Abstract
We reviewed the clinical, radiographic, and pathologic features of 15 patients with the acquired immune deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). Brain tissue from 10 autopsy and 6 biopsy specimens was studied using: in situ hybridization (ISH) for JC virus (JCV), immunohistochemistry for human immunodeficiency virus (HIV) p24 antigen, and electron microscopy. Thirteen patients presented with focal neurologic deficits, while 2 presented with a rapid decline in mental status. PML was commonly the initial opportunistic infection of AIDS and produced hemiparesis, dementia, dysarthria, cerebellar abnormalities; and seizures. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions, and often showed multifocal areas of PML. CD4+ T-cell counts were uniformly low (mean 84/mm3), except in 1 patient who improved on 3′-azido-3′-deoxythymidine (AZT). PML involved the cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord. The distribution of brain involvement was consistent with hematogenous dissemination of the virus. In 2 brain specimens, multiple HIV-type giant cells were present within the regions involved by PML. When co-infection by HIV and papovavirus was present, PML dominated the pathological picture. ISH for JCV showed virus in the nuclei of oligodendrocytes and astrocytes. Occasionally there was staining for JCV in the cytoplasm of glial cells and in the neuropil, the latter possibly a correlate of papovavirus spread between myelin sheaths, as seen by electron microscopy. ISH demonstrated more extensive foci of PML than did routine light microscopy.
Similar content being viewed by others
References
Aksamit AJ, Mourrain P, Sever JL, Major EO (1985) Progressive multifocal leukoencephalopathy: investigation of three cases using in situ hybridization with JC virus biotinylated DNA probe. Ann Neurol 18:490–496
Aksamit AJ, Sever JL, Major EO (1986) Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry. Neurology 36:499–504
Aksamit AJ, Major EO, Ghatak NR, Sidhu GS, Parisi JE, Guccion JG (1987) Diagnosis of progressive multifocal leukoencephalopathy by brain biopsy with biotin labeled DNA: DNA in situ hybridization. J Neuropathol Exp Neurol 46:556–566
Aksamit AJ, Gendelman HE, Orenstein JM, Pezeshkpour GH (1990) AIDS-associated progressive multifocal leukoencephalopathy (PML): comparison to non-AIDS PML with in situ hybridization and immunohistochemistry. Neurology 40:1073–1078
Anders KH, Guerra WF, Tomiyasu U, Verity MA, Vinters HV (1986) The neuropathology of AIDS. UCLA experience and review. Am J Pathol 124:537–558
Anders KH, Holden JL, Becker PS, Vinters HV (1990) Focal pontine leukoencephalopathy. A review of ten cases. J Neuropathol Exp Neurol 49:315
Aström KE, Mancall EL, Richardson EP (1958) Progressive multifocal leukoencephalopathy. Brain 81:93–111
Berger JR, Mucke L (1988) Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy. Neurology 38:1060–1065
Berger JR, Kaszovitz B, Post MJ, Dickinson G (1987) Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann Intern Med 107:78–87
Boerman RH, Arnoldus EP, Raap AK, Peters AC, Schegget J ter, Ploeg M van der (1989) Diagnosis of progressive multifocal leukoencephalopathy by hybridisation techniques. J Clin Pathol 42:153–161
Brooks BR, Walker DL (1984) Progressive multifocal leukoencephalopathy. Neurol Clin 2:299–313
Chesters PM, Heritage J, McCance DJ (1983) Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 147:676–684
Clark GL, Vinters HV (1987) Dementia and ataxia in a patient with AIDS [clinical conference]. West J Med 146:68–72
Conway B, Halliday WC, Brunham RC (1990) Human immunodeficiency virus-associated progressive multifocal leukoencephalopathy: apparent response to 3′-azido-3′-deoxythymidine. Rev Infect Dis 12:479–482
