Skip to main content
Log in

Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic

  • Case Report
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Serial sections of formalin-fixed, paraffinembedded blocks from two asymptomatic, non-AIDS cases of progressive multifocal leukoencephalopathy (PML) were stained with a double-label immunocytochemical method for detection of glial fibrillary acidic protein and JC virus (JCV) capsid proteins and with luxol fast blue/hematoxylin-eosin. In case 1 small, rounded lesions of about 1-mm diameter were seen within a restricted area in the posterior part of the superior frontal gyrus of both cerebral hemispheres, suggesting an early manifestation of the disease. Fully developed demyelinated lesions of the classical type with JCV-infected oligodendrocytes appeared in the white matter and along its border with the cortex. Lesswell-developed lesions, believed to be precursors to the fully developed ones, were seen in the gray and white matter. Of special interest were areas which contained small collections of enlarged, glial fibrillary acidic protein (GFAP)-positive astrocytes without capsid antigen and which seemed to lack destruction of myelin as judged from the appearance of matching serial sections stained for myelin. Large lesions in the brain of case 2 showed the well-known features of advanced PML. The close relation between some astrocytes and oligodendrocytes with viral antigen raises the possibility of early intercellular passage of virus. Vacuolation, seen within or near lesions in both cases, has previously been noted in the CNS infected by HIV, but not in PML. It is suggested that PML, a disease of both oligodendrocytes and astrocytes, may actually begin in astroglial cells which, under the influence of a restricted JCV infection, become reactive, express GFAP and pass on virus to the more highly susceptible oligodendrocytes with which they are in contact.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aksamit AJ, Leypold B (1993) JC virus is not present in B-cells in PML brain (abstract). J Neuropathol Exp Neurol 52:273

    Google Scholar 

  2. 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

    Google Scholar 

  3. Aksamit AJ, Sever JL, Major EO (1986) Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry. Neurology 36:499–504

    Google Scholar 

  4. 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

    Google Scholar 

  5. 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

    Google Scholar 

  6. Åström KE, Mancall EL, Richardson EP Jr (1958) Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphocytic leukemia and Hodgkin's disease. Brain 81:93–111

    Google Scholar 

  7. 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

    Google Scholar 

  8. Boerman RH, Arnoldus EP, Raap AK, Peters AC, ter Schegget J, van der Ploeg M (1989) Diagnosis of progressive multifocal leucoencephalopathy by hybridisation techniques. J Clin Pathol 42:153–161

    Google Scholar 

  9. Brooks BR, Walker DL (1984) Progressive multifocal leukoencephalopathy. Neurol Clin 2:299–313

    Google Scholar 

  10. Budka H (1991) Neuropathology of human immunodeficiency virus infection. Brain Pathol 1:163–176

    Google Scholar 

  11. Budka H, Shah KV (1983) Papovavirus antigens in paraffin sections of PML brains. In: Sever JL, Madden DL (eds) Polyomaviruses and human neurological disease. Alan R. Liss, New York, pp 299–309

    Google Scholar 

  12. Cavanagh JB, Greenbaum D, Marshall AHE, Rubinstein LJ (1959) Cerebral demyelination associated with disorders of the reticuloendothelial system. Lancet II:524–529

    Google Scholar 

  13. Christensen E, Fog M (1955) Case of Schilder's disease in adult with remarks on etiology and pathogenesis. Acta Psychiatr Neurol Scand 30:141–154

    Google Scholar 

  14. Dörries K, Johnson RT, Ter Meulen V (1979) Detection of polyoma virus DNA in PML-brain tissue by (in situ) hybridization. J Gen Virol 42:49–57

    Google Scholar 

  15. Fisher CM, Williams HW, Wing ES Jr (1961) Combined encephalopathy and neuropathy with carcinoma. J Neuropathol Exp Neurol 20:535–547

    Google Scholar 

  16. Ghatak NR (1992) Occurrence of oligodendrocytes within astrocytes in demyelinating lesions. J Neuropathol Exp Neurol 51:40–46

    Google Scholar 

  17. Greenlee JE (1989) Progressive multifocal leukoencephalopathy. Curr Clin Top Infect Dis 10:140–156

    Google Scholar 

  18. Greenlee JE, Keeney PM (1986) Immunoenzymatic labelling of JC papovavirus T antigen in brains of patients with progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 71:150–153

