Central nervous system tuberculosis Author John Leonard, MD Section Editors C Fordham von Reyn, MD Morven S Edwards, MD Deputy

Editor Elinor L Baron, MD, DTMH Disclosures Last literature review version 19.3: septiembre 2011 | This topic last updated: junio 11, 2010 (More) INTRODUCTION Central nervous system (CNS) tuberculosis (TB) includes three clinical categories: meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. All three forms of CNS infection are encountered frequently in regions of the world where the incidence of TB is high and the prevalence of post-primary dissemination is common among children and young adults [1,2]. In regions where the incidence rates are low, such as North America and Western Europe, extrapulmonary manifestations of diseases are seen primarily in adults with reactivation infection, and the dominant form of CNS disease is meningitis. CNS tuberculosis accounts for about one percent of all cases of TB and six percent of all extrapulmonary infections in immunocompetent individuals [3]. Although pulmonary TB in the United States has declined slowly over the past decade, the number of meningeal TB cases has changed little (172 in 2004), and the case fatality ratio remains relatively high at 15 to 40 percent despite effective treatment regimens [3,4]. Early recognition of TB meningitis is of paramount importance because the clinical outcome depends greatly upon the stage at which therapy is initiated. Empiric antituberculous therapy should be started immediately in any patient with meningitis syndrome and cerebrospinal fluid (CSF) findings of low glucose concentration, elevated protein, and lymphocytic pleocytosis, if there is evidence of TB elsewhere in the body or if prompt evaluation fails to establish an alternative diagnosis. Serial examination of the CSF by acid-fast stain and culture is the best diagnostic approach. Smears and cultures will yield positive results even days after therapy has been initiated. The pathogenesis, clinical presentation, diagnosis, and management of central nervous system tuberculous will be reviewed here. The general principles of treatment of TB are discussed separately. (See "Treatment of tuberculosis in HIV-negative patients".) PATHOGENESIS Scattered tuberculous foci (tubercles) are established in the brain, meninges, or adjacent bone during the bacillemia that follows primary infection or late reactivation TB elsewhere in the body. (See "Microbiology and pathogenesis of tuberculosis".) The chance occurrence of a subependymal tubercle, with progression and rupture into the subarachnoid space, is the critical event in the development of tuberculous meningitis [5]. The widespread and dense distribution of infectious foci seen in association with progressive miliary tuberculosis greatly increases the chance that

juxta-ependymal tubercles will be established. (See "Pathogenesis and epidemiology of miliary tuberculosis".) Consequently, meningitis develops most commonly as a complication of post-primary infection in infants and young children and from chronic reactivation bacillemia in older adults with immune deficiency caused by aging, alcoholism, malnutrition, malignancy, or human immunodeficiency virus (HIV) infection. Advancing age or head trauma may also lead to destabilization of an established quiescent focus resulting in meningitis in the absence of any evidence of generalized infection. The spillage of tubercular protein into the subarachnoid space produces an intense hypersensitivity reaction, giving rise to inflammatory changes that are most marked at the base of the brain. Three features dominate the pathology and explain the clinical manifestations [5,6]. Proliferative arachnoiditis, most marked at the base of the brain, produces a fibrous mass involving cranial nerves and penetrating vessels. Vasculitis with resultant thrombosis and infarction involves vessels that traverse the basilar or spinal exudate or are located within the brain substance itself. Multiple lesions are common and a variety of stroke syndromes may result, involving the basal ganglia, cerebral cortex, pons, and cerebellum [7]. Intracranial vasculitis is a common feature of autopsy studies and a major determinant of residual neurologic deficits. In one autopsy study of 27 cases, for example, phlebitis and varying degrees of arteritis were demonstrated in 22 cases, including eight patients with associated hemorrhagic cerebral infarction [8]. Communicating hydrocephalus results from extension of the inflammatory process to the basilar cisterns and impedance of CSF circulation and resorption. Obstruction of the aqueduct develops less frequently, from contraction of exudate surrounding the brainstem or from a strategically placed brainstem tuberculoma.

