Tuberculosis of the Central Nervous System

CHAPTER

Tuberculosis of the Central Nervous System

41

JOHN M. LEONARD

MENINGITIS  Pathogenesis  Pathology  Clinical Presentation  Symptoms and Signs  Atypical Features  Tuberculous Meningitis and HIV Infection  Diagnosis  Cerebrospinal Fluid Examination  Neuroradiologic Evaluation  Differential Diagnosis 

TUBERCULOMA 

Tuberculosis in all its forms remains a challenging clinical problem and a public health issue of considerable magnitude.1 Rates of new infection vary widely from country to country in relation to socioeconomic conditions. For example, the incidence is approximately 5 cases per 100,000 population in the United States, compared with rates in excess of 200 cases per 100,000 population in some developing countries of Asia and Africa. Tuberculosis of the central nervous system (CNS) accounts for 1 to 2 percent of all cases of tuberculosis and about 8 percent of all forms of extrapulmonary infection in immunocompetent individuals. Although pulmonary tuberculosis in the United States has been on the decline, the number of reported cases of meningeal tuberculosis has changed little over the past decade. CNS tuberculosis may be considered as comprising three clinical syndromes: meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis.2–5 All three forms of CNS infection are encountered with about equal frequency in regions of the world where the incidence of tuberculosis is high. In areas such as Europe and North America, where the incidence is

lower and extrapulmonary tuberculosis is seen primarily in adults with reactivation disease, the large majority of cases present with meningitis.

Aminoff’s Neurology and General Medicine, Fifth Edition. © 2014 Elsevier Inc. All rights reserved.

SPINAL TUBERCULOUS ARACHNOIDITIS  THERAPY  Antituberculous Chemotherapy  Recommended Regimen  Adjunctive Therapy  Corticosteroids  Surgery  PROGNOSIS AND OUTCOME  CONCLUDING COMMENTS 

MENINGITIS Pathogenesis Current understanding of the pathogenesis of CNS tuberculosis is based on a series of careful clinicopathologic correlations that date to the early part of the last century.6,7 Conceptually, there is a twophase process, beginning with the hematogenous dissemination of Mycobacterium tuberculosis (bacillemia) that follows primary pulmonary infection or late reactivation elsewhere in the body. During this hematogenous phase, small numbers of bacilli are scattered throughout the substance of the brain, meninges, and adjacent tissues, leading to the formation of multiple granulomatous foci of varying size and degree of encapsulation (tubercles). In the second phase that develops over time, such lesions may coalesce to form larger caseous foci, with some lying just beneath the pia mater (the

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FIGURE 41-1  Section from an autopsied case of tuberculous meningitis showing fresh granulomas beneath the surface of the brain, having eroded through the pia membrane into the subarachnoid space. (Hematoxylin and eosin, × 400.)

encapsulation. Subpial tuberculous foci arising in this manner may remain quiescent for months or years, later to destabilize when local injury or a general depression in host immunity supervenes. Risk factors include advanced age, alcoholism, drug-induced immunosuppression, lymphoma, and infection with human immunodeficiency virus (HIV), all of which impair cellular immunity and, in persons with smoldering chronic organ tuberculosis, can lead to late generalized tuberculosis including meningitis.9 A significant proportion of adult cases of tuberculous meningitis have no demonstrable extracranial infection or apparent defect in host immune function. Occasionally, there is a history of head trauma some weeks or months prior to the onset of symptoms, suggesting that intracranial caseous foci may be destabilized by physical factors.

Pathology thin vascular membrane consisting of blood vessels and lymphatics that covers the entire surface of the brain) or beneath the ependyma (the thin nucleated epithelial membrane that lines the surface of the ventricles). With time and circumstance, such tuberculomas, if unstable, may erode into the sub­ arachnoid space, producing meningitis (Fig. 41-1). It follows that the propensity for developing clinical illness is determined by the number of tubercles and their proximity to the surface of the brain, the rapidity of progression, and the rate at which encapsulation follows acquired immunity. The widespread and dense distribution of tubercles that occurs in progressive miliary tuberculosis greatly increases the chance that a juxtapial granuloma will be established and, from this critical location, break through into the subarachnoid space.8 This is the usual sequence in childhood tuberculous meningitis, as infants and young children are especially susceptible to progressive hematogenous dissemination after primary infection.9 Adult cases also develop in association with clinically apparent progressive miliary disease or from other less apparent or entirely hidden foci of chronic organ tuberculosis. Reactivation of latent foci with resultant secondary hematogenous dissemination may be intermittent or chronic and progressive. In either circumstance, the spread of bacilli to distant organs produces scattered tubercles of varying size and

