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HIV and the Nervous System, Part 3 Christina M. Marra, MD June 18, 2009

HIV and the Nervous System, Part 3 Christina M. Marra, MD June 18, 2009. JW. 57 yo man brought in by friend to ED “Not himself” X past 3 weeks Decline in self-care and increasingly forgetful Apartment messy Recently lost job, car repossessed Got lost while driving

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HIV and the Nervous System, Part 3 Christina M. Marra, MD June 18, 2009

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  1. HIV and the Nervous System, Part 3 Christina M. Marra, MD June 18, 2009

  2. JW • 57 yo man brought in by friend to ED • “Not himself” X past 3 weeks • Decline in self-care and increasingly forgetful • Apartment messy • Recently lost job, car repossessed • Got lost while driving • Needs to be cued to eat, drink, dress, undress • Complains of difficulty concentrating, dizziness, weight loss, depression

  3. JW Pre-morbid Function • Four years of college • Program assistant for public health system • Traveled to China and Tibet for his 50th birthday • Occasional tobacco, rare alcohol, no other recreational drugs

  4. JW PMH • B3 HIV • “Fearful of antiretrovirals” • Nadir CD4 74 (2 mo prior), VL 103,000 copies/ml • Hx neurosyphilis treated with IV PCN, 1987 • Peripheral neuropathy • Hx B12 deficiency

  5. JW Medications • Atripla • Poor adherence • Vitamin B12 • Bactrim DS one table PO q day

  6. JW Exam • Afebrile, thin, normal general medical examination • Neurological examination • MMSE score 22 • Variably oriented • Fluent speech • Brisk ankle reflexes, right Babinski

  7. JW Laboratory Data • Serum RPR non-reactive • TSH normal • Negative toxicology screen • Normal electrolytes • Plasma HIV RNA 33,900 copies/ml

  8. JW Laboratory Data • CSF • 10 WBC, all mononuclear • Protein 99 mg/dl • Cryptococcal Ag negative • CSF-VDRL nonreactive • CMV, HSV, VZV, JCV PCRs negative • Beta-2 microglobulin 4.5 • CSF HIV RNA 55,000 copies/ml

  9. JW T1 and FLAIR MR

  10. JW FLAIR MR

  11. JW Follow up • Admitted to nursing facility • Restarted Atripla • Plasma HIV RNA undetectable 1 month later • CD4 remains ~100 cells/ul 7 months later • Living independently • Driving • Still having trouble with math

  12. Approach to Diagnosis

  13. Approach to Diagnosis

  14. Clinical Features of HIV Dementia

  15. “HAND”: HIV Associated Neurocognitive Disorder

  16. Risk Factors for HIV Dementia • CASCADE (Bhaskaran K et al. Ann Neurol 2008;63:213) • 23 cohorts Europe, Canada, Australia • Pre-1997 to 2006 • 15,380 subjects • 222 HIV Dementia • Total follow-up 83,388 person-yrs

  17. Current CD4 and HIV Dementia

  18. HIV Dementia Epidemiology Dore GJ. AIDS 2003;17:1539

  19. HIV Dementia Evaluation • Infectious • Serum CrAg, TPPA • Imaging • CSF CMV PCR, HIV RNA, B-2-microglobulin, VDRL • Non-infectious • Medication history • Tox screen • Metabolic encephalopathy • Electrolytes, B12, TSH

  20. JW T1 and FLAIR MR

  21. PML T1 and FLAIR MR

  22. ADC Treatment • Potent ARV • Does good CNS penetration matter?

  23. CNS Penetration-Effectiveness Rank

  24. CPE and CSF HIV RNA 34% 23% 18% 18% 12% 11% 8% P = 0.03 Letendre et al, Archives of Neurology, 2008

  25. ACTG 736 • 101 patients starting or changing potent ARVs • 0, 12, 24 weeks • Plasma HIV RNA • CSF HIV RNA • Neuropsychological performance • Data analyzed for 79 patients

  26. NP Performance in Cognitively Impaired

  27. CNS Escape Venkataramana A et al. Neurol 2006;67

  28. EC • 38 yo man brought in by friend to clinic • “Not himself” X past 11 months • Began with change in personality • Less reserved • Decline work performance • Fired from job • Little insight

  29. EC Pre-morbid Function • BA degree in zoology • Laboratory soil analyst • No tobacco, occasional alcohol, no other recreational drugs