Host susceptibility The Toll-like receptor pathway appears to influence the susceptibility of man to tuberculous meningitis as illustrated in a case-population study design involving 175 HIV-negative patients with tuberculous meningitis, 183 HIVnegative patients with pulmonary tuberculosis, and 392 control patients [9]. A polymorphism in Toll-interleukin 1 receptor domain containing an adaptor protein that mediates signaling from mycobacteria activated Toll-like receptors was associated with susceptibility to meningeal tuberculosis (odds ratio [OR], 3.0) and to pulmonary tuberculosis (OR, 1.6). The polymorphism was also associated with decreased wholeblood interleukin-6 production, suggesting immunomodulation as a mechanism for susceptibility. MENINGITIS Clinical features The usual patient with tuberculous meningitis presents with a subacute febrile illness that progresses through three discernible phases [10-13].

The prodromal phase, lasting two to three weeks, is characterized by the insidious onset of malaise, lassitude, headache, low-grade fever, and personality change. The meningitic phase follows with more pronounced neurologic features, such as meningismus, protracted headache, vomiting, lethargy, confusion, and varying degrees of cranial nerve and long-tract signs. The paralytic phase, is the stage during which the pace of illness may accelerate rapidly; confusion gives way to stupor and coma, seizures, and often hemiparesis. For the majority of untreated patients, death ensues within five to eight weeks of the onset of illness.

About one-third of patients on presentation have underlying generalized (miliary) tuberculosis, in which case, careful fundoscopic examination often shows choroidal tubercles (picture 1). These are multiple, ill-defined, raised yellow-white nodules (granulomas) of varying size near the optic disk. If present in a patient with meningitis, choroidal tubercles are a valuable clue to the etiologic diagnosis. (See "Tuberculosis and the eye".) Signs of active TB outside the CNS are of diagnostic import, if present, but are often absent or nonspecific. Abnormalities on chest radiograph may be seen in 50 percent of patients, ranging from focal lesions to a subtle miliary pattern. A tuberculin skin test will be positive in the majority [10,11], although a negative result does not exclude the diagnosis. (See "Diagnosis of latent tuberculosis infection in adults".) Atypical presentations Cases with atypical features that mimic other neurologic conditions are important to recognize. As an example, patients may present with an acute, rapidly progressive, meningitic syndrome suggesting pyogenic meningitis or with a slowly progressive dementia over months or even years characterized by personality change, social withdrawal, loss of libido, and memory deficits. Less common is an encephalitic course manifested by stupor, coma, and convulsions without overt signs of meningitis [14]. Clinical stages It is useful for prognosis and therapy to categorize patients with tuberculous meningitis on presentation by the stage of illness, based upon the mental status and focal neurologic signs [15]. Stage I patients are lucid with no focal neurologic signs or evidence of hydrocephalus. Stage II patients exhibit lethargy, confusion; may have mild focal signs, such as cranial nerve palsy or hemiparesis. Stage III represents advanced illness with delirium, stupor, coma, seizures, multiple cranial nerve palsies, and/or dense hemiplegia.

HIV infection Although coinfection with HIV has been observed in 20 percent of patients with extrapulmonary TB in the United States, there are very few reports to indicate that CNS tuberculosis is a widespread problem in AIDS patients [16,17]. In one study comparing the clinical features, laboratory findings, and mortality rates in patients having TB meningitis with or without HIV infection, cerebral tuberculomas were more common in the HIV-infected group (60 versus 14 percent); otherwise,