The pathologic changes observed in the CNS result from an intense, cytokine-mediated hypersensitivity reaction induced by the presence of organisms and associated antigenic material in the substance of the brain and the subarachnoid space. Three features dominate the pathologic process and account for the clinical manifestations: (1) a proliferative, predominantly basilar, arachnoiditis, (2) vasculitis of the arteries and veins traversing this exudate, and (3) disturbance of cerebrospinal fluid (CSF) circulation or resorption leading to hydrocephalus.10 Proliferative arachnoiditis is most marked at the base of the brain and, in a matter of days, produces a thick, gelatinous exudate extending from the pons to the optic chiasm. With chronicity, the optochiasmic zone of arachnoiditis comes to resemble a fibrous mass encasing nearby cranial nerves and vessels coursing through this area. Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar or spinal exudate or those that are located within the brain substance itself. The vascular inflammatory reaction is initiated by direct invasion of the adventitia by mycobacteria or by secondary extension of adjacent arachnoiditis. An early polymorphonuclear reaction followed by infiltration of lymphocytes, plasma cells, and macrophages leads to progressive destruction of the adventitia, disruption of elastic fibers, and extension of the

Tuberculosis of the Central Nervous System

inflammatory process to the intima. Eventually, fibrinoid degeneration in small arteries and veins produces aneurysms, multiple thrombi, and focal hemorrhage in some combination. Depending on the location and extent of the vasculitis, a variety of stroke syndromes may result.10,11 Multiple lesions are common, and areas of ischemic injury that simulate lacunar infarctions most frequently involve the basal ganglia, cerebral cortex, pons, and cerebellum. Intracranial vasculitis and multiple infarcts are a common feature of autopsy studies, and account for many of the residual neurologic deficits in those who recover following therapy. Extension of the inflammatory process to the basilar cisterns may also impede CSF circulation and resorption, leading to communicating hydrocephalus in most cases that have been symptomatic for longer than 2 to 3 weeks.10,12 Less frequently, obstruction of the aqueduct develops from exudate surrounding the brainstem, inflammation of the ependymal lining of the ventricles, or a strategically placed tuberculoma. In far-advanced cases, increased intracranial pressure may cause brainstem compression and tentorial herniation.

Clinical Presentation Symptoms and Signs Typically, tuberculous meningitis begins with a prodrome of insidious onset characterized by malaise, lassitude, personality change, intermittent headache, and low-grade fever. This is followed, usually within 2 to 3 weeks, by more prominent neurologic symptoms and signs such as meningismus, protracted headache, vomiting, confusion, cranial nerve palsies, and long-tract signs. The pace of illness may accelerate rapidly at this stage; confusion gives way to stupor and coma, seizures may occur, and multiple cranial nerve palsies and hemiparesis or hemiplegia are common. In most untreated cases, death supervenes within 5 to 8 weeks of the onset of illness although in occasional patients the illness follows a more indolent, slowly progressive course over weeks or months.13–16 In children, the condition is characterized early by irritability, loss of interest in play, restlessness, and anorexia; headache is less common and vomiting often much more prominent, especially in the very young.15,17 Seizures are more common in children and are apt to be an early or presenting symptom. Table 41-1

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TABLE 41-1 ■ Presenting Symptoms and Signs of Tuberculous Meningitis Symptoms/Signs

Frequency (%)

Fever

60–90

Headache

40–90

Vomiting

30–60

Neck stiffness

40–80

Lethargy/drowsiness

25–80

Confusion

10–30

Stupor/coma

5–30

Focal neurologic signs

15–40

Cranial nerve palsy

20–40

Hemiparesis

10–20

Seizures Children Adults

40–50 5

lists common symptoms and signs at presentation, and the frequency range compiled from three clinical series in separate regions of the world.13,15,16 For purposes of prognosis and therapy, it is useful to categorize patient severity on presentation based mainly on mental status and focal neurologic signs. Stage I comprises patients who are conscious and rational, with or without meningismus but with no focal neurologic signs or evidence of hydrocephalus; stage II patients exhibit lethargy and confusion and may have mild focal neurologic signs such as single cranial nerve palsies and hemiparesis; stage III illness includes signs of advanced disease such as stupor and coma, seizures, multiple cranial nerve palsies, dense hemiplegia, and paraplegia.18 Some patients progress rapidly from one stage to the next within a few days. The response to treatment is influenced by the clinical stage of illness at the time therapy is initiated, with better responses obtained when it is initiated early.

