eMedicine Specialties > Neurology > Neurological Infections

HIV-1 Associated Opportunistic Infections - PML

Author: Niranjan N Singh, MD, DNB, Assistant Professor of Neurology, University of Missouri Columbia
Coauthor(s): Florian P Thomas, MD, MA, PhD, Drmed,, Director, Spinal Cord Injury Service, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Contributor Information and Disclosures

Updated: Feb 23, 2010

Introduction

Background

Progressive multifocal leukoencephalopathy (PML) is characterized by widespread demyelinative lesions due to infection of oligodendrocytes by a human papovavirus. It occurs almost exclusively in immunosuppressed individuals, such as patients with AIDS, leukemia, or tumors or those undergoing organ transplants. PML is associated with both HIV-1 and HIV-2.

HIV-associated PML also occurs during immune recovery following highly active antiretroviral therapy (HAART) initiation. Such cases are associated with inflammatory reaction and contrast enhancement. Their outcome is more variable than that of PML in end-stage AIDS.

Pathophysiology

PML is caused by reactivation of the endemic JC papovavirus (ie, polyomavirus). As many as 90% of healthy individuals have serum antibodies to this virus, but less than 10% show any evidence of ongoing viral replication.

According to a study of HIV-negative controls and HIV-positive patients with or without PML, a third of individuals from all subgroups had JC virus DNA in the urine. In the same study, JC virus DNA was detected in 43% of lymphocyte samples and in 63% of plasma samples in HIV-positive patients with PML. However, in HIV-positive patients without PML, JC virus DNA was detected in only 13% of lymphocyte samples and in 22% of plasma samples. In HIV-negative controls, no lymphocyte or plasma samples harbored JC viral DNA.

The site of viral replication remains to be determined. Candidate locations include bone marrow and the reticuloendothelial system. Whether PML develops when resident virus in the brain is reactivated or when the virus is reactivated and seeds the brain via blood lymphocytes or in free form is unclear.

HIV gene products, such as Tat, may be able to transactivate the JC viral promoter directly. This provides an additional pathogenic mechanism beyond general immunosuppression.

Frequency

United States

Before the advent of triple therapy, PML occurred in as many as 4% of AIDS cases. Unlike other HIV/AIDS-related opportunistic tumors and infections, the incidence of PML has not changed significantly in the post-HAART era. According to the Italian NeuroAIDS study 2000-2002 (IRINA), PML is the third most common cause of encephalopathy after toxoplasma encephalitis and HIV encephalopathy.1

International

Low incidence in India and Africa, possibly due to diagnostic challenges and differences in JC virus isolates.

Mortality/Morbidity

In the pre-HAART era, the prognosis of PML was dismal, with death occurring within 4-6 months after diagnosis. Now, several case series have shown prolonged survival for patients receiving HAART. In a series of 118 consecutive patients from Spain, 63.6% survived for a median duration of 114 weeks (2.2 y) after diagnosis of PML. Survival times with PML have increased with HAART.

CD4+ T-cell counts less than 100/μ L at baseline are associated with a higher mortality rate.

Approximately 8% of patients experience spontaneous recovery.

Clinical

History

  • Insidious onset of focal symptoms including behavioral, speech, cognitive, motor, and visual impairment
  • Rare headaches, seizures, and neck stiffness
  • Subacute evolution over several weeks
  • More rapid progression than AIDS dementia complex (ADC)
  • HIV-associated inflammatory PML has variable outcome, including fatal course.

Physical

  • Focal neurological signs include aphasia, hemiparesis, ataxia, cortical blindness, and less frequently head tremor. Focal signs tend to be related to posterior brain (eg, occipital lobes).
  • Conjugate gaze abnormalities are common. This is the initial presentation in more than 30% of patients.
  • Abnormalities may progress to quadriparesis and coma.
  • Occasionally, neurological signs are diffuse rather than focal.

More on HIV-1 Associated Opportunistic Infections - PML

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Follow-up: HIV-1 Associated Opportunistic Infections - PML
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References
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References

  1. Antinori A, Cingolani A, Lorenzini P. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol. 2003;9 Suppl 1:47-53. [Medline].

