535
102: Lehrer H. The angiographic triad in tuberculous meningitis. A radiographic and clinicopathologic correlation. Radiology 1966;87:829-35. PMID 5924895
103: Leiguarda R, Berthier M, Starkstein S, Nogues M, Lylyk P. Ischemic infarction in 25 children with tuberculous meningitis. Stroke 1988;19:200-4. PMID 3344536
104: Lepper MH, Spies HW. The present status of the treatment of tuberculosis of the central nervous system. Ann N Y Acad Sci 1963;106:106-23. PMID 13929802
105: Li H, You C, Yang Y, et al. Intramedullary spinal tuberculoma: report of three cases. Surg Neurol 2006;65:185-8. PMID 16427421
106: Lincoln EM, Sordillo SV, Davies PA. Tuberculous meningitis in children. A review of 167 untreated and 74 treated patients with special reference to early diagnosis. J Pediatr 1960;57:807-23. PMID 13762229
107: Liu PY, Shi ZY, Lau YJ, Hu BS. Rapid diagnosis of tuberculous meningitis by a simplified nested amplification protocol. Neurology 1994;44:1161-4. PMID 8208416
108: Loyerboym M, Wallach F, Estok L, et al. Thallium-201 retention in focal intracranial lesions for differential diagnosis of primary lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med 1998;39:1366-9. PMID 9708509
109: Lynch K, Farrell M. Cerebral tuberculoma in a patient receiving anti-TNF alpha (adalimumab) treatment. Clin Rheumatol 2010;29:1201-4. PMID 20419463
110: MacGregor RR. Tuberculosis: from history to current management. Semin Roentgenol 1993;28:101-8. PMID 8516686
111: Mandell GL, Sande MA. Drugs used in the chemotherapy of tuberculosis and leprosy. In: Gilman AG, Goodman L, Rall TW, Murad F, editors. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:1199-218.
112: Mani SSR, Mathansingh AJ, Kaur H, Iyyadurai R. Ruptured intracranial tuberculous aneurysm, a rare complication of central nervous system tuberculosis – a report and review of the literature. Neurol India 2017;65(3):626-8. PMID 28488632
113: Mann MD, Macfarlane CM, Verburg CJ, Wiggelinkhuizen J. The bromide partition test and CSF adenosine deaminase activity in the diagnosis of tuberculosis meningitis in children. S Afr Med J 1982;62:431-3. PMID 7112320
114: Manosuthi W, Kiertiburanakul S, Phoorisiri T, Sungkanuparph S. Immune reconstitution inflammatory syndrome of tuberculosis among HIV-infected patients receiving antituberculous and antiretroviral therapy. J Infect 2006;53(6):357-63. PMID 16487593
115: Marais S, Scholtz P, Pepper DJ, Meintjes G, Wilkinson RJ, Candy S. Neuroradiological features of the tuberculosis-associated immune reconstitution inflammatory syndrome. Int J Tuberc Lung Dis 2010;14:188-96. PMID 20074410
116: Mastroianni CM, Delia S, Vullo V, D'Agostino C, Lichtner M, Paoletti F. Cerebrospinal fluid cytokines in patients with tuberculous meningitis. Clin Immunol Immunopathol 1997;84:171-6. PMID 9245549
117: Medical Research Council. Streptomycin treatment of tuberculous meningitis. Report of the committee on streptomycin in tuberculosis trials. Lancet 1948;1:582-97.
118: Merkler AE, Reynolds AS, Gialdini G, et al. Neurological complications after tuberculous meningitis in a multi-state cohort in the United States. J Neurol Sci 2017;375:460-3. PMID 28320186
119: Miorner H, Sjobring U, Nayak P, Chandramuki A. Diagnosis of tuberculous meningitis: a comparative analysis of 3 immunoassays, an immune complex assay and the polymerase chain reaction. Tuber Lung Dis 1995;76:381-6. PMID 7495997
120: Misra UK, Kalita J, Roy AK, Mandal SK, Srivastava M. Role of clinical, radiological, and neurophysiological changes in predicting the outcome of tuberculous meningitis: a multivariable analysis. J Neurol Neurosurg Psychiatry 2000;68:300-3. PMID 10675210
121: Mizutani T, Kurosawa N, Matsuno Y, Miyagawa M, Matsuya S, Aiba T. Atypical manifestations of tuberculous meningitis. Eur Neurol 1993;33:159-62. PMID 8467825