    Google Scholar 

  19. Hallervorden J (1930) Eigenartige und nicht rubrizierbare Prozesse. In: Bumke O (ed) Handbuch der Geisteskrankheiten, vol 11. Springer, Berlin, pp 1063–1107

    Google Scholar 

  20. Hogan TF, Padgett BL, Walker DL (1991) Human polyomaviruses. In: Belshe RB (ed) Textbook of human virology. Mosby, St. Louis, pp 970–1000

    Google Scholar 

  21. Houff SA, Major EO, Katz DA, Kufta CV, Sever JL, Pittaluga S, Roberts JR, Gitt 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

    Google Scholar 

  22. 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

    Google Scholar 

  23. Itoyama Y, Webster HdeF, Sternberger NH, Richardson EP Jr., Walker DL, Quarles RH, Padgett BL (1982) Distribution of papovarirus, myelin-associated glycoprotein, and myelin basis protein in progressive multifocal leukoencephalopathy lesions. Ann Neurol 11:396–407

    Google Scholar 

  24. Kuchelmeister K, Gullotta F, Bergman M, Angeli G, Masini T (1993) Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome. A neuropathological study. Pathol Res Pract 189:163–173

    Google Scholar 

  25. Lang W, Miklossy J, Deruaz JP, Pizzolato GP, Probst A, Schaffner T, Gessaga E, Kleihues P (1989) Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathol 77:379–390

    Google Scholar 

  26. Ledoux S, Libman I, Robert F, Just N (1989) Progressive multifocal leukoencephalopathy with gray matter involvement. Can J Neurol Sci 16:200–202

    Google Scholar 

  27. Levy RM, Bredesen DE (1988) Central nervous system dysfunction in acquired immunodeficiency syndrome. J AIDS 1:41–64

    Google Scholar 

  28. Lipton HL (1991) Is JC virus latent in brain? Ann Neurol 29:433–434

    Google Scholar 

  29. Louarn F, Gray F, Gaston A, Gherardi R, Keohane C, Degos JDM (1987) Extensive form of progressive multifocal leukoencephalopathy associated with laryngeal carcinoma. J Neurol 234:107–111

    Google Scholar 

  30. Mancall EL (1965) Progressive multifocal leukoencephalopathy. Neurology 15:693–699

    Google Scholar 

  31. Mázló M, Herndon RM (1977) Progressive multifocal leukoencephalopathy: ultrastructural findings in two brain biopsies. Neuropathol Appl Neurol 3:323–339

    Google Scholar 

  32. Mázló M, Tariska I (1982) Are astrocytes infected in progressive multifocal leukoencephalopathy (PML)? Acta Neuropathol (Berl) 56:45–51

    Google Scholar 

  33. Nuovo GJ, Gallery F, Hom R, MacConnell P, Bloch W (1993) Importance of different variables for enhancing in situ detection of PCR-amplified DNA. PCR Methods Applic 2:305–312

    Google Scholar 

  34. Orenstein JM, Jannotta F (1990) Human immunodeficiency virus and papovavirus infections in acquired immunodeficiency syndrome: an ultrastructural study of three cases. Hum Pathol 19:350–361

    Google Scholar 

  35. Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH (1971) Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet I:1257–1260

    Google Scholar 

  36. Prineas JW, Kwon EE, Goldenberg PZ, Cho E-S, Sharer LR (1991) Interaction of astrocytes and newly formed oligodendrocytes in resolving multiple sclerosis lesions. Lab Invest 63:624–636

    Google Scholar 

  37. 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

    Google Scholar 

  38. Richardson EP Jr (1961) Progressive multifocal leukoencephalopathy. N Eng J Med 265:815–823

    Google Scholar 

  39. Richardson EP Jr, Webster HdeF (1983) Progressive multifocal leukoencephalopathy: its pathological features. In: Sever JL, Madden DL (eds) Polyomaviruses and human neurological disease. Alan R. Liss, New York, pp 191–203

    Google Scholar 

  40. Scaravilli F, Ellis DS, Tovey G, Harcourt-Webster JN, Guiloff RJ, Sinclair E (1989) Unusual development of polyoma virus in the brains of two paitents with the acquired immune deficiency syndrome (AIDS). Neuropathol Appl Neurobiol 15:407–418

