Central Nervous System Immune Reconstitution Disease: Pathology

Transcription

1 Central Nervous System Immune Reconstitution Disease: Pathology F.Gray, H.Adle-Biassette, F.Héran, G. Pialoux, A.Moulignier, APHP Hôpital Lariboisière Université Paris VII

2 Introduction of HAART, which is available for all patients in France since 1996, has dramatically modified the course and prognosis of HIV disease Annual number of autopsies from AIDS patients 0 < This benefit is mainly due to: a decrease of the viral load a restored functional immune system

3 Immune Reconstitution Inflammatory Syndrome (IRIS) (Shelburne et al. Medicine 2002;81: ) 1. Patient with AIDS 2. HAART induced CD4 Viral Load 3. Symptoms consistent with an infectious/inflammatory condition appear while on antiretroviral therapy 4. Symptoms cannot be explained by: - a newly acquired infection - the expected course of a previously recognized infection - side effects of therapy

4 Systemic IRIS (Shelburne et al. Medicine 2002;81: ) Mycobacterial infections - M. Avium Complex lymphadenitis - Pulmonary tuberculosis Herpes zoster infections Pneumocystis Carinii pneumonia Hepatitis B and C

5 IRIS and the CNS Paradoxical exacerbation - CNS M. Tuberculosis infection - Cryptococcus Neoformans meningitis - CMV retinitis (Shelburne et al. Medicine 2002;81: ) PML HIV encephalitis

6 HIV infection of the CNS and HAART-induced immune reconstitution

7 7 AIDS patients who failed HAART Severe leukoencephalopathy Intense perivascular infiltration by HIV-gp41 positive monocytes/macrophages

8 Cerebral CD8+ lymphocytosis following HAART-induced immune restoration (Miller et al. Acta Neuropathologica 2004;108: 17-23) 2 AIDS patients with low CD4 and high VL HAART CD4 VL Development (or worsening) of acute encephalopathy MRI: leukoencephalopathy (type?) Rapid neurological deterioration and death

9 Cerebral CD8+ lymphocytosis following HAART-induced immune restoration (Miller et al. Acta Neuropathologica 2004;108: 17-23) Case 1 Case 2

10 Cerebral CD8+ lymphocytosis following HAART-induced immune restoration (Miller et al. Acta Neuropathologica 2004;108: 17-23)

11 Cerebral CD8+ lymphocytosis following HAART-induced immune restoration (Miller et al. Acta Neuropathologica 2004;108: 17-23) Case 1 Case 2 p24 In situ PCR + CD68

12 Cerebral CD8+ lymphocytosis following HAART-induced immune restoration (Miller et al. Acta Neuropathologica 2004;108: 17-23) CD8

13 Encephalitis with CD8+ infiltration 8 biopsy cases Patients efficiently treated with HAART: CD4 VL Presenting with rapidly progressive subacute leukoencephalopathy

14 Encephalitis with CD8+ infiltration 4 cases consistent with IRIS Rapidly progressive onset of neurological signs following HAART-induced immune restoration, 2-9 months after treatment initiation

15 Encephalitis with CD8+ infiltration 4 patients receiving HAART for several months,with stable immunovirological status The neurological signs occurred after a transitory episode of CD4 and VL, related to interruption of treatment or intercurrent systemic opportunistic infection

16 Encephalitis with CD8+ infiltration Clinically Association of diffuse encephalopathy Confusion, Agitation, Behaviour and Mood Disturbances, Hallucinations, Headaches, Vertigo, Tremor, Gait disturbances, Apathy, Intellectual slowing, Memory disturbances and focal neurological signs Seizures, Aphasia, Hemiparesis Rapidly progressive onset and subacute course

17 Encephalitis with CD8+ infiltration MRI Remarkably similar, very distinctive changes Extensive diffuse or multifocal leukoencephalopathy on T2 weighted images Perivascular contrast enhancement +++

18 MRI: Diffuse Leukoencephalopathy on T2 weighted images

19 MRI: Perivascular Contrast Enhancement T1 Gado

20 MRI: Multifocal Leukoencephalopathy & Perivascular CE FLAIR T2 T1 gado

21 MRI: extremity of the spectrum: Cerebral vasculitis T2 Van de Ven et al. Cerebral vasculitis after initiation antiretroviral therapy. AIDS : T1 Gd

22 MRI: extremity of the spectrum: Focal, contrast enhancing, pseudo-ms lesions T2 T1 gado

23 Brain Biopsy Encephalitic changes Microglial Activation Reactive astrocytosis Variable expression of HIV proteins Infiltration by T-lymphocytes Perivascular (vasculitis?) Diffuse intraparenchymal CD8 +++, CD4 variable

