Tuberculous Meningitis

1. Tuberculous Meningitis CHCUMS DIVISION OF INFECTIOUS DISEASE AND GASTROENTEROLOGY November 24th, 2004

2. EPIDEMIOLOGY - TBM Tuberculous Meningitis (TBM) • The younger the children, the more readily to develop TBM. • 60% in Children aged 1-3 years • Death rate: 15-30%

3. TBM(Tuberculous meningitis) • TBM is the most serious complication of tuberculosis in children and is usually fatal without treatment. • TBM always be a part of systemic disseminated tuberculosis. • TBM often occurs within 1 year of initial infection, especially in the first 2 to 6 months of infection.

4. Meningitis PATHOPHYSIOLOGY Bacteremia Primary Complex Tuberculous Bacilli Miliary TB Subarachnoid Space Trauma/Diseases measles, pertussis Brain or Spinal Cord Perenchyma Tuberculomas Rich Foci

5. PATHOLOGICAL EFFECTS Meninges • Diffuse Hyperemia • Edema • Inflammatory Exudates • Conformation of Tubercles

6. PATHOLOGICAL EFFECTS Subarachnoid Space • A large amount of thick gelatinous exudates concentrate to the pavimentum cerebri, optic chiasma, bridge of varolius, bulbus rhachidicus and Sylvian fissure. • Basal meningitis accounts for the frequent dysfunction of cranial nerves III, VI, and VII.

7. PATHOLOGICAL EFFECTS Cerebral Parenchyma Tuberculous meningoencephalitis • swelling and hyperemia of the parenchyma contribute to the intracranial hypertension, then ischemia of parenchyma occur, finally lead to the foci of encephalomalacia and necrosis. Hemiplegia may be present because of this change. • Meninges, spinal, and spinal nerve root also involvement. The later always leads to paraplegina.

8. PATHOLOGICAL EFFECTS Cerebral Vessels • The bacteria invade the adventitia directly in the early stage and initiate the process of acute vasculitis. • Progressive destruction of adventitia, disruption of elastic fibers, and finally intimal destruction (endoarteritis), lead to the obliterative vasculitis, which may facilitate the ischemia, encephalomalacia and necrosis of parenchyma.

9. Circulation of CSF Choroid plexus Lateral ventricle Interventricular foramen the 3rd ventricle Cerebral aqueduct 4th ventricle 2 Lateral foramina 1 Medial foramen Subarachnoid space Arachnoid granulations Dural sinus Venous drainage

10. PATHOLOGICAL EFFECTS Hyperemia of choroids overproduction of CSF Hydrocephalus Inflammatory adherence of Meninge defective absorption of CSF Communicating hydrocephalus CSF flow is obstructed on the route before the cerebral aqueduct and the 4th ventricle Noncommunicatinghydrocephalus

11. In tuberculous meningitis there is a tendency for the exudate to be primarily located on the under surface of the brain, particularly over the ventral surface of the brain stem.

12. CLINICAL MANIFESTIONS A. Prodrome (1-2 week) • Fever, fatigue, malaise, myalgia, drowsiness, headache, vomiting • Mental status changes • Focal neurologic signs are absent • CSF abnormity

13. CLINICALMANIFESTIONS B. MeningealIrritationStage(1-2 week) • More serious TB toxic symptoms • Intracranial hypertension: severe headache, irritation, projectile vomiting, seizures; Bulging of anterior fontanelle, widening of cranial sutures in infant • Meningeal Irritation : nuchal rigidity, hypertonia Kernig sign or Brudzinski sign • Cranial nerve abnormalities: 3, 6, 7 • Some children have no evidence of meningeal irritation but may have signs of encephalitis: disorientation, abnormal movements and speech impairment

14. CLINICALMANIFESTIONS C. Coma Stage (1-3 week) • Frequent convulsion, progressive altered state of consciousness: lethargy, confusion, semicoma, deep coma, decerebrate or decorticate posturing • Depletion: extremely maransis, constipation, urinary retention • progressive abnormalities of vital signs, and eventual die from cerebral hernia

15. Characteristics of TBM in infants and young children • A rapid onset with convulsion, abruptly high fever • Atypical miningeal irritation • Intracranial hypertension manifests as bulging of anterior fontanelle and widening of cranial sutures in infant

16. PROGNOSIS • The prognosis of tuberculous meningitis correlates most closely with the clinical stage of diagnosis and treatment. • Age: infants or younger children are generally worse than that of older children • Drug resistant strain • Variation of host immunity • Appropriate therapeutic regimen • Completion of the antituberculor agent regimen

17. It is imperative that antituberculosis treatment be considered for any child who develops basilar meningitis and hydrocephalus, cranial nerve palsy, or stroke with no other apparent etiology.

