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AIDS-related optic neuropathy: a histological, virological and ultrastructural study

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Abstract

• Background: Clinical and histopathological evidence of optic nerve axonal loss has been reported in AIDS patients without retinitis. The study was carried out to investigate the possible involvement of HIV-infected cells in the development of optic nerve degeneration. • Methods: Optic nerves were obtained from eight AIDS patients and four normal controls. These nerves were morphologically and immunohistochemically analyzed. Additionally, using PCR amplification techniques, the retina and optic nerve samples obtained from three HIV-seropositive patients and one control were examined for the presence of HIV and cytomegalovirus antigens. • Results: We noted various stages of axonal degeneration in the optic nerves obtained from AIDS patients in whom there was an absence of retinal findings. Characteristic glial changes involving hypertrophic astrocytes, vacuolated oligodendrocytes, and mononuclear phagocyte series cells were also seen in the AIDS optic nerves. HIV DNA was present in at least four of five optic nerves but in only one of five retinas. Control specimens were each negative for all cytomegalovirus and HIV antigens. • Conclusions: Degeneration in the optic nerve may be mediated by HIV-infected macrophages rather than by direct viral infection of neurons. Axonal degeneration due to AIDS at the level of the optic nerve can occur independently of retinal infection.

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References

  1. Barna BP, Estes ML, Jacobs BS, Hudson S, Ransohoff RM (1990) Human astrocytes proliferate in response to tumor necrosis factor alpha. J Neuroimmunol 30:239–243

    Google Scholar 

  2. Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist, DL, Elkins KL, Ruff MR, Pert CB (1988) Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature 335:634–642

    Google Scholar 

  3. Brosnan CF, Selmaj K, Raine CS (1988) Hypothesis: a role for tumor necrosis factor in immune-mediated demyelination and its relevance to multiple sclerosis. J Neuroimmunol 18:87–94

    Google Scholar 

  4. Budka H (1986) Multinucleated giant cells in brain: a hallmark of the acquired immune deficiency syndrome (AIDS). Acta Neuropathol 69:253–258

    Google Scholar 

  5. Budka H (1989) Human immunodeficiency virus (HIV)-induced disease of the central nervous system: pathology and implications for pathogenesis. Acta Neuropathol 77:225–236

    Google Scholar 

  6. Budka H, Costanzi G, Cristina S, Lechi A, Parravicini C, Trabattoni R, Vago L (1987) Brain pathology induced by infection with the human immunodeficiency virus (HIV). A histological, immunocytochemical, and electron microscopic study of 100 autopsy cases. Acta Neuropathol 75:185–198

    Google Scholar 

  7. Cantrill HL, Henry K, Jackson B, Erice A, Ussery FM, Balfour HH (1988) Recovery of human immunodeficiency virus from ocular tissues in patients with acquired immune deficiency syndrome. Ophthalmology 95:1458–1462

    Google Scholar 

  8. Chung IY, Benveniste EN (1990) Tumor necrosis factor alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol 144:2999–3007

    Google Scholar 

  9. Currie J, Benson E, Ramsden B, Perdices M, Cooper D (1988) Eye movement abnormalities as a predictor of the acquired immunodeficiency syndrome dementia complex. Arch Neurol 45:949–953

    Google Scholar 

  10. Dickson DW, Mattiace LA, Kure K, Hutchins K, Lyman WD, Brosnan CF (1991) Microglia in human disease, with an emphasis on acquired immune deficiency syndrome. Lab Invest 64:135–156

    Google Scholar 

  11. Faber DW, Wiley CA, Lynn GB, Gross JG, Freeman WR (1992) Roles of HIV CMV in the pathogenesis of retinitis and retinal vasculopathy in AIDS patients. Invest Ophthalmol Vis Sci 33:2345–2353

    Google Scholar 

  12. Forster DJ, Dugel PU, Frangieh GT, Liggett PE, Rao NA (1990) Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol 110:341–348

    Google Scholar 

  13. Freeman WR, Chen A, Henderly DE, Levine AM, Lutrull JK, Urrea PT, Arthur J, Rasheed S, Cohen JL, Neuberg D, Leung RJ (1989) Prevalence and significance of acquired immunodeficiency syndrome-related retinal microvasculopathy. Am J Ophthalmol 107:229–235

    Google Scholar 

  14. Giulian D, Vaca K, Noonan CA (1990) Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 25:1593–1596

    Google Scholar 

  15. Grimaldi LME, Martino GV, Franciotta DM, Brustia R, Castagna A, Pristera R, Lazzarin A (1991) Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann Neurol 29:21–25