Atypical Features In some adults, the prodrome may be a slowly progressive dementia over months or even years, characterized by personality change, social withdrawal, loss of libido, and memory deficits. At the other end of the spectrum, some patients may present with an acute, rapidly progressive meningitic syndrome

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indistinguishable from pyogenic bacterial meningitis; at times, this accelerated form is superimposed on a chronic dementing illness. Seizures and focal neurologic disturbances such as cranial nerve palsies or hemiparesis may occur early and dominate the clinical presentation. Of the cranial nerves, the sixth is the most commonly involved, followed by the third and fourth. Occasionally the symptoms and signs of hydrocephalus with raised intracranial pressure (headache, papilledema, diplopia, and visual disturbance) precede signs of meningeal irritation. Movement disorders, including tremor, myoclonus, chorea, and ballismus, may follow basal ganglia infarction secondary to vasculitis.19

Tuberculous Meningitis and HIV Infection Coinfection with HIV has been reported in 21 percent of patients with extrapulmonary tuberculosis in the United States.20 Although CNS tuberculosis has not yet become a widespread problem in persons infected with HIV, there are reports that meningitis occurs with greater frequency in those HIV patients with active tuberculosis.21–23 In a study of 455 HIV-positive patients with tuberculosis, 10 percent developed meningitis compared with 2 percent of HIV-negative patients; HIV-positive patients accounted for 59 percent of all cases of tuberculous meningitis seen during the study period.21 Dube and colleagues compared the clinical features, laboratory findings, and in-hospital mortality rates in patients having tuberculous meningitis with or without HIV infection; intracerebral tuberculomas were more common in the HIV-infected group (60% compared with 14%), but otherwise, coinfection with HIV did not alter the clinical manifestations, CSF findings, or response to therapy.22

Diagnosis Few problems in medicine so critically challenge the physician’s diagnostic acumen and clinical judgment as a patient with CNS tuberculosis. Once the possibility of tuberculous meningitis has been considered, the central task is rapid and thorough assessment of clinical and laboratory features followed by a prompt decision regarding empiric therapy.6,24 Clues to the diagnosis include a positive family history of tuberculosis, recent exposure to others with active tuberculosis (especially in cases involving children and

immunosuppressed adults), a history of recent head trauma, and alcoholism. Evidence of active tuberculosis elsewhere in the body, observed in 20 to 70 percent of cases, provides the most reliable basis for the presumptive diagnosis in patients with CNS disease. A meticulous physical examination should include looking for lymphadenopathy, spinal and other joint lesions, splenomegaly, scrotal masses, and draining fistulas. In patients with generalized (miliary) infection, careful funduscopic examination often shows choroidal tubercles, which are multiple, ill-defined, raised yellow-white nodules (granulomas) of varying size near the optic disc.25 Abnormalities on chest radiography, including miliary infiltrate and, less commonly, hilar adenopathy or upper lobe nodular infiltrates, occur in most childhood cases and in approximately 50 percent of adults. Computed tomography (CT) of the chest likely has a higher yield for these findings. Patients with tuberculous meningitis may exhibit mild anemia and leukocytosis, but often the complete blood count and even the erythrocyte sedimentation rate are entirely normal. Hyponatremia related to inappropriate secretion of antidiuretic hormone occurs commonly and is a useful, though nonspecific, clue to the diagnosis. The tuberculin skin test is of limited utility. A positive skin test is nonspecific but supports the diagnosis; however, the reaction is commonly absent in all forms of active tuberculosis.