122: Moghtaderi A, Alavi Naini R. Tuberculous radiculomyelitis: review and presentation of five patients. Int J Tuberc Lung Dis 2003;7(12):1186-90. PMID 14677894
123: Mooney AJ. Some ocular sequelae of tuberculous meningitis. Am J Ophthalmol 1956;41:753-68. PMID 13313667
124: Naidu AK, Gogate A. Early detection of tuberculous meningitis using one step competitive ELISA. Indian J Pathol Microbiol 1997;40:531-8. PMID 9444867
125: Namer IJ, Steibel J. Antibody directed against mannan of the Mycobacterium tuberculosis cell envelope provokes blood-brain barrier breakdown. J Neuroimmunol 2000;103:63-8. PMID 10674990
126: Nand N, Sharma M, Saini DS. Evaluation of lactic dehydrogenase in cases of meningitis. Indian J Med Sci 1993;47:96-100. PMID 8354546
127: Narita M, Matsuzono Y, Shibata M, Togashi T. Nested amplification protocol for the detection of Mycobacterium tuberculosis. Acta Pediatr 1992;81:997-1001. PMID 1290866
128: Newton RW. Tuberculous meningitis. Arch Dis Child 1994;70:364-6. PMID 8017954
129: Niyongabo T, Aubry P. Simultaneous association of tubercular meningitis and cryptococcal meningitis in an African with human immunodeficiency virus HIV positive serology. Med Trop 1992;52:179-81. PMID 1406216
130: Nunes C, Gomes I, Tavares A, Melo A. Clinical and laboratory characteristics of 62 tuberculous meningoencephalitis cases. Arq Neuropsiquiatr 1996;54:222-6. PMID 8984979
131: Offenbacher H, Fazekas F, Schmidt R, et al. MRI in tuberculous meningoencephalitis: report of four cases and review of the neuroimaging literature. J Neurol 1991;238:340-4. PMID 1940987
132: Ogawa SK, Smith MA, Brennessel DJ, Lowy FD. Tuberculous meningitis in an urban medical center. Medicine 1987;66:317-26. PMID 3600257
133: Padayatchi N, Bamber S, Dawood H, Bobat R. Multidrug-resistant tuberculous meningitis in children in Durban, South Africa. Pediatr Infect Dis J 2006;25(2):147-50. PMID 16462292
134: Pagnoux C, Genereau T, Lafitte F, Congy F, Chiras J, Herson S. Brain tuberculomas. Ann Med Interne (Paris) 2000;151:448-55. PMID 11104923
135: Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM Jr. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003;3(10):633-43. PMID 14522262
136: Pardiwalla FK, Yeolekar ME, Wagle S, Bakshi SK. Persistent neutrophilic meningitis. An unusual presentation of tuberculous meningitis. J Assoc Physicians India 1992;40:632-3. PMID 1308029
137: Parney IF, Allen PB, Johnson ES. "Idiopathic" cranial hypertrophic pachymeningitis responsive to antituberculous therapy. Neurosurgery 1997;41:965-71. PMID 9316063
138: Patel VB, Burger I, Connolly C. Temporal evolution of cerebrospinal fluid following initiation of treatment for tuberculous meningitis. S Afr Med J 2008:98(8):610-3. PMID 18928039
139: Pepper DJ, Marais S, Maartens G, et al. Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis 2009;48:e96-107. PMID 19405867
140: Perriens JH, St Louis ME, Mukadi YB, et al. Pulmonary tuberculosis in HIV-infected patients in Zaire: a controlled trial of treatment for either 6 or 12 months. N Engl J Med 1995;332:779-84. PMID 7862181
141: Podlecka A, Dziewulska D, Rafalowska J. Vascular changes in tuberculous meningoencephalitis. Folia Neuropathol 1998;36:235-7. PMID 10079607
142: Porkert MT, Blumberg HM, Parrott-Moore P, Sotir M. Tuberculous meningitis at a large inner-city medical center. Am J Med Sci 1997;313:325-31. PMID 9186145
143: Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;23(1);CD002244. PMID 18254003
144: Pulido F, Pena JM, Rubio R, et al. Relapse of tuberculosis after treatment in human immunodeficiency virus-infected patients. Arch Intern Med 1997;157:227-32. PMID 9009982
145: Pumarola-Sune T, Navia BA, Cardon-Cardo C, et al. HIV antigen in the brain of patients with AIDS dementia complex. Ann Neurol 1987;21:490-6. PMID 3296948