  30. EC PMH • A1 HIV • No ARVs • CD4 530, plasma HIV RNA 13,000 copies/ml • No medications

  31. EC Exam • Afebrile, thin, normal general medical examination • Neurological examination • MMSE score 30 • Trouble following examination instructions • Mild left sided weakness

  32. EC Laboratory Data • Serum RPR 1:128 • TSH normal • Negative toxicology screen • Normal electrolytes • Plasma HIV RNA 12,247 copies/ml

  33. EC Laboratory Data • CSF • 78 WBCs, all mononuclear • Protein 120 mg/dl • Cryptococcal Ag negative • CSF-VDRL 1:128 • CMV, HSV, VZV, JCV PCRs negative • Beta-2 microglobulin ND • CSF HIV RNA ND

  34. EC FLAIR MR

  35. Two HIV+ Patients • EJ • 42 yo woman presented Sept 6, 2006 • HIV diagnosed in 1999 • CD4 293 cells/ul • Plasma HIV RNA 29,600 copies/ml • Hepatitis C • Burning pain and numbness in feet for 4 months • Began with stopping potent ARVs • Progressive weakness

  36. Two HIV+ Patients • RM • 53 yo man under my care since 1990 • Biopsy proven PML • Undetectable plasma HIV RNA and CD4 > 500 cells/ul X years • Type II DM X 4 years • Burning pain and numbness in feet for 2 years

  37. DSPN in HIV • Most common neurological complication of HIV • Increasing in prevalence • ARV-related • D-drugs (didanosine, stavudine) • ? PIs • Clinically indistinguishable from HIV DSPN

  38. Subjective Numbness Pain Burning Cramping Unsteadiness Objective Symmetrical Lower extremities involved before upper Loss of pinprick, temperature, vibration Absent or reduced ankle reflexes Mild intrinsic foot weakness HIV DSPN

  39. Stavudine and Neuropathy • Sacktor et al. (Neurology 2009;72) • 102 HIV+ beginning stavudine-lamivudine-nevirapine in Uganda • Baseline • Pain in feet in 37% • Neuropathy signs in 43% • Loss or diminished ankle reflexes • Diminished pin sensitivity in feet • Decreased vibration sensation at great toes

  40. Stavudine and Neuropathy • Sacktor et al. (Neurology 2009;72) • Six months, previously asymptomatic • Pain in feet in 38% • Neuropathy signs in 31% • Six months, previously symptomatic • No pain in feet in 22% • No neuropathy signs in 23%

  41. PIs and DSPN • Ellis et al. (Ann Neurol 2008;64) • 1159 patients in CHARTER • 58% neuropathy • Loss or diminished ankle reflexes • Diminished pin sensitivity in feet • Decreased vibration sensation at great toes • Symmetrical in all instances • 58% with neuropathy were symptomatic

  42. PIs and DSPN Ellis et al. Ann Neurol 2008;64

  43. PIs and DSPN Ellis et al. Ann Neurol 2008;64

  44. HOPS Immunodeficiency + Toxic Drugs Better immunity + ?Fewer Toxic Drugs Lichtenstein et al. Clin Infect Dis 2005;40

  45. HIV DSPN • Some other causes of neuropathy in HIV • Dapsone • INH • Vincristine, other chemotherapy • Ethambutol • Thalidomide • Megadose B6 • B12 deficiency • Alcohol • Diabetes

  46. Neuropathy Work-up • EMG, NCV • Large fiber • QST • Small fiber • ENFD • Small fiber • Labs • SPEP, immunofixation • B12, B6, folate • TSH • TPPA • HbA1c • Cryoglobulins • ESR, CRP

  47. DSPN Treatments • Gabapentin +/- SR morphine • Pregabalin • Lidocaine patches • Duloxetine • Amitriptyline • High dose capsaicin patch • Cannabis

  48. Capsaicin Patch • Simpson et al. (Neurology 2008;70) • Three doses high concentration capsaicin vs. low dose control • 12 weeks • 203 treated, 73 controls • > 30% pain reduction in 34% vs. 18% • No dose response

  49. Capsaicin Patch

  50. Cannabis • Abrams et al. (Neurology 2007;68) • Smoked marijuana • 32 mg delta-9-THC/cigarette 3 times per day X 5 days • Matched control cigarettes • 25 patients per group • > 30% pain reduction in 52% vs. 24%

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