    Google Scholar 

  41. Schmidbauer M, Budka H, Okeda R, Cristina S, Lechi A, Trabattoni GR (1990) Multifocal vacuolar leucoencephalopathy: a distinct HIV-associated lesion of the brain. Neuropathol Appl Neurobiol 16:437–443

    Google Scholar 

  42. Schmidbauer M, Budka H, Shah KV (1990) Progressive multifocal leukoencephalopathy (PML) in AIDS and in the pre-AIDS era. A neuropathological comparison using immunocytochemistry and in situ DNA hybridization for virus detection. Acta Neuropathol 80:375–380

    Google Scholar 

  43. Shapshak P, Tourtellotte WW, Wolman M, Verity N, Verity MA, Schmid P, Syndulko K, Bedows E, Boostanfar R, Darvish M (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

    Google Scholar 

  44. Silverman L, Rubinstein LJ (1965) Electron microscopic observations on a case of progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 5:215–224

    Google Scholar 

  45. Sima AA, Finkelstein SD, McLachlan DR (1983) Multiple multifocal leukoencephalopathy. Ann Neurol 14:183–188

    Google Scholar 

  46. Stoner GL, Ryschkewitsch CF, Walker DL, Webster HdeF (1986) JC papovavirus large tumor (T)-antigen expression in brain tissue of acquired immune deficiency syndrome (AIDS) and non-AIDS patients with progressive multifocal leukoencephalopathy. Proc Natl Acad Sci USA 83:2271–2275

    Google Scholar 

  47. Stoner GL, Mázló M, Ryschkewitsch CF, Walker DL, Webster HdeF (1988) Cerebellar progressive multifocal leukoencephalopathy: localization of JC virus T-antigen in granule cell neurons (abstract). Ann Neurol 24:475

    Google Scholar 

  48. Stoner GL, Soffer D, Ryschkewitsch CF, Walker DL, Webster HdeF (1988) A double-label method detects both early (T-antigen) and late (capsid) proteins of JC virus in progressive multifocal leukoencephalopathy brain tissue from AIDS and non-AIDS patients. J Neuroimmunol 19:223–236

    Google Scholar 

  49. Walker DL (1985) Progressive multifocal leukoencephalopathy. In: Hand Clin Neurol 47:503–524

  50. Walker DL, Padgett BL (1983) The epidemiology of human polyomaviruses. In: Sever JL, Madden DL, (eds) Polyomaviruses and human neurological diseases. Alan R. Liss, New York, pp 99–106

    Google Scholar 

  51. Watanabe I, Preskorn SH (1976) Virus-cell interaction in oligodendroglia, astroglia and phagocyte in progressive multifocal leukoencephalopathy. An electron microscopic study. Acta Neuropathol (Berl) 36:101–115

    Google Scholar 

  52. Winkelman NW, Moore MT (1941) Lymphogranulomatosis (Hodgkin's disease) of the nervous system. Arch Neurol Psychiatry 4530:304–318

    Google Scholar 

  53. Wu E, Raine CS (1992) Multiple sclerosis: interactions between oligodendrocytes and hypertrophic astrocytes and their occurrence in other, nondemyelinating conditions. Lab Invest 67:88–99

    Google Scholar 

  54. Yao D-L, Webster HdeF, Hudson LD, Brenner M, Liu D-S, Escobar AI, Komoly S (1993) Concentric sclerosis (Baló): morphometric and in situ hybridization study of the lesions in six patients. Ann Neurol 34:(in press)

  55. ZuRhein GM, Chou SM (1965) Particles resembling papova viruses in human cerebral demyelinating disease. Science 148:1477–1479

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Supported in part by a grant N.S.07596 from the National Institute of Neurological Disorders and Stroke. The work was carried out in the Laboratory of Experimental Neurophathology, NINDS, and in the Department of Pathology II, Karolinska Institute, Stockholm

Rights and permissions

Reprints and permissions

About this article

Cite this article

Åström, K.E., Stoner, G.L. Early pathological changes in progressive multifocal leukoencephalopathy: a report of two asymptomatic cases occurring prior to the AIDS epidemic. Acta Neuropathol 88, 93–105 (1994). https://doi.org/10.1007/BF00294365

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00294365

Key words

Navigation