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Extrapulmonary Tuberculosis: Tuberculous Meningitis New Developments

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Extrapulmonary Tuberculosis: Tuberculous Meningitis New Developments Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2011; 15: 365-386 Extrapulmonary tuberculosis: tuberculous meningitis new developments R. GALIMI From the Department of Neurology, Local Health Unit of Valtellina and Valchiavenna, Sondalo Hospital, Sondrio (Italy) Abstract. – Tuberculosis (TB) can involve Mycobacterium tuberculosis (Mtb). The emer - any organ system in the body. Extrapulmonary gence of drug resistant tuberculosis poses a se - involvement can occur in isolation or along with rious threat to the control of this pathogen, and a pulmonary focus as in the case of patients with the development of drugs that are active against disseminated tuberculosis. Tuberculosis menin - the resistant strains is vital. Further research into gitis (TBM) is the most severe form of extrapul - the epidemiology, immune mechanisms, diagno - monary tuberculosis. TBM a medical emergency, sis, treatment, and prevention of TBM is urgently is still a major cause of serious illness in many needed . parts of the world. TBM remains difficult to diag - Key Words: nose, and it is usually due to hematogenous dis - semination of the tubercle bacillus. The exact in - Mycobacterium tuberculosis, Bacillus Calmette-Guérin, cidence and prevalence are not known. The clini - Extrapulmonary tuberculosis, Tuberculous meningitis, cal spectrum is broad and may be non-specific Human immunodeficiency virus, Dexamethasone, Anti- making early diagnosis difficult. Improved out - tuberculosis agents, Neurological sequelae. come requires early recognition and treatment of these conditions. Clinical features included fever for more than 7 days, headache, or neck stiff - ness. While TBM is a disease of childhood, tu - berculomas and spinal tuberculosis are invari - Introduction ably an adult manifestation. In HIV infection, TB is often atypical in presentation, frequently caus - Tuberculosis (TB) is a major cause of morbid - ing extrapulmonary disease, and patients have a high incidence of TBM. Clinical response to anti - ity and mortality. It is a major global health prob - tuberculous therapy in all forms of neurotuber - lem with 9 million new cases and almost 2 mil - culosis is excellent if the diagnosis is made early lion deaths per year, of which the majority (55%) before irreversible neurological deficit is estab - are in Asia 1. Extrapulmonary tuberculosis usual - lished. Diagnosis is based on the characteristic ly presents more of a diagnostic problem than clinical picture, neuroimaging abnormalities, pulmonary tuberculosis. In part this relates to its cerebrospinal fluid changes and the response to anti-tuberculosis drugs. Diagnosis is best made being less common and, therefore, less familiar with lumbar puncture and examination of the to most clinicians. Extrapulmonary tuberculosis cerebrospinal fluid (CSF). Suspect TBM if there has become more common since the advent of is a CSF leucocytosis (predominantly lympho - human immunodeficiency virus (HIV) infection. cytes), the CSF protein is raised, and the CSF In addition, extrapulmonary tuberculosis in - plasma glucose is <50%. Rapid techniques volves relatively inaccessible sites and, because based on nucleic acid amplification such as PCR of the nature of the sites involved, fewer bacilli are more sensitive and specific as they attempt to detect specific DNA sequences of the organ - can cause much greater damage. In 2007, over 13 ism. The hallmark pathological processes are 000 tuberculosis (TB) cases were reported in the meningeal inflammation, basal exudates, vasculi - USA 2. Nearly 20% of patients with TB develop tis and hydrocephalus. Treatment delay is extrapulmonary manifestations 3. While pul - strongly associated with death and empirical an - monary disease is the most common manifesta - ti-tuberculosis therapy should be started prompt - tion of TB, the involvement of the central ner - ly in all patients in whom the diagnosis of TBM is suspected. Corticosteroids reduce the number of vous system (CNS) is associated with the most deaths. Development of an effective vaccine severe form of disease, namely tuberculous against tuberculosis hinges on an improved un - meningitis (TBM). TBM is one of the most com - derstanding of the human immune response to mon forms of central nervous system infections, Corresponding Author: Rocco Galimi, MD; e-mail: [email protected] 365 R. Galimi especially in many developing countries where It is a gram-positive, aerobic, non-spore-forming, tuberculosis remains highly endemic, and it is a non-motile, pleomorphic rod that is distantly relat - severe form of extrapulmonary tuberculosis. ed to the Actinomycetes. Mtb is the most com - TBM occurs when Mycobacterium