Cerebrospinal Fluid Examination Careful examination of the CSF is the key to diagnosis in most instances. The opening pressure is usually elevated, the fluid is clear or “ground glass” in appearance, and, on standing, a delicate, web-like clot often forms. The typical CSF formula shows elevated protein and low glucose concentrations as well as a mononuclear pleocytosis.24 The CSF protein concentration ranges from 100 to 500 mg/dl in most patients, is less than 100 mg/dl in 25 percent, and is more than 500 mg/dl in 10 percent. Patients with subarachnoid block may exhibit extremely high protein concentrations, in the range of 2 to 6 g/dl, associated with xanthochromia and a poor prognosis. The CSF glucose concentration is usually low, being less than 45 mg/dl in approximately 80 percent of cases. The CSF cell count is between 100 and 500/mm3 in most patients, less than 100 cells/mm3 in approximately 15 percent, and between 500 and 1,500 cells/mm3 in 20 percent.

Tuberculosis of the Central Nervous System

Although the characteristic cellular reaction is lymphocytic, early in the course of meningitis the findings are often atypical with only a few cells, a mixed pleocytosis, or polymorphonuclear predominance. Cases with an atypical cellular reaction at the outset evolve in the direction of more typical findings on repeat CSF examination. Misinterpretation of this sequence as improvement in response to antibacterial therapy (when an erroneous diagnosis of pyogenic meningitis is being entertained) can have serious consequences. On occasion, an initial mononuclear pleocytosis may briefly change in the direction of polymorphonuclear predominance after therapy is initiated (“therapeutic paradox”), a change that may be associated with clinical deterioration. Bacteriology

Specific diagnosis rests on the demonstration of Mycobacterium tuberculosis in the CSF. Cultures are positive in approximately 75 percent of cases but often require weeks for detectable growth. Consequently, the careful examination of a stained smear for acidfast bacilli (AFB) is the most effective means of making a prompt diagnosis. The importance of repeated, careful examination and culture of CSF specimens cannot be overemphasized; the diagnostic yield by smear and culture is enhanced when multiple CSF specimens from repeated lumbar punctures are submitted to the laboratory. In a prospective study designed specifically to evaluate the effectiveness of careful bacteriologic technique, acid-fast bacilli were seen on smear in 77 of 132 adult patients (58%) and cultured from 94 of 132 (71%); the overall sensitivity of smear and culture was 82 percent.26 This study confirmed earlier observations regarding the importance of high CSF volume and meticulous microscopy in the bacteriologic diagnosis of tuberculous meningitis. In suspect cases, it is recommended that at least two CSF samples from separate lumbar punctures be obtained for stain and culture. It is best to submit 5 to 10 ml of the last portion removed; the AFB stain should be examined for 30 minutes. It is not necessary to defer treatment as the yield remains high for several days after the institution of antituberculous chemotherapy. Molecular Diagnostic Techniques

The nucleic acid–based amplification methodology, based on the polymerase chain reaction (PCR), is

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an effective method for the rapid detection of bacterial DNA. Although simple, rapid, and appealing in principle, the reliability of PCR for the identification of mycobacteria is not well established, in part because of variability in sensitivity and specificity across multiple laboratories.27 In a blind comparison study of seven facilities, the rate of false-positive results ranged from 3 to 20 percent, and levels of sensitivity varied widely.28 There are few studies comparing PCR with stains and cultures in large series of patients with suspected or confirmed infection. In one, the sensitivity of PCR testing was 60 percent in 15 patients classified as having definite or probable tuberculous meningitis.29 In a metaanalysis of nucleic acid amplification tests used for the diagnosis of tuberculous meningitis, the pooled sensitivity was 56 percent and the specificity was 98 percent.30 CSF should be submitted for PCR testing whenever clinical suspicion is sufficiently high to warrant empiric therapy and initial stains for acidfast bacilli are negative, recognizing that a negative PCR test result neither excludes the diagnosis nor obviates the need for continued treatment. Work to develop more sensitive PCR-based methods is continuing.