Cornford ME, Said JW, Vinters HV (1991) Immunohistochemical localization of human immunodeficiency virus (HIV) in central nervous system: lymphoproliferative disorders of patients with AIDS. Mod Pathol 4:232–238
Cummings JL, Benson DF (1984) Subcortical dementia: review of an emerging concept. Arch Neurol 41:874–879
Dörries K, Meulen V ter (1983) Progressive multifocal leucoencephalopathy: detectgion of papovavirus JC in kidney tissue. J Med Virol 11:307–317
Dörries K, Johnson RT, Meulen V ter (1979) Detection of polyoma virus DNA in PML-brain tissue by (in situ) hybridization. J Gen Virol 42:49–57
Dupuis M, Fernandes Xavier FG, Gonsette RE, Brucher JM (1986) Progressive multifocal leukoencephalopathy mimicking multiple sclerosis as the sole clinical manifestation of acquired immunodeficiency syndrome. Acta Neurol Belg 86:285–296
Einsiedel RW von, Minami E, Secor DL, Pang S, Chen ISY, Vinters HV (1990) Structural components of the AIDS dementia complex: correlation of brain parenchymal astrogliosis with HIV-1 DNA in cerebral tissues. J Neuropathol Exp Neurol 49:351
Eng LF, DeArmond SJ (1983) Immunochemistry of the glial fibrillary acidic protein. In: Zimmerman HM (ed) Progress in neuropathology, vol 5. Raven Press, New York, pp 19–41
Fahey JL, Taylor JMG, Detels R, Hofmann B, Melmed R, Nishanian P, Giorgi JV (1990) The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med 22:322–1886
Fiala M, Cone LA, Cohen N, Patel D, Williams K, Casareale D, Shapshak P, Tourtelotte W (1988) Responses of neurologic complications of AIDS to 3′-azido-3′-deoxythymidine and 9 (1,3-dihydroxy-2-propoxymethyl) guanine. I. Clinical features. Rev Infect Dis 10:250–256
Frisque RJ, Bream GL, Cannella MT (1984) Human polyomavirus JC virus genome. J Virol 51:458–469
Gendelman HE, Phelps W, Feigenbaum L, Ostrove JM, Adachi A, Howley PM, Khoury G, Ginsberg HS, Martin MA (1986) Trans-activation of the human immunodeficiency virus long terminal repeat sequence by DNA virus. Proc Natl Acad Sci USA 83:9759–9763
Giorgi JV, Detels R (1989) T-cell subset alterations in HIV-infected homosexual men: MAID multicenter AIDS cohort study. Clin Immunol Immunopathol 52:10–18
Goswami KK, Kaye S, Miller R, McAllister R, Tedder R (1991) Intrathecal IgG synthesis and specificity of oligoclonal IgG in patients infected with HIV-1 do not correlate with CNS disease. J Med Virol 33:106–113
Greenlee JE (1989) Progressive multifocal leukoencephalopathy. Curr Clin Top Infect Dis 10:140–156
Grinnell BW, Padgett BL, Walker DL (1983) Distribution of nonintegrated DNA from SC papovavirus in organs of patients with progressive multifocal leukoencephalopathy. J Infect Dis 147:669–675
Guilleux MH, Steiner RE, Yong IR (1986) MR imaging in progressive multifocal leukoencephalopathy. Am J Neuroradiol 7:1033–1035
Hedley-Whyte ET, Smith BP, Tyler HR, Peterson WP (1966) Multifocal leukoencephalopathy with remission and five year survival. J Neuropathol Exp Neurol 25:107
Heinz ER, Drayer BP, Haenggeli CA, Painter MJ, Crumrine P (1979) Computed tomography in white-matter disease. Radiology 130:371–378
Holmann RC, Janssen RS, Buehler JW, Zelasky MT, Hooper WC (1991) Epidemiology of progressive multifocal leukoencephalopathy in the United States: analysis of national mortality and AIDS surveillance data. Neurology 41:1733–1736
Holtzman DM, Kaku DA, So YT (1989) New-onset seizures associated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med 87:173–177
Houff SA, Major EO, Katz DA, Kufta CV, Sever JL, Pittaluga S, Roberts JR, Girt J, Saini N, Lux W (1988) Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. N Engl J Med 318:301–305
Hunter EE (1984) Practical electron microscopy: a beginner's illustrated guide. Praeger, New York