18. DIAGNOSIS • History • Clinical Symptoms and Signs • Auxiliary Examinations

19. DIAGNOSIS - History Elucidate the following: • Medical and social history, including recent contact with patients with TB • Negative history for Bacille Calmette-Guerin (BCG) vaccination • History of immunosuppression from a known disease or drug therapy

20. DIAGNOSIS – Symptoms and signs • A gradual onset • Fever, headache, alternant of irritability and drowsiness, vomiting, constipation of unknown origin • Altered mental status

21. DIAGNOSIS – Tuberculin Skin Test Purified protein derivative (PPD) • Injected intradermally on the volar surface of the forearm • Reaction peaks at 48 to 72 hours • A nonreactive result does not excludeM. tuberculosis infection or disease, the tuberculin skin test is nonreactive in up to 50% of cases

22. DIAGNOSIS – Spinal Tap Cerebrospinal Fluid • Gross appearance Clear or slightly turbid a fine clot resembling a pellicle or cobweb may form • Cell counts, differential count 50-500cells/mm3 Lymphocytic predominance but Polymorphonuclear cells may predominate early • Glucose Hypoglycorrhachia • Protein High protein level with 1-3g/L

23. DIAGNOSIS – Spinal Tap Cerebrospinal Fluid • Chloridate：low • Acid-fast stain (+),Gram stain, India ink • Culture for M tuberculosis (+) • ELISA test for Specific PPD-IgM and PPD-IgG in CSF • ELISA test for Specific TB-antigen in CSF is a sensitive and rapid method

24. DIAGNOSIS – Spinal Tap Cerebrospinal Fluid • Total IgG, IgA and IgM • PCR : specific PCR to detect the gene of M tuberculosis bacilli can provide a rapid and reliable diagnosis of TBM, although false-negative results potentially occur

25. DIAGNOSIS – Chest X-ray Chest x-ray: Posteroanterior and lateral views may reveal the following • Hilar lymphadenopathy • Simple pneumonia • Infiltrate • Pleural effusion/pleural scar

26. DIAGNOSIS – CT or MRI • CT scan and MRI of the brain reveal hydrocephalus, basilar meningeal thickening, infarcts, edema, and tuberculomas, all these are helpful clues, but nonspecific • MRI and CT scan lack specificity, but help in monitoring complications that require neurosurgery, making the differentiations, and knowing the prognosis

27. DIFFERENTIALDIAGNOSIS • Viral Meningocephalitis • Pyogenic Meningitis • CNS Cryptococcosis

28. DIFFERENTIALDIAGNOSIS Viral Meningocephalitis Mumps, polio, enteroviruses, Measles, Herpes viruses, EBV, and Japanese encephalitis virus, etc CSF examination is the most important test in differentiating the cause of meningitis: • Clear appearance • Cells: 50 -200 cells/mm3 , Mononuclear cell predominance • Protein: slightly elevated or normal • Glucose and Chloridate : normal

29. DIFFERENTIALDIAGNOSIS Pyogenic Meningitis Clinical manifestation Acute onset of intense headache, fever, nausea, vomiting, photophobia, and stiff neck Group B streptococci, Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, and Staph. aureus, etc. • Pyogenic foci located other sites of the host • Typical rash of meningococcal infection • Examination of CSF

30. DIFFERENTIALDIAGNOSIS Pyogenic Meningitis Typical CSF abnormalities in meningitis include the following: • Appearance is turbid • Pleocytosis of PMN ( WBC counts always above 1000, even to a very high level as 10,000 cells/mm3, predominantly neutrophils) • Decreased glucose concentration • Increased protein concentration • Gram stain and culture of CSF identify the etiological organism