Neuroradiologic Evaluation CT and magnetic resonance imaging (MRI) have greatly enhanced understanding of the pathogenesis, clinical assessment, and management of all forms of CNS tuberculosis.31–34 CT can define the presence and extent of basilar arachnoiditis, the presence of cerebral edema and infarction, and the presence and course of hydrocephalus. In a study of 289 cases (214 children and 75 adults), hydrocephalus was demonstrated in 80 percent of patients, basilar meningeal enhancement in 39 percent, cerebral infarcts in 15 percent, and tuberculomas in 5 percent.33 Hydrocephalus was associated with a longer duration of symptoms prior to treatment and was seen more often in children than adults. The CT findings are of prognostic significance and useful to monitor the effectiveness of adjunctive therapy such as corticosteroids and neurosurgical shunting procedures. In patients presenting with tuberculous meningitis, approximately 30 percent of those with stage I and 8 percent with stage II disease have a normal CT scan. Virtually all stage III patients have abnormalities, including hydrocephalus. Hydrocephalus alone without other features is uncommon and

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carries a good prognosis. Any degree of basilar meningeal enhancement combined with hydrocephalus is strongly suggestive of tuberculosis, and the combination is indicative of advanced disease, correlates well with the presence of vasculitis, and portends serious risk for basal ganglia infarction.33 MRI is the preferred imaging modality for defining lesions of the basal ganglia, midbrain, and brainstem.35,36 In a prospective study of 27 childhood cases, including clinical, radiographic, and pathologic findings, MRI proved superior to CT in delineating focal infarcts of the basal ganglia and diencephalon and in defining the presence and extent of associated brainstem lesions.35 The character and severity of MRI-defined brainstem abnormalities correlates well with clinical evidence of brainstem disease.

Differential Diagnosis A variety of inflammatory, vascular, and neoplastic conditions of the CNS may mimic tuberculosis. In most cases, the differential diagnosis involves a patient presenting with clinical features of a granulomatous meningitis syndrome: fever, headache, meningeal signs, altered mentation, and a CSF profile showing lymphocytic pleocytosis, lowered glucose concentration, and high protein content. In addition to tuberculosis, the other primary infectious considerations include fungal disease (principally cryptococcosis), brucellosis, and syphilis. On occasion subacute aseptic meningitis with these CSF findings may be encountered in patients with unrecognized parameningeal suppurative infection such as sphenoid sinusitis, brain abscess, and endocarditis. Patients with herpes simplex virus and mumps meningoencephalitis can be confusing as they may present with fever, rapid neurologic deterioration, and on occasion, mild lowering of the CSF glucose concentration (see Chapter  43). Noninfectious etiologies to be considered include neurosarcoidosis and lymphomatous or carcinomatous meningitis. A careful evaluation for tuberculosis is warranted in every patient suspected of any of the diagnoses listed in Table 41-2.

TUBERCULOMA Tuberculomas are conglomerate caseous foci within the substance of the brain that develop from deep-seated tubercles acquired during a recent or remote period of bacillemia. Centrally located,

TABLE 41-2 ■ Differential Diagnosis of Tuberculous Meningitis Fungal meningitis (e.g., cryptococcosis, histoplasmosis, blastomycosis, coccidioidal mycosis) Neurobrucellosis Viral meningoencephalitis (e.g, herpes simplex virus, mumps) Partially treated bacterial meningitis Neurosyphilis Focal parameningeal infection (sphenoiditis, brain abscess, endocarditis, spinal epidural abscess) Central nervous system toxoplasmosis Neoplastic meningitis (lymphoma, carcinoma) Stroke Neurosarcoidosis

active lesions may reach considerable size without producing signs of meningeal inflammation. Under conditions of poor host resistance, this process may result in focal areas of cerebritis or frank abscess formation, but the more usual course is coalescence of caseous foci and fibrous encapsulation (tuberculoma).37,38 The characteristic CT finding is a nodular enhancing lesion with a central hypodense region. In the early stage, however, lesions may be isodense, often with edema out of proportion to the mass effect along with little encapsulation. Late in their development, well-encapsulated tuberculomas appear as isodense or hyperdense lesions with peripheral ring enhancement. CT is useful for assessing the presence of cerebral edema, the risk of herniation, and the response to therapy. The MRI appearance depends on the stage of tuberculoma: focal cerebritis is manifest by nonspecific edema on T2-weighted images and ill-defined enhancement, whereas a caseating lesion typically shows central hypointensity and peripheral enhancement. Clinically silent, single or multiple, small parenchymal tuberculomas are seen commonly in cases of tuberculous meningitis and often in miliary tuberculosis without meningitis. These lesions usually disappear with medical therapy, although cases have been reported in which tuberculomas enlarged early during the course of antituberculous therapy.39 In contrast to lesions demonstrated by imaging studies that produce few or no symptoms, clinical tuberculomas presenting as symptomatic