Ironside JW, Lewis FA, Blythe D, Wakefield EA (1989) The identification of cells containing JC papovavirus DNA in progressive multifocal leukoencephalopathy by combined in situ hybridization and immunocytochemistry. J Pathol 157:291–297
Itoyama Y, Webster HD, Sternberger NH, Richardson EP Jr, Walker DL, Quarles RH, Padgett BL (1982) Distribution of papovavirus, myelin-associated glycoprotein, and myelin basic protein in progressive multifocal leukoencephalopathy lesions. Ann Neurol 11:396–407
Jones HR Jr, Hedley-Whyte ET, Freidberg SR, Kelleher JE Jr, Krolikowski J (1982) Primary cerebellopontine progressive multifocal leukoencephalopathy diagnosed premortem by cerebellar biopsy. Ann Neurol 11:199–202
Kepes JJ, Chou SM, Price LW Jr (1975) Progressive leukoencephalopathy with 10 year survival in a patient with nontropical sprue. Report of a case with unusual light and electron microscopic features. Neurology 25:1006–1012
Kleihues P, Lang W, Burger PC, Budka H, Vogt M, Maurer R, Luthy R, Siegenthaler W (1985) Progressive diffuse leukoencephalopathy in patients with acquired immune deficiency syndrome (AIDS). Acta Neuropathol (Berl) 68:333–339
Knight RS, Hyman NM, Gardner SD, Gibson PE, Esiri MM, Warlow CP (1988) Progressive multifocal leucoencephalopathy and viral antibody titres. J Neurol 235:458–461
Knobler RL, Lublin FD, Northrup BE, Barolat GR, Duckett S (1986) Progressive multifocal leukoencephalopathy in the posterior fossa of patients with AIDS. Neurology 36 [Suppl 1]:206
Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093
Koeppen S, Lehmann HJ (1987) Progressive multifocal leukoencephalopathy: neurological findings and evaluation of magnetic resonance imaging and computed tomography. Neurosurg Rev 10:127–132
Koyanagi Y, Miles S, Mitsuyasu RT, Merrill JE, Vinters HV, Chen ISY (1987) Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms, Science 236:819–822
Krupp LB, Lipton RB, Swerdlow ML, Leeds NE, Llena J (1985) Progressive multifocal encephalopathy: clinical and radiographic features. Ann Neurol 17:344–349
Ledoux S, Libman I, Robert F, Just N (1989) Progressive multifocal leukoencephalopathy with gray matter involvement. Can J Neurol Sci 16:200–202
Levy JD, Cottingham KL, Campbell RJ, Moore GK, Gyorkey F, Ashizawa T, Goldman AM (1986) Progressive multifocal leukoencephalopathy and magnetic resonance imaging. Ann Neurol 19:399–401
Levy RM, Bredesen DE, Rosenblum ML (1988) Opportunistic central nervous system pathology in patients with AIDS. Ann Neurol [Suppl] 23:7–12
Levy EM, Wu J, Cohn SE, Liebman H, Black PH (1989) Increased T-cell colony formation in AIDS patients treated with zidovudine: a possible mechanism for increased lymphocyte number. J Acquir Immune Defic Syndr 3:605–607
Li XL, Moudgil T, Vinters HV, Ho DD (1990) CD4-independent, productive infection of a neuronal cell line by human immunodeficiency virus type 1. J Virol 64:1383–1387
Lipton RB, Krupp L, Horoupian D, Hershkovitz S, Arezzo JC, Kurtzberg D (1988) Progressive multifocal leukoencephalopathy of the posterior fossa in an AIDS patient: clinical, radiographic and evoked potential findings. Eur Neurol 28:258–261
Livingstone DM, Bikel I (1985) Replication of papovaviruses. In: Fields BN (ed) Virology. Raven Press, New York, pp 393–410
Major E, Vacante DA (1989) Human fetal astrocytes in culture support the growth of the neurotropic polyomavirus, JCV. J Neuropathol Exp Neurol 48:425–436
Mark AS, Atlas SW (1989) Progressive multifocal leukoencephalopathy in patients with AIDS: appearance on MR images. Radiology 173:517–520
Mázló M, Tariska I (1982) Are astrocytes infected in progressive multifocal leukoencephalopathy (PML)? Acta Neuropathol (Berl) 56:45–51
