Central Nervous System TuberculosisUPTODATE NOV 2015 (1)
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4/12/2015
Central nervous system tuberculosis
Official reprint from UpToDate® www.uptodate.com ©2015 UpToDate®
Central nervous system tuberculosis Author John M Leonard, MD
Section Editors C Fordham von Reyn, MD Morven S Edwards, MD
Deputy Editor Elinor L Baron, MD, DTMH
All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2015. | This topic last updated: Mar 16, 2015. INTRODUCTION — Central nervous system (CNS) tuberculosis (TB) includes three clinical categories: tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. All three categories 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. The pathogenesis, clinical presentation, diagnosis, and treatment of central nervous system tuberculosis will be reviewed here. The general principles of treatment of TB are discussed separately. (See "Treatment of pulmonary tuberculosis in HIVuninfected adults".) PATHOGENESIS — During the bacillemia that follows primary infection or late reactivation tuberculosis (TB), scattered tuberculous foci (tubercles) are established in the brain, meninges, or adjacent bone. (See "Natural history, 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 [3]. 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 "Epidemiology and pathology of miliary and extrapulmonary tuberculosis".) Consequently, meningitis develops most commonly as a complication of postprimary infection in infants and young children and from chronic reactivation bacillemia in older adults with immune deficiency caused by aging, alcoholism, malnutrition, malignancy, human immunodeficiency virus (HIV) infection, or drugs (eg, tumor necrosis factor [TNF]alpha inhibitors). Advancing age or head trauma may also lead to destabilization of an established quiescent focus resulting in meningitis in the absence 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 [3,4]: ● Proliferative arachnoiditis, most marked at the base of the brain, eventually produces a fibrous mass that encases adjacent cranial nerves and penetrating vessels. ● Vasculitis with resultant aneurysm, thrombosis, and infarction affects vessels that traverse the basilar or spinal exudate or are located within the brain itself [5]. Multiple lesions are common and a variety of stroke syndromes may result, involving the basal ganglia, cerebral cortex, pons, and cerebellum [6]. 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 [7]. ● Communicating hydrocephalus results from extension of the inflammatory process to the basilar cisterns and impedance of cerebrospinal fluid circulation and resorption. Obstruction of the aqueduct develops less frequently, from contraction of exudate surrounding the brainstem or from a strategically placed brainstem http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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tuberculoma. Host susceptibility — The Tolllike receptor pathway appears to influence the susceptibility of man to tuberculous meningitis; this was illustrated in a casepopulation study design involving 175 HIVuninfected patients with tuberculous meningitis, 183 HIVuninfected patients with pulmonary tuberculosis, and 392 control patients [8]. A polymorphism in Toll–interleukin1 receptor domain containing an adaptor protein that mediates signaling from mycobacteria activated Tolllike 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 whole blood interleukin6 production, suggesting immunomodulation as a mechanism for susceptibility. FORMS OF CNS TUBERCULOSIS Tuberculous meningitis — Tuberculous meningitis accounts for about 1 percent of all cases of tuberculosis (TB) and 5 percent of all extrapulmonary disease in immunocompetent individuals [9]. Although pulmonary TB in the United States has declined, the number of meningeal TB cases has changed little and the case fatality ratio remains relatively high (15 to 40 percent) despite effective treatment regimens [9,10]. Early recognition of tuberculous 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 or if prompt evaluation fails to establish an alternative diagnosis. Serial examination of the CSF by acidfast stain and culture is the best diagnostic approach. Smears and cultures will yield positive results even days after treatment has been initiated. Nucleic acid amplification (NAA) testing also may be helpful (See 'Diagnosis' below.) Clinical manifestations — Typically, patients with tuberculous meningitis present with a subacute febrile illness that progresses through three discernible phases [1114]: ● The prodromal phase, lasting two to three weeks, is characterized by the insidious onset of malaise, lassitude, headache, lowgrade 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 longtract signs. ● The paralytic phase supervenes as the pace of illness accelerates rapidly; confusion gives way to stupor and coma, seizures, and often hemiparesis. For the majority of untreated patients, death ensues within five to eight weeks of the onset of illness. It is useful to categorize patients 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; they 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. About