1. Cryptococcal Meningitis Dr N Thumbiran Infectious Diseases Department UKZN

2. Index patient 27 year old female 27 year old female Presented to King Edward Hospital on 17/07/2005 with: Presented to King Edward Hospital on 17/07/2005 with: Severe headaches Severe headaches Vomiting Vomiting Photophobia Photophobia X 2/52

3. Past Medical History Pulmonary Tuberculosis 2001 – smear positive treated x 6/12 – good response Pulmonary Tuberculosis 2001 – smear positive treated x 6/12 – good response Pneumonia in 2002 – fully treated with good response Pneumonia in 2002 – fully treated with good response

4. Physical examination Generalized lymphadenopathy Generalized lymphadenopathy CNS CNS Conscious, co-operative, Conscious, co-operative, Neck stiffness Neck stiffness No clinical features of raised ICP No clinical features of raised ICP No focal neurological signs No focal neurological signs Other systems NAD Other systems NAD

5. Investigations Chest X-Ray – miliary pattern Chest X-Ray – miliary pattern Lumbar puncture: Lumbar puncture: No cells No cells Total Protein: 0.58g/L, glucose 1.4 mmol/L; CL – 126 mmol/L (plasma glucose 4.5mmol/L) ‏ Total Protein: 0.58g/L, glucose 1.4 mmol/L; CL – 126 mmol/L (plasma glucose 4.5mmol/L) ‏ Cryptococcal Ag - positive Cryptococcal Ag - positive Cryptococcal culture – positive Cryptococcal culture – positive HIV test – positive HIV test – positive CD4 count – 47 cells/ul CD4 count – 47 cells/ul

6. Management Anti TB treatment Anti TB treatment Antifungal treatment : Amphotericin B Antifungal treatment : Amphotericin B

7. 2 days later Worsening headaches Worsening headaches Diplopia Diplopia O/E: mental state normal, neck stiffness ++, bilateral CN VI palsy, no focal signs O/E: mental state normal, neck stiffness ++, bilateral CN VI palsy, no focal signs CT Brain – no abnormalities CT Brain – no abnormalities

8. 2 weeks later Headaches persisted with seizures Headaches persisted with seizures Clinical exam: Clinical exam: Fundoscopy blurred margins on Left Fundoscopy blurred margins on Left Persistent cranial nerve VI palsy Persistent cranial nerve VI palsy Bilateral cranial nerve VIII palsy Bilateral cranial nerve VIII palsy The repeat LP = OP : 39 cm H 2 O The repeat LP = OP : 39 cm H 2 O

9. 2 weeks CSFInitial2/52 Total Protein 0.58 g/L 0.73 g/L GlobulinRaisedRaised Chloride 126 mmol/L 121 mmol/L Glucose 1.4 mmol/L 3 mmol/L Crypto Antigen PositivePositive Crypto Culture PositivePositive Treatment: Amphotericin B x 1 month then Fluconazole Treatment: Amphotericin B x 1 month then Fluconazole

10. CSF pressures over time

11. 2 months after admission: Review by IDU - problems: Review by IDU - problems: AIDS- CD4 47cells/uL, not on ARVs AIDS- CD4 47cells/uL, not on ARVs Miliary TB on anti-TB treatment Miliary TB on anti-TB treatment Crypto meningitis: Crypto meningitis: Persistent headaches Persistent headaches Persistently high opening pressures Persistently high opening pressures Deafness – 2 weeks into admission Deafness – 2 weeks into admission Loss of vision – 2 months into admission Loss of vision – 2 months into admission

12. Management by IDU ARVs commenced as an inpatient on 08/10/2005 ARVs commenced as an inpatient on 08/10/2005 Neurosurgery consulted for CSF shunting: Neurosurgery consulted for CSF shunting: CT Brain – mild ventriculomegaly with hydrocephalus CT Brain – mild ventriculomegaly with hydrocephalus Lumbar Puncture : OP – 35 cm H 2 O Lumbar Puncture : OP – 35 cm H 2 O Ventriculo-peritoneal shunt placed Ventriculo-peritoneal shunt placed Headaches – improved post surgery Headaches – improved post surgery Vision and hearing – remained ISQ post surgery Vision and hearing – remained ISQ post surgery

13. Progress… Continued on ARV’s and Fluconazole Continued on ARV’s and Fluconazole Completed 9 months anti-TB treatment Completed 9 months anti-TB treatment One year later re-admitted to King Edward Hospital One year later re-admitted to King Edward Hospital

14. Readmission ( 30/10/06) ‏ Headache and vomiting Headache and vomiting O/E: O/E: Marked neck stiffness Marked neck stiffness No new clinical signs remained blind and deaf No new clinical signs remained blind and deaf Fundoscopy: bilateral optic atrophy Fundoscopy: bilateral optic atrophy CT Brain – no hydrocephalus CT Brain – no hydrocephalus

15. Management Lumbar Puncture – OP: 16 cm H 2 O Lumbar Puncture – OP: 16 cm H 2 O Total Protein – 2.99g/L Total Protein – 2.99g/L Globulin – 3+, Cl – 125mmol/L Glucose – 0.9mmol/L Globulin – 3+, Cl – 125mmol/L Glucose – 0.9mmol/L Poly – 2 Lymph – 86 RBC – 20 Poly – 2 Lymph – 86 RBC – 20 Crypto Ag - pos, culture - neg Crypto Ag - pos, culture - neg Rx – Ampho B x 5/7 followed by Fluconazole Rx – Ampho B x 5/7 followed by Fluconazole ENT consult - Dead L ear ENT consult - Dead L ear Ophthalmology - bilateral optic atrophy Ophthalmology - bilateral optic atrophy for conservative Rx

