Tuberculosis of the Central Nervous System

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, such lesions coalesce to form larger caseous foci, some of which may lie 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, a subpial or subependymal tuberculoma may destabilize and erode into the subarachnoid space, producing meningitis ( Fig. 40-1 ). It follows that the propensity for developing clinical disease 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 following primary infection. Adult cases also develop in association with the bacillemia of progressive miliary disease or other less apparent or entirely hidden foci of chronic organ tuberculosis. 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, then destabilize when local injury or a 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 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 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 or weeks, 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 blood vessels.

Vasculitis with resultant thrombosis and hemorrhagic infarction develops 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 much of the residual neurologic disabilities observed in patients who survive.

Extension of the inflammatory process to the basilar cisterns impedes CSF circulation and resorption, leading to communicating hydrocephalus in most cases that have been symptomatic for longer than 2 to 3 weeks. Obstruction of the aqueduct develops less frequently from contraction of exudate surrounding the brainstem or from a strategically placed brainstem tuberculoma. In far-advanced cases, increased intracranial pressure may lead to brainstem compression and tentorial herniation.

Clinical Presentation