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PubMed1986

Progressive multifocal leukoencephalopathy (PML): clinical and pathological findings in two short-duration patients.

The clinical features and neuropathological findings of two patients suffering from progressive multifocal leukoencephalopathy (PML) are reported. These patients had cancer and died two months and one month after onset of their neurological symptoms, respectively. In both demyelination was discovered only as a result of autopsy due to different reasons: the CAT-scan findings were misinterpreted in the first patient, while in the second diagnosis was overshadowed by the sudden progress towards a fatal outcome preceded by myoclonus and other encephalitis-like manifestations. The major findings were the extreme paucity of the mesodermal elements on the one hand, and the modest spread of the affected areas on the other. It is pointed out that, whatever the size of the lesions, characters were the same and that their formation could hardly be traced in time. The intriguing similarities between PML and several types of demyelination obtained experimentally using certain virus strains are remarked.

Aged↗
PubMed1997

Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2.

A patient with low-grade lymphoma presented 8 months after autologous marrow transplantation with dizziness, aphasia and hemiparesis. Magnetic resonance imaging (MRI) showed an abnormal T2 signal in the frontoparietal region unilaterally. Biopsy of the area demonstrated progressive multifocal leukoencephalopathy positive for JC virus and p53. Treatment with interleukin-2 at 0.5 MU/m2/day i.v. continuous infusion resulted in near complete resolution of symptoms and MRI abnormalities. The absolute number of CD3+CD4+ and CD3-CD56+ cells in the peripheral blood also increased, and the CD4/CD8 ratio normalized. She remains free of evidence of progressive multifocal leukoencephalopathy 1 year off therapy.

Blood Cell Count↗
PubMed1997

[Progressive multifocal leukoencephalopathy. Study of the demyelination by magnetization transfer].

PURPOSE: magnetization transfer imaging (MT) has been used to study the degree of demyelination in progressive multifocal leukoencephalopathy (PML). MATERIAL AND METHOD: two groups were studied: a group of 10 HIV + patients with clinical, MR features, biological and/or biopsy proven PML, and a group of 11 normal volunteers with matched age. MT ratio (MTR) were obtained from the center of the PML lesions and 11 areas of normal appearing white matter (NAWM) in the control group. RESULTS: the mean MTR of NAWM in the control group was 46.6% (SD = 2,3). PML lesions demonstrated a strong and significant (p = 0) decreased of the MTR with mean MTR value of 22.4% (SD = 2,3). CONCLUSION: MT characterized the demyelinating process in PML, and can be used to improve diagnosis. Furthermore, MT allowed a quantification of the degree of demyelination which can be helpful in other demyelinating process of CNS such as multiple sclerosis.

Adult↗
PubMed1996

Polyomavirus-infected oligodendrocytes and macrophages within astrocytes in progressive multifocal leukoencephalopathy (PML).

Polyomavirus-infected oligodendrocytes and in some instances virus-carrying macrophages were demonstrated within the cytoplasm of astrocytes by double immunostaining of brain lesions in a case of PML following bone marrow transplantation. The infected oligodendrocytes and CD68+ cells were usually partially or completely invested by the cytoplasm of reactive and infected or noninfected giant pleomorphic astrocytes. By electron microscopy (EM), internalized infected oligodendrocytes were shown to release polyomavirus particles possibly infectious to the astrocytes. These observations seem to indicate that astrocytes in PML can become infected by direct contact with internalized infected oligodendrocytes and possibly also by virus-loaded macrophages. Correspondingly, astrocyte/oligodendrocyte/macrophage cell-to-cell interactions appear to play an important role in the pathogenesis of PML lesions.

Astrocytes↗
PubMed1985

[Patient with progressive multifocal leukoencephalopathy by in situ hybridization: comparison of in situ hybridization using isotopic and biotinylated probes].

Ward et al developed biotinylated probes to hasten virus nucleic acid detection. We used these probes to trace SV 40 and JC virus nucleic acids in PML brain. This procedure visualizes the hybridization of viral sequences by affinity cytochemistry with avidin-biotin peroxidase complexes and diaminobenzidine. In the PML frozen white matter numerous oligodendroglial nuclei hybridized with JC virus biotinylated and tritium labelled probes in areas adjacent to active demyelination. Although tritium labeled probes was most sensitive and gave lowest background this biotinylated method showed be useful as a rapid diagnostic test for the specific detection of viral nucleic acid sequences in brain tissues from patients with central nervous system (CNS) infectious diseases.

