Central Nervous System Tuberculosis.pptx

Medical lecture on Central Nervous System Tuberculosis

1. CNS Tuberculosis Y.Nilukshana

2. Outline The change in the epidemiology Pathogenesis Clinical presentation Microbiological diagnosis Radiological diagnosis WHO recommendations The challenges encountered Novel drugs at the horizon Prognostic markers

3. The current epidemiology The global incidence > 1 milllion / year Mortality > 40% in patients with HIV1 coinfection The rapidly escalating prevalence of HIV Drug resistant TB meningitis is on the rise

4. Who are at higher risk? Immunocompromised Elderly Malnutrition Malignancies HIV coinfection Alcoholism Drugs: TNF alpha inhibitors

5. Pathogenesis Post primary/ as extrapulmonary tuberculosis during reactivation Transmission of airborne Mycobacterium tuberculosis Enters the lung (first focus) Bacterial replication Invasion of lymphnodes Enters the blood stream Disseminated disease Extrapulmonary disease

6. ‘ Rich focus ’: initial intracranial lesion in TBM; as single/ multiple parameningeal granulomata Rupture of focus Resulting in proliferative arachnoiditis , inflammation of meninges Bacilli traverse the BBB and are taken up by the microglia inside which the organism replicates

7. Intraparenchymal tuberculoma Associated vasculitis causing vascular occlusion and ischaemia Communicating hydrocephalus Rarely pituitary dysfunction Factors involved: Immune and metabolic Bacillary factors Host genetics: Toll like receptor pathway, SPN, TLR9 etc….

8. CNS tuberculosis Tuberculous meningitis Intracranial tuberculoma Spinal tuberculous arachnoiditis

9. Clinical presentation

10. Prodromal phase 2-3/ 52 duration Low grade fever Lassitude Headache Personality changes etc

11. Meningitic phase Protactable headache Meningism Confusion Vomiting Cranial nerve lesions and long tract signs 50% develop V, III cranial nerve palsies! 10% develop hemi/ paraparesis

12. Choroidal tubercles in miliary TB

13. Paralytic phase Seizures Stupor Coma etc Rapid progression in immunocompromised and HIV1 coinfected Death if untreated

14. MRC- TBM severity grading

15. Presentation of spinal TB arachnoiditis Radicular pain Cord compression Lower motor neurone weakness Sphincter dysfunction Anterior spinal artery syndrome

16. Atypical presentation Slowly progressive dementia Rapid course mimicking acute pyogenic meningitis Encephalitic course

17. Therapeutic paradox In females with illness of a shorter duration Worsening of the clinical signs ie fever, mental state just after the commencement of ATT. Well known even in HIV negative patients Seen in 1/3 of patients with TB meningitis CSF: lymphocytic switches to neutrophilic !

18. CSF findings WBC 150-1000/ μ L lymphocytic predominant; can be mixed Neutrophilic in: Early stages HIV1 coinfection IRIS (Immune Reconstitution Syndrome) Protein 0.8-2.0g/ dL CSF glucose/ RBS < 0.5 in 90% patients Low glucose and high lactate predict a poorer prognosis Novel markers in CSF: TNF, IL1 В , VEGF

19. Microbiological diagnosis ZN Staining: Detects the bacilli if > 10,000/ mL Sensitivity in cavitatory PTB 30% Paucibacillary TB, TB meningitis 10-20%

20. How to increase the ZN stain sensitivity? CSF > 10 mL Preferrably the fluid removed last from the lumbar puncture centrifuged at 3000 g Examine the smear of the clot/ sediment of CSF If not clotted: add 95% alcohol 2 ml Apply 0.02 ml of the centrifuged deposit onto the slide to < 1cm diameter Examine under 200-500 HPF By > one observer For > 30 minutes!

21. Mycobacterium TB culture of CSF More sensitive than the microscopy Takes 10 days in liquid medium and 8 weeks in solid medium Ideal laboratory safety settings are warranted

22. Microscopic Observation Drug Susceptibility (MODS) assay in CSF Microscopy used to diagnose the Mycobacterium tuberculous ‘specific cord’ of bacterial growth Takes 6 days duration Sensitivity 65%

23. Molecular assays/ Nucleic acid tests Gene Xpert MTB/ RIF : Real time PCR Allows to diagnose mutations associated with rifampicin resistance Sensitivity 60% specificity 100% Sensitivity further increased by using larger volume of CSF

24. Second generation Gene Xpert test (Ultra): Sensitivity 95% for diagnosing TB meningitis 99% Negative predicitve value in HIV patients

25. Mycobacterium tuberculous glycolipid lipoarabinomannan in CSF Uses LFA (Lateral Flow Assay) or ELISA Sensitivity in HIV1 coinfected patients are 75%, 43% respectively Other n ovel nucleic acid tests: Modified Gene Probe Amplified Direct Test MTBDR plus- Detects resistance to INAH and rifampicin