coinfection with HIV did not alter the clinical manifestations, CSF findings, or response to therapy [18]. In other parts of the world where TB is endemic, there have been reports of an increase in TB meningitis in HIV-infected patients [19-21]. As an example, in a study of 200 patients with confirmed meningitis from Zaire, 12 percent had TB meningitis compared to 45 percent with cryptococcal meningitis [20]. Eighty percent of all patients with suspected meningitis were HIV-positive in this series; HIV seropositivity was 88 and 100 percent, respectively for those with TB and cryptococcal meningitis. TUBERCULOMA Defined pathologically, tuberculomas are conglomerate caseous foci within the substance of the brain that develop from deep-seated tubercles acquired during a recent or remote hematogenous bacillemia. Radiologically, they are clinically silent, single or multiple enhancing nodular lesions often apparent on CT scanning of patients with meningitis or miliary TB without meningitis [22,23]. Tuberculoma is also a distinct clinical syndrome manifested by focal neurologic symptoms and signs of an intracranial mass lesion, usually without evident systemic illness or meningeal inflammation [24]. Distinctly uncommon in the West, this syndrome accounts for 20 to 30 percent of all intracranial space occupying lesions found in children in India and Asia [25]. SPINAL TUBERCULOUS ARACHNOIDITIS This form of nervous system infection is also seen more commonly in countries outside Europe and the Americas [1,2]. The pathogenesis is similar to that of meningitis, with focal inflammatory disease at single or multiple levels producing gradual encasement of the spinal cord by a gelatinous or fibrous exudate. Symptoms develop and progress slowly over weeks to months and may terminate with a meningitis syndrome. Patients present with the subacute onset of nerve root and cord compression signs: spinal or radicular pain, hyperesthesia or paresthesias; lower motor neuron paralysis; and bladder or rectal sphincter dysfunction [26]. Vasculitis may lead to thrombosis of the anterior spinal artery and infarction of the spinal cord. Other forms include extradural or intradural tuberculoma and epidural abscess. The treatment for this form of disease is the same as for TB meningitis. DIFFERENTIAL DIAGNOSIS The differential diagnosis of CNS TB is that of a subacute or chronic meningitis syndrome with a CSF formula characterized by a lymphocytic pleocytosis, lowered glucose concentration, and a high protein content. This is seen most commonly with cryptococcosis, occasionally with other deep-seated granulomatous fungal infections, brucellosis, and neurosyphilis. A similar syndrome may be encountered in patients with a parameningeal suppurative infection, (eg, sphenoid sinusitis, brain abscess, or spinal epidural space infection). Patients with herpes encephalitis may exhibit a similar CSF formula, including mild lowering of CSF glucose concentration. Careful evaluation for CNS tuberculosis is warranted in the patient suspected of any of the diagnoses listed in the following table (table 1). DIAGNOSIS As noted above, the diagnosis of CNS TB can be difficult. Maintaining a high degree of suspicion is vital in order to initiate therapy promptly.

Cerebrospinal fluid examination The examination of CSF specimens is of critical importance to early diagnosis of TB meningitis. Typically, the CSF formula shows elevated protein and lowered glucose concentrations with a mononuclear pleocytosis [27,28]. CSF protein ranges from 100 to 500 mg/dL in most patients; however, patients with subarachnoid block may show extremely high levels in the range of 2 to 6 g/dL, associated with xanthochromia and a poor prognosis. The CSF glucose is less than 45 mg/dL in 80 percent of cases. The usual CSF cell count is between 100 and 500 cells/microL. Early in the course of illness, the cellular reaction is often atypical with only a few cells or with polymorphonuclear leukocyte (PMN) predominance. Such cases usually rapidly change to a lymphocytic cellular response on subsequent CSF examinations. Upon initiation of antituberculous chemotherapy, the CSF of some patients briefly reverts to a PMN cellular reaction, associated with transient clinical deterioration ("therapeutic paradox") [29]. The diagnosis of spinal tuberculous arachnoiditis is based upon the findings of abnormal CSF protein indicative of spinal block and MRI changes of nodular arachnoiditis, combined with tissue biopsy. Bacteriology The importance of repeated, careful examination and culture of CSF specimens for M. tuberculosis cannot be overemphasized. The demonstration of acidfast bacilli (AFB) in the CSF remains the most rapid and effective means of reaching an early diagnosis. In one series, 37 percent of cases were diagnosed on the basis of an initial positive AFB smear [11]. However, the diagnostic yield increased to 87 percent when up to four serial specimens were examined, despite administration of antituberculous therapy to some patients before the first smear was positive. In a study designed to evaluate the variables that affect the sensitivity of smear and culture, a bacteriologic diagnosis was reached in 107 of 132 (82 percent) adults; AFB were seen on smear in 77 of 132 (58 percent) and cultured from 94 of 132 (71 percent) [30]. We recommend that a minimum of three lumbar punctures be performed at daily intervals, bearing in mind that empiric therapy need not be delayed during this time. The sensitivity of the AFB smear may be enhanced by attention to the following principles [11,27,30]: It is best to use the last fluid removed at lumbar puncture, and recovery of the organism improves if a large volume (10 to 15 mL) is removed. Organisms can be demonstrated most readily in a smear of the clot or sediment. If no clot forms, the addition of 2 mL of 95 percent alcohol gives a heavy protein precipitate that carries bacilli to the bottom of the tube upon centrifugation. 0.02 mL of the centrifuged deposit should be applied to a glass slide in an area not exceeding one centimeter in diameter and stained by the standard Kinyoun or Ziehl-Neelsen method. Between 200 and 500 high-powered fields should be examined (approximately 30 minutes), preferably by more than one observer.