31. Brain surface (Pyogenic meningitis )

32. TBM

33. DIFFERENTIALDIAGNOSIS CNS Cryptococcosis • Cryptococcosis is the most common fungal infection of the central nervous system • It is the fourth most common cause of opportunistic infections in patients with AIDS • Disease onset is usually insidious and has a longer latent period • Fever always be absent at beginning of disease • Very notable intracranial hypertension: severe headache • Visual disturbances and papilledema are common

34. DIFFERENTIALDIAGNOSIS CNS Cryptococcosis CSF • Appearance can be clear or turbid. • Protein levels exceed • Glucose and Chloridate • Mononuclear pleocytosis , numbers vary from 50 to 500 mononuclear cells/mm3. • It is easy to get the positive result for C neoformans of CSF • India ink stain is positive CSF or serum cryptococcal antigen tests are positive

35. Cryptococcus is a cause of meningitis, a common complication in AIDS. The organisms are usually easy to demonstrate histologically. In this slide they are the circular-to-ovoid structures with thick capsules.

36. TREATMENT • Supportive treatment • Antituberculous drugs • Decreasing intracranial pressure • Corticosteriods • Symptomatic treatment • Follow-up visit

37. TREATMENT Supportive treatment • Bed rest and close respiratory contacts • Nutritional support are paramount • Keep good hygiene for the coma children to prevent of secondary infections, help them to change position frequently to prevent decubital • Management of electrolyte abnormalities • Antipyretics • Control of seizures: Diazepam (Valium)

38. TREATMENT Antituberculous drugs • isoniazid INH, rifampin RIF, pyrazinamide PZA, streptomycin SM, and sometimes ethambutol EMB. • INH and RIF are bactericidal for all M. tuberculosis population in any milieu. • SM is most effective against rapidly multiplying organisms. • PZA is most effective against organisms found in macrephages. • enter CSF readily in the presence of meningeal inflammation.

39. TREATMENT Antituberculous drugs • Any regimen must contain multiple drugs • In addition, the therapy must be taken regularly and continued for a sufficient period.

40. TREATMENT Antituberculous drugs • intensification chemotherapy stage: 3-4 months INH (15-25mg/kg) , RFP, PZA, SM • consolidation chemotherapy stage: with total course 1 year at least in order to prevent relapse, permit elimination organisms persistent exist in the host INH, RFP or EMB (ethambutol)

41. TREATMENT Decreasing intracranial pressure • Dehydrant: Mannitol (MNT) • Diuretic agent: Acetazolamide Decreasing CSF secretion by the choroid plexus • Ventricular tap or Open ventricular drainage • Repeat LPs and intrathecal injection • Shunting: to establish a communication between the CSF (ventricular or lumbar) and a drainage cavity. Performed only in cases of communicating hydrocephalus. Ventricular shunt to cisterna magna

42. TREATMENT Corticosteriods • Children should be treated for 6-8 weeks • More effective in early stage • Decrease the immflamatory exudates, there fore lower the intracranial pressure. Relieve the meningeal irritation. Improve the CSF circulation Reduce the adherence and prevent the hydrocephalus. • Dexamethasone • pay attention to the side effects of corticosteriods

43. Criteria for Recovery Follow-up visit • Disappearance of all clinical manifestations • CSF examination is normal • No relapse within 2 years after completion of antituberculosis treatment

44. Which symptom should be excluded in the early stage of TBM? • Drowsiness • Low fever, night sweat, poor appetite, loss of weight • Personality changes • Headache • Recurrent convulsion ?

45. A baby who was definited as TBM when he was 1 years old and began to receive regular treatment with antituberculosis drugs. How old is he when he can be definited as full recovery? • 11/2 y • 2 y • 21/2 y • 3 y • 4 y ?

46. Which one is the typically cellular characteristics of CSF in TBM? ? • 50-500 cells/mm3, with neutrophils predominance • 50-500 cells/mm3, with mononuclear predominance • 0-50 cells/mm3,with mononuclear predominance • >1000, sometimes can above 10,000 with neutrophil predominance • 0-50cells/mm3 with neutrophils predominance

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