Mazzarello P, Poloni M, Ceroni M, Scelsi R (1985) Is progressive multifocal leukoencephalopathy associated with intrathecal IgG synthesis? J Neuroimmunol 10:167–172
Monte SM de la, Ho DD, Schooley RT, Hirsch MS, Richardson EP Jr (1987) Subacute encephalomyelitis of AIDS and its relation to HTLV-111 infection. Neurology 37:562–569
Moss AR, Bachetti P, Osmond D, Krampf W, Chaisson RE, Stites D, Wilber J, Allain JP, Carlson J (1988) Seropositivity for HIV and the development of AIDS or AIDS related condition: three year follow up of the San Francisco General Hospital cohort. BMJ 296:745–750
Myers C, Frisque RJ, Arthur RR (1989) Direct isolation and characterization of JC virus from urine samples of renal and bone marrow transplant patients. J Virol 63:4445–4449
Nakamura S, Tourttelotte WW, Shapshak P, Darvish M (1985) The detection of papovavirus nucleotide sequences in cortical neurons of a patient with progressive multifocal leukoencephalopathy (PML) by in situ hybridization. Rinsho Skinkeigaku 25:1148–1151
Navia BA, Cho E-S, Petito CK, Price RW (1986) The AIDS dementia complex. II. Neuropathology. Ann Neurol 19:525–535
Olsen WL, Longo FM, Mills CM, Norman D (1988) White matter disease in AIDS: findings at MR imaging. Radiology 169:445–448
Orenstein JM, Janotta F (1988) Human immunodeficiency virus and papovavirus infections in acquired immunodeficiency syndrome: an ultrastructural study of three cases. Hum Pathol 19:350–361
Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH (1971) Cultivation of papova-like virus from human brain with progressive multifocal leukoencephalopathy. Lancet I:1257–1260
Pang S, Koyanagi Y, Miles S, Wiley C, Vinters HV, Chen ISY (1990) High levels of unintegrated HIV-1 DNA in brain tissue of AIDS dementia patients. Nature 343:85–89
Petito CK, Cho E-S, Lemann W, Navia BA, Price RW (1986) Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol 45:635–646
Portegies P, Algra PR, Hollak CEM, Prins JM, Reiss P, Valk J, Lange JMA (1991) Response to cytarabine in progressive multifocal leukoencephalopathy in AIDS. Lancet 337:680–681
Price RW, Nielsen S, Horten B, Rubino M, Padgett B, Walker D (1983) Progressive multifocal leukoencephalopathy: a burnout case. Ann Neurol 13:485–490
Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P (1988) The brain in AIDS: central nervous system HIV infection and AIDS dementia complex. Science 239:586–592
Rhodes RH, Ward JM, Walker DL, Ross AA (1988) Progressive multifocal leukoencephalopathy and retroviral encephalitis in acquired immunodeficiency syndrome. Arch Pathol Lab Med 112:1207–1213
Richardson EP (1961) Progressive multifocal leukoencephalopathy. N Engl J Med 265:815–823
Richardson EP, Johnson PC (1975) Atypical progressive multifocal leukoencephalopathy with plasma-cell infiltrates. Acta Neuropathol (Berl) [Suppl] 6:247–250
Schmidbauer M, Budka H, Shah KV (1990) Progressive multifocal leukoencephalopathy (PML) in AIDS and in the preAIDS era: a neuropathological comparison using immunocytochemistry and in situ DNA hybridisation for virus detection. Acta Neuropathol (Berl) 80:375–380
Shafran B, Roke ME, Barr RM, Cairncross JG (1987) Contrast enhancing lesions in progressive multifocal leukoencephalopathy: a clinicopathological correlation. Can J Neurol Sci 14:600–602
Shapshak P, Tourtellotte WW, Wolman M, Verity N, Verity MA, Schmid P, Syndulko K, Bedows E, Boostanfar R, Darvish M, Nakamura S, Tomiyasu U, Steiner RC, Hawkins S, Hoffman D, Adhami F, Martinez S (1986) Search for virus nucleic acid sequences in postmortem human brain tissue using in situ hybridization technology with cloned probes: some solutions and results on progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis tissue. J Neurosci Res 16:281–301