Polymerase chain reaction Methods for the rapid detection of M. tuberculosis in CSF include the nucleic acid-based amplification test (NAAT) that relies upon the polymerase chain reaction (PCR) [31]. One evaluation of the reliability of PCR for detecting M. tuberculosis DNA showed considerable variability in sensitivity and specificity among seven participating laboratories [32]. In another study comparing PCR with Ziehl-Neelsen stains and cultures of the CSF, the sensitivity of PCR testing was only 60 percent in 15 patients classified as having definite or probable tuberculous meningitis [33]. (See "Molecular diagnosis of central nervous system infections", section on 'Mycobacteria'.) In a meta-analysis of NAATs for tuberculous meningitis, the pooled sensitivity was 56 percent and pooled specificity was 98 percent [34]. This surprisingly poor sensitivity has been largely attributed to the difference in sample volume between PCR (typically around 50 microL) and culture (several mL) but may also reflect differences in target sensitivity between populations [35]. We recommend that CSF specimens be submitted for PCR testing whenever clinical suspicion is sufficiently high to warrant empiric therapy and AFB stains of the initial samples are negative. However, it is important to recognize that a negative test result neither excludes the diagnosis nor obviates the need for continued therapy. Neuroradiology Computed tomography (CT) and magnetic resonance imaging (MRI) have improved greatly characterization and management of CNS infections [36]. CT can define the presence and extent of basilar arachnoiditis, cerebral edema and infarction, and the presence and course of hydrocephalus. In two large communitybased series hydrocephalus was seen in approximately 75 percent of patients, basilar meningeal enhancement in 38 percent, cerebral infarcts in 15 to 30 percent, and tuberculomas in 5 to 10 percent [37,38]. A case series from Hong Kong documented hydrocephalus on presentation in 9 of 31 patients with TB meningitis; hydrocephalus occurred after the start of antituberculous therapy in only one of the remaining 22 patients [39]. The following observations can be derived from a review of selected clinical series [37,38,40]: In a patient with compatible clinical features, CT evidence of basilar meningeal enhancement combined with any degree of hydrocephalus is strongly suggestive of tuberculous meningitis. The CT scan is normal in approximately 30 percent of cases with Stage I meningitis, and patients with a normal scan nearly always recover completely on therapy. Hydrocephalus combined with marked basilar enhancement is indicative of advanced meningitic disease and carries a poor prognosis. Marked basilar enhancement correlates well with vasculitis and, therefore, with a risk for basal ganglia infarction.

The diagnosis of tuberculoma is made on the basis of clinical and radiographic findings or by needle biopsy. The diagnosis of spinal tuberculous arachnoiditis is based upon MRI changes of nodular arachnoiditis, combined with tissue biopsy. MRI is superior to