146: Radhakrishnan VV, Mathai A. Detection of mycobacterial antigen in cerebrospinal fluid: diagnostic and prognostic significance. J Neurol Sci 1990;99:93-9. PMID 2250177
147: Rafi W, Venkataswamy MM, Ravi V, Chandramuki A. Rapid diagnosis of tuberculous meningitis: a comparative evaluation of in-house PCR assays involving three mycobacterial DNA sequences, IS6110, MPB-64 and 65 kDa antigen. J Neurol Sci 2007;252:163-8. PMID 17182062
148: Ramdrug SR, Gupta DK, Suri A, et al. Spinal intramedullary tuberculosis: a series of 15 cases. Clin Neurol Neurosurg 2009;111:115-8. PMID 19058910
149: Reiser M, Diehl V, Fatkenheurer G. Paradoxical expansion of intracranial tuberculomas during chemotherapy. J Infect 1997;35:88-90. PMID 9279735
150: Ribera E, Martinez-Vazquez JM, Ocana I, Segura RM, Pascual C. Activity of adenosine deaminase in cerebrospinal fluid for the diagnosis and follow-up of tuberculous meningitis in adults. J Infect Dis 1987;155:603-7. PMID 3102627
151: Rich AR, McCordock HA. The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hospital 1933;52:5-37.
152: Riggs HE, Rupp C, Ray H. Clinicopathologic study of tuberculous meningitis in adults. Am Rev Tuberc 1956;74:830-4. PMID 13372970
153: Roa GP, Nadh BR, Hemaratnan A, Srinivas TV, Reddy PK. Paradoxical progression of tuberculous lesions during chemotherapy of central nervous system tuberculous. Report of 4 cases. J Neurosurg 1995;83:359-62. PMID 7616286
154: Sanchez-Portocarrero J, Perez-Cecilia E, Jimenez-Escrig A, et al. Tuberculous meningitis: clinical characteristics and comparison with cryptococcal meningitis in patients with human immunodeficiency virus infection. Arch Neurol 1996;53:671-6. PMID 8929175
155: Schoeman J, Donald P, van Zyl L, Keet M, Wait J. Tuberculous hydrocephalus: comparison of different treatments with regard to ICP, ventricular size and clinical outcome. Dev Med Child Neurol 1991;33:396-405. PMID 2065826
156: Schoeman CJ, Herbst I, Nienkemper DC. The effect of tuberculous meningitis on the cognitive and motor development of children. S Afr Med J 1997a;87:70-2. PMID 9063319
157: Schoeman JF, Rutherfoord GS, Hewlett RH. Acute stroke in a child with miliary tuberculosis. Clin Neuropathol 1997b;16:303-8. PMID 9401796
158: Schoeman JF, Springer P, Ravenscroft A, et al. Adjunctive thalidomide therapy of childhood tuberculous meningitis possible anti-inflammatory role. J Child Neurol 2000;15:497-503. PMID 10961786
159: Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Serial CT scanning in childhood tuberculous meningitis: prognostic features in 198 cases. J Child Neurol 1995;10:320-9. PMID 7594269
160: Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997c;99:226-31. PMID 9024451
161: Schurz H, Glanzmann B, Bowker N, et al. Deciphering genetic susceptibility to tuberculous meningitis. Front Neurol 2022;13:820168. PMID 35401413
162: Schwoebel V, Hubert B, Grosset J. Tuberculous meningitis in France in 1990: characteristics and impact of BCG vaccination. Tuber Lung Dis 1994;75:44-8. PMID 8161764
163: Selvaraj JU, Suhalini BB, Rohiston MS, Gorge AA, Arvind VH, Mishra AJ. Identification of predictors of cerebrovascular infarct sin patients with tuberculous meningitis. Int J Mycobacteriol 2020;9(3):303-8. PMID 32862165
164: Serrano Duenas M. Transitory cranial dyskinesias and tubercular meningitis: report of three cases. Neurologia 1997;12:421-5. PMID 9471180
165: Shanley DJ. Computed tomography and magnetic resonance imaging of tuberculous meningitis. J Am Osteopath Assoc 1993;93:497-501. PMID 8478223
166: Shao PP, Wang SM, Tung SG, et al. Clinical analysis of 445 adult cases of tuberculous meningitis. Chin J Tuberc Respir Dis 1980;3:131-2.
167: Sharma SK, Mohan A. Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control. Chest 2006;130:261-72. PMID 16840411
