Central nervous system

Central nervous system (CNS) disease caused by Mycobacterium tuberculosis is an uncommon yet highly devastating manifestation of tuberculosis, which was universally fatal in the era before antituberculosis therapy. CNS tuberculosis accounts for approximately 1% of all cases of tuberculosis, carries a high mortality and a distressing level of neurological morbidity, and disproportionately afflicts children and human immunodeficiency virus (HIV)-infected individuals. Due to its relative rarity and the protean nature of the symptoms, tuberculosis of the CNS remains a formidable diagnostic challenge. Because the burden of CNS tuberculosis lies largely in resource-starved regions of the world, additional challenges in implementing practical and usable methods to diagnose and treat this disease remain largely unmet

While other clinical manifestations of tuberculosis have received considerable research attention, fundamental questions regarding the pathogenesis, diagnosis, treatment, and management of CNS tuberculosis remain unanswered. What is the best way to diagnose CNS tuberculosis? What is the optimal treatment for this disease? How can we mitigate the significant neurological morbidity among survivors? How can we more rapidly diagnose CNS tuberculosis? These questions remain open. Because infection with M. tuberculosis afflicts primarily humans, in order to advance our understanding of the neuropathogenesis of M. tuberculosis, the need for an appropriate animal model is paramount. Although several animal models have been described, none truly mimics human infection.

The purpose of this review is to highlight the current understanding of the neuropathogenesis of M. tuberculosis and to discuss certain epidemiological, clinical, diagnostic, and therapeutic aspects of CNS tuberculosis.

EPIDEMIOLOGY

In 2005, there were an estimated 8.8 million new cases of active tuberculosis reported annually, resulting in an estimated 1.6 million deaths per year (242). Tuberculosis remains a worldwide burden, with a large majority of new active tuberculosis cases occurring in underdeveloped and developing countries (242). In 80% of new tuberculosis cases, demographic factors such as poverty, crowding, malnutrition, and a compromised immune system play a major role in the worldwide epidemic, while the remaining 20% of tuberculosis cases are associated with HIV in sub-Saharan Africa (235, 242)

Infection of the CNS is one of the most devastating clinical manifestations of tuberculosis. In a large-scale epidemiological study of extrapulmonary tuberculosis in the United States, CNS involvement was noted in 5 to 10% of extrapulmonary tuberculosis cases (172), with more recent CDC data in 2005 indicating that 6.3% of extrapulmonary cases (1.3% of total tuberculosis cases) involve the CNS (31). In the largest prospective epidemiological study on CNS tuberculosis, the chance of developing CNS tuberculosis was 1.0% among 82,764 tuberculosis cases from 1970 to 2001 in a Canadian cohort (157).

Several risk factors for CNS tuberculosis have been identified. Both children (56) and HIV-coinfected patients (14, 52, 169) are at high risk for developing CNS tuberculosis. Other risk factors include malnutrition and recent measles in children (246) and alcoholism, malignancies, and the use of immunosuppressive agents in adults (101, 143, 233). Studies conducted in developed countries have also identified that foreign-born individuals (individuals born outside of developed countries) are overrepresented among CNS tuberculosis cases (19, 157).

Looking at the impact of CNS tuberculosis, a study in Spain documented that CNS tuberculosis accounted for 3.2% of tuberculosis deaths in 1993 (the rate was 0.06), a rate that had steadily declined over the previous 20 years (60). In a large study in Taiwan, Lu et al. reported that 1.5% of tuberculosis deaths between 1997 and 2001 were attributable to CNS disease, a percentage that had increased from previous years (118).

PATHOGENESIS OF TUBERCULOSIS OF THE CENTRAL NERVOUS SYSTEM

Overview of Pathogenesis

M. tuberculosis is an aerobic, nonmotile, non-spore-forming, acid-fast bacillus (AFB) that infects primarily humans. Its doubling time is quite slow (15 to 20 h) and requires several weeks to grow on conventional Löwenstein-Jensen medium, where it tends to grow in parallel groups, producing the colonial characteristic of serpentine cording. Biochemical as well as RNA/DNA-based methods can identify M. tuberculosis from other AFB.