Tuberculosis of the Central Nervous System

intracranial mass lesions are encountered frequently in areas of the world where the prevalence of tuberculosis is high. The usual patient is a child or young adult with headache, seizure, focal neurologic deficits, or signs of raised intracranial pressure. Symptoms of systemic illness and meningeal inflammation are usually lacking. The diagnosis is made with clinical, epidemiologic, and radiographic data or via needle biopsy. Surgery for purposes other than diagnosis may be required when lesions are critically located and produce obstructive hydrocephalus or compression of the brainstem. Corticosteroids aid in selected cases in which cerebral edema disproportionate to the mass effect contributes to altered mental state or focal neurologic deficits; however, they may mask the characteristic pathology of other diagnostic mimics such as CNS lymphoma, and therefore should be reserved for patients in whom the diagnosis is secure.

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vasculitis may lead to thrombosis of spinal arteries and infarction of the cord. The diagnosis of spinal tuberculous arachnoiditis should be considered in the patient with any combination of the following clinical and laboratory features: subacute onset of spinal or nerve root pain; rapidly ascending transverse myelopathy or multiple-level myelopathy; increased CSF protein concentration and cell count; signs of arachnoiditis or epidural space infection by MRI; and evidence of tuberculosis elsewhere in the body. Surgical intervention and tissue biopsy are often required for diagnosis. Some patients progress from an initial spinal syndrome to tuberculous cranial meningitis; this progression carries an extremely poor prognosis.

THERAPY Antituberculous Chemotherapy

SPINAL TUBERCULOUS ARACHNOIDITIS Tuberculous arachnoiditis or tuberculoma may arise at any level of the spinal cord in association with either breakdown of a granulomatous focus in the spinal cord or nearby meninges or through extension from an adjacent area of inapparent spondylitis. The inflammatory process is usually confined locally, gradually producing partial or complete encasement of the spinal cord in a gelatinous or fibrous exudate. In other cases, tuberculomas of the extradural, intradural, or intramedullary space may produce symptoms resembling local tumor. Patients usually present with some combination of signs of nerve root and spinal cord compression secondary to impingement by the advancing arachnoiditis. The clinical manifestations are more neurologic than infectious, protean in nature, and often take the form of an ascending or transverse radiculomyelopathy of variable pace involving single or multiple levels.40–42 Common symptoms and signs include pain, hyperesthesia or paresthesias in the distribution of the nerve root, lower motor neuron paralysis, and urinary or fecal incontinence. On occasion, the granulomatous mass or abscess may be confined largely to the epidural space, producing symptoms of spinal cord compression with no evidence of meningeal inflammation. Localized

The decision to begin antituberculous chemotherapy must be made promptly, usually based on clinical suspicion and presumptive diagnosis rather than direct evidence of mycobacterial infection. The prognosis is favorable when therapy is started before the development of focal signs and altered mentation. There are no randomized trials to establish the optimal drug combination, dosage, and duration of treatment for tuberculous meningitis; the regimens used are extrapolated from the management of pulmonary tuberculosis.43 The use of combination drug regimens is intended to enhance the bactericidal effect, cover the possibility of drug resistance, and reduce the risk of emerging resistance while on therapy. Isoniazid, rifampin, and pyrazinamide are each bactericidal, can be administered orally, penetrate inflamed meninges, and achieve CSF concentrations required for activity against sensitive strains.44 These drugs, usually along with ethambutol or streptomycin, are considered first-line therapy. Isoniazid diffuses readily into CSF and achieves concentrations many times that required for bactericidal activity. The recommended daily dose is 10 mg/kg for children and 300 mg for adults. Pyridoxine, 25 or 50 mg daily, should be given concurrently to avoid the neurologic complications of isoniazid-induced pyridoxine deficiency, including peripheral neuropathy.