168: Shekhawat SD, Jain RK, Gaherwar HM, et al. Heat shock proteins: possible biomarkers in pulmonary and extrapulmonary tuberculosis. Hum Immunol 2014;75(2):151-8. PMID 24269695
169: Sheller JR, Des Prez RM. CNS tuberculosis. Neurol Clin 1986;4:143-58. PMID 3523199
170: Simmons CP, Thwaites GE, Quyen NT, et al. The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses. J Immunol 2005;175(1);579-90. PMID 15972695
171: Singh L, Javali M, Mehta A, Pradeep R, Srinivasa R, Acharya PT. Study of cerebrospinal fluid levels of lactate, lactate dehydrogenase and adenosine deaminase in the diagnosis and outcome of acute meningitis. Neurol Res 2022;44(5):463-7. PMID 34850673
172: Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, Hopewell PC. Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 1991;324:289-94. PMID 1898769
173: Smith AL. Tuberculous meningitis in childhood. Med J Aust 1975;1:57-60. PMID 1128368
174: Smith HV, Vollum RL. The treatment of tuberculous meningitis. Tubercle 1956;37:301-20. PMID 13371684
175: Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of the acquired immunodeficiency syndrome: analysis of 50 patients. Ann Neurol 1983;14:403-18. PMID 6314874
176: Solari L, Soto A, Agapito JC, et al. The validity of cerebrospinal fluid parameters for the diagnosis of tuberculous meningitis. Int J Infect Dis 2013;17(12):e1111-5. PMID 23973430
177: Spanos JP, Hus NJ, Jacobs M. Microglial are crucial regulators of neuro-immunity during central nervous system tuberculosis. Fron Cell Neurosci 2015;9:182. PMID 26041993
178: Steiner P, Portugaleza C. Tuberculous meningitis in children. A review of 25 cases observed between the years 1965 and 1970 at the Kings County Medical Center of Brooklyn with special reference to the problem of infection with primary drug-resistant strains of M tuberculosis. Am Rev Resp Dis 1973;107:22-9. PMID 4630312
179: Stockstill MT, Kauffman CA. Comparison of cryptococcal and tuberculous meningitis. Arch Neurol 1983;40:81-5. PMID 6824455
180: Stoeckli TC, Mackin GA, De Groote MA. Lumbosacral plexopathy in a patient with pulmonary tuberculosis. Clin Infect Dis 2000;30:226-7. PMID 10619771
181: Sumaya CV, Simek M, Smith MH, Seidemann MF, Ferriss GS, Rubin W. Tuberculous meningitis in children during the isoniazid era. J Pediatr 1975;87:43-9. PMID 807696
182: Sutlas PN, Unal A, Forta H, Senol S, Kirbas D. Tuberculous meningitis in adults: review of 61 cases. Infection 2003;31(6):387-91. PMID 14735380
183: Suzer T, Coskun E, Tahta K, Bayramoglu H, Duzcan E. Intramedullary spinal tuberculoma presenting as a conus tumor: a case report and review of the literature. Eur Spine J 1998;7:168-71. PMID 9629944
184: Tacconi L, Arulampalam T, Johnston FG, Thomas DG. Intramedullary spinal cord abscess: case report. Neurosurgery 1995;37:817-9. PMID 8559313
185: Tandon PN. Tuberculous meningitis (cranial and spinal). In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. Amsterdam: Elsevier, 1978.
186: Teoh R, Humphries M. Tuberculous meningitis. In: Lambert HP, editor. Infections of the central nervous system. Philadelphia: BC Dekker, 1991:189-206.
187: Thonell L, Pendel S, Sacks L. Clinical and radiological features of South African patients with tuberculomas of the brain. Clin Infect Dis 2000;31:619-20. PMID 10987736
188: Thwaites GE, Duc Bang N, Huy Dung N, et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis 2005;192(12):2134-41. PMID 16288379
189: Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T, Innes J. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect 2009;59:167-87. PMID 19643501
190: Topley JM, Bamber S, Coovadia HM, Corr PD. Tuberculous meningitis and co-infection with HIV. Ann Trop Paediatr 1998;18:261-6. PMID 9924579
191: Traub M, Colchester AC, Kingsley DP, Swash M. Tuberculosis of the central nervous system. Q J Med 1984;53:81-100. PMID 6709824
