1. 1 Neurologic Diseases and HIV HAIVN Harvard Medical School AIDS Initiative in Vietnam

2. 2 Learning Objectives By the end of this session, participants should be able to: Outline the 2 most common causes of headache and fever in PLHIV Describe how to diagnose, including potential differential diagnoses, a focal neurological deficit Describe causes and treatment for peripheral neuropathy in PLHIV

3. 3 I. Headache

4. 4 Differential Diagnoses of Headache and Fever Meningitis: Cryptococcal Meningitis Tuberculosis Meningitis Bacterial Meningitis Strep pneumoniae, Neisseria meningitidis Syphilitic Meningitis Other Infectious Causes: Toxoplasma Encephalitis Brain Abscess (Staph aureus especially with IDU) Sinusitis (bacterial or viral) Herpes Meningoencephalitis

5. 5 Cryptococcal Meningitis Occurs in advanced AIDS: CD4<100 Clinical manifestations: Headache Fever Nuchal rigidity (only 25%) Vomiting Confusion Blurred vision, photophobia Often associated with elevated intracranial pressure

6. 6 Cryptococcus Neoformans Disseminated disease may occur Fungal pneumonias Skin lesions 10-40% of patients with disseminated cryptococcal disease have no neurological symptoms

7. 7 Cryptococcus Meningitis: Diagnosis (1) Lumbar Puncture: High CSF pressure WBC often not elevated (usually < 50 cells/μl) Glucose normal to low Protein normal to high

8. 8 Cryptococcus Meningitis: Diagnosis (2) Positive CSF India Ink in 75% Cryptococcal Antigen (CRAG) CSF > 90% positive Serum > 99% positive

9. 9 Cryptococcus Meningitis: Management TreatmentDosage Standard Treatment Amphotericin B: 0.7-1mg/kg/day x 14 days, then Fluconazole 800-900 mg/day for 8 weeks If symptoms are mild or if amphotericin is not available or not tolerated Fluconazole 800-900 mg/day for 8-10 weeks Maintenance therapy Fluconazole 150-200 mg/day until on ARV with CD4 > 200 for 6 months Vietnam MOH, HIV/AIDS Treatment Guidelines, 2009

10. 10 Cryptococcus Meningitis: Management of High Intracranial Pressure (1) Normal pressure < 20 cm/H2O (200 mm/H2O) Elevated pressure causes severe headache and results in increased mortality and morbidity Visual loss as consequence of high pressure

11. 11 Cryptococcus Meningitis: Management of High Intracranial Pressure (2) Daily lumbar punctures (LP) Each time remove 15-20 CC CSF or until the patient’s headache improves Mannitol and corticosteroids not effective for lowering pressure

12. 12 Tuberculosis Meningitis Common in HIV, slow chronic onset is usual Typical symptoms: fever, headache, confusion May be focal signs or cranial nerve palsies due to space occupying lesions and/or cerebral mass effect Often other features of TB examine chest and lymph nodes Main differential is cryptococcal meningitis

13. 13 TB Meningitis: Diagnosis CSF: Pressure may be raised Lymphocytosis or mixed cells in CSF Typically: Protein very high (2-6 g/dL) Low glucose (<45 mg/dL) AFB are difficult to find in CSF Perform India Ink staining to help exclude or confirm cryptococcal meningitis Look for TB elsewhere in body by CXR, sputum, and aspiration of lymph nodes where appropriate

14. 14 TB: National Treatment Protocol Induction Phase 2 months Maintenance Phase MOH Protocol SRHZHE x 6 months Alternate regimens for HIV patients* (S)ERHZRH x 4 months Alternate regimens for HIV patients with severe TB disease* SRHZE HRZE x 1 month, then H 3 R 3 E 3 x 5 months 9-12 month regimens recommended for TB meningitis

15. 15 TB Meningitis Treatment: Steroids Concurrent steroid treatment reduces mortality by 31% Doses: Thwaites, NEJM, 2004; CDC, MMWR 58:RR-4, 2009 MedicationDosing Dexamethasone 0.3-0.4 mg/kg/day x 1 week then taper over 5-7 weeks Prednisone 1 mg/kg/day x 3 wks then taper over 3-5 wks or...

