2. HIV and the Brain Chris Farnitano, MD Noon Conference Friday, October 31, 2008

3. Learning Objectives -Review the differential diagnosis, workup and treatment of three common presentations of central neurologic disease in AIDS:*Dementia*Headache *focal neuro signs

4. Forms

5. Case Study #1: R.D. n R.D. is a 44 y.o. male with AIDS n Hx of non-adherence to meds and clinic visits n brought to clinic 2/03 by teenage daughter who has been caring for him

6. Case Study #1: R.D. n c/o incontinence, increased confusion, trouble walking n requiring help with bathing, dressing, feeding n Sx developed over months n T cells 15, Viral load 16,000 n What could his diagnosis be?

7. Case Study #1: R.D. n exam shows MMSE 14/30 n CSF: protein 324, glucose 8 n CSF WBC 24: 90% lymphs, 7% monos

8. CT scan Patient R. D.

9. Diffuse low attenuation periventricular white matter disease, no mass effect

10. MRI Patient R.D.

11. Case Study #1: R.D. n What is no longer in your differential?

12. Case Study #1: R.D. n Toxo titer neg n India ink prep negative n CSF Smears bacteria, AFB neg n CSF PCR HSV, MTB neg n serum and CSF crypo antigen low titer positive

13. Case Study #1: R.D. n Diagnosis?

14. Case Study #1: R.D. n Diagnosis? –Cryptococcal meningitis (CRAG) –Progressive Multifocal Leukencephalopathy (clinical picture, imaging studies) –AIDS dementia complex (clinical picture)

15. AIDS Dementia Complex n Also known as HIV associated cognitive- motor complex n Occurs in 1/3 of adults with AIDS

16. AIDS Dementia Complex n Pathogenesis: –Neurons not directly infected –CNS macrophages overrespond to infection with release of neurotoxic substances

17. AIDS Dementia Complex n process is slowly progressive over months n T cells usually <200 (median = 18)

18. AIDS Dementia Complex n Symptoms: –1) Declining mental acuity (difficulty in memory, concentration, mathematical calculations) –2) Preservation of alertness(even a patient with advanced dementia can be aroused to a level of alertness. This is an important distinction between this and other CNS etiologies

19. AIDS Dementia Complex n Neuro exam: –non-focal

20. AIDS Dementia Complex n Neuro exam: Cognition –Early: Inattention, decr. concentration, forgetfulness, slowing of thought processes –Late: Global Dementia

21. AIDS Dementia Complex n Neuro exam: Motor –Early: Slowed movements, clumsiness, ataxia –Late: paraplegia

22. AIDS Dementia Complex n Neuro exam: Behavior –Early: apathy, blunting of personality, agitation –Late: mutism

23. AIDS Dementia Complex n CSF findings –normal vs. mild pleocytosis, incr. Protein –similar to asymptomatic HIV+ individuals

24. AIDS Dementia Complex n CT/MRI –usually normal in early disease –atrophy can be seen in late disease

25. HIV Dementia n Note widened sulci and enlarged ventricles

26. AIDS Dementia Complex n Treatment –Antiviral therapy useful in preventing as well as reversing dementia –importance of CSF penetration of various antivirals not clear –Case P.J. –complete reversal of severe dementia with Combivir

27. Headache in AIDS n Differential Diagnosis - with any T cell count –medications (especially zidovudine) –aseptic HIV meningitis –bacterial meningitis (usuals plus increased risk of Listeria) –TB meningitis –Syphilitic meningitis - may have focal neuro findings, i.e. cranial nerve palsies

28. Headache in AIDS n Differential Diagnosis - with any T cell count –bacterial sinusitis - occurs in 1/3 to 2/3 of adults with AIDS n xray: 79% have air fluid level n 60% recur or fail to respond to ABT Rx n refer to ENT for antral puncture and Cx if fail to respond

29. Headache in AIDS n Differential Diagnosis - with T cells <100 –Above plus Fungal meningitis n most common is Cryptococcus (most have T cells <50) n also consider Coccidiomycosis (Sonoran life zone including all of California Central Valley) and Histoplasmosis (Missisipi Valley and Central America) in endemic areas.