CT in defining lesions of the basal ganglia, midbrain, and brainstem and for evaluating all forms of suspected spinal TB [41,42]. (See "Skeletal tuberculosis".) TREATMENT Specific antituberculous chemotherapy should be initiated on the basis of strong clinical suspicion and should not be delayed until proof of infection has been obtained. The clinical outcome depends greatly on the stage at which therapy is initiated; much more harm results from delay, even for only a few days, than from inappropriate therapy as long as efforts are continued to confirm the diagnosis. Chemotherapy There are no randomized, controlled trials to establish the optimal drug combination, dosage, or duration of antituberculous chemotherapy for CNS tuberculosis. The principles of treatment are those that govern the management of pulmonary TB (table 2). We agree with recommendations of the American and British Thoracic Societies, Infectious Disease Society of America, and the Centers for Disease Control and Prevention, which recommend an initial two month period of intensive therapy, with four drugs, followed by a prolonged continuation phase lasting seven to 10 months, depending on clinical response and established drug sensitivity of the isolate [43,44]. (See"Treatment of tuberculosis in HIV-negative patients".) The American Thoracic Society (ATS) statement on targeted tuberculin testing and the treatment of latent tuberculosis, as well as other ATS guidelines, can be accessed through the ATS web site at http://www.thoracic.org/statements/. First line drugs Isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) are bactericidal, can be administered orally, penetrate inflamed meninges, and achieve CSF levels that exceed the inhibitory concentration needed for sensitive strains. INH INH has excellent CNS penetration and is more active against rapidly-dividing than semidormant organisms. The initial dose is 10 mg/kg per day for adults and children; once a favorable response is achieved, the dose should be reduced to 5 mg/kg (300 mg per day for adults). (See"Isoniazid: An overview".) Rifampin Rifampin (RIF) is active against both rapidly dividing organisms and semidormant subpopulations of organisms. The dose is 10 mg/kg per day (600 mg in adults). (See "Rifampin and other rifamycins".) Pyrazinamide Pyrazinamide (PZA) readily penetrates the CSF and is highly active against intracellular mycobacteria. Within the dosing range of 15 to 30 mg/kg per day (maximum 2 g dose), PZA augments the regimen without added risk for hepatotoxicity when the drug's use is limited to two months. Streptomycin In the past, streptomycin (15 mg/kg per day IM in adults to a maximum dose of 1 g; 20 to 40 mg/kg per day in children) was added to INH in order to enhance sterilization and to reduce the risk of clinical relapse from resistant organisms. With the availability of newer, less toxic agents (eg, RIF and PZA), reliance upon streptomycin is generally limited to regions of the world with high prevalence ofisoniazid resistance. Ethambutol Ethambutol (15 to 25 mg/kg per day) achieves moderate CSF concentrations but carries the risk of optic neuritis at higher doses. Ocular toxicity is

rare at the recommended dose of 15 mg/kg per day. Patients receiving ethambutol should undergo baseline Snellen visual acuity and red-green color perception testing and should be referred to an ophthalmologist if visual complaints develop while on therapy [45]. (See "Ethambutol: An overview".) Recommended regimen Intensive phase A four drug regimen that includes INH, RIF, PZA, and either EMB or STM for two months followed by: Continuation phase INH and RIF alone if the isolate is fully susceptible, for an additional seven to 10 months. Duration of therapy We recommend that therapy be administered for nine to 12 months in drug-sensitive infections. If PZA is omitted or cannot be tolerated, treatment should be extended to 18 months. The antituberculous chemotherapy regimen for clinical tuberculoma is the same as for meningitis, except that duration of treatment is extended to 18 months. Drug-resistant M. tuberculosis CNS infection caused by strains resistant to one or more first line drugs is becoming increasingly prevalent. Those most at risk for drug-resistant disease include individuals from areas of the world where TB is endemic, those with a history of previous antituberculous treatment, homeless persons, and those with exposure to source patients harboring drug-resistant organisms. The World Health Organization estimates that approximately 10 percent of clinical isolates worldwide of M. tuberculosis are resistant to one or more first-line antituberculosis drugs [46]. The impact of resistance on treatment outcome varies according to which drug is ineffective. A prospective study from Vietnam of 180 adults with TB meningitis examined the effect of drug resistance on response to treatment and outcome [47]. Resistance to at least one antituberculosis drug was identified in 72 of 180 (40 percent) isolates and 10 isolates (5.6 percent) were resistant to at least INH and rifampin (multidrug resistance [MDR]). INH and STM resistance was significantly associated with slower CSF bacterial clearance, but not with any difference in clinical response or outcome. Combined INH and rifampin resistance, however, was strongly predictive of death (relative risk of death, 11.6 [95% CI 5.2-26.3]) and independently associated with HIV infection. The negative impact of MDR TB meningitis on outcome was similar in a study from South Africa [48]. Investigators reported that 30 of 350 cases of TB meningitis were resistant to at least INH and rifampin (8.6 percent); 17 of the 30 patients (57 percent) died. Twenty-two patients had received previous therapy for TB and 18 were HIVinfected. There are no guidelines for the duration of therapy in patients with multi-drug resistant infection. In such cases, it may be advisable to extend the duration of therapy to 18 to 24 months, taking into account the severity of illness, rate of clinical response, and the status of the patient's immune system.