Sima AAF, Finkelstein SD, McLachlan DR (1983) Multiple malignant astrocytomas in a patient with spontaneous progressive multifocal leukoencephalopathy. Ann Neurol 14:183–188
Speelman JD, Schegget J ter, Bots GT, Stam J, Verbeeten B (1985) Progressive multifocal leukoencephalopathy in a case of acquired immune deficiency syndrome. Clin Neurol Neurosurg 87:27–33
Stara FC (1966) Multifocal leuko-encephalopathy with slow progression and very long survival. Psychiatr Neurol Neurochir 69:453–459
Stoner GL, Softer D, Ryschkewitsch C, Walker DL, Webster HD (1988) A double-label method detects both early and (Tantigen) and late (capsid) proteins of JC virus in progressive multifocal leukoencephalopathy brain tissue from AIDS and non-AIDS patients. J Neuroimmunol 19:223–236
Tada H, Rappaport J, Lashgari M, Amini S, Staal F, Khalih K (1990) Trans-activation of the JC virus late promoter by the tat protein of type 1 human immunodeficiency virus in glial cells. Proc Natl Acad Sci USA 87:3479–3483
Taguchi F, Kajioka J, Miyamura T (1982) Prevalence rate and age of acquisition of antibodies against JC virus and BK virus in human sera. Microbiol Immunol 26:1057–1064
Tashiro K, Doi S, Moriwaka G, Maruo Y, Nomura M (1987) Progressive multifocal leukoencephalopathy with magnetic resonace imaging verification and therapeutic trials with interferon. J Neurol 234:427–429
Trotot PM, Vazeuz R, Yamashita HK, Sandoz-Tronca C, Mikol J, Vedrenne C, Thiebaut JB, Gray F, Cikurel M, Pialoux G, Levillain R (1990) MRI pattern of progressive multifocal leukoencephalopathy (PML) in AIDS: pathologic correlations. J Neuroradiol 17:233–254
Vazeux R, Cumont M, Girard PM, Nassif X, Trotot P, Marche C, Matthiessen L, Vedrenne C, Mikol J, Henin D, Katlama C, Bolgert F, Montagnier L (1990) Severe encephalitis resulting from coinfection with HIV and JC virus. Neurology 40:944–948
Vinters HV, Anders KH (1990) Neuropathology of AIDS. CRC Press, Boca Raton
Vinters HV, Anders KH, Barach P (1987) Focal pontine leukoencephalopathy in immunosuppressed patients. Arch Pathol Lab Med 111:192–196
Walker DL (1985) Progressive multifocal leukoencephalopathy. In: Vinken PJ, Bruyn GW, Klawans HL (eds) Demyelinating diseases. (Handbook of clinical neurology, vol 47) Elsevier, Amsterdam, pp 503–524
Walker DL, Padgett BL (1983) The epidemiology of human polyomaviruses. In: Server JL, Madden DL (eds) Polyomaviruses and human neurological diseases. Liss, New York, pp 96–106
Watanabe J, Preskorn SH (1976) Virus-cell interaction in oligodendroglia, astroglia and phagocytes in progressive multifocal leukoencephalopathy. An electron microscopic study. Acta Neuropathol (Berl) 36:101–115
Weiner LP, Herndon RM, Narayan O, Johnson RT, Shah K, Rubinstein LJ, Preziosi TJ, Conley FK (1972) Isolation of virus related to SV40 from patients with porogressive multifocal leukoencephalopathy. N Engl J Med 286:385–390
Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83:7089–7093
Wiley CA, Grafe M, Kennedy C, Nelson JA (1988) Human immunodeficiency virus (HIV) and JC virus in acquired immunodeficiency syndrome (AIDS) patients with progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 76:338–346
Yarchoan R (1990) Taking anti-AIDS drugs from the test tube to patients. In: Broder S (ed) Antiretroviral therapy in AIDS. Ann Intern Med 113:604-618
ZuRhein GM, Chou SM (1965) Particles resembling papova viruses in human cerebral demyelinating disease. Science 148:1477–1479
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
von Einsiedel, R.W., Fife, T.D., Aksamit, A.J. et al. Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature. J Neurol 240, 391–406 (1993). https://doi.org/10.1007/BF00867351
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF00867351