Mycobacterium tuberculosis

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Epidemiology and Risk Factors. Chopin, Keats, Thoreau, Paginini, Modigliani, Elizabeth Browning, and Thomas Wolfe died of tuberculosis. y y y In the beginning of the 20th century, tuberculous meningitis was common; then after the Second World War a dramatic decrease in the incidence of tuberculosis occurred in the United States and Europe. Tuberculosis and CNS tuberculosis continued to be prevalent in developing countries. Beginning, however, in 1985 the incidence rates of tuberculosis began to increase in the United States. This resurgence of disease was concentrated among males, 25 to 44 years of age, and particularly among immigrants from areas with a high prevalence of tuberculosis infection. A marked increase in the incidence of tuberculosis in long-term residents of American nursing homes was also noted. CNS tuberculosis is considerably more frequent in individuals with AIDS and tuberculosis involving other organ systems than in immunocompetent persons with tuberculosis. In some parts of the world, the most common AIDS-associated CNS infection is tuberculous meningitis. y

Pathogenesis and Pathophysiology. Tuberculous meningitis does not develop acutely from the hematogenous spread of tubercle bacilli to the meninges from a pulmonary source of acute infection. Isolated miliary tubercles form in the parenchyma of the brain or the meninges during the hematogenous dissemination of tubercle bacilli during the course of the primary infection or episodically from the endogenous reactivation of latent tuberculosis elsewhere in the body. The tubercles tend to enlarge and are usually caseating. y The fate of these tubercles and the subsequent course of infection are at least, in part, a function of the immunological capacity of the host. Minute caseous foci may be completely eliminated by macrophages leaving no residua of infection. Larger caseous foci may shelter viable mycobacteria that cause reactivated disease only in the presence of impaired host immunity. y The propensity for a caseous lesion to produce meningitis is determined by its proximity to the subarachnoid space, the rate at which fibrous encapsulation develops, and the rate at which the lesions enlarge. Organisms proliferate in the caseous centers, eventually leading to the rupture of the tubercle. Subependymal caseous foci may remain quiescent for months or years but then cause meningitis through the discharge of bacilli and tuberculous antigens into the subarachnoid space. y , y The neurological complications of tuberculous meningitis are initiated by a hypersensitivity reaction that occurs in the subarachnoid space when tuberculoproteins are released by the rupture of a caseous lesion. The exudate is located predominantly in the basilar cisterns and surrounds the cranial nerves and major blood vessels at the base of the brain. As the basilar cisterns are filled with a purulent exudate, the flow of CSF is blocked and an obstructive hydrocephalus may develop. The inflammatory exudate also obstructs the resorption of CSF by the arachnoid granulations, the result of which is a communicating hydrocephalus. Cerebral ischemia and infarction occur either as the result of vasculitis caused by direct invasion of the arterial walls by mycobacteria and inflammatory cells or by the compression of the blood vessels at the base of the brain from the inflammatory exudate.y , y Cranial nerve abnormalities resulting from tuberculous meningitis may result from either mechanical compression of the nerve by the purulent exudate or as a result of vasculitic infarction of the nerve. y Border-zone encephalitis describes an inflammatory reaction in the brain tissue underlying areas of thick, adherent exudate.y y y y Tuberculous encephalopathy refers to the development of cerebral edema occasionally with perivascular demyelination or hemorrhagic leukoencephalopathy deep in the white matter of the brain at a distance from vascular abnormalities and purulent exudate. It is hypothesized that this is a purely allergic phenomenon mediated by tissue hypersensitivity, either to the bacilli or their antigens or possibly to a myelin-related antigen of brain tissue itself. y

Clinical Features. The clinical presentation of tuberculous meningitis is either an acute meningoencephalitis characterized by coma, raised intracranial pressure, seizures, and focal neurological deficits or a slowly progressive illness with persistent and intractable headache followed by confusion, lethargy, and cranial nerve deficits. Fever may or may not be present in the course of this infection. The sixth cranial nerve is the most frequently affected by

tuberculous meningitis followed by the third, fourth, seventh, and less commonly, the second, eighth, tenth, eleventh, and twelfth cranial nerves. y Hemiparesis may develop as a result of ischemic infarction in the medial striate and thalamoperforating arteries. The most commonly reported symptoms in children include nausea, vomiting, and behavioral changes. Seizures are an infrequent presenting sign, although more than 50 percent develop seizures during the initial hospitalization. y In patients with an acute meningoencephalitis syndrome, coma may evolve rapidly and is because of increased ICP from both cerebral edema and communicating and obstructive hydrocephalus. The clinical syndrome of tuberculous encephalopathy is characterized by convulsions, stupor, coma, involuntary movements, paralysis, and decerebrate spasms or rigidity with or without clinical signs of meningitis or CSF abnormalities of tuberculous meningitis. y The clinical presentation of tuberculous meningitis in HIV-infected individuals is similar to the clinical presentation in immunocompetent patients; however, HIV-infected patients are more likely to have an acellular spinal fluid at presentation and have a higher incidence of intracerebral mass lesions. y

Evaluation. The combination of an unrelenting headache (+/- low grade fever) with malaise and anorexia and a CSF lymphocytic pleocytosis with a mild decrease in the glucose concentration is suggestive of tuberculous meningitis. The initiation of therapy should not await bacteriological proof of tubercle bacilli by smear or culture. The development of hydrocephalus and the clinical scenario just described is additional strong evidence for tuberculous meningitis. The absence of radiographical evidence of pulmonary tuberculosis and/or a negative tuberculin skin test does not exclude the possibility of tuberculous meningitis. The classic "Ghon complex" refers to Anton Ghon's observation from autopsy specimens that the primary lesion of tuberculosis is in the lung with secondary infection in the tracheobronchial lymph nodes.y In addition to the primary complex, chest radiographic abnormalities suggestive of pulmonary tuberculosis are hilar adenopathy, a miliary pattern, upper lobe infiltrate, cavitations, and lobar consolidation. CNS disease may develop from caseous foci in organs other than the lung with subsequent hematogenous dissemination of virulent tubercle bacilli to the CNS. The adrenal gland, bone, genitourinary tract, and the mediastinal and abdominal lymph nodes are all potential sources of caseous foci, which may serve as "seed beds" for the later development of hematogenous dissemination of tubercle bacilli. y The intradermal tuberculin skin test is negative in 50 to 70 percent of patients with tuberculous meningitis and often becomes positive during the course of therapy. y , y The classic CSF abnormalities in tuberculous meningitis are as follows: (1) an elevated opening lumbar pressure; (2) increased WBC count between 10 to 500 cells/mm 3 with a predominance of lymphocytes; (3) an elevated protein concentration in the range of 100 to 500 mg/dL; (4) a decreased glucose concentration (the median glucose concentration is approximately 40 mg percent); and, (5) a positive culture in 75 percent of patients requiring 3 to 6 weeks for growth. A cobweb-like "skin" may form at the top of the CSF specimen and is the classic pellicle of tuberculous meningitis. Tubercle bacilli may become entangled in the skin of the pellicle and are more easily located by smear or culture of the pellicle than elsewhere in the CSF. y The last tube of CSF collected should be sent for acid-fast bacilli (AFB) smear. Positive smears are typically reported in only 10 to 40 percent of patients with tuberculous meningitis. The CSF chloride concentration and the bromide partition test have been disappointing in their ability to differentiate tuberculous meningitis from other etiologies of lymphocytic meningitis. The CSF chloride concentration typically decreases as the CSF protein concentration increases; therefore, this is a rather nonspecific test. The bromide partition test measures the ratio of serum to CSF bromide 24 hours after the oral administration of sodium bromide or the intravenous injection of radioactive bromide. y A low bromide partition ratio is seen in any infectious or inflammatory CNS disease that increases the permeability of the blood-CSF barrier. The concentration of tuberculostearic acid in CSF has been reported to be a sensitive marker for CNS tuberculosis and enjoyed a brief period of popularity, even though it was extremely difficult to find a laboratory that was able to run this assay. The PCR technique and other molecular diagnostic techniques for the detection of M. tuberculosis DNA in the CSF hold the greatest promise. y The sensitivity of the PCR technique for the detection of M. tuberculosis DNA in CSF is approximately 54 percent; however, false-positive results occur with rates of 3 to 20 percent.y

Management. The American Academy of Pediatrics recommends a combination of isoniazid (INH), rifampin, pyrazinamide, and streptomycin as the initial therapy of tuberculous meningitis in children. y The doses are listed in Tabje 42:3 . When antimicrobial sensitivities are known, the treatment regimen may be altered. Standard therapy uses four drugs for 2 months followed by INH and rifampin alone for S to 9 months. Most drug regimens include isoniazid, rifampin, and pyrazinamide and either ethambutol or streptomycin (in children too young to be monitored for visual acuity). y When the results of drug susceptibility studies are available, and if the organism is sensitive to INH and rifampin, ethambutol and pyrazinamide are continued



Isoniazid (INH)







10 mg/kg/d once daily

10 mg/kg/d 30 mg/kg/d 15 to 25 mg/kg/d 20 to 40 mg/kg/d

Dosage Adults

300 mg/d 50 mg/d S00 mg/d 30 mg/kg/d 15 to 25 mg/kg/d

Corticosteroids Dexamethasone


0.15 mg/kg every 6 hr

*When antimicrohial resistance is suspected.

0.15 mg/kg every 6 hr

The American Academy of Pediatrics recommends a combination of INH, rifampin, pyrazinamide, and streptomycin for tuberculous meningitis in children.

For altered consciousness, papilledema, focal neurological signs, impending herniation, spinal block, hydrocephalus. Ā§For intractable headache, papilledema with otherwise normal neurological examination .




10 to 15 mg/kg/d


10 to 15 mg/kg/d

Pyridoxine plus

50 mg/d

Ethambutol or

25 mg/kg/d

Pyrazinamide plus

20 to 30 mg/kg/d

Streptomycin or

20 to 40 mg/kg/d

Rifabutin or

300 mg/d


300 mg/d

for only 2 months, and then INH and rifampin are continued for a total of 9 to 12 months. Empiric therapy for tuberculous meningitis in HIV-infected individuals should include a combination of INH, pyridoxine, and rifampin plus ethambutol or pyrazinamide and either streptomycin or rifabutin or clofazimine ( ...JabJe.42-4: ). Corticosteroid therapy decreases meningeal inflammation. Isoniazid and pyrazinamide penetrate the CSF with or without meningeal inflammation, but the penetration of rifampin, streptomycin, and ethambutol is considerably better in the presence of meningeal inflammation. Dexamethasone therapy is recommended for patients with altered consciousness, papilledema, focal neurological signs, impending herniation, spinal block, and hydrocephalus. In addition, as patients are treated for tuberculous meningitis, the slow resolution of the inflammatory exudate in the basilar cisterns may obstruct the flow and resorption of CSF with the subsequent development of hydrocephalus. These patients may benefit from a short course of oral prednisone. A basic principle of management for patients with organisms that are resistant to one or more drugs is the administration of at least two agents to which a demonstrated susceptibility exists. For example, for patients with isolated INH resistance, INH should be discontinued and pyrazinamide and rifampin continued for the entire course of therapy. [81]

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