Pathology and pathogenetic mechanisms in neurotuberculosis.

The mechanisms and the changes described herein typically begin with a dense basal meningeal exudate often resulting from a "Rich focus" along the basal surface of the cerebrum or ventricular ependyma. In the interpeduncular fossa, when the exudate is copious, among other structures the proximal parts of the optic nerves and of the internal carotid arteries are seen surrounded and compressed by the exudate. This exudate is made up of small and large mononuclear cells, including epithelioid cells, which also act as macrophages and may fuse to form Langhans' giant cells. Further extension of this exudate along small proliferating blood vessels into the brain substance constitutes a border zone encephalitis with the development of focal and diffuse ischemic brain changes due to vasculitis. Entrapment and occasional arteritic occlusion of larger arteries, such as the middle cerebral in the Sylvian fissures, results in infarction. Blockage of the basal subarachnoid cisterns around the midbrain and pons by the dense basal exudate or narrowing of aqueduct and third ventricle by a small tuberculoma causes consequent hydrocephalus. Development of many or one large focal granuloma (i.e., tuberculoma) occurs in the cerebrum, cerebellum, and/or brain stem. Similar pathogenetic mechanisms produce tuberculous spinal meningitis myeloradiculopathy that may be secondary to or occur before cranial tuberculous meningitis. More extensive damage to the white matter may occur together with the infrequent onset of perivascular demyelination on the basis of a hypersensitivity reaction to tuberculoprotein (i.e., "allergic tuberculous encephalopathy"). Finally, there may be a part played by NO in the production of the vascular and perivascular inflammatory central nervous system changes and a role for the the potential beneficial action of corticosteroids, especially in cases of tuberculous encephalopathy.

BCG vaccination in India and tuberculosis in children: newer facets.

With the extended programme of immunisation and since 1985 the universal programme of immunisation and the coverage status of BCG vaccination in India has been very good, although it is still unsatisfactory in the eastern states. It is emphasized that BCG vaccination cannot prevent natural tuberculous infection of the lungs and its local complications, although it reduces the haematogenous complications of primary infection. However, this is not true for malnourished children who, inspite of BCG vaccination, develop serious, and often fatal types of tuberculosis such as miliary, meningitic and disseminated tuberculosis. The tuberculin anergy in malnourished children, is mainly responsible for high morbidity and mortality. BCG vaccinated, well-nourished children manifest modified patterns of tuberculous disease, following infection. The most important manifestation is the increased incidence of intrathoracic tuberculosis, specially enlargement of the various groups of mediastinal nodes and their local complications. Localisation of the disease by T cell immunity, due to BCG vaccination is responsible for this and the much lower incidence of haemotological complications such as neurotuberculosis and disseminated disease. In these children, the clinical picture of neurotuberculosis is also modified, with a tendency for more localised involvement of the brain and meninges. Similarly, vaccinated children may present with hepatomegaly, splenomegaly or isolated organ disease. It is important to relearn the new patterns of tuberculosis disease seen in vaccinated, non-malnourished children, and to a lesser extent in children with grade 1 to 2 protein energy malnutrition (PEM). With these limitations of BCG vaccination, other strategies like chemoprophylaxis need multicentric trials in high risk children, in different parts of the country.

PIP: Tuberculosis is a major global public health problem with 8 million new cases of pulmonary tuberculosis in the world per year and 2.89 million deaths. In India in 1989, the approximate morbidity of tuberculosis was 2%, i.e., there were 15 million cases of pulmonary tuberculosis. Of these 25% were sputum positive, posing a serious threat of transmitting the infection to children. Of the 4 million infectious patients, over 1 million would be considered as chronic or relapsing cases who have been partially treated. The Indian National Tuberculosis Program (NTP) has now completed 25 years. Every year, 1 million new cases of adult tuberculosis are detected. 70% of these patients do not complete standard regimens and 45% do not complete short course regimens. In 1983 about 80.71 million children under 16 years old in India were infected. In a survey carried out in 1990 in urban and rural areas of Delhi, BCG vaccination coverage was 90% in the urban and 84.7% in the rural areas. Impact of BCG vaccination has demonstrated that classical or generalized tuberculosis meningitis, miliary TB, disseminated tuberculosis, and other serious complications of primary infections go on occurring in malnourished BCG-vaccinated children. The variable efficacy of the present BCG vaccine observed in different prospective human trials has shown the necessity of conducting research of immunoregulatory mechanisms, and developing newer vaccines for global control of tuberculosis. Other topics include immune responses to the present BCG vaccine (cellular immunity, macrophage, T-lymphocytes); BCG vaccination and tuberculin test; BCG vaccination by nebulization (aerosol BCG vaccine) by the respiratory route; a booster dose of BCG vaccine in the preschool period; protein energy malnutrition and delayed hypersensitivity reaction; BCG test in non-vaccinated and vaccinated children; HIV infections or their symptoms as a contraindication to BCG vaccination; and BCG lymphadenitis in children (7% in seropositive HIV children).