    Google Scholar 

  16. Harried LM, Schatz NJ, Galetta SL (1988) Brainstem ocular motility defects and AIDS. Am J Ophthalmol 106:437–442

    Google Scholar 

  17. Hirt B (1967) Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol 26:365

    Google Scholar 

  18. Ho DD, Rota TR, Schooley RT, Kaplan JC, Allan JD, Groopman JE, Resnick WI, Felsenstein D, Andrews CA, Hirsch MS (1985) Isolation of HTLV-111 from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med 313:1493–1497

    Google Scholar 

  19. Ho DD, Pomerantz RJ, Kaplan JC (1987) Pathogenesis of infection with human immunodeficiency virus. N Engl J Med 317:278–286

    Google Scholar 

  20. Holman FM, Hinton DR (1992) Tumor necrosis factor-a in the retina in acquired immune deficiency syndrome. Invest Ophthalmol Vis Sci 33:1829–1835

    Google Scholar 

  21. Holland GN, Gottlieb MS, Foos RY (1982) Retinal cotton-wool patches in acquired immunodeficiency syndrome. N Engl J Med 307:1704–1705

    Google Scholar 

  22. Holland GN, Pepose JS, Pettit TH (1983) Acquired immune deficiency syndrome. Ocular manifestations. Ophthalmology 90:859–873

    Google Scholar 

  23. Jabs DA, Green WR, Fox R, Polk BF, Bartlett JG (1989) Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 96:1092–1099

    Google Scholar 

  24. Johnson BM, Sadun AA (1988) Ultrastructural and paraphenylene studies of degeneration in the primate visual system: degenerative remnants persist for much longer than expected. J Electron Microsc Tech 8:179–183

    Google Scholar 

  25. Kaiser PK, Offerman NJT, Lipton SA (1990) Neuronal injury due to HIV-1 envelope protein is blocked by anti-gp120 antibodies but not by anti-CD4 antibodies. Neurology 40:1757–1761

    Google Scholar 

  26. Kato T, Hirano A, Llena JF, Dembitzer HM (1987) Neuropathology of acquired immune deficiency syndrome (AIDS) in 53 autopsy cases, with particular emphasis on microglial nodules and multinucleated giant cells. Acta Neuropathol 73:287–294

    Google Scholar 

  27. Kennedy PGE, Newsome DA, Hess J, Narayan O, Suresch DL, Green WR, Gallo RC, Polk BF (1986) Cytomegalovirus but not human T lymphotrophic virus type III/lymphadenopathy associated with virus detected by in situ hybridization in retinal lesions in patients with the acquired immune deficiency syndrome. Br Med J 293:162–164

    Google Scholar 

  28. Khadem M, Kalish SB, Goldsmith J, Fetkenhour C, O'Grady RB, Phair JP, Chrobak M (1984) Ophthalmologic findings in acquired immune deficiency syndrome (AIDS). Arch Ophthalmol 102:201–206

    Google Scholar 

  29. Kleihues P, Lang W, Burger PC, Budka H, Vogt M, Maurer R, Lüthy R, Siegenthaler W (1989) Progressive diffuse leukoencephalopathy in patients with acquired immune deficiency syndrome (AIDS). Acta Neuropathol 68:333–339

    Google Scholar 

  30. Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksmait A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093

    Google Scholar 

  31. Lahdevirta J, Maury CPJ, Teppo AM, Repo H (1988) Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85:289–291

    Google Scholar 

  32. Levy J A, Shimabukuro J, Hollander H, Mills J, Kaminsky L (1985) Isolation of AIDS-associated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms. Lancet 2:586–588

    Google Scholar 

  33. Levy RM, Bredesen DE, Rosenblum ML (1985) Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): experience at UCSF and review of the literature. J Neurosurg 62:475–495

    Google Scholar 

  34. Locardi C, Petrini C, Boccoli G, Testa U, Dieffenbach C, Butto S, Belardelli F (1990) Increased human immunodeficiency virus (HIV) expression in chronically infected U937 cells upon in vitro differentiation by hydroxyvitamin D3: roles of interferon and tumor necrosis factor in regulation of HIV production. J Virol 64:5874–5882

    Google Scholar 

  35. Mastrioanni CM, Liuzzi GM, Vullo V, Delia S, Riccio P (1991) Cerebrospinal fluid markers for the monitoring of AIDS dementia complex severity: usefulness of anti-myelin basic protein antibody detection. AIDS 5:464–465

    Google Scholar 

  36. Meltzer MS, Nakamura M, Haassen BD, Turpin JA, Kalter DC, Gendelman HE (1990) Macrophages as susceptible targets for HIV infection, persistent viral reservoirs in tissue, and key immunoregulatory cells that control levels of virus replication and extent of disease. AIDS Res Hum Retroviruses 6:967–971