192: Uchino H, Terasaka S, Yamaguchi S, et al. Multiple infectious intracranial lesions of Mycobacterium genavense in an immunocompromised patient. Brain Nerve 2011;63:79-83. PMID 21228452
193: Udani PM, Parekh UC, Dastur DK. Neurological and related syndromes in CNS tuberculosis. Clinical features and pathogenesis. J Neurol Sci 1971;14:341-57. PMID 5316340
194: Unal A, Sutlas PN. Clinical and radiological features of symptomatic central nervous system tuberculomas. Eur J Neurol 2005;12:797-804. PMID 16190918
195: van der Harst JJ, Luijckx GJ. Treatment of central nervous system tuberculosis infections and neurologic complications of tuberculosis treatment. Curr Pharm Des 2011;17:2940-7. PMID 21834764
196: van Toorn R, Schaaf HS, Laubscher JA, van Elsland SL, Donald PR, Schoeman JF. Short intensified treatment in children with drug-susceptible tuberculous meningitis. Pediatr Infect Dis J 2014;33(3):248-52. PMID 24168978
197: Verma R, Dhamija R. Disseminated Mycobacterium avium-intracellulare infection presenting as multiple ring-enhancing lesions on brain MRI. Mayo Clin Proc 2009;84:394. PMID 19411433
198: Villoria MF, de la Torre J, Fortea F, et al. Intracranial tuberculosis in AIDS: CT and MRI findings. Neuroradiology 1992;34:11-4. PMID 1553031
199: Vlcek B, Burchiel KJ, Gordon T. Tuberculous meningitis presenting as an obstructive myelopathy. Case report. J Neurosurg 1984;60:196-9. PMID 6689719
200: Waecker NJ Jr, Connor JD. Central nervous system tuberculosis in children: a review of 30 cases. Pediatr Infect Dis J 1990;9:539-43. PMID 2235168
201: Wallis RS. Biologics and infections: lessons from tumor necrosis factor blocking agents. Infect Dis Clin North Am 2011;25(4):895-910. PMID 22054762
202: Wang YY, Xie BD. Progress on the diagnosis of tuberculous meningitis. Methods Mol Biol 2018;1754:375-86. PMID 29536453
203: Wasz-Hockert O, Donner M. Late prognosis in tuberculous meningitis. Acta Pediatr 1963;141(Suppl):93-102.
204: Watson JD, Shnier RC, Seale JP. Central nervous system tuberculosis in Australia: a report of 22 cases. Med J Aust 1993;158:408-13. PMID 8479355
205: Watt G, Zaraspe G, Bautista S, Laughlin LW. Rapid diagnosis of tuberculous meningitis by using an enzyme-linked immunosorbent assay to detect mycobacterial antigen and antibody in cerebrospinal fluid. J Infect Dis 1988;158:681-6. PMID 3139775
206: Whiteman M, Espinoza L, Post MJ, Bell MD, Falcone S. Central nervous system tuberculosis in HIV-infected patients: clinical and radiological findings. AJNR Am J Neuroradiol 1995;16:1319-27.
207: Whiteman ML. Neuroimaging of central nervous system tuberculosis in HIV-infected patients. Neuroimaging Clin N Am 1997;7:199-214. PMID 9113686
208: Witrack BJ, Ellis GT. Intracranial tuberculosis: manifestations on computerized tomography. Southeast Asian J Trop Med Public Health 1985;78:386-92. PMID 3983659
209: World Health Organization. International Union Against Tuberculosis and Lung Disease. The WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance 1999-2002. Anti-tuberculosis drug resistance in the world; third global report. Geneva, Switzerland: World Health Organization, 2004.
210: Yaramis A, Gurkan F, Elevli M, et al. Central nervous tuberculosis in children: a review of 214 cases. Pediatrics 1998;102:E49. PMID 9794979
211: Ye Q, Yan W. Adenosine deaminase from the cerebrospinal fluid for the diagnosis of tuberculous meningitis: a meta-analysis. Trop Med Int Health 2023;28:175-85. PMID 36591905
212: Zarabi M, Sane S, Girdany BR. The chest roentgenogram in the early diagnosis of tuberculous meningitis in children. Am J Dis Child 1971;121:389-92. PMID 5091533
213: Zodpey SP, Maldhure BR, Shrikhande SN, Tiwari RR. Effectiveness of bacillus of Calmette-Guerin (BCG) vaccination against tuberculous meningitis: a case-control study. J Indian Med Assoc 1996;94:338-40. PMID 9019079

