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Neurology > Neurological Infections
HIV-1 Associated Opportunistic Infections: PML
Article Last Updated: May 8, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 9  
Author: Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine
Niranjan N Singh is a member of the following medical societies: American Academy of Neurology
Coauthor(s):
Florian P Thomas, MD, MA, PhD, DrMed, Associate Chief of Staff, St Louis VA Medical Center; Associate Director, Neurology Residency Program; Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, Saint Louis University School of Medicine
Editors: Stephen A Berman, MD, PhD, Professor, Department of Internal Medicine, Section of Neurology, Dartmouth Medical School; Chief, Neurology Service, White River Junction Veterans Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; Consulting Staff, Barnes Jewish Hospital; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Author and Editor Disclosure
Synonyms and related keywords:
AIDS, acquired immunodeficiency syndrome, PML, progressive multifocal leukoencephalopathy, human papovavirus, JC papovavirus, polyomavirus, JC virus, highly active antiretroviral therapy, HAART
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 encephalopathy1.
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 PML2. Survival times with PML have increased with HAART. CD4+ T-cell counts less than 100/μL at baseline are associated with a higher mortality rate. Approximately 8% of patients experience spontaneous recovery.
History
- Insidious onset of focal symptoms including behavioral, speech, cognitive, motor, and visual impairment
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- Rare headaches, seizures, and neck stiffness
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- Subacute evolution over several weeks
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- More rapid progression than AIDS dementia complex (ADC)
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- HIV-associated inflammatory PML has variable outcome, including fatal course.
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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).
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- Conjugate gaze abnormalities are common. This is the initial presentation in more than 30% of patients.
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- Abnormalities may progress to quadriparesis and coma.
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- Occasionally, neurological signs are diffuse rather than focal.
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Aphasia
Apraxia and Related Syndromes
Confusional States and Acute Memory Disorders
HIV-1 Associated Opportunistic Infections: CNS Cryptococcosis
HIV-1 Associated Opportunistic Infections: CNS Toxoplasmosis
HIV-1 Associated Opportunistic Neoplasms: CNS Lymphoma
HIV-1 Encephalopathy and AIDS Dementia Complex
Primary CNS Lymphoma
Lab Studies
- Cerebrospinal fluid
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- Cerebrospinal fluid (CSF) is usually normal, but protein may be elevated slightly.
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- Normal CSF findings serve to rule out other etiologies.
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- Polymerase chain reaction
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- Polymerase chain reaction (PCR) of the CSF has been shown to be highly specific (92-99%) and sensitive (74-93%) for the detection of JC virus in patients with PML. Measuring CSF JC virus DNA load is a reliable marker of disease activity in patients receiving HAART and has a potential use in drug trials.
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- Conceivably, this test could eliminate the need for brain biopsy.
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Imaging Studies
- CT scan or MRI of the brain
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- Single or multiple confluent lesions without mass effects are seen most frequently in the parietooccipital white matter. Occasional infratentorial lesions are usually asymmetrical. Sparing of subcortical U fibers is characteristic.
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- Subcortical gray matter or spinal cord may be involved, but rarely.
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- PML sometimes can resemble lymphoma, toxoplasmosis, or HIV encephalitis.
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- CT scan
- Hypodense lesions
- Rare contrast enhancement with inflammatory PML
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- MRI
- T1 images - Hypointense lesions
- T2 images - Hyperintense lesions
- Rare contrast enhancement with inflammatory PML
- Occasional gray matter involvement with scalloped appearance
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Procedures
Histologic Findings
- Brain biopsy has a sensitivity of 74-92% and a specificity of 92-100%.
- Mild cortical atrophy may be seen on biopsy specimens.
- Multiple demyelinative foci may be seen in the cerebral, cerebellar, and brainstem white matter and at the gray-white matter junction; in severe cases, such foci may be seen in the cortical gray matter. Foci may become confluent.
- Perivascular inflammatory infiltrates are observed.
- Necrotic and cystic lesions may be present but are rare.
- Nuclear inclusions may be seen in large ballooned oligodendrocytes and rarely in astrocytes, both of which show bizarre-looking nuclei. The inclusions contain viruses as identified by electron microscopy and immunohistochemistry.
