CASE REPORTTUBERCULOUS MENINGITIS

PRESENTED BY MUKHAMAD FARIED 110100351TESAR AKBAR NUGRAHA110100511

SUPERVISED BY:dr. Wisman Dalimunthe, Sp.A (K)

PEDIATRIC HEALTH DEPARTMENTHAJI ADAM MALIK GENERAL HOSPITALUNIVERSITY OF NORTH SUMATERA2015

ACKNOWLEDGMENTS

We are greatly indebted to the Almighty One for giving us blessing to finish this case report about Tuberculous Meningitis. This case report is a requirement to complete the clinical assistance program in Department of Child Health in H. Adam Malik General Hospital, Medical Faculty of North Sumatra University.

We are also indebted to our supervisor and adviser, dr. Wisman Dalimunthe, Sp.A (K) for much spent time to give us guidances, comments, and suggestions. We are grateful because without him this case report wouldnt have taken its present shape.

This case report has gone through series of developments and corrections. There were critical but constructive comments and relevants suggestions from the reviewers. Hopefully the content will be useful for everyone in the future.

Medan, 15th October 2015

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PresentatorsTABLE OF CONTENTS

ACKNOWLEDMENTSiiTABLE OF CONTENTS1CHAPTER 1 INTRODUCTION2CHAPTER 2 LITERATURE REVIEW4CHAPTER 3 CASE REPORT17CHAPTER 4 DISCUSSION56CHAPTER 5 SUMMARY58REFERENCES59

CHAPTER 1BACKGROUND1.1 BackgroundTuberculosis (TB) is a significant bacterial disease which principally affects the lungs. Its causal agent is Mycobacterium tuberculosis (Mtb) an intracellular facultative organism which can produce progressive disease or latent asymptomatic infection. Although TB is essentially a pulmonary disease, other organs and tissues can be infected, being cerebral TB is the most severe form.1 There is high prevalence of tuberculous meningitis (TBM) in developing countries, including indonesia, and the disease has a high mortality rate among infants and children. Neurological complication are common, and early diagnoseis and specific treatment for tuberculosis (TB) are essential for prevention of squelae or fatal outcomes.2TBM is the most severe complication of TB and frequently occurs in childhood. Lympho-hematogenous spread from primary pulmonary focus leads to the development of Rich focus in the brain. Rupturing of this cseous granuloma into the subarachnoid space causes 3 features responsible for the clinical manifestations of TBM: development of further tuberculomata; basal inflammatory exudates that cause cranial nerve palsies and obstruct cerebrospinal fluid (CSF) passages, resulting in hydrocephalus; and obliterative vasculitis leading to infarctions. Once the Rich focus has ruptured, a prodormal period of nonspecific symptoms, such s fever, vomiting, and behavioral changes, develops. As the disease progresses, neck stiffness, loss of consciousness, motor deficits, and convulsions will follow. TBM diagnosis is often only considered once irreversible neurologic damage has already occured.2 The outcome of TBM is known to be affected by age, stage of the disease at admission, and whether riased intracranial pressure (ICP) caused by obstructive hydrocephalus is actively treated.2

1.2 ObjectiveThis paper is one of the requirements to fullfil in the senior clinical assistance programs in Pediatric Department of Haji Adam Malik General Hospital, University of North Sumatra. In addition, this paper can be used as reference to know and understanding a litle about meningitis TB.

CHAPTER 2LITERATURE REVIEW2.1 Tuberculous Meningitis2.1.1 DefinitionTuberculous meningitis is an inflammation of the meningen that cause by primary tuberculosis (IKA UI, 2007). Tuberculous meningitis (TBM) is caused by Mycobacterium tuberculosis (M. tuberculosis) and is the most common form of central nervous system (CNS) tuberculosis (TB).4 Central nervous system (CNS) tuberculosis occurs in approximately 1% of all patients with active tuberculosis. It results from the haematogenous dissemination of Mycobacterium tuberculosis from primary pulmonary infection and the formation of small subpial and subependymal foci (Rich foci) in the brain and spinal cord. In some individuals foci rupture and release bacteria into the subarachnoid space causing meningitis. In others, foci enlarge to form tuberculomas without meningitis. Tuberculous meningitis (TBM) is the most dangerous form of infection with Mycobacterium tuberculosis.5

