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François-Xavier Lescure , Françoise Gray, Julien Savatovsky,

Lymphocytes T8 infiltrative encephalitis: a new form of neurological complication in HIV infection. François-Xavier Lescure , Françoise Gray, Julien Savatovsky, Corinne Amiel, Jérome Pacanowski, Pierre-Marie Girard, Jean-Michel Molina, Gilles Pialoux, Antoine Moulignier. Background.

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François-Xavier Lescure , Françoise Gray, Julien Savatovsky,

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  1. Lymphocytes T8 infiltrative encephalitis: a new form of neurological complication in HIV infection François-Xavier Lescure, Françoise Gray, Julien Savatovsky, Corinne Amiel, Jérome Pacanowski, Pierre-Marie Girard, Jean-Michel Molina, Gilles Pialoux, Antoine Moulignier

  2. Background • Improvement of severity in neuro-cognitivedisorderssince HAART (Jellinger et al. 2000, ArminioMonforte et al. 2004) • Persistance of overallneuro-cognitivedisorders • Brainis a HIV sanctuary(Lambotte et al. 2005)with a complicatedpharmacology for ARV (Antinori et al. 2005, Letendre et al. 2008) • Chronicneuro-inflammation hypothesis(Nath et al. 2006, Yilmaz et al. 2008) • Improvement of survival in HIV-infected patients (Lhose et al. 2007, Leyden et al. 2007) • Emergence of atypicalneurological cases • Central discordant HIV diseases(Stingele et al. 2001, Canestri et al. 2009) • Severedemyelinatingleukoencephalopathies(Langford et al. 2002, Miller et al. 2004, Rackstrawet al. 2006)

  3. Method • Aim • Review of medical files • Historical, clinical, paraclinical and pathological data • Design • Retrospective • Descriptive • Study period: 1999-2008

  4. Features of patients • N=14 • Sex ratio M/F: 8/6 • Risk groups: • 9 heterosexuals, 4 MSM, 1 transfusion • Ethnicorigin: • 7 American Africans, 2 Arabics, 5 Caucasians • Co infections: • 2 HBV, 1 HCV • Othercomorbidities: • 1 lupus, 1 DILS, 1 diabetes, 1 HTA, 1 renaldisease, 1 bullouspemphygoid

  5. Features of HIV infections at BL • Median duration of HIV infection = 10 years [1-18] • CD4 cells count nadir < 200 μL/mL: 78% • AIDS history: 71% • HAART: 86% • Median ART duration: 4 years [0-14] • Median ART Charter: 1.6 [1.5-2] • Median plasma VL (copies/mL) = 117 [<40-10,000] • Median CD4 cells count (μL/mL) = 493 [6-900]

  6. Clinical characteristics • Clinicalsigns • Epilepsy , n=6 (4 statusepilepticus) • Headhache , n=5 • Coma, n=4 • Dizziness, n=4 • Confusion, n=4 • Dementia, n=4 • Mildmemorydisorders, n=3 • Neurologicaldeficit , n=3 • Mood troubles, n=1 • Presentation • Acute, n=5 • Subacute, n=6 • Chronic, n=2

  7. Paraclinical characteristics • Clinicalsigns • Epilepsy , n=6 (4 statusepilepticus) • Headhache , n=5 • Coma, n=4 • Dizziness, n=4 • Confusion, n=4 • Dementia, n=4 • Mildmemorydisorders, n=3 • Neurologicaldeficit , n=3 • Mood troubles, n=1 • Presentation • Acute, n=5 • Subacute, n=6 • Chronic, n=2 • Plasma VL (copies/μL) • 692 [<40-65,800] • vs 117 before event • CD4 cells count (μL/mL) • 182 [84-742] • vs 493 before event • CSF • Lymphocytes = 40 [1-220] • Protein = 0.9 [0.4-1.5] • Glucose = normal • CSF VL (copies/μL) • 2236 [1,100-36,242] • vs 692 in the plasma

  8. WM T2 high signal

  9. Areas with restricted diffusion

  10. perivascular contrast enhancement

  11. Differential diagnosis • JCV • CMV • HSV • VZV • EBV • HHV6 • Enterovirus • Syphilis • Lyme • Cryptococcosis • Toxoplasmosis • TB • Lymphoma • MS • …