    Google Scholar 

  37. Merril JE, Chen ISY (1991) HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J 5:2391–2397

    Google Scholar 

  38. Mintz M, Rapaport R, Oleske J M, Connor EM, Koenigsberger MR, Denny T, Epstein LG (1989) Elevated serum levels of tumor necrosis factor are associated with progressive encephalopathy in children with acquired immunodeficiency syndrome. Am J Dis Child 143:771–774

    Google Scholar 

  39. Mondino BJ, Sidikaro Y, Mayer FJ, Sumner HL (1990) Inflammatory mediators in the vitreous humor of AIDS patients with retinitis. Invest Ophthalmol Vis Sci 31:798–804

    Google Scholar 

  40. Navia BA, Cho ES, Petito CK, Price RW (1986) The acquired immune deficiency syndrome dementia complex. II. Neuropathology. Ann Neurol 19:525–535

    Google Scholar 

  41. Navia BA, Jordan BD, Price RW (1986) The acquired immune deficiency syndrome dementia complex. I. Clinical features. Ann Neurol 19:517–524

    Google Scholar 

  42. Newman NJ, Lessell S (1992) Bilateral optic neuropathies with remission in two HIV-positive men. J Clin Neuro Ophthalmol 12:1–5

    Google Scholar 

  43. Ou CY, Kwok S, Mitchell SW, Mack DH, Sninsky JJ, Krebs JW, Feorino P, Warfield D, Schochetman G (1988) DNA amplification for direct detection of HIV-1 in DNA of peripheral blood mononuclear cells. Science 239:295–297

    Google Scholar 

  44. Palestine AG, Rodrigues MM, Macher AM, Chan CC, Lane HC, Fauci AS, Masur H, Longo D, Reichert CM, Steis R, Rook AH, Nussenblatt AB (1984) Ophthalmic involvement in acquired immunodeficiency syndrome. Ophthalmology 91:1092–1099

    Google Scholar 

  45. Pepose JS (1989) Ophthalmic manifestations of HIV infection. Curr Topics AIDS 2:191–206

    Google Scholar 

  46. Pepose JS, Nestor MS, Holland GN, Cochran AJ, Foos RY (1983) An analysis of retinal cotton-wool spots and cytomegalovirus retinitis in the acquired immunodeficiency syndrome. Am J Ophthalmol 95:118–120

    Google Scholar 

  47. Pepose JS, Holland GN, Nestor MS, Cochran AJ, Foos RY (1985) Acquired immune deficiency syndrome. Pathogenic mechanisms of ocular disease. Ophthalmology 92:472–484

    Google Scholar 

  48. Pereira L, Hoffman M, Gallo D, Cremer N (1982) Monoclonal antibodies to human cytomegalovirus: three surface membrane proteins with unique immunological and electrophoretic properties specify cross-reactive determinants. Infect Immun 36:924–932

    Google Scholar 

  49. Petito CK, Cho ES, Lemann W, Navia BA, Price RW (1986) Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol 45:635–646

    Google Scholar 

  50. Pomerantz RJ, Kuritzkes DR, de la Monte SM, Rota TR, Baker AS, Albert D, Bor DH, Feldman EL, Schooley RJ, Hirsch MS (1987) Infection of the retina by human immunodeficiency virus type I. N Engl J Med 317:1643–1647

    Google Scholar 

  51. Qavi HB, Green MT, SeGall GK, Lewis DE, Hollinger FB (1992) Transcriptional activity of HIV-1 and HHV-6 in retinal lesions from AIDS patients. Invest Ophthalmol Vis Sci 33:2759–2767

    Google Scholar 

  52. Quiceno JI, Capparelli E, Sadun AA, Mungula D, Listhaus A, Crapotta J, Lambert B, Freeman WR (1992) Visual dysfunction in AIDS patients without retinitis. Am J Ophthalmol 113:8–13

    Google Scholar 

  53. Resnick L, Di Marzo-Veronese F, Schupbach J, Tourtellotte WW, Ho DD, Muller F, Shapshak P, Vogt M, Groopman JE, Markham PD, Gallo RC (1985) Intra-blood-brain-barrier synthesis of HTLV-III-specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex. N Engl J Med 313:1498–1504

    Google Scholar 

  54. Rhodes RH (1987) Histopathology of the central nervous system in the acquired immunodeficiency syndrome. Hum Pathol 18:636–643

    Google Scholar 

  55. Righi M, Mori L, De Libero G, Sironi M, Biondi A, Mantovani A, Donini SD, Ricciardi-Castagnoli P (1989) Monokine production by microglial cell clones. Eur J Immunol 19:1443–1448

    Google Scholar 

  56. Robbins DS, Shirazi Y, Drysdale BE, Lieberman A, Shin HS, Shin ML (1987) Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. J Immunol 139:2593–2597