16. 16 II. Focal Neurological Deficit

17. 17 Focal Neurologic Deficit Common causes in HIV: Toxoplasma encephalitis Tuberculoma Progressive Multifocal Leukoencephalopathy (PML) Primary CNS lymphoma Abscess Bacterial brain abscess in active IDUs Cryptococcoma Stroke

18. 18 Tuberculoma Less common than meningitis, but should be considered in any patient with a history of TB Lesions may present as single or multiple mass lesions Look for TB elsewhere in body by CXR, sputum, etc

19. 19 Tuberculomas

20. 20 Cerebral Toxoplasmosis Seen in patients with CD4<100 Manifestations: Focal neurological signs (unilateral paralysis) Generalized neurological signs (confusion, epilepsy, coma, etc.) Meningeal signs are rare

21. 21 Cerebral Toxoplasmosis – Diagnosis (1) MRI of cerebral toxoplasmosis showing 2 ring enhancing lesions – “lighting up” with intravenous contrast

22. 22 Cerebral Toxoplasmosis – Diagnosis (2) CT scan of brain done without intravenous contrast showing edema around multiple lesions

23. 23 Cerebral Toxoplasmosis: Treatment Treatment TypeMedication Regimen Acute Treatment for 6 weeks Cotrimoxazole: TMP 10 mg/kg/day IV or orally divided into twice daily doses Pyrimethamine 200 mg loading dose, then 50-75 mg once daily Sulfadiazine 2-4 g initial dose, then 1- 1.5 g every 6 hours Maintenance Therapy: Discontinue when patient is on ART with CD4 count > 100 cells/mm 3 ≥ 6 months Cotrimoxazole: 960 mg (SMX 800mg / TMP 160mg) orally once per day Pyrimethamine 25-50 mg/day Sulfadiazine 1g x every 6 hours + OR: +

24. 24 Progressive Multifocal Leukoencephalopathy (PML) (1) Etiology: JC Virus (JCV) Polyomavirus Most adults colonized Clinical: Focal deficit Gate disturbance, Visual loss, sensory loss Diagnosis: CT or MRI Hypodense white-matter lesions No mass effect, no contrast enhancement CSF examination normal Treatment: ARV

25. 25 Progressive Multifocal Leukoencephalopathy (PML) (2) 27 year old male patient in HCMC with right arm weakness and dysarthria

26. 26 Bacterial Brain Abscess and Emboli Etiology: Endocarditis secondary to IDU Staphylococcus aureus infection Clinical: Signs of recent injecting Embolic events: subungal hematoma, Osler’s nodes (palms and feet), hematuria Diagnosis: Cardiac ultrasound Positive blood culture

27. 27 Primary Cerebral Lymphoma (1) Etiology Associated with Epstein-Barr Virus (EBV) CD4 < 100 cells/mm3 Clinical Headache, usually no fever Onset usually slower than toxoplasmosis

28. 28 Primary Cerebral Lymphoma (2) Diagnosis and Treatment: Difficult to distinguish from toxoplasmosis on CT/MRI Incurable so rule out and try empiric treatment for treatable causes before making diagnosis Treatment: radiation, chemotherapy May show brief initial response to steroids ARV may improve survival

29. 29 Diagnostic Approach to Focal CNS Deficit Perform head CT scan if available If head CT not available: - begin empiric treatment for toxoplasma and - follow clinical course over 1-2 weeks If patient improves, complete treatment course and commence maintenance therapy If status worsens or diagnosis remains in question, proceed with head CT and further evaluation

30. 30 III. Peripheral Neuropathy

31. 31 Causes of Peripheral Neuropathy Vitamin deficiency B12 Folate Pyridoxine Thiamine Infectious Diseases Syphilis CMV HIV Metabolic Diseases Diabetes Drug induced Alcohol ARV: d4T, ddI TB: INH

32. 32 Clinical Manifestations of Neuropathy Usually starts distally (toes or finger tips) and progresses towards center Numbness, burning, cold Reduced sensation of: Pain Temperature vibration Reflexes reduced Strength and joint position usually normal unless severe With treatment can improve, but very slowly Can be irreversible if not treated

33. 33 Peripheral Neuropathy: Prevention Type of Patient Prevention Management Patients on ARV Switch d4T to AZT after 12 months Patients on TB treatment Ensure that patients are given pyridoxine (B6) 25-50 mg/day

34. 34 Peripheral Neuropathy: Treatment 1. Treat the Cause 2. Treat the pain CauseRecommendation d4T switch to AZT or TDF Alcohol stop drinking INH vitamin B6 50 mg/day consider stopping INH early Vitamin supplements: B6, folate, B12 DrugType/Dosing Analgesics Paracetamol NSAIDs Amitriptyline25 – 75 mg/day Carbamazepine Morphine if very severe

35. 35 Quick Quiz

36. 36 CSF Profile of HIV-related OIs CSF Opening pressure Protein content Cell countMicroscopyCulture TB meningitis Cryptococcal meningitis Very high Toxoplasmal encephalitis Bacterial meningitis HighVery high Granulocytes predominate +/-+ Lymphoma Normal -- Normal or slightly elevated Slightly elevated or normal Slightly elevated to very high Normal High or normal Slightly elevated or normal Elevated (lymphocytes predominate) Normal + India ink stain - +/- - - + +/- -

37. 37 Key Points Fever and headache in PLHIV are indications for a lumbar puncture to evaluate for meningitis The most common causes of focal neurologic deficits are Toxoplasma, TB, and CNS Lymphoma Medications (d4T, INH) are common causes of peripheral neuropathy

38. 38 Thank you! Questions?