onethird of patients on presentation have underlying generalized (miliary) tuberculosis, in which case careful funduscopic examination often shows choroidal tubercles (image 1). These are multiple, illdefined, 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 central nervous system (CNS) are of diagnostic import if present but are often absent or nonspecific. Abnormalities on chest radiograph may be seen in half of cases, ranging from focal lesions to a subtle miliary pattern. A tuberculin skin test will be positive in the majority [11,12], although a negative result http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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does not exclude the diagnosis. (See "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV uninfected adults".) 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 [16]. Diagnosis — The diagnosis of CNS TB can be difficult; maintaining a high degree of suspicion is vital in order to initiate therapy promptly. Diagnostic tools consist of cerebrospinal fluid examination (including culture and nucleic acid testing) and radiography. Spinal fluid examination — The examination of cerebrospinal fluid specimens is of critical importance to early diagnosis of tuberculous meningitis. Typically, the CSF formula shows elevated protein and lowered glucose concentrations with a mononuclear pleocytosis [17,18]. 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") [19]. Culture and sensitivity — The importance of repeated, careful examination and culture of CSF specimens for Mycobacterium tuberculosis cannot be overemphasized. In general, a minimum of three serial lumbar punctures should be performed at daily intervals, although empiric therapy need not be delayed during this time. In one series, 37 percent of cases were diagnosed on the basis of an initial positive acidfast bacilli (AFB) smear; the diagnostic yield increased to 87 percent when up to four serial specimens were examined, even though antituberculous therapy had been administered before a positive smear was obtained in some cases [12]. In a study including 132 adults with clinical tuberculous meningitis, a bacteriologic diagnosis was achieved in 82 percent of cases; AFB smear and culture were positive in 58 and 71 percent of cases, respectively [20]. The sensitivity of the AFB smear of spinal fluid may be enhanced by attention to the following principles [12,17,20]: ● 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 ZiehlNeelsen method. ● Between 200 and 500 highpowered fields should be examined (approximately 30 minutes), preferably by more than one observer. Nucleic acid tests — CSF specimens should be submitted for nucleic acid testing whenever possible, particularly in the setting of high clinical suspicion and negative AFB staining. We are in agreement with the World Health Organization, which has recommended use of the Xpert MTB/RIF assay as an initial test for diagnosis of tuberculous meningitis [2128]. In a systemic review and metaanalysis including 18 studies, the sensitivity and specificity for the Xpert MTB/RIF assay in cerebrospinal fluid (compared with culture) were 81 and 98 percent, respectively [27]. http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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The assay MTBDRplus is a molecular probe capable of detecting rifampin and isoniazid resistance mutations (rpoB gene for rifampin resistance; katG and inhA genes for isoniazid resistance) [29]. The assay has been shown to be useful for detection of drug resistance for CSF samples that have a polymerase chain reaction (PCR) positive result [30]. (See "Diagnosis, treatment, and prevention of drugresistant tuberculosis", section on 'Nucleic acid tests'.) Radiography — Computed tomography (CT) and magnetic resonance imaging (MRI) have greatly improved characterization and management of CNS infections [31]. In patients with tuberculous meningitis, CT and MRI can define the presence and extent of basilar arachnoiditis (image 2), cerebral edema, infarction, and hydrocephalus (image 3). 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 [32,33]. A case series from Hong Kong documented hydrocephalus on presentation in 9 of 31 patients with tuberculous meningitis; hydrocephalus occurred after the start of antituberculous therapy in only one of the remaining 22 patients [34]. The following observations can be derived from a review of selected clinical series [32,33,35]: ● In a patient with compatible clinical features, CT or MRI evidence of basilar meningeal enhancement combined with any degree of hydrocephalus is strongly suggestive of tuberculous meningitis (image 3). ● 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. MRI is superior to CT in defining lesions of the basal ganglia, midbrain, and brainstem and for evaluating all forms of suspected spinal TB (image 2) [36,37]. (See "Skeletal tuberculosis".) Differential diagnosis — The differential diagnosis of tuberculous meningitis 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 and occasionally with other deepseated 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 similar