1. Progressive Multifocal Leukoencephalopathy July 31, 2007 Margo Smith, M.D. Department of Medicine Washington Hospital Center

2. Case 5 A 43 y o man with AIDS presents with a 4 week history of ataxia, progressive R hand weakness, and tremor. On exam he is ataxic and weak on the R when compared to his L side. He is afebrile, CD4 of 56/mm3 and a serum toxoplasma antibody was negative on his first visit to you and he does take TMP- SMX. You order a MRI and it shows a 2x4- cm lesion in the L cerebellar hemisphere on the T 2 - weighted images. There is no enhancement with gadolinium and no mass effect noted

4. Case 5 The most likely diagnosis is? –A. Toxoplasmosis –B. Primary CNS lymphoma –C. Progressive multifocal leukoencephalopathy (PML) –D. Pyogenic brain abscess

5. Case 5 The most likely diagnosis is? –A. Toxoplasmosis –B. Primary CNS lymphoma –C. Progressive multifocal leukoencephalopathy (PML) –D. Pyogenic brain abscess

6. Progressive Multifocal Leukoencephalopathy Basics –JC virus, papovavirus (DNA) –1958 first report –Cytolytic to oligodendrocytes – 5-HT2 receptor –Demylinating disease of brain –Optic nerve and spinal cord oligodendrocytes not affected

7. Progressive Multifocal Leukoencephalopathy –Asymmetric involvement Brainstem – more common in AIDS cerebellum cerebral – 10:1 non-AIDS –Progresses to death rapidly

8. PML Basics –Immunocompromised AIDS Leukemia –Symptoms Cognitive, personality, motor weakness Seizures

10. PML Epidemiology –BK and SV40 related –? Upper respiratory acquisition –Antibody prevalence increases with age –Latent virus reticuloendothelial system –No proof of CNS latency –2 strains Kidney Brain

11. PML HIV/AIDS –2-5% –Viral DNA in ~ 55% peripheral lymphocytes –AIDS defining illness –CD4 < 100 –Dx MRI – nonenhancing, no shift CSF-PCR ~ 80% sensitive 90% specific

12. PML HIV/AIDS –Treatment Highly active antiviral therapy small studies ~ 50% respond ~ 50% progress Immune reconstitution – BAD NEWS

13. PML PML without HIV –T-cell immunodeficincy Lymphoproliferative disorders Chronic granulomatous diseases Solid organ transplantation Monoclonal antibody Rx –MS/Crohn’s Rx natalizumab 1:1000 Hematologic malignancy prevalence ~ 0.07% –M:F = 3:2 –Pk age 60s

14. PML Survival –AIDS  weeks – months –Non-AIDS  months – one year Treatment Non-AIDS –Case reports Interleukin-2 Cytarabine Cidofovir 5-HT2 serotonin antagonizer – anti-depressant –Mitazapine = Remeron™

15. Dilemma Can one predict who is at risk to develop PML?

16. Progressive Multifocal Leukoencephalopathy No pre-morbid serologic testing available No pre-morbid CNS screen available No pre-morbid imaging available Not clear if there is an at risk subgroup –~1/3 of healthy urine + JCV-DNA – Urine +JCV-DNA found more frequently immune suppressed –+JCV DNA mononuclear cells poor predictor

17. Progressive Multifocal Leukoencephalopathy More questions and no clear answers –Does prior immune suppression increase risk? –If so, does the length of time increase risk? –Is there a role in monitoring antigen specific CD-8 cells? –Is a risk of 1:1000 reasonable?