Glucocorticoids There is considerable experimental evidence and a growing base of clinical data that adjunctive glucocorticoid therapy is beneficial in both adults and children with tuberculous meningitis [49-51]. A randomized, double-blind trial in Vietnam compared dexamethasone (for the first six to eight weeks of treatment in a tapering dose regimen) with placebo in 545 patients over 14 years of age [49]. The following findings were noted: Mortality was reduced significantly in the dexamethasone-treated group (32 versus 41 percent). The mortality benefit was most evident for patients with Stage I disease (17 versus 30 percent), approached significance for Stage II (31 versus 40 percent), and was not significant in patients with Stage III disease (55 versus 60 percent). There was no demonstrable reduction in residual neurologic deficits and disability among surviving patients evaluated by questionnaire at nine months follow-up. The survival benefit associated with steroid therapy may have been in part due to a reduction in severe adverse events (9.5 versus 16.6 percent), particularly hepatitis that necessitated changes in antituberculosis drug regimens. No mortality benefit from dexamethasone was evident in 98 HIV-infected patients included in the study.

In another randomized trial, 141 children with tuberculous meningitis were assigned to either prednisone (usually 4 mg/kg per day) or placebo for the first month of treatment [50]. Prednisone therapy was associated with a significant reduction in mortality in children with stage III disease (4 versus 17 percent); only two deaths occurred in other patients (see 'Clinical stages' above). Among survivors, there was a significantly higher rate of having an IQ above 75 in children receiving prednisone (52 versus 33 percent). In addition, there was enhanced resolution of the basal exudate and of tuberculomas with prednisone therapy. We recommend adjunctive glucocorticoid therapy for all children and adults with convincing epidemiologic or clinical evidence for tuberculous meningitis, the possible exception being adults with early mild Stage I manifestations. Specific clinical indications for adjunctive therapy based upon urgent warning signs include: Patients who are progressing from one stage to the next at or before the introduction of chemotherapy, especially if associated with any of the conditions listed below. Patients with an acute "encephalitis" presentation, especially if the CSF opening pressure is 400 mm H2O or if there is clinical or CT evidence of cerebral edema Patients who demonstrate "therapeutic paradox," an exacerbation of clinical signs (eg, fever, change in mentation) after beginning antituberculous chemotherapy Spinal block or incipient block (CSF protein >500 mg/dL and rising) Head CT evidence of marked basilar enhancement (portends an increased risk for infarction of the basal ganglia) or moderate or advancing hydrocephalus

Patients with intracerebral tuberculoma, where edema is out of proportion to the mass effect and there are any clinical neurologic signs (altered mentation or focal deficits)

Glucocorticoid regimen Either dexamethasone or prednisone may be used, as follows: Dexamethasone A total dose of 8 mg/day for children weighing <25 kg; 12 mg/day for adults and children >25 kg, for 3 weeks, then tapered off gradually over the following 3 to 4 weeks. Prednisone A dose of 2 to 4 mg/kg per day for children; 60 mg/day for adults, for 3 weeks, then tapered off gradually over the following 3 weeks.

Surgery Patients with hydrocephalus may require surgical decompression of the ventricular system in order to effectively manage the complications of raised intracranial pressure. In such patients with clinical stage II disease, the combination of serial lumbar puncture and steroid therapy may suffice while judging the early response to chemotherapy. However, surgical intervention should not be delayed in patients with stupor and coma or when the clinical course on therapy is marked by progressive neurologic impairment [52]. Unlike other CNS mass lesions, medical management is preferred for clinical tuberculomas, as surgical removal has often been complicated by severe fatal meningitis, unless the lesion produces obstructive hydrocephalus or compression of the brainstem. In the past, surgical resection was often complicated by severe, fatal meningitis. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Beyond the Basics topics (see "Patient information: Tuberculosis")

SUMMARY AND RECOMMENDATIONS Clinical manifestations

Central nervous system (CNS) tuberculosis (TB) includes three clinical categories: meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. (See 'Introduction' above.) Clinical manifestations in patients with tuberculous meningitis progress through three phases: The prodromal phase, lasting two to three weeks, characterized by the insidious onset of malaise, lassitude, headache, low-grade fever, and personality change. The meningitic phase with more pronounced neurologic features, (eg, meningismus, protracted headache, vomiting, lethargy, confusion, and varying degrees of cranial nerve and long-tract signs). The paralytic phase, in which the pace of illness accelerates rapidly; confusion gives way to stupor and coma, seizures, and often hemiparesis. (See 'Clinical features' above.)