26. What is the place of ADA in CSF? No clear cut off values to differentiate from acute pyogenic meningitis

27. Radiological diagnosis Gadolinium enhanced MRI is superior to CT DWI imaging for early diagnosis of cerebral ischaemia , borderzone necrosis Marked basilar enhancement correlates with vasculitis and also predicts infarctions CT angiography useful as supraclinoid parts of internal carotid artery, proximal parts of anterior and middle cerebral arteries are commonly affected

28. Gadolinum MRI

29. What to look for? Cerebral oedema Basilar arachnoiditis Tuberculoma : Initial low/ isodense regions becoming hyperdense with ring enhancement Mostly disappear with treatment; may get calcified Hydrocephalus Infarctions

30. Mimickers Fungal, viral meningoencephalitis Parameningeal infections like sphenoidal sinusitis Partially treated meningitis Neurosyphilis Carcinomatous meningitis Neurosarcoid Neurobrucellosis Neurocysticercosis

31. CNS toxoplasmosis

32. Challeneges in radiological diagnosis 30% patients in early stages, MRC grade1 will have normal CT and 15% have normal MRI Basal enhancement is less prominent in presence of HIV1 with low CD4 counts >50% patients have concomitant TB spine which is commonly overlooked* 50% have a normal CXR

33. AntiTB therapy Intensive phase: HRZE for two months Continuation phase: HR for 10 months Treatment of tuberculoma for a total duration of 18 months

34. The place of glucocorticoids In patients with tuberculous meningitis, an initial adjuvant corticosteroid therapy with dexamethasone or prednisolone tapered over 6-8 weeks should be used (Strong recommendation, moderate certainty in the evidence). Dexamethasone 0.3-0.4mg/kg/day for 2 weeks and taper over total of 8 weeks Prednisolone 60 mg/day for 2 weeks and taper over 8 weeks

35. Pros and cons of adjuvant steroid therapy Reduces intracerebral inflammation, inhibits the production of cytokines by microglia, astrocytes and improves outcome Lack of evidence in HIV coinfected patients No difference in the longterm neurological disability in either groups ? Does not prevent brain infarctions 2 small scale trial evidence suggests addition of aspirin to reduce infarctions

36. Urgent indications for steroids Progressive neurological deterioration Encephalitis with CSF opening pressure > 400 mmwater , clinical/ CT evidence of cerebral oedema Therapeutic paradox CT revealing marked basilar enhancement, moderate to advanced hydrocephalus Tuberculoma with disproportionate oedema IRIS

37. Other general measures Monitor sodium, oxygenations, temperature, intracranial pressure Bedside transcranial doppler to assess for vascular compromise Hypertonic saline is equally effective as mannitol

38. Pitfalls in using routine ATT regime in CNS TB CSF concentration of rifampicin is 10-20% of that of plasma *? Need to use ‘ Hyperintense regime’ ( ie > 10mg/kg) for a better mortality benefit Ethambutol hardly crosses the BBB even in the presence of inflammation (CSF concentration <20%) Contribution of ethambutol for a better outcome is minimal even in the presence of INAH resistance Streptomycin poorly penetrates once the inflammation subsides Higher prevalence of resistance to Streptomycin Vestibular and ototoxic effects of Streptomycin Second line drugs to be considered in patients with resistance to rifampicin

39. Drugs at the horizon Ethionamide : better penetration than ethambutol and streptomycin Fluoroquinolones : Levofloxacin , Moxifloxacin have good penetration and highly active against drug susceptible as well as many drug resistant bacilli Trial evidence of improved survival with usage of high dose rifampicin (15mg/kg) with levofloxacin as fifth agent Thalidomide useful in tuberculoma invading the optic chiasm Infliximab has similar evidence to Thalidomide

40. Predictors of poor prognosis Delayed diagnosis and delayed treatment Advanced disease Resistance to ATT HIV coinfection Complications: ischaemia , hydrocephalus Hyponatraemia

41. HIV1 and TB coinfection Multiple seeding of meninges by the Mycobacterium on invasion of CNS Increases mortality & prevalence of drug resistance Patients initially diagnosed with TB and on ATT can clinically deteriorate once commenced on HAART Patients newly commenced on ART can get progression of preexisting active TB (paradoxical IRIS) Patients newly commenced on ART can get reactivation of unrecognised latent TB (unmasking IRIS)

42. Should be individualized according to CD4 counts Trials: ? For and against a gap of 2 months WHO 2017: ART should be started in all TB patients living with HIV regardless of their CD4 cell count (Strong recommendation, high certainty in the evidence). TB treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks of treatment (Strong recommendation, high certainty in the evidence). HIV-positive patients with profound immunosuppression (e.g. CD4 counts less than 50 cells/mm3) should receive ART within the first 2 weeks of initiating TB treatment .

43. References Guidelines for treatment of drug-susceptible tuberculosis and patient care, WHO 2017 update National TB manual Tuberculous meningitis nature reviews 2017 Treatment of Drug-Susceptible Tuberculosis Guidelines CDC 2016 updates

44. Thank you