  2. Travis J, Varma A, duPlessis D, Turnbull I, Vilar FJ. Immune reconstitution associated with progressive multifocal leukoencephalopathy in human immunodeficiency virus: a case discussion and review of the literature. Neurologist. September 2008;14(5):321-6. [Medline].

  3. [Best Evidence] Marzocchetti A, Tompkins T, Clifford DB, Gandhi RT, Kesari S, Berger JR, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology. November 2009;73(19):1551-8. [Medline].

  4. Antinori A, Ammassari A, Giancola ML. Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era. J Neurovirol. Aug 2001;7(4):323-8. [Medline].

  5. Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. Curr Opin Neurol. Aug 2006;19(4):341-9. [Medline].

  6. Berenguer J, Miralles P, Arrizabalaga J. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis. Apr 15 2003;36(8):1047-52. [Medline].

  7. Bienaime A, Colson P, Moreau J. Progressive multifocal leukoencephalopathy in HIV-2-infected patient. AIDS. Jun 12 2006;20(9):1342-3. [Medline].

  8. Bossolasco S, Calori G, Moretti F. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis. Mar 1 2005;40(5):738-44. [Medline].

  9. Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology. Feb 1999;52(3):623-5. [Medline].

  10. Dalsgaard Hansen NJ, Madsen C, Stenager E. Progressive multifocal leucoencephalopathy. Ital J Neurol Sci. Dec 1996;17(6):393-9. [Medline].

  11. de Gans J, Portegies P. Neurological complications of infection with human immunodeficiency virus type 1. A review of literature and 241 cases. Clin Neurol Neurosurg. 1989;91(3):199-219. [Medline].

  12. De Luca A, Fantoni M, Tartaglione T, Antinori A. Response to cidofovir after failure of antiretroviral therapy alone in AIDS-associated progressive multifocal leukoencephalopathy. Neurology. Mar 10 1999;52(4):891-2. [Medline].

  13. Di Giambenedetto S, Vago G, Pompucci A. Fatal inflammatory AIDS-associated PML with high CD4 counts on HAART: a new clinical entity?. Neurology. Dec 28 2004;63(12):2452-3. [Medline].

  14. Geraci AP, Simpson DM. Neurological manifestations of HIV-1 infection in the HAART era. Compr Ther. 2001;27(3):232-41. [Medline].

  15. Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med. May 7 1998;338(19):1345-51. [Medline].

  16. Huang SS, Skolasky RL, Dal Pan GJ. Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol. Jun 1998;4(3):324-32. [Medline].

  17. Koralnik IJ, Boden D, Mai VX, et al. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology. Jan 15 1999;52(2):253-60. [Medline].

  18. Rieder CR, Ziomkowski SC. Head tremor and progressive multifocal leukoencephalopathy in AIDS patients: report of two cases. Arq Neuropsiquiatr. Mar 2005;63(1):150-3. [Medline].

  19. Simpson DM, Berger JR. Neurologic manifestations of HIV infection. Med Clin North Am. Nov 1996;80(6):1363-94. [Medline].

  20. Vendrely A, Bienvenu B, Gasnault J, et al. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl). Apr 2005;109(4):449-455. [Medline].

  21. Verma A. Neurological manifestations of human immunodeficiency virus infection in adults. In: Neurology in Clinical Practice. 2. 2004:1581-1602.

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Further Reading

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Keywords

AIDS, acquired immunodeficiency syndrome, PML, progressive multifocal leukoencephalopathy, human papovavirus, JC papovavirus, polyomavirus, JC virus, highly active antiretroviral therapy, HAART

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Contributor Information and Disclosures

Author

Niranjan N Singh, MD, DNB, Assistant Professor of Neurology, University of Missouri Columbia
Niranjan N Singh, MD, DNB is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

Florian P Thomas, MD, MA, PhD, Drmed,, Director, Spinal Cord Injury Service, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed, is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Medical Editor

Ronald A Greenfield, MD, Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine
Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology
Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist  Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Ortho McNeil Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace  Speaking, consulting

 
 
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