16. Further progress Patient fully suppressed on ARVs Patient fully suppressed on ARVs Cotrimoxazole and Fluconazole discontinued Cotrimoxazole and Fluconazole discontinued Vision improved –from perception of shapes to being able to see and recognize objects. Vision improved –from perception of shapes to being able to see and recognize objects. Hearing – much improvement Hearing – much improvement (reviewed - 22 months later)

17. RVD Date CD4 (cells/uL) VL (copies/ml) Aug 05 95 200 000 Mar 06 104<25 Dec 06 229<25 Mar 07 273<25

18. Summary 27 year old female, with stage 4 RVD, developed persistent  ICP 2° to CM with neurological sequelae 27 year old female, with stage 4 RVD, developed persistent  ICP 2° to CM with neurological sequelae Had a ventriculo-peritoneal shunt 3 months after admission. Had a ventriculo-peritoneal shunt 3 months after admission. Patient had a recurrence of symptoms of meningitis 1 year on HAART following good virological suppression & immune recovery (?IRIS) ‏ Patient had a recurrence of symptoms of meningitis 1 year on HAART following good virological suppression & immune recovery (?IRIS) ‏ Vision and hearing gradually improved following shunt. Vision and hearing gradually improved following shunt.

19. Discussion Diagnostic issues Diagnostic issues Current management of CM Current management of CM Management of raised ICP in CM Management of raised ICP in CM CM IRIS CM IRIS Prognostic markers Prognostic markers

20. Diagnostics India ink – sensitivity 70-90% India ink – sensitivity 70-90% Cryptococcal antigen test – sensitivity >90% Cryptococcal antigen test – sensitivity >90% CSF culture - gold standard CSF culture - gold standard Blood fungal culture – sensitivity 66-80% Blood fungal culture – sensitivity 66-80% Bicanic and Harrison, British Medical Bulletin 2004 Aberg and Powderly, www.HIVinsite.com 2006 Guidelines, SA Journal of HIV Medicine 2007

21. Recommended regimen Recommended regimen Induction: Amphotericin B 0.7–1 mg/kg/d plus Flucytosine 100 mg/kg/d for 2 w Induction: Amphotericin B 0.7–1 mg/kg/d plus Flucytosine 100 mg/kg/d for 2 w Consolidation: Fluconazole 400 mg/d x 8 weeks Consolidation: Fluconazole 400 mg/d x 8 weeks Suppression: Fluconazole 200mg/d lifelong / until immune reconstituted Suppression: Fluconazole 200mg/d lifelong / until immune reconstituted Guidelines, SA Journal of HIV Medicine 2007 Saag et al, Clinical Infectious Diseases 2000

22. Current Regimen In RLS Induction: Amphotericn B 1mg/kg/d x 2 weeks Induction: Amphotericn B 1mg/kg/d x 2 weeks or or Fluconazole 800mg/d po x 4 weeks Consolidation: Fluconazole 400 mg/d x 8 weeks Consolidation: Fluconazole 400 mg/d x 8 weeks Suppression: Fluconazole 200mg/d lifelong / until immune reconstituted Suppression: Fluconazole 200mg/d lifelong / until immune reconstituted Guidelines, SA Journal of HIV Medicine 2007 Saag et al, Clinical Infectious Diseases 2000

23. Management of  ICP Management of  ICP Optimal therapy is not firmly established Optimal therapy is not firmly established Available treatment options : Available treatment options : Frequent high volume percutaneous lumbar punctures Frequent high volume percutaneous lumbar punctures Lumbar drains Lumbar drains Shunting : VP and LP Shunting : VP and LP Medical: Medical: Corticosteroids Corticosteroids Acetazolamide, Mannitol Acetazolamide, Mannitol Bicanic and Harrison, British Medical Bulletin 2004 Saag et al, Clinical Infectious Diseases 2000 Bicanic et al, AIDS 2009

24. Cryptococcal Meningitis IRIS 2 types: Unmasking IRIS or Paradoxical IRIS 2 types: Unmasking IRIS or Paradoxical IRIS Management (paradoxical): Management (paradoxical): Continuation of ARV Continuation of ARV Lumbar puncture Lumbar puncture CT brain CT brain Appropriate antifungal treatment Appropriate antifungal treatment Corticosteroids – Prednsione 1mg/kg/d po x 1 week Corticosteroids – Prednsione 1mg/kg/d po x 1 week Guidelines, SA Journal of HIV Medicine 2007 Bicanic et al, J Acquir Immune Defic Syndr 2009

25. Prognostic factors An important predictor of early mortality is an abnormal mental status at presentation: 25% mortality An important predictor of early mortality is an abnormal mental status at presentation: 25% mortality Other poor prognostic markers: Other poor prognostic markers: Baseline high opening pressures Baseline high opening pressures Poor WCC response in CSF Poor WCC response in CSF High CSF titers of Crypto Ag >1024 High CSF titers of Crypto Ag >1024 Positive blood culture Positive blood culture CSF India ink / Gram stain positivity CSF India ink / Gram stain positivity Bicanic and Harrison, British Medical Bulletin 2004

26. Conclusion CM is the commonest cause of meningitis in HIV adults in Africa CM is the commonest cause of meningitis in HIV adults in Africa Early diagnosis and appropriate aggressive management is essential Early diagnosis and appropriate aggressive management is essential Prognosis remains poor currently Prognosis remains poor currently HAART – alter the risk of acquiring CM in AIDS HAART – alter the risk of acquiring CM in AIDS