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Rifampin is active early against rapidly dividing organisms and achieves reliable CSF concentrations only in the presence of meningeal inflammation. Because rifampin is active against semidormant organisms, its major contribution may relate to the resolution of residual foci in the CNS and elsewhere in the body. The daily dose in children and adults is 10 mg/kg (maximum 600 mg), and an intravenous formulation is available. Studies of pulmonary tuberculosis have demonstrated that the addition of pyrazinamide to regimens that include isoniazid and rifampin produces a more powerful antituberculous effect without increasing the incidence of hepatotoxicity, as long as the duration of pyrazinamide therapy is restricted to 2 months or less. CSF penetration is excellent in the presence or absence of inflammation, and the drug is highly active against intracellular mycobacteria. It is recommended that pyrazinamide be included in the treatment regimen for meningitis during the first 2 months of therapy. In children, the daily dose is 15 to 20 mg/kg (maximum 2,000 mg). In adults, the dose is based on weight: 40 to 55 kg, 1,000 mg; 56 to 75 kg, 1,500 mg; 76 to 90 kg, 2,000 mg. Ethambutol is a weak drug that reaches the sub­ arachnoid space in moderate concentration. Its major toxicity, optic neuropathy, occurs in as many as 3 percent of patients receiving 25 mg/kg daily but is rare at the recommended dose of 15 mg/kg. When ethambutol is used, it is advisable to check visual acuity, red-green color vision, and visual fields if possible.

Recommended Regimen Guidelines published by American and British societies and by the Centers for Disease Control and Prevention recommend an initial intensive phase of treatment with four drugs for 2 months followed by a prolonged continuation phase with two drugs for 7 to 10 months for drug-sensitive infections.45,46 The initial four-drug regimen includes isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin, administered for 2 months. This is followed by isoniazid and rifampin alone if the isolate is fully susceptible, the risk of drug resistance is small, and the clinical course satisfactory. If pyrazinamide is omitted or not tolerated initially, the total course of treatment should be extended to 18 months. The possibility of drug-resistant infection should be anticipated in high-risk individuals such as those from

areas of the world where tuberculosis is endemic, the homeless, in those having received previous antituberculous drugs, and in individuals with known exposure to persons harboring resistant organisms. The impact on therapeutic outcome is variable, depending on whether the isolate is resistant to isoniazid or rifampin or both.47 The best drug combination for resistant infection is uncertain and to some extent depends on the particular sensitivity pattern of a given isolate. The second-line drugs ethionamide and cycloserine penetrate the CSF well and may be useful. The fluoroquinolones also have good activity against mycobacteria. In addition to streptomycin, other aminoglycides such as kanamycin and amikacin are effective and have been given for resistant organisms via intrathecal injection.48 The duration of treatment should be extended to 18 to 24 months when resistant organisms are encountered.

Adjunctive Therapy Corticosteroids The role of corticosteroids in the management of tuberculous meningitis has long been a matter of uncertainty. Older studies were limited by small patient numbers and failure to stratify severity of illness according to neurologic manifestations. There is, however, a growing body of clinical data demonstrating that adjunctive corticosteroid therapy is beneficial in children and adults with CNS tuberculosis.49–52 In most major clinical centers in Europe, Asia, and Africa, corticosteroids are administered routinely to patients with clinical stage II and III disease. A meta-analysis of the various trials demonstrated a significant benefit of corticosteroids in tuberculous meningitis across a variety of patient populations.49 In a randomized trial in 141 children, prednisone administered for the first month improved survival and intellectual outcome and enhanced resolution of basilar exudate and tuberculomas.51 In those children with stage III disease, prednisone therapy was associated with a significant reduction in mortality (4 versus 17 percent). Adjunctive corticosteroid therapy is recommended for all patients with convincing clinical evidence of CNS tuberculosis, the possible exception being adults with early stage I meningitis. Complications for which corticosteroids are thought to be most beneficial include increased intracranial pressure, cerebral edema, stupor, focal neurologic signs, and spinal