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

Author

Joseph R Berger MD

Dr. Berger of the Perelman School of Medicine, University of Pennsylvania, received consultant honorariums from Celegene/BMS, Cellevolve, EMD Serono/Merck, Genentech, Genzyme, Janssen/J&J, Morphic, Novartis, Roche, Sanofi, Takeda, and TG Therapeutics. He received honorariums from MAPI and ExcisionBio as a scientific advisory or data safety monitoring board member. And he received research support from Biogen and Genentech/Roche.
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John E Greenlee MD

Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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Mauricio Concha 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

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Tuberculosis of the CNS

Associated Disorders

AIDS
Congenital HIV-1 infection
Diabetes mellitus

Differential Diagnosis

fungal infections
neurosyphilis
bacterial infections
bacterial abscesses
brucellosis
- neoplastic meningitis
- sarcoidosis
- viral meningoencephalitis
- neurosarcoidosis
- cerebrovascular accidents
- astrocytomas
- mycotic granulomas
- metastasis
- pyogenic abscess
- lymphoma
- toxoplasmosis
- cysticercosis
- carcinomatous meningitis
- hypertrophic interstitial polyneuritis

Also Relevant

AIDS and HIV: neurologic manifestations and complications
Brain abscess
Brucellosis of the nervous system
Congenital HIV-1 infection
Intracranial epidural abscess
- Molecular diagnosis of CNS infections
- Movement disorders associated with infection
- Neurologic complications of vaccination
- Vaccines for neurologic disorders

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Tuberculosis of the CNS …

Tuberculosis of the CNS

Introduction

Overview

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Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Table 1. Chemotherapeutic Regimens for Tuberculous Meningitis

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Neuropathies associated with cytomegalovirus infection

Genital herpes: neurologic complications

Zika virus: neurologic complications

Gram-negative bacillary meningitis

Pneumococcal meningitis

HTLV-1 associated myelopathy

Infective endocarditis

Japanese encephalitis

Tuberculosis of the CNS

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Table 1. Chemotherapeutic Regimens for Tuberculous Meningitis

Outcomes

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

Neuropathies associated with cytomegalovirus infection

Genital herpes: neurologic complications

Zika virus: neurologic complications

Gram-negative bacillary meningitis

Pneumococcal meningitis

HTLV-1 associated myelopathy

Infective endocarditis

Japanese encephalitis

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