CSF findings, 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 Table (table 1). Tuberculoma — Tuberculomas are conglomerate granulomatous foci within the brain parenchyma; they may be observed on histopathology or radiographic imaging (image 4) [38]. They develop from coalescing tubercles acquired during an earlier period of hematogenous bacillemia. Centrally located lesions may reach considerable size without producing meningeal inflammation. Clinically silent single or multiple nodular enhancing lesions are commonly seen in the setting of meningitis; occasionally, they are seen in patients with miliary tuberculosis and no meningitis [39,40]. These lesions generally disappear on therapy but may heal with calcification. Symptomatic intracranial mass lesions ("clinical tuberculomas") are observed most frequently in individuals from areas where the prevalence of tuberculosis is high. Typically, a child or young adult presents with seizure or headache; occasionally, hemiplegia or signs of raised intracranial pressure are observed [41,42]. On contrast CT imaging, early stage lesions are low density or isodense, often with edema out of proportion to the mass effect and little encapsulation [4143]. Laterstage tuberculomas are well encapsulated, isodense or hyperdense, and have peripheral ring enhancement. Symptoms of systemic illness and signs of meningeal inflammation are rarely observed. Lumbar puncture is usually avoided because of concern for raised intracranial pressure and risk of brainstem herniation; in the http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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occasional reported case where cerebrospinal fluid has been examined, the findings are normal or nonspecific. The diagnosis is made in relation to clinical, epidemiologic, and radiographic features or by needle biopsy. Unless the location of the lesion threatens obstructive hydrocephalus or brainstem herniation, surgical intervention should be avoided as it may precipitate severe meningitis. Differential diagnosis — The diagnostic distinction between clinical tuberculoma and intraparenchymal neurocysticercosis (NCC) can be challenging, particularly in children. Both CNS infections share similar clinical, epidemiologic, and radiographic features. (See "Clinical manifestations and diagnosis of cysticercosis".) In adults, NCC is a pleomorphic disease that tends to occur months to years after primary infection, and brain imaging usually demonstrates multiple lesions of varying age and morphology. The range of radiographic features includes cystic lesions showing the scolex, multiple cysts, giant cyst, ring or disc enhancing lesions, and multiple punctuate parenchymal calcifications. Cases with solitary CNS granulomas may be misdiagnosed as tumor and identified only after surgical resection. Clinical tuberculoma arises as an early postprimary infection event and typically presents as a single, large, dense mass. Children with early NCC may present with focal seizures and a single ring enhancing lesion, often with surrounding edema. In such cases, the distinction between tuberculoma and NCC requires careful attention to subtle radiographic features combined with thorough evaluation for evidence of tuberculosis elsewhere in the body [44]. Spinal tuberculous arachnoiditis — Spinal tuberculous arachnoiditis is observed most commonly in endemic areas [1,2]. The pathogenesis is similar to that of meningitis, with focal inflammatory disease at single or multiple levels leading to gradual encasement of the spinal cord by a gelatinous or fibrous exudate. Symptoms develop and progress slowly over weeks to months and may culminate 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 [45]. 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 diagnosis of spinal tuberculous arachnoiditis is based on findings of elevated cerebrospinal fluid protein levels and MRI findings of nodular arachnoiditis combined with tissue biopsy. The treatment for this form of disease is the same as for tuberculous meningitis. TREATMENT — Specific antituberculous chemotherapy should be initiated on the basis of strong clinical suspicion and should not be delayed until bacteriologic proof 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. Antituberculous therapy General approach — Treatment begins with an "intensive phase" that consists of a fourdrug regimen that includes isoniazid, rifampin, pyrazinamide, and a fourth drug, either a fluoroquinolone (moxifloxacin or levofloxacin) or an injectable aminoglycoside, administered daily for two months. Drug doses are shown in the Tables (table 2 and table 3). This is followed by a "continuation phase" that consists of isoniazid and rifampin alone (if the isolate is fully susceptible) administered daily or three times a week (table 2). Ethambutol penetrates poorly into even inflamed meninges and can be replaced in standard treatment regimens with a fluoroquinolone (moxifloxacin or levofloxacin) [46]. Aminoglycoside penetration is optimized during acute inflammation and its value beyond initial treatment is not clear [46]. There are no randomized, controlled trials to establish