Autoradiography↗
PubMed1980

Morphological demonstration of the first phase of polyomavirus replication in oligodendroglia cells of human brain in progressive multifocal leukoencephalopathy (PML).

Ultrastructural characteristics of adsorption, penetration and intracellular transport of polyomavirus is demonstrated in oligodendrocytes in PML. The findings are compared with those obtained by virological examinations of polyomavirus infections described in cell cultures. The morphology of the eclipse phase and the site of the beginning of virus assembly are also described. The vacuolization of the cytoplasm is considered to be the consequence of the production of viral protein and nucleic acid. The cytoplasmic virions surrounded by membrane in the early and late phases of replication are considered to be "infective virions", while those in the cytoplasm in a "free" state, aligned along membrane fragments or arranged in crystals are classified as "virus progenies". The first demonstration of polyoma virions between the separated lamellae of the myelin sheath of a viable axon is presented; their presence, however, is not considered to play a direct pathogenetic role in demyelination.

Aged↗
PubMed1993

Progressive multifocal leukoencephalopathy (PML) in the acquired immunodeficiency syndrome (AIDS). A neuropathological autopsy study of 21 cases.

In a neuropathological autopsy study of 21 cases of AIDS-associated PML no fundamental morphological differences to non-AIDS PML were found. PML in AIDS often showed very large foci as well as necrotizing lesions. Partial involvement of cerebral cortex and deep gray matter were common findings; infratentorial lesions could be observed in more than three quarters of cases. Perivascular mononuclear infiltrates within PML foci were frequent and obviously not associated with a more benign clinical course. Possible reasons for these peculiarities of PML in AIDS are discussed. In 7 cases evidence of concomitant HIV encephalopathy was found; this may be one relevant factor contributing to severity of PML in AIDS. PML has to be regarded as a common complication of HIV infection, which may show atypical morphological and neuroradiological features.

AIDS-Related Opportunistic Infections↗
PubMed2003

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).

Human immunodeficiency virus (HIV)-associated progressive multifocal leukoencephalopathy (PML) remains a relevant clinical problem even in the era of highly active antiretroviral therapy (HAART). Aims of the study were to analyze clinical and treatment-related features and the survival probability of PML patients observed within the Italian Registry Investigative Neuro AIDS (IRINA) during a 29-month period of HAART. Intravenous drug use, the presence of focal signs, and the involvement of white matter at neuroradiology increased the risk of having PML. A reduced probability of PML was observed when meningeal signs were reported. Patients starting HAART at PML diagnosis and previously naïve for antiretrovirals showed significantly higher 1-year probability of survival (.58), compared to those continuing HAART (.24), or never receiving HAART (.00). Higher CD4 cell count were associated with a higher survival probability (.45). At multivariate analysis, a younger age, higher CD4, starting HAART at PML diagnosis, the absence of previous acquired immunodeficiency syndrome (AIDS)-defining events, and the absence of a severe neurologic impairment were all associated with a reduced hazard of death. The use of cidofovir showed a trend towards a reduced risk of death.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Convection-enhanced intraparenchymal delivery (CEID) of cytosine arabinoside (AraC) for the treatment of HIV-related progressive multifocal leukoencephalopathy (PML).

AIDS-related PML continues to be a relatively common and rapidly fatal infection in patients with AIDS, and no effective therapy has been established to alleviate the effects of this disease. Through the years, isolated reports and small case studies have shown somewhat encouraging results using cytosine arabinoside (AraC) in the treatment of PML. The optimism behind the use AraC for this disease began to fade with ACTG trial 243, which suggested that AraC had no benefit in patients with HIV-related PML. In this article, we provide evidence that suggests that the failure of AraC in the ACTG trial may have been due to insufficient delivery of the drug through traditional intravenous and intrathecal routes. Furthermore, we provide evidence that convection-enhanced intraparenchymal delivery of AraC may prove to be a safe and effective means of treating this infection, and we outline a clinical trial that we have recently undertaken to test this hypothesis.

AIDS-Related Opportunistic Infections↗
PubMed2001

The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS.

To explore the respective roles of highly active antiretroviral therapy (HAART) and alpha-interferon in improving survival of patients with AIDS-related PML, we retrospectively analyzed all patients with AIDS and PML who were referred to Johns Hopkins University HIV Neurology Program from 1985 to 2000. For 97 evaluable patients, we compared survival of those who were on HAART (three or more antiretroviral drugs) to those who were not on HAART. The effect of alpha-interferon was also studied. Multivariate analysis showed no difference in survival among patients on none, one, or two forms of antiretrovirals; however, survival was significantly greater for those on HAART. Whereas alpha-interferon use was shown to be associated with longer survival (P < 0.057), this effect was not independent of the effects of HAART. HAART significantly increases survival for patients with PML and AIDS; however, alpha-interferon does not appear to provide additional benefit.