tuberculo - mon species to cause TB in humans. It is an ob - sis (Mtb), the bacterium responsible for tubercu - ligate pathogen and cannot multiply outside host losis, invades the membranes and fluid surround - cells. It can survive for long periods under ad - ing the brain and spinal cord. TBM is related to verse conditions. Human to human transmission the prevalence of TB in the community, and it is is most common. Mtb is an acid-fast bacterium, still the most common type of chronic CNS in - and it is very small, only 2 to 4 micrometers in fection in developing countries. Bacterial and length. It is known as acid fast because of stain - host’s genetic factors play a crucial role in its ing characteristics. pathogenesis. TBM usually results from the The characteristic staining quality of these haematogenous spread of primary or post-prima - organisms is their ability to resist decolorization ry pulmonary infection, or from the rupture of a of carbol fuchsin by acid-alcohol in the Ziehl- subependymal tubercle into the subarachnoid Neelsen process due to the high lipid content of space. TBM differs from that caused by most the cell wall. The Ziehl-Neelsen (ZN) stain and other common bacteria in that the course is more its modifications historically have been essen - prolonged, the mortality rate is higher, it is al - tial tools in the identification of mycobacteria ways secondary to tuberculosis elsewhere in the (Figure 1). body. The infection usually begins in the lungs, Lowenstein-Jensen medium is most popular and then travels through the bloodstream to the and widely available culture medium to grow meninges where small abscesses are formed. Mtb. Like other microbes, it can mutate and af - Many investigations have confirmed that ge - fect characteristics such as drug sensitivity, netic factors are involved in the disease, and which is the focus of this review. In order for these include adoption studies, twin studies, Mtb to establish infection it must first gain entry genome-wide linkage and population-based case- into resident alveolar macrophages following in - control association studies 4. Initially, differences halation of infectious aerosols. in susceptibility to TBM were recognised The main cellular reservoirs of these organisms through numerous observations, such as the wide in the host are tissue macrophages, although the range of responses seen after exposure to Mtb. organisms also exist extracellularly. Macrophages The clinical features of TBM mimic those of other chronic meningoencephalitides, causing considerable diagnostic difficulty 5. The disease is difficult to recognize, and a high index of suspi - cion is necessary to establish the diagnosis. In low-incidence geographic areas, clinicians should suspect tuberculous meningitis in mem - bers of immigrant groups from high-incidence areas, as well as in patients who abuse alcohol or drugs and those with immunosuppression from any cause. Early diagnosis is important for the success of the treatment 6. If detected early, tuber - culous meningitis usually responds to standard chemotherapy supplemented with corticos - teroids. Meningitis is the most common form of CNS disease and is discussed in depth here. This review focuses on the various aspects of TBM, and special emphasis is given to recent de - velopments in the early detection, phatogenesis and management of this dreaded disease. Etiology Figure 1. Mycobacterium tuberculosis stains with Ziehl- Mtb, the causative agent of tuberculosis (TB), is Neelsen stain (one of the most widely used acid-fast stain - a facultative intracellular parasite of macrophages. ing method). 366 Extrapulmonary tuberculosis: tuberculous meningitis new developments patrolling the distal airways avidly engulf inhaled defined as a positive tuberculin skin test (TST) bacteria using a variety of phagocytic receptors. In and no evidence of TB disease, has to be detect - order for Mtb to establish infection it must first ed and treated to prevent extension and dissemi - gain entry into resident alveolar macrophages fol - nation of TB, especially in children. lowing inhalation of infectious aerosols. A number The majority of human immunodeficiency virus- of different phagocytic receptors have been impli - infected patients with culture-positive tuberculous cated in Mtb entry to macrophages, with comple - meningitis had clinical or radiologic evidence of ment receptor and mannose receptor likely the extra-meningeal tuberculosis as well 11 . The inci - predominant pathways. Intracellular parasitism is dence in neonates was 31.5 per 100 000 as com - accomplished by a variety of mechanisms that in - pared with 0.7 per 100 000 among older children 12 . clude altered trafficking of bacteria during endo - In Germany, 26 302 tuberculosis cases were regis - cytosis, interference with host Ca 2 signaling path - tered
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