the optimal drug combination, dose, or duration of antituberculous therapy for central nervous system (CNS) tuberculosis. The principles of treatment are those that govern the management of pulmonary TB. In general, treatment consists of an initial 2month period of intensive http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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therapy (with four drugs) followed by a prolonged continuation phase (with isoniazid and rifampin) lasting 9 to 12 months, depending on the clinical response and drug sensitivity of the isolate [47,48]. The regimen for tuberculoma generally warrants treatment duration of 18 months. The nature and duration of treatment may require adjustment depending on individual patient circumstances. (See "Treatment of pulmonary tuberculosis in HIVuninfected adults".) Isoniazid, rifampin, and pyrazinamide are bactericidal, can be administered orally, penetrate inflamed meninges, and achieve cerebrospinal fluid (CSF) levels that exceed the inhibitory concentration needed for sensitive strains. Isoniazid has excellent CNS penetration and is more active against rapidly dividing than semidormant organisms. Rifampin is active against both rapidly dividing organisms and semidormant subpopulations of organisms. Pyrazinamide readily penetrates the CSF and is highly active against intracellular mycobacteria. Likewise, moxifloxacin and levofloxacin exhibit good CNS penetration [46]. In the past, streptomycin (15 mg/kg per day intramuscularly [IM] in adults to a maximum dose of 1 g; 20 to 40 mg/kg per day in children) was added to isoniazid in order to enhance sterilization and to reduce the risk of clinical relapse from resistant organisms. With the availability of rifampin and pyrazinamide, reliance upon streptomycin or other drugs of its class is generally limited to regions of the world with high prevalence of isoniazid resistance. Drug resistance — There are no definitive guidelines for the duration of therapy in patients with multidrug 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 patient's immune status. (See "Diagnosis, treatment, and prevention of drugresistant tuberculosis".) The prevalence of CNS infection caused by strains resistant to one or more firstline drugs is increasing [49]. Those at greatest risk for drugresistant disease include individuals from areas of the world where tuberculosis (TB) is endemic, those with a history of previous antituberculous treatment, homeless individuals, and those with exposure to source patients harboring drugresistant organisms. One study in Vietnam including 180 adults with tuberculous meningitis noted resistance to at least one antituberculosis drug in 40 percent of isolates; resistance to isoniazid and rifampin was observed in 5 percent of cases [50]. Combined isoniazid and rifampin resistance was strongly predictive of death (relative risk of death 11.6 [95% CI 5.226.3]) and independently associated with HIV infection. Similarly, among 350 cases of tuberculous meningitis in South Africa, resistance to isoniazid and rifampin was observed in 8 percent of cases; 57 percent of patients died [51]. Glucocorticoids — In general, glucocorticoid therapy is warranted for HIVuninfected patients with convincing epidemiologic or clinical evidence for tuberculous meningitis [5255]. Urgent warning signs that warrant prompt initiation of glucocorticoids include: ● Patients who are progressing from one stage to the next at or before the introduction of chemotherapy ● Patients with an acute encephalitis presentation, especially if the CSF opening pressure is ≥400 mmH2O or if there is clinical or computed tomographic (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) The regimen consists of dexamethasone or prednisone, as follows [52]: http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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● Dexamethasone – Children 25 kg: 0.3 to 0.4 mg/kg/day for two weeks, then 0.2 mg/kg/day week three, then 0.1 mg/kg/day week four, then 4 mg per day and taper 1 mg off the daily dose each week; total duration approximately eight weeks. ● Prednisone – Children: 2 to 4 mg/kg per day. Adolescents and adults: 60 mg/day. Administer initial dose for two weeks, then taper gradually over the next six weeks (ie, reduce daily dose by 10 mg each week); total duration approximately eight weeks. A review including seven trials involving 1140 participants established that adjunctive corticosteroids reduce death and disability from tuberculous meningitis by about 30 percent [55]. A randomized trial including 545 adolescents and adults with CNS tuberculosis in Vietnam noted reduced mortality among those who received dexamethasone (32 versus 41 percent) [52]. 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 at nine months followup. 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 (which necessitated changes in antituberculosis drug regimens). No mortality benefit from dexamethasone was evident in 98 HIVinfected patients included in the study. Another randomized trial including 141 children with tuberculous meningitis noted reduced mortality among children with stage III disease who received prednisone for the first month of treatment (4 versus 17 percent) [53]. In addition, those who received prednisone were more likely to have subsequent IQ >75 (52 versus 33 percent), and enhanced resolution of basal exudate and tuberculomas was observed radiographically. 