30. Endemic Areas For Histo and Cocci

31. Cryptococcal Meningitis n Sx: –Subacute meningitis w/ fever, HA, malaise n Clinical exam: –Stiff neck in 1/4 –focal neuro exam in 1/5 (often cranial nerve palsy), altered mental status (ie encephalitis) in some –skin lesions resembling molluscum in 3- 10%

32. Cutaneous Cryptococcus n Note similar appearance to molluscum

33. Cryptococcal Meningitis n Diagnosis: –Serum CRAG >99% positive. Excellent screening test. Not useful for monitoring response to therapy. –CT scan: always do in AIDS patient before LP to rule out mass lesion, given the increased frequency of space occupying lesions in AIDS pts with HA even without focal neuro findings.

34. Cryptococcal Meningitis n Diagnosis: –LP opening pressure >200 in 60% –Cell counts low (mean 4 lymphs/mm3) –india ink prep positive in 75% –Blood Cx positive in 75% –Serum CRAG positive in 95% –CSF CRAG positive in >90%

35. Cryptococcal Meningitis n Increase intracranial pressure: –associated with obtundation, cranial nerve palsies, papilledema, blindness and incr. Mortality –13/14 deaths in one trial with opening pressure (OP)>250 –In observational studies, aggressive management of increased pressure often led to survival without permanent neuro sequellae.

36. Cryptococcal Meningitis n Increase intracranial pressure: –if opening pressure >300, urgently Rx with drainage of enough CSF to decrease OP by 50% (at least 10-20 ml) –follow up with daily LP drainage until OP normal x 2 days –Consider placement of lumbar drain if OP>400 or daily LP fails to control Sx –No proven benefit to dexamethasone, diamox or mannitol.

37. Cryptococcal Meningitis n Treatment: –Amphotericin B associated with less mortality than initial treatment with Fluconazone –Adding Flucytosine to Ampho B gave significantly higher rate of CSF sterilization and lower relapse rate than Ampho alone

38. Cryptococcal Meningitis n Treatment: –Amphotericin B IV and Flucytosine PO x 2 weeks (or until afebrile, HA, N/V resolved) –then Fluconazole 400mg PO qd x 8 weeks –then Fluconazole 200 mg PO qd until Tcells >100 for six months

39. Cryptococcal Meningitis n Treatment: –If normal mental status, >20 WBC in CSF, and CSF CRAG 20 WBC in CSF, and CSF CRAG <1:32, can use fluconazole alone

40. Cryptococcal Meningitis n Treatment: –High failure rate and high mortality (often weeks after Tx started) in pre-combo antiviral era

41. Focal Brain Dysfunction in AIDS n Presenting Signs or symptoms: –Focal neuro complaint or exam –New onset seizure

42. Focal Brain Dysfunction in AIDS n Differential Diagnosis - Abrupt onset: –CVA –TIA

43. Focal Brain Dysfunction in AIDS n Differential Diagnosis - subacute onset (days): –Toxoplasmosis –Primary CNS lymphoma –Tubercular brain abcess –Cryptococcoma –Varicella encephalitis –CMV –Herpes Simplex Encephalitis

44. Focal Brain Dysfunction in AIDS n Differential Diagnosis - insidious onset (weeks): –Progressive Multifocal Leucoencephalopathy (PML)

45. Focal Brain Dysfunction in AIDS n Workup: –CT with and without contrast –MRI –LP if no midline shift or other signs of herniation: send for fungal and AFP smears and Cx, VDRL, cytology, CRAG

46. Focal Brain Dysfunction in AIDS n Workup: –Serum Toxo IgG –Serum CRAG –CSF for PCR

47. Toxoplasmosis: –almost all have positive Toxo IgG (this is a reactivation disease) –Toxo acquired from undercooked meat or cysts in cat feces –15% US adults Toxo IgG+, 50-75% in Europe –In advanced AIDS, if Toxo IgG+ and not on prophylaxis, 12 mo. incidence of Toxo encephalitis is 33% –rare if adherent to Septra prophylaxis