    Google Scholar 

  57. Roy S, Wainberg MA (1988) Role of the mononuclear phagocyte system in the development of acquired immunodeficiency syndrome (AIDS). J Leuk Biol 43:91–97

    Google Scholar 

  58. Sadun AA, Smith LEH, Kenyon KR (1983) Paraphenylenediamine: a new method for tracing visual pathways. J Neuropathol Exp Neurol 4:200–206

    Google Scholar 

  59. Sawada M, Kondo N, Suzumura A, Marunouchi T (1989) Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res 491:394–397

    Google Scholar 

  60. Scharf SJ, Friedmann A, Brautbar C, Szafer F, Steinman L, Horn G, Gyllensten U, Erlich HA (1988) HLA class II allelic variation and susceptibility to pemphigus vulgaris. Proc Natl Acad Sci USA 85:3504–3508

    Google Scholar 

  61. Schmitt-Graff A, Neuen-Jacob E, Rettig B, Sundmacher R (1990) Evidence for cytomegalovirus and human immunodeficiency virus infection of the retina in AIDS. Virchows Arch A Pathol Anat 416:249–253

    Google Scholar 

  62. Selmaj KW, Raine CS (1988) Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 23:339–346

    Google Scholar 

  63. Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF (1990) Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol 144:129–135

    Google Scholar 

  64. Selmaj K, Raine CS, Farooq M, Norton WT, Brosnan CF (1991) Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol 147:1522–1529

    Google Scholar 

  65. Shaw GM, Harper ME, Hahn BH, Epstein LG, Gajdusek DC, Price RW, Navia BA, Petito CK, O'Hara CV, Groopman JE, Cho ES, Oleske JM, Wong-Staal F, Gallo RC (1985) HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science 227:177–182

    Google Scholar 

  66. Skolnik PR, Pomerantz RJ, de la Monte SM, Lee SF, Hsiung GD, Foos RY, Cowan GM, Kosloff RR, Hirsch MS, Pepose JS (1989) Dual infection of retina with human immunodeficiency virus type 1 and cytomegalovirus. Am J Ophthalmol 107:361–372

    Google Scholar 

  67. Sotrel A (1989) The nervous system. In: Harawi SJ, O'Hara CJ (eds) Pathology and pathophysiology of AIDS and HIV-related diseases. Chapman and Hall, London, pp 201–268

    Google Scholar 

  68. Sydow M von, Sonnerberg A, Gaines H, Strannegard O (1991) Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1 infected patients with central nervous system involvement. Ann Neurol 7:375–380

    Google Scholar 

  69. Tenhula WN, Xu SZ, Heller K, Freeman WR, Sadun AA (1992) Optic nerve axon losses in AIDS: morphometric comparisons. Am J Ophthalmol 113:14–20

    Google Scholar 

  70. Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE (1992) Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol 31:349–360

    Google Scholar 

  71. Ward RC, Weiner MJ, Albert DM (1989) The eye. In: Harawi SJ, O'Hara CJ (eds) Pathology and pathophysiology of AIDS and HIV-related diseases. Chapman and Hall, London pp 363–377

    Google Scholar 

  72. Williams AE, Blakemore WF (1990) Monocyte-mediated entry of pathogens into the central nervous system. Neuropathol Appl Neurobiol 16:377–392

    Google Scholar 

  73. Winward KE, Hamed LM, Glaser JS (1989) The spectrum of optic nerve disease in human immunodeficiency virus infection. Am J Ophthalmol 107:373–380

    Google Scholar 

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Authors and Affiliations

  1. Doheny Eye Institute, 1.450 San Pablo Street, 90033, Los Angeles, CA, USA

    Alfredo A. Sadun, Michele C. Madigan & Wendy N. Tenhula

  2. Departments of Ophthalmology and Neurosurgery, University of Southern California School of Medicine, Los Angeles, California, USA

    Alfredo A. Sadun, Michele C. Madigan & Wendy N. Tenhula

  3. Departments of Ophthalmology, Washington School of Medicine, St. Louis, Missouri, USA

    Jay S. Pepose & Keith A. Laycock

  4. Departments of Pathology, Washington School of Medicine, St. Louis, Missouri, USA

    Jay S. Pepose

  5. Shiley Eye Center and Department of Ophthalmology, University of California, San Diego, California, USA

    William R. Freeman

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  1. Alfredo A. Sadun
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  2. Jay S. Pepose
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Sadun, A.A., Pepose, J.S., Madigan, M.C. et al. AIDS-related optic neuropathy: a histological, virological and ultrastructural study. Graefe's Arch Clin Exp Ophthalmol 233, 387–398 (1995). https://doi.org/10.1007/BF00180941

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