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 of therapy is marked by progressive neurologic impairment [56]. Unlike other CNS mass lesions, medical management is preferred for clinical tuberculomas unless the lesion produces obstructive hydrocephalus or compression of the brainstem. In the past, surgical resection was often complicated by severe, fatal meningitis. HIV COINFECTION — There are few reports to indicate that central nervous system (CNS) tuberculosis (TB) is a widespread problem in AIDS patients [57,58]. In one study comparing the clinical features, laboratory findings, and mortality rates in patients having tuberculous meningitis with or without HIV infection, cerebral tuberculomas were more common in the HIVinfected group (60 versus 14 percent); otherwise, coinfection with HIV did not alter the clinical manifestations, cerebrospinal fluid (CSF) findings, or response to therapy [59]. In other parts of the world where TB is endemic, there have been reports of an increase in tuberculous meningitis in HIVinfected patients [6062]. As an example, in a study of 200 patients with confirmed meningitis from Zimbabwe, 12 percent had tuberculous meningitis compared with 45 percent with cryptococcal meningitis [61]. Eighty percent of all patients with suspected meningitis were HIV infected in this series; HIV seropositivity was 88 and 100 percent, respectively for those with TB and cryptococcal meningitis. Patients with HIV and CNS tuberculosis who are not already on antiretroviral therapy should delay initiation of antiretroviral therapy until after completion of TB therapy. Timing of initiation of antiretroviral therapy is discussed separately. (See "Treatment of pulmonary tuberculosis in HIVinfected adults", section on 'Timing of ART in the treatmentnaive patient'.) Among patients with tuberculosis and immune reconstitution inflammatory syndrome (IRIS), CNS tuberculosis occurs in approximately 12 percent of cases, and mortality of up to 30 percent has been reported [63]. http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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Manifestations include meningitis, intracranial tuberculoma, brain abscess, radiculomyelitis, and spinal epidural abscess [6366]. Tuberculous meningitis in the setting of IRIS is characterized by high CSF neutrophil counts and CSF culture positivity at presentation [67]. 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, easytoread 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 indepth 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 email 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 (Beyond the Basics)") 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 (see 'Clinical manifestations' above): • The prodromal phase, lasting two to three weeks, characterized by the insidious onset of malaise, lassitude, headache, lowgrade 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 longtract signs). • The paralytic phase, in which the pace of illness accelerates rapidly; confusion gives way to stupor and coma, seizures, and often hemiparesis. ● 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; they 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. ● 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 http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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the clinical outcome depends greatly upon the stage at which therapy is initiated. (See 'Diagnosis' above.) ● The examination of cerebrospinal fluid (CSF) specimens is of critical importance to early diagnosis of tuberculous meningitis. Typically, the CSF formula shows elevated protein and lowered glucose concentrations with a mononuclear pleocytosis. (See 'Spinal fluid examination' above.) ● The demonstration of acidfast 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 'Culture and sensitivity' above.) ● CSF specimens should be submitted for nucleic acid testing whenever feasible, particularly in the setting of high clinical suspicion and negative AFB staining. We are in agreement with the World Health Organization, which has recommended use of the Xpert MTB/RIF assay as an initial test for diagnosis of tuberculous meningitis. (See 'Nucleic acid tests' above.) ● Magnetic resonance imaging (MRI) is superior to computed tomography (CT) in defining lesions of the basal ganglia, midbrain, and brainstem and for evaluating all forms of suspected spinal TB. (See 'Radiography' above.) Treatment ● We recommend initiation of antituberculous therapy 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 (Grade 1B). The usual four drug regimen includes daily isoniazid, rifampin, pyrazinamide, and either moxifloxacin or levofloxacin or streptomycin for fully sensitive isolates. (See 'Antituberculous therapy' above.) ● Typically, intensive therapy is followed by a prolonged continuation phase lasting 9 to 