Epstein-Barr virus infections of the nervous system
Nov. 11, 2023
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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.
• 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.
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 (109). Despite these and other early characterizations, the unequivocal association between tuberculosis and meningitis occurred with the discovery of the tubercle bacillus by Koch 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 afterwards, 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 (109). 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.
• 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 a variety of 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 (86). 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 (86). 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 that is associated with diffuse white matter edema and extensive demyelination (88). Granulomas can be demonstrated in the brain, and the entity has been attributed to delayed hypersensitivity to tuberculoproteins (88).
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 (105; 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 have been observed in the vertebrobasilar distribution, exclusively, in rare cases (157). A moyamoya pattern of vascular involvement has been reported with tuberculous meningitis in a 1-year-old child (94). Stroke-like manifestations consequent to cerebral venous thrombosis have also been observed with tuberculous meningitis (48). 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 (87). 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 (63). Radiographic studies often show features of adhesive arachnoiditis (121). Intramedullary spinal cord abscesses and spinal infections with epidural abscess due to M tuberculosis may also result in myelopathy (61; 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 (52). 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 (51). 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 (45). 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 (91). 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 (51). 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% (45). Histopathological findings include caseating granuloma and giant cells, which are strongly supportive of the diagnosis. Histopathological examination has been reported to confirm the diagnosis in about 60% of patients (45).
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 (98). Most studies suggest that concomitant HIV infection does not appear to significantly alter the clinical manifestations or cerebrospinal fluid analysis (17; 13; 44). 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 (83). 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 on the basis of 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; 44). 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 (37).
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 (72). 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).
Outcome in tuberculous meningitis is strongly associated with the stage of disease at presentation (31; 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 (116). 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 (69; 86). 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 (119). The presence of abnormalities on head CT imaging may also be predictive of a poorer outcome (66), particularly evidence of brain infarction (78).
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 (66). 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 (81) as are high levels of CSF adenosine deaminase (74). Prior neonatal BCG vaccination appears to have little effect on the clinical findings and course of subsequent CNS tuberculosis (57). 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% (117). 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% (117).
In AIDS patients, a CD4 lymphocyte count of less 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 (60). 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).
• 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. During this process 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.
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 are dependent 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, and 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 (73).
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 (67). 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) and in some series, as many as 50% of patients are found to have cerebral infarction with tuberculous meningitis (79). 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 (115). 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-α blockers in the treatment of 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 (49). 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).
• 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 ranging in age from 4 months to 86 years (33). 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% (33). Additionally, intravenous drug use had been identified to be a risk factor for tuberculous meningitis prior to 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 cases of tuberculosis 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 (96). 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 occur frequently in AIDS and are often extrapulmonary in nature (145).
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 (108). 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 (36). 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 (212).
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.
Solitary tuberculoma accounts for 80% of the cases of cerebral tuberculoma (43). 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 (93). 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.
• 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; 102). 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 (64; 191). On occasion, the CSF white cell count may be normal or exceed 4000 cells/mm3 (89; 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 cells counts and 21% had an upward course over 4 weeks (40). 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; 120). 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 (86). 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; 97). Normal or acellular CSF appears to be more common in the elderly patient (greater than 60 years of age), even in the absence of concomitant HIV infection (82). The CSF glucose is low, with values usually less than 50% of serum glucose and median values between 18 and 45 mg/dL (10; 35). 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 (40). 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; 89). 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 (85). CSF cultures for M tuberculosis are not invariably positive either; rates of positivity 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). With lack of 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 (99). In some laboratories, the sensitivity of CSF polymerase chain reaction may not exceed 50% (92). The use of nested polymerase chain reaction can improve the sensitivity, enhancing it as much as 1000-fold (127; 106). 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 (106). 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 (41). 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 (60). 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% (112; 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 (112; 28; 50; 150). In a study of 157 patients of whom 59 had confirmed tuberculous meningitis, adenosine deaminase levels of greater than 6 U/L was the best parameter to diagnose tuberculous meningitis (176). 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 various success (77; 205). Similarly, a variety of immunological techniques have been employed to detect M tuberculosis antigen in the CSF, and high levels of sensitivity and specificity have been reported (76; 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 (118). 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% (34). 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) (68). The antibodies that appear to have the greatest sensitivity and specificity are anti-M37Ra, anti-antigen5, and anti-M37Rv (68).
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% (105; 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 (211; 173; 59; 35; 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; 71; 59; 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 on the basis of 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).
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; 33). 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 (55). The focal lesions are typically en plaque, homogeneous, uniformly enhancing, and dural-based (55). 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 early appear as isodense or hypodense areas with uniform enhancement, and they later show a ringlike enhancement (43). Chronic tuberculomas calcify. Davis found tuberculomas in 16% of patients with culture positive for presumptive tuberculous meningitis (33). 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 (53; 46). 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 (95). 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 (101). 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 (93). 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 (93; 63).
FLAIR abnormalities along the cerebellar folia or hydrocephalus may be suggestive of tuberculous meningitis (70). Ruptured intracranial tuberculous aneurysms may be seen on rare occasion (111).
Neuroradiological findings can be helpful in distinguishing 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 (58). The presence of lipids detected in brain lesions by MRS may prove helpful in establishing the diagnosis of CNS tuberculosis (75). 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 (107). Patients with intracranial infections, eg, tuberculosis, Cryptococcus, and bacterial abscess, typically have thallium negative scans but positive gallium scans (100).
• 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 the reduction of 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 (90). There are currently 10 new or repurposed tuberculosis drugs in clinical trials with the potential to shorten the treatment of drug-susceptible tuberculosis and improve the treatment of multidrug-resistant tuberculosis (123). 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 (47). 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 (110). 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 (39). 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 its 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 the treatment of tuberculous include para-aminosalicylic acid, ethionamide, cycloserine, amikacin, kanamycin, rifabutin, viomycin, and capreomycin.
A combination of isoniazid (15-20 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 (62).
Low probability of drug resistance:
Usual daily dose
5 to10 mg/kg
High probability of drug resistance:
5 to 10 mg/kg
In cases of documented drug resistance, chemotherapy must be tailored to the demonstrated sensitivities.
Optimal regimens in the treatment of 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 (84). Current 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 (80). 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 (65). 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 (54). 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 the tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) (139).
In spite of 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 (56). 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 (104). 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 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 the CSF pleocytosis requires more than 6 months to resolve in 25% and the CSF protein remains elevated in 40% at this time (103; 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 (113) but has 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 (114).
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 (122; 174; 42; 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).
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 (38).
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 have an impact on functional abilities (32).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Joseph R Berger MD
Dr. Berger of the Perelman School of Medicine, University of Pennsylvania, received grant support from Biogen and Genentech/Roche. He received honorariums from Celegene/BMS, Cellevolve, EMD Serono/Merck, Genentech, Genzyme, Janssen/J&J, Morphic, Novartis, Roche, Sanofi, Takeda, and TG Therapeutics for his role as a consultant and from MAPI and ExcisionBio for service on Scientific Advisory or Data Safety Monitoring boards.See Profile
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.See Profile
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