All treatments are experimental. HAART is a combination therapy used in patients with HIV disease. A recent study provides evidence of efficacy: patients with advanced HIV disease on HAART survived an average of 46 weeks, while historical controls survived an average of only 11 weeks. Survival correlated with suppression of plasma levels of HIV RNA. In some individuals, especially those with very low CD4+ counts, worsening of PML or new-onset PML can be observed after the initiation of HAART. This is thought to be secondary to immune reconstitution inflammatory syndrome (IRIS). IRIS is considered as a paradoxical deterioration of a preexisting infection that is related to the recovery of the immune system. It is suggested to occur due to an imbalance of CD8+/CD4+ T cells. HAART consists of a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and a protease inhibitor (PI). For information on specific drug choices, dosages, adverse effects, and precautions, please refer to standard text on the treatment of AIDS.
Treatment trials with cidofovir (used in AIDS patients with CMV), topotecan (topoisomerase inhibitor), and interferon alpha have been inconclusive.
The treatment of HIV-2–associated PML is challenging because HIV-2 is not susceptible to NNRTIs. Two NRTIs combined with PIs can be tried. Further studies are underway.
Drug Category: Antiviral agents
The goal of these agents in patients with HIV is to prevent further complications, decrease transmission, and extend survival time.
| Drug Name | Cytosine arabinoside, cytarabine (Cytosar-U) |
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| Description | Inhibits DNA polymerase, which in turn results in killing of cells that undergo DNA synthesis in S phase of cell proliferation cycle. This in turn halts viral replication. Has been reported to be effective against JC virus, but a recent trial failed to show extension of life expectancy. |
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| Adult Dose | 2 mg/kg IV qd for 5 d q4wk |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Decreases effects of gentamicin and flucytosine; toxicity increased by alkylating agents and radiation |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Reduce dose in patients with hepatic or renal insufficiencies, who are at higher risk of CNS toxicity after high-dose cytarabine; If significant worsening of bone marrow suppression, reduce dose by decreasing number of days of administration |
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| Drug Name | Cidofovir (Vistide) |
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| Description | Nucleotide analog that selectively inhibits DNA production by certain viruses. Efficacy in HIV-associated opportunistic infections only anecdotal. |
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| Adult Dose | 5 mg IV once/wk |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity; concurrent nephrotoxic agents; serum creatinine >1.5 mg/dL, CrCl <55 mL/min, urine protein >100 mg/dL |
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| Interactions | Aminoglycosides, amphotericin B, IV pentamidine, and foscarnet may increase nephrotoxicity |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | May cause granulocytopenia, monitor neutrophil counts during therapy; IV prehydration (normal saline) and coadministration of probenecid in each infusion can minimize nephrotoxicity; monitor serum creatinine and urine protein <48 h before each dose; modify dose in patients with renal insufficiency |
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Drug Category: Biological response modulator
These are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha, beta, and gamma interferons may be given topically, systemically, and intralesionally.
| Drug Name | Interferon alpha (Intron A) |
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| Description | Protein product manufactured by recombinant DNA technology that uses genetically engineered Escherichia coli. Mechanism of antiviral activity not clearly understood, but modulation of host immune response may play important role. Mostly used experimentally, and effectiveness appears promising. |
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| Adult Dose | Not established |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity, documented anaphylactic sensitivity to mouse IgG, egg protein, or neomycin |
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| Interactions | Concurrent IL-2 poses potential risk of renal failure; may increase aminophylline and zidovudine levels |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Severe or fatal GI hemorrhage may occur; may cause depression and suicidal ideation; measure peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells before therapy; monitor for response periodically (eg, monthly); if no response within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed and laboratory parameters have been stable for about 3 mo; not known whether continuing treatment after that time beneficial |
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Prognosis
- Treatment with HAART gives the best outcome in HIV-associated PML.
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- Progression is more rapid in AIDS-associated PML than in non–AIDS-associated PML.
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- Prognosis may be better in patients who have higher CD4+ lymphocyte counts.
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- Death may result not from the neurological condition but from end-stage immune deficiency.
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| Media file 1:
T2-weighted MRI shows left occipital hyperintense white matter changes with the lesion margin reaching the cortex. |
 |  View Full Size Image | |
Media type: MRI
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| Media file 2:
This sliced fixed brain shows multiple isolated or confluent gray demyelinative foci. Atrophy may be present. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri. |
 | View Full Size Image | |
Media type: Photo
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| Media file 3:
Microscopically, multiple demyelinative foci are detected. The microscopic hallmark of the disease is intranuclear basophilic or eosinophilic inclusions within the swollen nuclei of oligodendrocytes, often at the periphery of lesions. Large, occasionally multinucleated astrocytes with prominent processes are another characteristic feature. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri. |
 | View Full Size Image | |
Media type: Photo
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HIV-1 Associated Opportunistic Infections: PML excerpt Article Last Updated: May 8, 2007
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