12 months, depending on clinical response and established drug sensitivity of the isolate. The usual regimen in drugsensitive disease is isoniazid and rifampin, given daily or three times a week. (See 'Antituberculous therapy' above.) ● Treatment of drugresistant 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 resistance' above.) ● We recommend adjunctive glucocorticoid therapy for all children and adults with convincing epidemiologic or clinical evidence for tuberculous meningitis (Grade 1A). Dosing is summarized above. (See 'Glucocorticoids' above.) ● Patients with HIV and CNS tuberculosis who are not already on antiretroviral therapy should delay initiation of antiretroviral therapy until after completion of TB therapy. (See 'HIV coinfection' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. alDeeb SM, Yaqub BA, Sharif HS, Motaery KR. Neurotuberculosis: a review. Clin Neurol Neurosurg 1992; 94 Suppl:S30. 2. Bahemuka M, Murungi JH. Tuberculosis of the nervous system. A clinical, radiological and pathological study of 39 consecutive cases in Riyadh, Saudi Arabia. J Neurol Sci 1989; 90:67. http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tub…
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3. Rich AR, McCordock HA. Pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933; 52:5. 4. Dastur DK, Manghani DK, Udani PM. Pathology and pathogenetic mechanisms in neurotuberculosis. Radiol Clin North Am 1995; 33:733. 5. Wasay M, Farooq S, Khowaja ZA, et al. Cerebral infarction and tuberculoma in central nervous system tuberculosis: frequency and prognostic implications. J Neurol Neurosurg Psychiatry 2014; 85:1260. 6. Chan KH, Cheung RT, Lee R, et al. Cerebral infarcts complicating tuberculous meningitis. Cerebrovasc Dis 2005; 19:391. 7. Poltera AA. Thrombogenic intracranial vasculitis in tuberculous meningitis. A 20 year "post mortem" survey. Acta Neurol Belg 1977; 77:12. 8. Hawn TR, Dunstan SJ, Thwaites GE, et al. A polymorphism in Tollinterleukin 1 receptor domain containing adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis 2006; 194:1127. 9. Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2013. US Department of Health and Human Services, Atlanta, GA 2014. 10. Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol 1979; 109:205. 11. Hinman AR. Tuberculous meningitis at Cleveland Metropolitan General Hospital 1959 to 1963. Am Rev Respir Dis 1967; 95:670. 12. Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979; 241:264. 13. Farinha NJ, Razali KA, Holzel H, et al. Tuberculosis of the central nervous system in children: a 20year survey. J Infect 2000; 41:61. 14. Kent SJ, Crowe SM, Yung A, et al. Tuberculous meningitis: a 30year review. Clin Infect Dis 1993; 17:987. 15. STREPTOMYCIN treatment of tuberculous meningitis. Lancet 1948; 1:582. 16. Udani PM, Dastur DK. Tuberculous encephalopathy with and without meningitis. Clinical features and pathological correlations. J Neurol Sci 1970; 10:541. 17. Merritt HH, FremontSmith F. The cerebrospinal fluid, WB Saunders, Philadelphia 1938. 18. Karandanis D, Shulman JA. Recent survey of infectious meningitis in adults: review of laboratory findings in bacterial, tuberculous, and aseptic meningitis. South Med J 1976; 69:449. 19. SMITH HV. TUBERCULOUS MENINGITIS. Int J Neurol 1964; 4:134. 20. Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin Microbiol 2004; 42:378. 21. Patel VB, Theron G, Lenders L, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous meningitis in a high burden setting: a prospective study. PLoS Med 2013; 10:e1001536. 22. Vadwai V, Boehme C, Nabeta P, et al. Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 2011; 49:2540. 23. Tortoli E, Russo C, Piersimoni C, et al. Clinical validation of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis. Eur Respir J 2012; 40:442. 24. Chang K, Lu W, Wang J, et al. Rapid and effective diagnosis of tuberculosis and rifampicin resistance with Xpert MTB/RIF assay: a metaanalysis. J Infect 2012; 64:580. 25. AlvarezUria G, Azcona JM, Midde M, et al. Rapid Diagnosis of Pulmonary and Extrapulmonary Tuberculosis in HIVInfected Patients. Comparison of LED Fluorescent Microscopy and the GeneXpert MTB/RIF Assay in a District Hospital in India. Tuberc Res Treat 2012; 2012:932862. 26. Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol 2013; 12:999. 27. Denkinger CM, Schumacher SG, Boehme CC, et al. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and metaanalysis. Eur Respir J 2014; 44:435. 28. http://apps.who.int/iris/bitstream/10665/112472/1/9789241506335_eng.pdf (Accessed on February 19, 2015). 29. Barnard M, Albert H, Coetzee G, et al. Rapid molecular screening for multidrugresistant tuberculosis in a highvolume public health laboratory in South Africa. Am J Respir Crit Care Med 2008; 177:787. 30. Duo L, Ying B, Song X, et al. Molecular profile of drug resistance in tuberculous meningitis from southwest china. Clin Infect Dis 2011; 53:1067. http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tu…