Patients with tuberculous meningitis are categorized by stage on presentation, based upon mental status and focal neurologic signs as follows: Stage I patients are lucid with no focal neurologic signs or evidence of hydrocephalus. Stage II patients exhibit lethargy, confusion; may have mild focal signs, such as cranial nerve palsy or hemiparesis. Stage III represents advanced illness with delirium, stupor, coma, seizures, multiple cranial nerve palsies, and/or dense hemiplegia. (See 'Clinical stages' above.)

Tuberculomas are conglomerate caseous foci within the substance of the brain that develop from deep-seated tubercles acquired during a recent or remote hematogenous bacillemia. (See 'Tuberculoma' above.) Spinal tuberculous arachnoiditis is a focal inflammatory disease at single or multiple levels producing gradual encasement of the spinal cord by a gelatinous or fibrous exudate. (See 'Spinal tuberculous arachnoiditis' above.)

Diagnosis The diagnosis of CNS TB can be difficult. However, early recognition is of paramount importance because the clinical outcome depends greatly upon the stage at which therapy is initiated. (See 'Diagnosis' above.) The examination of CSF specimens is of critical importance to early diagnosis of TB meningitis. Typically, the CSF formula shows elevated protein and lowered glucose concentrations with a mononuclear pleocytosis. (See 'Cerebrospinal fluid examination' above.) The demonstration of acid-fast bacilli (AFB) in the CSF remains the most rapid and effective means of reaching an early diagnosis. We recommend that a minimum of three lumbar punctures be performed at daily intervals, bearing in

mind that empiric therapy need not be delayed during this time. (See 'Bacteriology' above.) We recommend that CSF specimens be submitted for PCR testing whenever clinical suspicion is sufficiently high to warrant empiric therapy and AFB stains of the initial samples are negative. However, it is important to recognize that a negative test result neither excludes the diagnosis nor obviates the need for continued therapy. (See 'Polymerase chain reaction' above.) MRI is superior to CT in defining lesions of the basal ganglia, midbrain, and brainstem and for evaluating all forms of suspected spinal TB. (See 'Neuroradiology' above.)

Treatment We recommend specific antituberculous chemotherapy should be initiated on the basis of strong clinical suspicion of CNS tuberculosis and should not be delayed until proof of infection has been obtained. (Grade 1B). (See 'Treatment' above.) We agree with recommendations of the American and British Thoracic Societies, Infectious Disease Society of America, and the Centers for Disease Control and Prevention, which recommend an initial two month period of intensive therapy, with four drugs (table 1) (Grade 1B). The usual four drug regimen includes INH, RIF, PZA, and either EMB or STM for fully sensitive isolates. (See 'Chemotherapy' above.) Typically intensive therapy is followed by a prolonged continuation phase (table 1) lasting seven to 10 months, depending on clinical response and established drug sensitivity of the isolate. The usual regimen in drug sensitive disease is INH and RIF alone. (See'Chemotherapy' above.) Treatment of drug-resistant CNS TB must be individualized and should be guided by the drug susceptibility pattern of the particular isolate. We suggest extending the duration of therapy to 18 to 24 months. (See 'Drug-resistant M. tuberculosis' above.) We recommend adjunctive glucocorticoid therapy for all children and adults with convincing epidemiologic or clinical evidence for tuberculous meningitis (Grade 1A). (See 'Glucocorticoids' above.) We typically treat with either dexamethasone or prednisone, as follows: Dexamethasone A total dose of 8 mg/day for children weighing <25 kg; 12 mg/day for adults and children >25 kg, for 3 weeks, then tapered off gradually over the following 3 to 4 weeks. Prednisone A dose of 2 to 4 mg/kg per day for children; 60 mg/day for adults, for 3 weeks, then tapered off gradually over the following 3 weeks.

(See 'Glucocorticoid regimen' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES