Keywords
tuberculous meningitis, hypoglycorachia (low CSF glucose), tuberculoma, hydrocephalus, CNS vasculitis, basal ganglia infarction, arachnoiditis, spinal arachnoiditis
Tuberculosis in all its forms remains a challenging clinical problem and a public health issue of considerable magnitude. 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. 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.
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. Conceptually, there is a two-phase 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 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 subarachnoid 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. This is the usual sequence in childhood tuberculous meningitis, as infants and young children are especially susceptible to progressive hematogenous dissemination after primary infection. 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 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.
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
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.
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 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. 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. 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. 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. Seizures are more common in children and are apt to be an early or presenting symptom. Table 41-1 lists common symptoms and signs at presentation, and the frequency range compiled from three clinical series in separate regions of the world.
| 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 | 40–50 |
| Adults | 5 |
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. 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 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.
Tuberculous Meningitis and HIV Infection
Coinfection with HIV has been reported in 21 percent of patients with extrapulmonary tuberculosis in the United States. 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. 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. 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.
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. 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.
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.
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/mm 3 in most patients, less than 100 cells/mm 3 in approximately 15 percent, and between 500 and 1,500 cells/mm 3 in 20 percent. 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 acid-fast 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. 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 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. 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. 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. In a meta-analysis of nucleic acid amplification tests used for the diagnosis of tuberculous meningitis, the pooled sensitivity was 56 percent and the specificity was 98 percent. CSF should be submitted for PCR testing whenever clinical suspicion is sufficiently high to warrant empiric therapy and initial stains for acid-fast 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. 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. 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 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.
MRI is the preferred imaging modality for defining lesions of the basal ganglia, midbrain, and brainstem. 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. 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 .
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