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31. Bernaerts A, Vanhoenacker FM, Parizel PM, et al. Tuberculosis of the central nervous system: overview of neuroradiological findings. Eur Radiol 2003; 13:1876. 32. Bhargava S, Gupta AK, Tandon PN. Tuberculous meningitisa CT study. Br J Radiol 1982; 55:189. 33. Ozateş M, Kemaloglu S, Gürkan F, et al. CT of the brain in tuberculous meningitis. A review of 289 patients. Acta Radiol 2000; 41:13. 34. Chan KH, Cheung RT, Fong CY, et al. Clinical relevance of hydrocephalus as a presenting feature of tuberculous meningitis. QJM 2003; 96:643. 35. Kingsley DP, Hendrickse WA, Kendall BE, et al. Tuberculous meningitis: role of CT in management and prognosis. J Neurol Neurosurg Psychiatry 1987; 50:30. 36. Schoeman J, Hewlett R, Donald P. MR of childhood tuberculous meningitis. Neuroradiology 1988; 30:473. 37. Offenbacher H, Fazekas F, Schmidt R, et al. MRI in tuberculous meningoencephalitis: report of four cases and review of the neuroimaging literature. J Neurol 1991; 238:340. 38. Jinkins JR. Computed tomography of intracranial tuberculosis. Neuroradiology 1991; 33:126. 39. Stevens DL, Everett ED. Sequential computerized axial tomography in tuberculous meningitis. JAMA 1978; 239:642. 40. Weisberg LA. Granulomatous diseases of the CNS as demonstrated by computerized tomography. Comput Radiol 1984; 8:309. 41. Harder E, AlKawi MZ, Carney P. Intracranial tuberculoma: conservative management. Am J Med 1983; 74:570. 42. Traub M, Colchester AC, Kingsley DP, Swash M. Tuberculosis of the central nervous system. Q J Med 1984; 53:81. 43. Whelan MA, Stern J. Intracranial tuberculoma. Radiology 1981; 138:75. 44. Singhi P, Ray M, Singhi S, Khandelwal N. Clinical spectrum of 500 children with neurocysticercosis and response to albendazole therapy. J Child Neurol 2000; 15:207. 45. Wadia NH, Dastur DK. Spinal meningitides with radiculomyelopathy. 1. Clinical and radiological features. J Neurol Sci 1969; 8:239. 46. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb) 2010; 90:279. 47. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Joint Tuberculosis Committee of the British Thoracic Society. Thorax 1998; 53:536. 48. Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603. 49. World Health Organization (WHO). Global tuberculosis control: surveillance, planning, financing. Geneva: WHO, 2004. 50. Thwaites GE, Lan NT, Dung NH, et al. Effect of antituberculosis drug resistance on response to treatment and outcome in adults with tuberculous meningitis. J Infect Dis 2005; 192:79. 51. Patel VB, Padayatchi N, Bhigjee AI, et al. Multidrugresistant tuberculous meningitis in KwaZuluNatal, South Africa. Clin Infect Dis 2004; 38:851. 52. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004; 351:1741. 53. Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997; 99:226. 54. Girgis NI, Farid Z, Kilpatrick ME, et al. Dexamethasone adjunctive treatment for tuberculous meningitis. Pediatr Infect Dis J 1991; 10:179. 55. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008; :CD002244. 56. VanBeusekom GT. Complications in hydrocephalus shunting procedure. In: Advances in Neurosurgery, 6th ed, Wellenbur R, Brock M, Klinger M (Eds), SpringerVerlag, New York City 1968. p.28. http://www.uptodate.com/contents/centralnervoussystemtuberculosis?topicKey=ID%2F8009&elapsedTimeMs=1&source=search_result&searchTerm=tu…
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57. Braun MM, Byers RH, Heyward WL, et al. Acquired immunodeficiency syndrome and extrapulmonary tuberculosis in the United States. Arch Intern Med 1990; 150:1913. 58. Berenguer J, Moreno S, Laguna F, et al. Tuberculous meningitis in patients infected with the human immunodeficiency virus. N Engl J Med 1992; 326:668. 59. Dubé MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992; 93:520. 60. SánchezPortocarrero J, PérezCecilia E, JiménezEscrig A, et al. Tuberculous meningitis. Clinical characteristics and comparison with cryptococcal meningitis in patients with human immunodeficiency virus infection. Arch Neurol 1996; 53:671. 61. Hakim JG, Gangaidzo IT, Heyderman RS, et al. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000; 14:1401. 62. Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD. The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 2000; 181:118. 63. Pepper DJ, Marais S, Maartens G, et al. Neurologic manifestations of paradoxical tuberculosisassociated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis 2009; 48:e96. 64. Asselman V, Thienemann F, Pepper DJ, et al. Central nervous system disorders after starting antiretroviral therapy in South Africa. AIDS 2010; 24:2871. 65. Tuon FF, Mulatti GC, Pinto WP, et al. Immune reconstitution inflammatory syndrome associated with disseminated mycobacterial infection in patients with AIDS. AIDS Patient Care STDS 2007; 21:527. 66. Lee CH, Lui CC, Liu JW. Immune reconstitution syndrome in a patient with AIDS with paradoxically deteriorating brain tuberculoma. AIDS Patient Care STDS 2007; 21:234. 67. Marais S, Meintjes G, Pepper DJ, et al. Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis 2013; 56:450. Topic 8009 Version 24.0
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GRAPHICS Choroidal tuberculosis
Miliary choroids (tubercles) appear as illdefined nodules varying in size from pinpoint to several disc diameters on funduscopic examination. Reprinted with permission. Copyright © American Society of Contemporary Ophthalmology. Annals of Ophthalmology 1989.21(6);226. Graphic 61826 Version 5.0
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Meningeal enhancement in TB meningitis on MRI
Image A is T1weighted sequence following contrast and shows extensive basilar meningeal enhancemen Image B is also a contrastenhanced study showing meningeal enhancement (arrows). MRI: magnetic resonance imaging; TB: tuberculous. Courtesy of Asim Mian, MD and Glenn Barest, MD. Graphic 98270 Version 2.0
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Hydrocephalus in TB meningitis on MRI
A T1weighted MRI of the brain in the sagittal projection shows hydrocephalus of the lateral ventricle (as and fourth ventricle (arrow). Image B is a FLAIR sequence in axial projection and shows moderate hydrocephalus of the lateral ventricles (asterisks) with transependymal edema (arrows), and diffuse cer edema and effacement of the sulci (arrowhead). Image C is a FLAIR sequence showing hydrocephalus of third ventricle (asterisk), transependymal edema (arrows), and effacement of the sulci (arrowhead) indic cerebral edema. MRI: magnetic resonance imaging; TB: tuberculous. Courtesy of Asim Mian, MD and Glenn Barest, MD. Graphic 98269 Version 1.0
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Differential diagnosis of central nervous system tuberculosis Fungal meningitis (cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis) Viral meningoencephalitis (herpes simplex, mumps) Parameningeal infection (sphenoid sinusitis, brain abscess, spinal epidural abscess) Partially treated bacterial meningitis Neurosyphilis Neoplastic meningitis (lymphoma, carcinoma) Neurosarcoidosis Neurobrucellosis Graphic 69843 Version 2.0
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Tuberculoma of the brain on CT and MRI
A noncontrast CT scan (A) of a sixyearold male presenting with leftsided hemiplegia and seizures shows a large soft tissue density mass (asterisk) containing central calcification (arrowhead) involving almost the entire visualized frontoparietal region. Image B is a contrastenhanced CT scan reformatted in the coronal plane and shows the large mass (asterisk) with central calcification (arrowhead) and an enhancing border (arrows). Image C is a T1 weighted sagittal sequence showing an iso to hypointense lesion (asterisk). Image D is a contrastenhanced T1 weighted MRI in the axial plane and shows the mass (asterisk) with an enhancing rim (arrows). Image E is a T2 weighted MRI and shows the characteristic low intensity mass (asterisk), surrounding edema (delta), midline shift (arrowhead), and a dilated, partially obstructed left lateral ventricle (arrow). CT: computed tomography; MRI: magnetic resonance imaging. Courtesy of Fourie Bezuidenhout, MD. Graphic 99864 Version 1.0
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Doses of firstline antituberculosis drugs for adults* Drug
Doses
Preparation
Daily
1x/week
2x/week
3x/week
Firstline drugs Isoniazid
Tablets (50 mg, 100 mg, 300 mg); elixir (50 mg/5 mL); aqueous solution (100 mg/mL) for intravenous or
5 mg/kg (300 mg)
15 mg/kg (900 mg)
15 mg/kg (900 mg)
15 mg/kg (900 mg)
10 mg/kg (600 mg)
10 mg/kg (600 mg)
10 mg/kg (600 mg)
5 mg/kg
5 mg/kg
5 mg/kg
(300 mg)
(300 mg)
intramuscular injection Rifampin
Capsule (150 mg, 300 mg); powder may be suspended for oral administration; aqueous solution for intravenous injection
Rifabutin
Capsule (150 mg)
(300 mg) Rifapentine
Tablet (150 mg, film coated)
10 mg/kg (continuation phase) (600 mg)
Pyrazinamide
Tablet (500 mg, scored)
Weight based dosing summarized in separate table
Ethambutol
Tablet (100 mg, 400
Weight
mg)
based dosing summarized in separate table
* Doses per weight is based on ideal body weight. For purposes of this document, adult dosing begins at age 15 years. Data from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603. Graphic 55978 Version 3.0
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Suggested pyrazinamide doses, using whole tablets, for adults weighing 40 to 90 kilograms
Weight (kg)* 40 to 55
56 to 75
76 to 90
Daily, mg (mg/kg)
1000 (18.2 to 25)
1500 (20 to 26.8)
2000 ¶ (22.2 to 26.3)
Thrice weekly, mg (mg/kg)
1500 (27.3 to 37.5)
2500 (33.3 to 44.6)
3000 ¶ (33.3 to 39.5)
Twice weekly, mg (mg/kg)
2000 (36.4 to 50)
3000 (40 to 53.6)
4000 ¶ (44.4 to 52.6)
* Based on estimated lean body weight. ¶ Maximum dose regardless of weight. Reproduced with permission from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603. Official Journal of the American Thoracic Society. Copyright ©2003 American Thoracic Society. Graphic 73765 Version 4.0
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Disclosures Disclosures: John M Leonard, MD Nothing to disclose. C Fordham von Reyn, MD Nothing to disclose. Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B Streptococcus]. Consultant/Advisory Boards: Novartis Vaccines [Group B Streptococcus]. Elinor L Baron, MD, DTMH Nothing to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multilevel review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy
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