24 Brain Biopsy Extremities of the spectrum HIV encephalitis HIV protein expression +++, MGC Pseudo MS Clear cut Demyelinating Foci Axons relatively spared Inflammation CD8 +++ CD25 + 0

25 Encephalitic Changes H&E HLA-DR H&E GFAP

26 Microglial Activation HLA-DR

27 CD68 p24 Microglial nodules and mild expression of p24

28 HIV Encephalitis, MGC & CD8+ Lymphocyte Infiltration CD68 CD8 p24

29 Perivascular inflammation Van de Ven et al. Cerebral vasculitis after initiation antiretroviral therapy. AIDS :

30 CD68 H&E CD20

31 CD3 CD4 CD8 CD25

32 CD3 CD20 CD8 CD4

33 Intraparenchymal CD8+ Lymphocyte Infiltration H&E CD3 CD8

34 CD3 CD20 CD8+ Lmphocyte Infiltration CD8 CD4

35 Pseudo-MS Demyelinating Changes Hematoxylin & Eosin CD68 Bielschowsky Neurofilament

36 C D8 C D25

37 Treatment HAART continued + Steroids 6 cases : Favourable outcome Normalisation of neurological status Normal levels of CD4 & CD8 MRI: regression or disappearance of signs 2 cases: Unfavourable outcome Several remitting/relapsing episodes Death

38 Klüver & Barrera

39 HIV encephalitic changes GFAP CD68 p24 p24

40 Diffuse Lymphocytic Infiltration CD3 CD4 CD8 CD25

41 Perivascular Lymphocytic Infiltration H&E H&E CD8 CD4

42 ADEM changes Klüver & Barrera Klüver & Barrera H&E CD8

43 Fatal HIVE and IRIS In Summary Acute HIVE, with marked inflammation, MGC and HIV protein expression (absent on the previous biopsy) Acute perivenous leukoencephalitis (ADEM)

44 Immune Reconstitution Inflammatory Syndrome (IRIS) 1) Inflammatory reaction unmasking a smouldering active infection Symptomatic cryptococcal meningitis Woods et al. AIDS 1998; 12: Breton et al. Am J Med : CMV Retinitis Jacobson et al. Lancet 1997;349:1443-5

45 Immune Reconstitution Inflammatory Syndrome (IRIS) 2) Non specific immunopathologic reaction Aseptic meningitis in patients with C. Neoformans infection Woods et al. AIDS 1998; 12: Vitritis in patients successfully treated for CMV retinitis Karavellas et al. J Infect Dis 1999; 179:

46 Immune Reconstitution Inflammatory Syndrome (IRIS) Pathophysiology Exaggerated «overzealous» response of a newly reconstituted immune system to infectious antigens already present in the patient when therapy started

47 Immune Reconstitution Inflammatory Syndrome (IRIS) Pathophysiology Restoration of T-cell function allows an influx of memory CD8+ T-cells that recognize infectious antigens This may result in an unusually intense inflammatory reaction with influx of CD8+ lymphocytes and impairment of the BBB with contrast enhancement at imaging

48 IRIS and HIV infection Pathophysiology The influx of lymphocytes may be beneficial resulting in macrophage activation and control of HIV infection It also may be harmful: (Dysregulation of the CD8+/CD4+ T cell balance) CD8+cytotoxicity in the absence of CD4+, causing accentuation of HIV infection and/or perivenous leukoencephalitis

49 Conclusion (1) In AIDS patients with HIVE or PML, HAARTinduced restoration of a pathogen-specific immune response may result in an unusually intense inflammatory reaction Impairment of the BBB & Contrast enhancement on MRI Influx of T lymphocytes predominantly CD8+

50 Conclusion (2) The influx of CD8+ lymphocytes may explain the 2 types of pathological processes that are variably associated in the patients: An acute worsening of the underlying infection (HIV or JCV) A non specific immunopathologic reaction (ADEM or MS type)

51 Conclusion (3) This inflammatory syndrome is usually reversible spontaneously or following treatment (HAART and steroids) However, in some case it may have a fatal outcome In our experience, the only factor constantly associated with an unfavourable outcome is a dysregulation of the CD4/CD8 balance in brain tissue, with absence of CD4+ lymphocytes

52 F. Gray H. Adle-Biassette F. Chrétien M. Polivka F. Scaravilli G. Corcket M.A. Bretel P. Castagnet K. Dossou S. Portenguen C. Poiron C. Sanchez A.Moulignier G. Pialoux F. Héran J.B. Thiebault

53 Thank you for your attention