2.1.2 EpidemiologyTuberculosis of the central nervous system is the most severe manifestation of extrapulmonary TB and constitutes approximately 1% of all new cases annually, with Tuberculous Meningitis (TBM) being the commonest form of the disease. Several studies have attempted to assess its epidemiology with variable conclusions as the diseases incidence and mortality rates differ from country to country according to their individual socioeconomic and public health statuses. Mortality rates for instance have been described to range from 7 40% in developed countries, while the percentages from TB endemic countries as well as countries with high HIV prevalence have been found to be significantly higher, reaching a 69% in South Africa. The key point in understanding the epidemiological pattern of the disease is the fact that TBM and tuberculosis infection are closely related in this aspect, so that it is generally accepted that occurrence of the former in a community is correlated with incidence of the latter and vice versa. It is therefore considered safe to assume that at a global level these two entities share a common trend. According to the latest available data, in 2009 the global incidence of TB was 9.4 million cases which is equivalent to 137 cases per 100.000 population with most of them occurring in Asia and Africa and a smaller proportion occurring in Europe and the Region of the Americas. Developing countries in particular account for more than 80% of the active cases in the world. The global incidence rate after an initial fall during the 20th century rose due to the HIV epidemic with a peak in 2004 and a subsequent slow but steady decline that also involves the absolute number of TB related deaths. This impact of HIV on TB has accordingly influenced the pattern of TBMs incidence rates. In fact, HIV infection constitutes the most important determinant for the development of TBM followed by age. As far as the latter is concerned it is in turn determined by the socioeconomic status of a certain population. Therefore in populations with a low TB prevalence adults seem to be more affected than children. This is reversed in populations with a higher TB prevalence. Concerning childhood disease, TBM appears to affect mainly children under the age of 5 years with the mean age ranging from 23 to 49 months and according to literature close contact with a confirmed case of pulmonary tuberculosis is usually the culprit.6

2.1.3 EtiologyMycobacteria are aerobic, nonmotile, gram-positive rods ranging in appearance from spherical to short filaments, which may be branched. Their cell wall contains lipids, peptidoglycans, and arabinomannans. One distinct characteristic is their ability to retain dyes that are usually removed from other microorganisms by alcohols and dilute solutions of strong mineral acids such as hydrochloric acid. This ability is attributed to a waxlike layer composed of mycolic acids in their cell wall. As a result, they are termed acid-fast bacilli (AFB) after Ziehl-Neelsen (ZN) staining. The causative agents of TBM are mainly the members of M. tuberculosis complex and less commonly NTM. The incidence of CNS infection due to the latter has increased substantially since the onset of the HIV epidemic.6

2.1.4 PathogenesisThe initial point of tuberculosis infection is entry of the bacilli into the lungs via inhalation of infectious droplets, whereupon the bacteria colonize macrophages within the alveoli. During the progression of active pulmonary disease, bacteria may disseminate to local lymph nodes and bloodstream, whereupon spread throughout the systemic circulatory system may occur. It is also likely that extensive bacteremia following dissemination from the lungs increases the probability that a sub-cortical focus will be established in the CNS. Therefore, higher numbers of bacilli in the circulatory system may be associated with increased likelihood of CNS invasion and subsequent CNS TB.7The CNS is protected from the systemic circulatory system by the physiological blood brain barrier (BBB). This barrier is principally composed of tightly apposed human brain microvascular endothelial cells (Fig. 1). The basal portion of these endothelial cells is supported by astrocyte processes interspersed with the extracellular matrix. Paracellular transport is limited by the presence of endothelial cell tight junctions, while transcellular movement is restricted by the relative paucity of endocytic vesicles. Such properties render the barrier impermeable to many large, hydrophilic molecules and circulating pathogens. Also protective of the CNS is the blood-cerebrospinal fluid (CSF) barrier, providing spatial separation of the circulatory system from the CSF at the choroid plexus. Cells lining the blood-CSF barrier share similar properties to those lining the BBB, with enhanced tight junctions and more stringent regulation of transcytosis. Despite the integrity of this barrier, however, there are a number of bacterial and viral pathogens capable of crossing the BBB and causing subsequent meningitis / encephalitis.7

Fig. (1). Blood Brain Barrier.7

Much of the current understanding of the pathogenesis of CNS TB and subsequent meningitis comes from the meticulous work of Arnold Rich and Howard McCordock, who demonstrated upon autopsy that the majority of TB meningitis patients displayed a caseating focus in the brain parenchyma or the meninges. Rich postulated that these foci, also termed as Rich foci, develop around bacteria deposited in the meninges and brain parenchyma during the initial bacteremic phase. Much later, the rupture of these foci allowed dissemination of the bacilli into the subarachnoid space, causing diffuse, inflammatory meningitis (Fig. 2). Since the meninges and the brain parenchyma are anatomically and physiologically protected from the systemic circulation by the BBB, the mechanism by which the bacilli initially invade this barrier need to be elucidated. Theoretically, M. tuberculosis can cross the BBB as a free (extra-cellular) organism or via infected monocytes/neutrophils. While the latter hypothesis seems attractive, such cellular traffic is severely restricted into the CNS prior to invasion by the offending pathogen. Intravenous inoculation of free M. tuberculosis or M. bovis in guinea pigs and rabbits has been shown to produce CNS invasion as evidenced by the formation of tuberculomas in their brain parenchyma. Further, one report utilizing CD18 leukocyte adhesion deficient mice, suggests that free mycobacteria may transverse the BBB independent of leukocytes or macrophages. Finally, it is unclear whether, after invading the CNS, M. tuberculosis reside primarily within the parenchyma of the brain, the vessel wall, or the endothelial cells lining the microvasculature. Significant vasculitis associated with CNS tuberculosis and robust human endothelial cell invasion observed in vitro may suggest that M. tuberculosis reside, at least initially, in the endothelial cells lining the microvasculature.7