AIDS-Related Opportunistic Infections↗
PubMed1994

[Progressive multifocal leukoencephalopathy and AIDS. Response to cytarabine].

PML affects 4% of patients with AIDS and there is no effective treatment. Five cases of PML-AIDS have been described, showing clinical and radiological improvement after treatment with C-ara. We describe the case of a 33-year-old woman, addict to heroin, her clinical record including VIH infection, pneumonia by P. carinii, milliary tuberculosis, infection by virus B and C and treatment with AZT and tuberculostatics since January, 1992. In May, she began to develop a cerebellar syndrome. Images obtained with nuclear magnetic resonance were typical of PML. Subsequently, treatment with C-ara (2 mg/kg/day IV during 5 days each 4-6 weeks) was begun. From the third month of treatment on, the patient showed a clinical improvement and as of the sixth month, the affected areas of white substance were reduced in size. In addition, CD4 improved. Although in this patient a positive effect was observed after treatment with C-area, it should be verified in a controlled clinical trial.

AIDS-Related Opportunistic Infections↗
PubMed2005

Rearrangement of simian virus 40 regulatory region is not required for induction of progressive multifocal leukoencephalopathy in immunosuppressed rhesus monkeys.

Rearrangements of the JC virus (JCV) regulatory region (RR) are consistently found in the brains of patients with progressive multifocal leukoencephalopathy (PML), whereas the archetype RR is present in their kidneys. In addition, the C terminus of the large T antigen (T-Ag) shows greater variability in PML than does the rest of the coding region. To determine whether similar changes in simian virus 40 (SV40) are necessary for disease induction in monkeys, we sequenced the SV40 RR and the C terminus of the T-Ag from the brain of simian/human immunodeficiency virus (SHIV)-infected monkey 18429, which presented spontaneously with an SV40-associated PML-like disease, as well as from the peripheral blood mononuclear cells (PBMC), kidneys, and brains of SV40-seronegative, SHIV-infected monkeys 21289 and 21306, which were inoculated with the 18429 brain SV40 isolate. These animals developed both SV40-associated PML and meningoencephalitis. Thirteen types of SV40 RR were characterized. Compared to the SV40 archetype, we identified RRs with variable deletions in either the origin of replication, the 21-bp repeat elements, or the late promoter, as well as deletions or duplications of the 72-bp enhancer. The archetype was the most prominent RR in the brain of monkey 18429. Shortly after inoculation, a wide range of RRs could be found in the PBMC of monkeys 21289 and 21306. However, the archetype RR became the predominant type in their blood, kidneys, and brains at the time of sacrifice. On the contrary, the T-Ag C termini remained identical in all compartments of the three animals. These results indicate that unlike JCV in humans, rearrangements of SV40 RR are not required for brain disease induction in immunosuppressed monkeys.

Amino Acid Sequence↗
PubMed2000

Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy.

HIV-1 infection can lead to severe central nervous system (CNS) clinical syndromes in more than 50% of HIV-1 positive individuals. Progressive multifocal leukoencephalopathy (PML) is the frequent opportunistic infection of the CNS which is seen in as high as 5% of AIDS patients. Results from previous cell culture studies showed that the HIV-1 regulatory protein, Tat can potentiate transcription of the human neurotropic virus, JCV, the causative agent for PML in cells derived from the human CNS. In this communication we examine the presence of the HIV-1 regulatory protein, Tat, as well as the HIV-1 and JCV structural proteins, p24 and VP1, respectively in AIDS/PML clinical samples. We demonstrate high level expression of the JCV capsid protein, VP1, in oligodendrocytes and to some degree in astrocytes of AIDS with PML. In HIV-1+ samples expression of HIV-1 core protein, p24 was detected in perivascular monocytic cells and to a lesser extent in astrocytes and endothelial cells. A lack of p24 expression in oligodendrocytes suggested no infection of these cells with HIV-1. Interestingly, HIV-1 Tat was detected in various infected cells as well as in uninfected oligodendrocytes from HIV-1+ tissue, supporting the earlier in vitro findings that secreted Tat from the infected cells can be localized in the neighboring uninfected cells. The presence of Tat in oligodendrocytes was particularly interesting as this protein can up-modulate JCV gene transcription and several key cell cycle regulatory proteins including cyclin E, Cdk2, and pRb. The data presented here provide in vivo evidence for a role of HIV-1 Tat in the pathogenesis of AIDS/PML by acting as a positive regulatory protein that affects the expression of JCV and other cell regulatory proteins in the CNS.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy.