48. Toxo Encephalitis: 80% have T cells <100 –Clinical: altered MS (70%), focal signs (60%), HA (50%), fever –CT/MRI: multiple ring enhancing lesions

49. Cerebral Toxoplasmosis n CT with contrast: Note ring enhancement and surrounding edema

50. Cerebral Toxoplasmosis n Note lesions on medial surface of both hemispheres

51. Cerebral Toxoplasmosis n Recurrent Sx 6 mo later: CT shows only old calcified lesion

52. Cerebral Toxoplasmosis n Recurrent Sx 6 mo later: MRI shows multiple new lesions

53. Primary CNS lymphoma: –Used to occur in up to 10% of AIDS pts. –T cells almost always <50 –CSF cytology pos in <15%, CSF PCR for EBV high specificity and sensitivity –median survival 10-18 months (used to be <3 mo) –whole brain radiation improves survival by 5 months –cases of remission with antiviral induced immune reconstitution

54. Primary CNS lymphoma n Note edema and mass effect, similar radiographic appearance to Toxo

55. Progressive Multifocal Leucoencephalopathy (PML): n caused by JC virus n Most humans infected early in life; 70% of adults are Ab+ n MRI: multiple non-enhancing fluffy lesions in sub-cortical white matter n no mass effect n CSF PCR for JC 58% sens, 92-100% specific n No specific treatment n death usual within 6 months n prolonged survival and remission with antivirals reported

56. Progressive Multifocal Leukoencephalopathy n Note vague hypodense region suggestive of stroke

57. Progressive Multifocal Leukoencephalopathy n T2-weighted MRI

58. Progressive Multifocal Leukoencephalopathy n Note extensive white matter degeneration in parietal lobe

59. Focal Brain Lesion Rx Algorithm n If Toxo IgG pos and not on prophylaxis: –Treat for Toxo, Bx if no response in 10-14 d or worsens

60. Focal Brain Lesion Rx Algorithm n If Toxo IgG neg or Toxo IgG pos but on prophylaxis: –Consider sending CSF for PCR for EBV, JC virus, CMV; also CSF Toxo IgG

61. Focal Brain Lesion in AIDS –PCR EBV pos = lymphoma, Bx to confirm –PCR JCV pos = PML Bx to confirm only if there is mass effect as this is atypical of PML, likely have more than one diagnosis –PCR CMV pos =Treat for CMV encephalitis –If CSF Toxo IgG pos then treat for Toxo, Bx if no response in 7-10 d or worsens –If all tests negative proceed with brain bx

62. Role of Brain Biopsy –Definitive diagnosis reached in 93- 96% of AIDS patients with focal CNS lesions –0 to 3.1 percent mortality –0.5 to 9 percent major morbidity –2 to 4 percent minor morbidity

63. Return to Case R.D. n Treated with Ampho B/Flucytocine followed by high dose Fluconazone n Triple drug anti-HIV therapy initiated

64. Case R.D.: 6 weeks later: n T cells improve 15 -> 25, viral load 16,000 -> 600 n Despite this lab response, clinical status deteriorates n patient becomes nonverbal, nonambulatory, more confused n significant nausea and vomiting appear to be due to antivirals

65. Return to Case R.D. n What do you do now? n After discussion with his children, agree to d/c to SNF and hospice n antivirals are stopped, fluconazole continued as “palliation”

66. Return to Case R.D. n 1 Month later: n patient much improved, ambulating, talking, more oriented n discharged from SNF to home care with children, hospice n patient offered to resume antivirals, but declines, decides to go to Mexico to stay with extended family

67. Return to Case R.D. n Lessons from this case: –Ockham’s Razor does not apply in advanced AIDS –remissions of previously untreatable diseases are seen with immune reconstitution –“It ain’t over til its over” - Yogi Berra

68. Forms

69. Summary –HIV related CNS disease is less common in U.S. today but still occurs, especially in non-adherent patients –Three major categories of disease are dementia, headache and focal brain dysfunction –The advent of CSF PCR tests has made it possible to avoid brain biopsy on some patients with focal mass lesions