  12. Differential diagnosis • JCV • CMV • HSV • VZV • EBV • HHV6 • Enterovirus • Syphilis • Lyme • Cryptococcosis • Toxoplasmosis • TB • Lymphoma • MS • … NEGATIVE

  13. Pathological data (N=9/14)

  14. Treatment and outcome • Treatment: • Steroids: 8/14 • Change ART: 9/14 • Cyclophosmamide: 3/14 • Prognosis • Initial efficacy of steroids • But, frequent relapses (35%) • And, very severe overall prognosis • Death: 35% • Survival with Sequellae: 35% • Survival without sequellae: 30%

  15. How to do the diagnosis Patients profile Stable patients on an immunological point of view but not perfectly virologicaly controled Additional sensitive criteria Acute or subacute diffuse severe encephalitis CD8+ lymphocytes meningitis Imaging Diffuse leukoencephalopathy  Areas with restricted diffusion Perivascular contrast enhancement (better depicted using spin-echo T1 with magnetization transfer)

  16. How to do the diagnosis Patients profile Stable patients on an immunological point of view but not perfectly virologicaly controled Sensitive criteria Acute or subacute diffuse severe encephalitis CD8+ lymphocytes meningitis Imaging Diffuse leukoencephalopathy  Areas with restricted diffusion Perivascular contrast enhancement (better depicted using spin-echo T1 with magnetization transfer) « A crash of thunder in an apparently serene sky » « Central DILS »

  17. How to entry in this disease? Stop ART Blip T8 encephalitis

  18. How to entry in this disease? Stop ART Blip T8 encephalitis Virological escape Langford et al. 2002

  19. How to entry in this disease? Stop ART Blip T8 encephalitis Virological escape IRIS Langford et al. 2002 Miller et al. 2004

  20. Pathogenesis hypothesis tat TNFɑ nef IL1ß HIV M-T8 GP120 RANTES • Asymptomatic patients = stable balance • - HIV neuro-pathogenicityvs central immunogenicity

  21. Pathogenesis hypothesis tat TNFɑ nef IL1ß HIV M-T8 GP120 RANTES • Asymptomatic patients = stable balance • - HIV neuro-pathogenicity vs central immunogenicity • Patients with chronic NCD = mild unstable balance • - Persistent neuro-virulence or persistent neuro-inflammation

  22. Pathogenesis hypothesis tat TNFɑ nef IL1ß HIV M-T8 GP120 RANTES • Asymptomatic patients = stable balance • - HIV neuro-pathogenicity vs central immunogenicity • Patients with chronic NCD = mild unstable balance • - Persistent neuro-virulence or persistent neuro-inflammation • Subacute phenomenon = acute unbalanced mecanism • - HIV central sanctuarisation or • - Directly or secondary HIV driven immunological burnt-out according to the domino or « hit and run » theory Wang et al. 2006, Scaravilli et al. 2007, McCrossan et al. 2006, Price et al. 2000, Tsunoda et al. 2005, Shacklett et al. 2004

  23. In conclusion • An emergent form of neurological complication in HIV population • In well controlled but long term infected and not perfectly virological suppressed patients • A peripheral increase of HIV replication and decrease of CD4 • An acute, severe and diffuse meningoencephalitis • Specific abnormalities in MRI • Good initial response to corticotherapy and ARV intensification if necessary • Overall severe prognosis

  24. Acknowlegments Fondation Ophtalmologique Rothschild : Antoine Moulignier, Julien Savatovsky Hôpital Bichat : Homa Adle-Biassette Hôpital La Pitié Salpétrière : Brigitte Autran, Guislaine Carcelain Hôpital Lariboisière : Françoise Gray, Jacqueline Mikol Hôpital Saint Antoine : Jean-Luc Meynard, Jérôme Pacanowsky, Nadia Vallin, Pierre-Marie Girard Hôpital Saint Louis : Jean Michel Molina Hôpital Tenon : Corinne Amiel, Gilles Pialoux Xavier.lescure@tnn.aphp.fr

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