The acquisition of M. tuberculosis infection occurs through the inhalation of droplet nuclei containing the bacilli, eventually leading to deposition in the lung alveoli. Once in the alveoli, the bacilli interact with alveolar macrophages through a multitude of different receptors (15, 53, 113, 158, 232). Once these innate immune cells are triggered, numerous cytokines and chemokines are released, the activation of a type 1 T-helper cell-mediated immune response occurs, and, ultimately, a granuloma is formed. Early in this process, prior to the actual containment of the infection, bacilli are filtered into draining lymph nodes, and there exists a low-level bacteremia in which M. tuberculosis disseminates to distant sites in the body (177). This hematogenous seeding occurs most frequently in regions of the body that are highly oxygenated, including the brain. A complex interplay of host immune factors and M. tuberculosis virulence factors in the end determines whether or not the infection is contained and whether, or to what extent, the dissemination of the bacilli leads to clinical disease (177).

In Vitro Models of CNS Tuberculosis

The mechanism by which M. tuberculosis crosses the BBB into the CNS is not well characterized. Some have postulated that free bacilli traverse across the endothelial barrier, while others suggested that bacilli enter via the passage of infected macrophages. One method of examining this question is to develop an in vitro model of the BBB and evaluate how M. tuberculosis interacts with this barrier. Adapting an in vitro model used for examining other bacteria that cause meningitis (98), Jain et al. used an in vitro monolayer of human brain microvascular endothelial cells and infected them with several strains of mycobacteria (75). They reported that M. tuberculosis H37Rv and CDC1551 were able to invade and traverse the endothelial monolayer, thus supporting the notion that extracellular mycobacteria are capable of traversing these highly specialized endothelial cells. However, while their in vitro model utilized brain microvascular endothelial cells, cells that form the brain side of the BBB (mainly astrocytes) were not included in the model, and thus, it is unclear what role these cells play in defense against entry into the brain parenchyma. Despite this, the model proposed by Jain et al. will go a long way toward understanding the important interaction of mycobacteria and endothelial cells.

Animal Models of CNS Tuberculosis

PATHOLOGY

TBM

After the release of tubercle bacilli from granulomatous lesions into the subarachnoid space, a dense gelatinous exudate forms; it is most florid in the interpeduncular fossa and suprasellar region anteriorly, and it may extend throughout the prepontine cistern and surround the spinal cord. This exudate envelops arteries and cranial nerves, creating a bottleneck in the flow of cerebrospinal fluid at the level of the tentorial opening, which leads to hydrocephalus. The exudate contains erythrocytes, neutrophils, and macrophages, followed by lymphocytes in more mature exudates. The Rich foci typically follow the vascular pattern and are located both in the meninges and in the brain parenchyma. Of note, Rich foci are not preferentially distributed to the basilar areas of the brain where the exudate is typically located.

Tuberculoma

Tuberculomas are thought to arise when tubercles in the brain parenchyma enlarge without rupturing into the subarachnoid space. As such, they often occur in the absence of TBM but certainly may occur along with TBM. They more commonly arise as solitary lesions, but multiple tuberculomas are seen. Tuberculomas of the brain show a typical granulomatous reaction consisting of epithelioid cells and giant cells mixed with predominantly lymphocytes around a central area of caseating necrosis.

Tuberculous Brain Abscess

Brain abscess formation is a rare manifestation of CNS tuberculosis. Tuberculous brain abscess develops either from parenchymal tubercular granulomas or via the spread of tuberculous foci from the meninges and is characterized by an encapsulated collection of pus containing viable bacilli without evidence of the classic tubercular granuloma and must be distinguished from granuloma with central caseation and liquefaction mimicking pus

CLINICAL FEATURES