Fig. (2). Pathogenesis of Central Nervous System tuberculosis and subsequent tuberculous meningitis.7The spread of M. tuberculosis into the subarachnoid space following rupture of a Rich focus triggers a robust inflammatory T cell response. Studies of CSF cytokine levels in patients with TB meningitis have found elevated levels of TNF- and IFN-. The clinical manifestation of CNS tuberculosis is primarily a consequence of the inflammation which develops in response to M. tuberculosis in the CNS. Obstruction of the CSF by inflammatory infiltrate leads to hydrocephalus, and vasculitis contributes to infarction, causing potentially irreparable neurological damage. Inhibition of this inflammation may therefore help in preventing the sequelae of CNS TB. Though thalidomide, which inhibits TNF-, has not be shown to be beneficial for the treatment of TB meningitis in children, corticosteroids such as dexamethasone which suppress the production of inflammatory cytokines and chemokines lead to better outcomes and are recommended as adjunctive treatment for patients with TB meningitis.72.1.5 Clinical manifestationGenerally, the progression of tuberculous meningitis has 3 stage:81. Stage I: ProdormalThis stadium will progress in 1 3 week without any special clinical symptoms and without any neurological disorder. Experienced symptoms include fever, malaise, anorexia, abdominal pain and headaches, sleep cycles change, nausea, vomiting, constipation, irritable to apathy, but without loss of consciousness. Physical examination showed the large fontanelle bulging in infants. older children will experience a change of mood and decreased school performance. intermittent seizures may arise.8Prodromal stage may last a very short when tubercles broke into the subarachnoid space arrived - arrived so the trip can last clinical jump to the next stage quickly.82. Stage II: TransitionalAt this stage exudate was collected in cerebral gyrus which make the meningeal refleks positive, ie a stiff neck, Kernig, and brudzinsky (except in infants frequently meningeal refleks is negative). Decreased of consciousness (but not coma or delirium), hydrocephalus, papilaedema light, and the presence of tubercles in the choroid, and cranial nerve palsy. Cranial nerve that most commonly affected are N. VI that was followed by N. III, N. IV, and N. VII which can cause strabismus, diplopia, ptosis, and decreased pupil reaction to light. Older children will complain of severe headache and vomiting, while the baby would seem irritable and vomiting. The child may have symptoms of encephalitis in the form of a real focal neurological deficits accompanied by involuntary movements and speech disorders. Hydrocephalus that occure before symptoms of encephalitis is one characteristic of tuberculous meningitis.83. Stage III: Terminal.This stage takes place quickly, as long as 2-3 weeks. brainstem infarction due to vascular lesions or strangulation by exudates which experienced organization. Consciousness decreased to stupor or coma, more severe form of focal neurological deficits (hemiplegia to paraplegia). hyperpyrexia, papilaedema, hyperglycemia, opistotonus, decerebrate posture, pulse and irregular breathing, dilated pupils, and not react to light, or even death.8 2.1.6 DiagnosisThe diagnosis of tuberculous meningitis is not a simple work up especially on mild stage. It cannot be made or excluded on the basis of clinical findings2. Suspecting a tuberculous meningitis is a must if there is prolonged fever (>14 days, or >7 days if there is contact history with TB-confirmed family), patient still unconscious after antimicrobial treatment, positive meningeal sign, hydrocephalus and stroke with unclear etiology.8Evaluate contact history to TB-confirmed family, immunodeficiency possibility or drug-induced immunodepression. Evaluate BCG vaccination history, because BCG vaccination can decrease tuberculous meningitis risk until 50-80%.8Positive tuberculin test and chest radiography can confirm the suspicion, but the negative result doesnt eliminate the suspicion because non-reactive tuberculin and normal chest radiography is found at almost 50% patient. A complete blood count testing should be performed, and the erythrocyte sedimentation rate should be determined.8 Positive tuberculin test, chest radiography abnormal finding and the finding of infection source in family only can support the diagnoses. Tuberculin test often negative because of anergy, especially on terminal stage.9The gold standard of diagnosis is to find M. tuberculosis bacilli on cerebrospinal fluid (CSF) culture, but to growing the bacteria up needs long time at least 3-6 weeks and the positive result is found only on 50-75% cases if the CSF is enough (5-10 ml). So the therapy can be given based on CSF analysis result or the finding of acid-resistant bacteria on the microscopic test.8 Spinal tap carries some risk of herniation of the medulla in any instance when intracranial pressure (ICP) is increased, but if meningitis is suspected, the procedure must be performed regardless of the risk, using suitable precautions and obtaining informed consent before the procedure. Use manometrics to check CSF pressure. Typically, the pressure is higher than normal.10CSF analysis result show xhantochromic color, with fibrin sediment, leucocyte count increases to 10-500 cell/mm3 (almost of them is lymphocyte, but on early stage PMN is dominantly found), protein is very increased (0,4-1,3 g/dL) low glucose (