Protein energy malnutrition (PEM), brain and various facets of child development.

Protein energy malnutrition (PEM) is a global problem. Nearly 150 million children under 5 years in the world and 70-80 million in India suffer from PEM, nearly 20 million in the world and 4 million in India suffer from severe forms of PEM, viz., marasmus, kwashiorkor and marasmic kwashiorkor. The studies in experimental animals in the west and children in developing countries have revealed the adverse effects of PEM on the biochemistry of developing brain which leads to tissue damage and tissue contents, growth arrest, developmental differentiation, myelination, reduction of synapses, synaptic transmitters and overall development of dendritic activity. Many of these adverse effects have been described in children in clinical data, biochemical studies, reduction in brain size, histology of the spinal cord, quantitative studies and electron microscopy of sural nerve, neuro -CT scan, magnetic resonance imaging (MRI) and morphological changes in the cerebellar cells. Longer the PEM, younger the child, poorer the maternal health and literacy, more adverse are the effects of PEM on the nervous system. Just like the importance of nutrients on the developing brain, so are the adverse effects on the child development of lack of environmental stimulation, emotional support and love and affection to the child. When both the adverse factors are combined, the impact is severe. Hence prevention of PEM in pregnant and lactating mothers, breast feeding, adequate home based supplements, family support and love will improve the physical growth, mental development, social competence and academic performance of the child. Hence nutritional rehabilitation, psychosocial and psychomotor development of the child should begin in infancy and continue throughout. It should be at all levels, most important being in family, school, community and various intervention programmes, local, regional and national. Moreover medical students, health personnel, all medical disciplines concerned with total health care and school teachers should learn and concentrate on the developmental stimulation and enrichment of the child.

Pediatric tuberculosis pyramid and its fate with and without chemotherapy/chemoprophylaxis.

The latest available information on total and infectious cases of tuberculosis in the country and also large number of sputum positive cases being detected annually, particularly after the involvement of multipurpose workers in the primary health care programme for the control of tuberculosis, is presented. The consequences of the large pool of infectious cases in the population lead to spread of bacilli to children with development of primary infection in them. These children with primary infection, specially high risk group in infancy and early childhood, get serious complications of the disease. It may be emphasized that BCG vaccination cannot prevent the lodgement of tubercle bacilli in the lung but can only contain or restrict haematogenous spread. Inspite of increasing coverage of infants with BCG vaccination there are an increasing number of cases of intrathoracic tuberculosis, particularly various groups of mediastinal nodes. However, to a lesser extent haematogenous complications do occur in malnourished children, as BCG has a limited value in preventing serious complications in children with malnutrition. The clinical pattern of pediatric tuberculosis has also changed in vaccinated and partly or inadequately drug treated children. Hence, chemoprophylaxis/chemotherapy to prevent complications of primary infection has been tried. Even relatively privileged children in developed countries are reported to have complications of primary infection to an extent of 10 to 15%, as per the studies all over world. So preventive chemoprophylaxis, preferably with two bactericidal drugs, should be considered as the main strategy for controlling primary infection. Chemoprophylaxis with two drugs should be used as incidence of isoniazid resistant bacilli has increased. All concerned with child health should consider the strategy of treatment of primary infection in high risk children by chemoprophylaxis by starting a large multicentric trial both in urban and rural areas, as a part and parcel of primary health care intervention already in practice for cases of sputum positive pulmonary tuberculosis.

Humoral response to defined epitopes of tubercle bacilli in adult pulmonary and child tuberculosis.

In order to investigate the humoral response to tuberculosis in different categories of patients, serum antibody levels to six epitopes of Mycobacterium tuberculosis in adult pulmonary and child tuberculosis were determined. Serum antibody titres were determined by competitive inhibition with radio-labelled murine monoclonal antibodies in 67 adults and 85 children with tuberculosis and in 79 age-matched controls. BCG vaccination (n = 39) and self-healed tuberculosis (n = 11) in adults gave rise to higher antibody titres to TB68, TB23 and TB72 epitopes (all p less than 0.003) when compared to non-vaccinated controls (n = 18). TB68 titres were higher (p = 0.006) in self-healed than in vaccinated adults. Adult sputum-negative patients (n = 15) had higher titres to TB71 (p = 0.015) and ML34 (p = 0.02) epitopes compared to BCG-vaccinated healthy controls, while sputum-positive patients (n = 41) had higher titres to all epitopes tested (all p less than 10(-4]. The diagnostic sensitivity, with a 95% specificity, was best with the combination of probes TB23, TB68, TB72 for sputum-positive (85%) and TB78, ML34 (53%) for sputum-negative patients. Antibody titres in children with tuberculosis were lower than in adult patients; diagnostic sensitivity in histologically or microbiologically proven cases (n = 18) was only 44%, while that in mediastinal lymph-adenitis (n = 67) was 13.5%. This study suggests that the magnitude and specificity of the humoral response to tubercle bacilli varies with site and severity of infection; the implications for pathogenesis or protective immunity are discussed.