Procedures involved in the diagnosis of JC virus central nervous system infection range from detection of virus specific products in biopsy material to demonstration of viral DNA in cerebrospinal fluid by PCR. Despite the fact that PCR is the most sensitive method for the detection of virus in clinical specimens, diagnostic evaluation is increasingly difficult in view of the possible subclinical activation of persistent JCV infection in the central nervous system of high risk patients. Therefore, PML diagnosis by molecular detection of JCV DNA in biopsy material was compared with diagnosis by PCR on CSF of patients with and without PML. Evaluation of the diagnostic techniques revealed that stereotactic biopsy based PCR diagnosis at present combines speed and sensitivity with the highest specificity available. Although the non invasive technique of JCV detection in CSF by PCR is even more sensitive leading to detection of about 20 genome equivalents per 1 microl of CSF, the specificity of the method is limited by subclinical presence of JCV DNA in CSF of neurologically asymptomatic HIV infected patients. Additionally, autopsy proven PML cases remaining JCV negative in PCR on CSF become a common finding. Therefore, in cases where biopsy is not performed, diagnosis of PML can only be achieved in combination with neurological and radiological diagnosis.

Brain↗
PubMed1990

[Simultaneous in situ detection of JC virus antigens and RNA in progressive multifocal leukoencephalopathy (PML) by immunocytochemistry and in situ hybridization].

We detected simultaneously JC virus (JCV) antigen and RNA in the frozen brain tissue from a patient with PML using immunocytochemistry and in situ hybridization. Histologically, the majority of JCV antigen positive cells were mainly located at the margin of demyelinated lesions. By simultaneous in situ detection of JCV antigen and RNA, the percentage of both JCV antigen and RNA positive cells in total number cells were 20 in the periplaque region and 2.3 in the central region of plaque respectively. On the contrary, only JCV RNA positive cells were detected 3.6% in the periplaque region and 4.6% in the central region of plaque, while there was not found any positive cells in apparently normal white matter. Moreover, JCV antigen in both antigen and RNA positive cells found in the periplaques was stained homogeneous and filled the whole swollen nucleus, whereas most of both antigen and RNA positive cells appeared in the center of plaques showed small amounts of antigen in the nucleus. From the results, it seems likely that most of the cells displaying only RNA detected in the periplaque were oligodendrocytes in the early stages of productive infection prior to viral protein synthesis. However, a small number of cells displaying only RNA in the center of plaques were likely to be oligodendrocytes and seemed to be in the nonproductive stages of a JCV infection, limited expression of viral protein, influenced by the host immune response including the infiltration of macrophages and humoral immunity.

Antigens, Viral↗
PubMed1987

[The detection of viral nucleic acid sequences in paraffin-embedded subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML) brain tissues by in situ hybridization].

We have been able to detect the viral nucleic acid sequences in formalin-fixed paraffin embedded tissue sections of the brain from SSPE and PML respectively by in situ hybridization using cloned and radiolabelled complementary DNA (cDNA) measles nucleocapsid (NP) and JC virus probes which are gene specific respectively. We have mainly followed in situ hybridization procedure reported by Haase et al, but partly modified the technique including the extensive wash by buffer solution and the elevated concentration of proteinase K. Firstly, to compare with the number of hybridized cells and grain counts, the in situ hybridization were performed in SV 40 infected cells treated with ethanol-acetic acid for 15 minutes or 10% neutral formalin for at least one week to simulate procedure used by pathologists. Similar findings were obtained in both treatment of 1 microgram/ml concentration of proteinase K in ordinary fixed cells and in 100 micrograms/ml in formalin-fixed cells. In addition we investigated the ability of in situ hybridization technique to detect measles in SSPE and papova virus in PML obtained postmortem that were been formalin-fixed paraffin-embedded routinely. In paraffin-embedded SSPE cerebral cortex positive hybridization were obtained in oligodendroglias and neurons using 125I-labelled measles NP probe in 6 days' autoradiographic exposure (Fig. 2 and 3) in our modified technique. Additionally, in PML tissue JC virus nucleic acid sequences were also detected in many oligodendroglias and swollen neurons using 3H-labelled JC virus probe.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