Tuberculosis of the Central Nervous System

block. Specific clinical indications based on urgent warning signs include: progression from one stage to the next at or before the start of chemotherapy, CT evidence of marked basilar enhancement, moderate or advancing hydrocephalus, spinal block, or incipient block (CSF protein ≥500 mg/dl), and intracerebral tuberculoma when edema is out of proportion to mass effect with clinical signs. Either dexamethasone or prednisone may be used. For dexamethasone, the daily dose is 8 mg for children weighing less than 25 kg and 12 mg for adults and children weighing more than 25 kg. For prednisone, the dose is 2 to 4 mg/kg daily for children and 60 mg/day for adults. This initial dose is given for 3 weeks and then tapered gradually over the following 3 to 4 weeks. The decision to use corticosteroids should rest on a strong presumptive or positive diagnosis. Caution is advisable in the face of diagnostic uncertainty, especially in cases in which fungal CNS infection is considered a strong possibility. The expected benefit from corticosteroids must be weighed carefully against the potential for adverse consequences, bearing in mind that initial improvement may be nonspecific for tuberculosis. In select cases, systemic antifungal therapy should be administered concurrently until a specific etiologic diagnosis has been reached.

Surgery The management of hydrocephalus may require surgical decompression of the ventricular system in order to prevent neurologic complications of sustained raised intracranial pressure. In patients with clinical stage II disease, serial lumbar puncture combined with corticosteroids, diuretics, and osmotic agents may suffice while awaiting the early response to chemotherapy.53 However, surgical intervention should not be delayed when these measures fail or when the clinical course while on therapy is one of progressive neurologic impairment.34,54 Surgical removal of intracranial tuberculoma may be necessary in the patient presenting with clinical features of a single space-occupying lesion, midline shift, raised intracranial pressure, and lack of satisfactory response to chemotherapy.

PROGNOSIS AND OUTCOME The clinical outcome in any individual case is greatly influenced by age, duration of illness,

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clinical stage at the initiation of therapy, and the extent and character of optochiasmic arachnoiditis and vascular complications. In general, when antituberculous treatment is started before patients progress beyond stage I or during early stage II disease, cure rates of 85 to 90 percent may be achieved. Ages younger than 5 years and older than 50 years are associated with a poor prognosis. The observed mortality rate exceeds 50 percent in patients older than 50 years and in those with stupor and coma. The impact of stage of disease on therapeutic outcome is illustrated in a well-studied clinical series of 58 patients from Australia.13 Of 50 patients presenting with stage I or II disease, 1 died and 5 were left with mild or moderate neurologic sequelae. Of the 8 patients with stage III disease, 3 died and 3 were left with severe neurologic impairment.13 The incidence of residual neurologic deficits after recovery from tuberculous meningitis varies from 10 to 30 percent in recent series. Late sequelae include cranial nerve deficits, gait disturbance, hemiplegia, blindness, deafness, learning disability, dementia, and various syndromes of hypothalamic or pituitary dysfunction.

CONCLUDING COMMENTS Tuberculosis of the CNS, principally meningitis, remains the most devastating form of active mycobacterial infection. The natural history is that of insidious onset and subacute progression, prone to rapid deterioration once focal neurologic deficits supervene, usually resulting in stupor, coma, and death within 5 to 8 weeks of the onset of illness. Antituberculous chemotherapy is effective, but in order to achieve a favorable outcome, it is important that treatment be started promptly in the early stages of disease, before the occurrence of serious changes in mentation or progression of focal neurologic deficits. Of necessity, this requires understanding of the pathophysiology and clinical features of granulomatous meningitis. Patients with subacute meningitis syndrome and CSF findings of low glucose concentration, elevated protein level, and mononuclear pleocytosis should be treated immediately if there is evidence of tuberculosis elsewhere in the body or if prompt evaluation fails to establish an alternative diagnosis. Serial sampling of the CSF for culture and meticulous examination of stained smears remain the best means for

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AMINOFF’S NEUROLOGY AND GENERAL MEDICINE

reaching a bacteriologic diagnosis. Treatment need not be delayed as culture and stain for acid-fast bacilli remain positive for some days after antituberculous therapy has been started. In the 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. Serial CT or MRI is useful for following the course of therapy and for managing hydrocephalus and tuberculoma. The recommended chemotherapy regimen for presumed drug-sensitive infection is isoniazid and rifampin in all patients, together with pyrazinamide and ethambutol for the first 2 months. Adjunctive corticosteroid therapy can ameliorate complications and reduce mortality in patients with stage II and III disease. Surgical shunting should be considered early in the patient with advancing hydrocephalus and symptoms or signs attributable to raised intracranial pressure.

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