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Results for “Leukoencephalopathy, Progressive Multifocal”

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PubMed2002

[Progressive multifocal leukoencephalopathy revealing AIDS in a 13-year-old girl].

CASE REPORT: A 13-year-old girl with an immunosuppression developed a right hemiparesis and a cerebellar syndrome. She was seropositive for HIV. A progressive multifocal leukoencephalopathy (PML) was suspected because of white matter lesions (MRI) and established on detection of JC virus in CSF by polymerase chain reaction (PCR). In spite of highly active antiretroviral treatment (HAART) and cidofovir, she died three months later. CONCLUSION: Late AIDS diagnosis was established during a neurological complication, 13 years after a neonatal transmission. PML caused by JC opportunistic virus still has a poor prognosis.

Acquired Immunodeficiency Syndrome↗

PubMed1983

Glial and divergent cells in primate central nervous system tumors induced by JC virus isolated from human progressive multifocal leukoencephalopathy (PML).

Immunofluorescent stains for fibronectin (FN) and glial fibrillary acidic protein (GFAP) were used in conjunction with routine histologic stains to study tumors induced in squirrel and owl monkeys by JC virus from progressive multifocal leukoencephalopathy (PML). Three varieties of glioma were identified. The first and most common variety was a neoplasm similar to grade 4 astrocytoma in humans. The second had thin, normal-appearing FN-positive vessel walls and a vastly expanded neuroectodermal parenchyma which could not be characterized by routine histologic stains. Anti-GFAP revealed the glial nature of the parenchyma. Isolating glial parenchymal cells from divergent FN-positive cells has become important to neurooncology. This type of tumor may be of particular interest for such isolations due to its high ratio of glial cells to divergent cells. The third variety was not a homogeneous neoplasm. It occurred as focal regions within tumors of the first type, and consisted of giant cells with huge nuclei. These cells resemble the cells of a human giant cell glioblastoma and bear a slight similarity to the bizarre glial cells seen in PML. The rare human giant cell glioblastoma might have an association with JC virus or with PML.

Animals↗

PubMed1992

JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy.

Sections of normal and diseased brain and kidney tissues were screened for the presence of JC virus (JCV) DNA by using the polymerase chain reaction. As expected, all samples obtained from patients with progressive multifocal leukoencephalopathy (PML) tested positive when multiple JCV-specific primer and probe combinations were used. Unexpectedly, more than 50% of non-PML-affected brains were also found to harbor low levels of JCV DNA. To confirm that the positive signals seen in the tissue sections were not the result of contamination, amplified DNA was cloned and sequenced and in some cases was shown to represent strains of JCV not identified previously. Two predominant regulatory region configurations of JCV have been detected in the human host: archetype JCV, which is excreted in the urine of normal and immunocompromised individuals, and "PML-type" JCV found in diseased brains. This latter group of variants appears to derive from archetype JCV by the deletion and duplication of sequences within the promoter-enhancer region. In the present study, the archetype strain of JCV was identified only in normal kidney samples; JCV DNA found in non-PML-affected brain specimens and in kidney tissue from patients with PML resembled that of strains isolated from PML-affected brain tissue. Our findings indicate that JCV reaches the brain more frequently than previously thought and may persist at this site without causing demyelinating disease. A subsequent episode of prolonged immunodeficiency or a direct interaction with an immunocompromising agent (e.g., human immunodeficiency virus type 1) might activate the latent JCV infection and lead to the development of PML.

Base Sequence↗

PubMed2005

Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies.

The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts <or=0.2 x 10(9)/L as risk factors for PML in patients treated with purine analogues. Mortality rates were 95.4% (group A patients), 90% (purine analogues), and 62.5% (HDT/HSCT recipients). At univariate analysis, the only factor that significantly correlated with recovery from infection was female sex. Our findings indicate (1) the possible reduction in reported cases associated with Hodgkin disease and the increasing number of published cases associated with the new antineoplastic therapies (purine analogues and HDT/HSCT); (2) among patients treated with purine analogues, PML is more common in male patients with CD4 cell counts <or=0.2 x 10(9)/L; (3) the use of rituximab after HDT/HSCT seems to delay the onset of PML; and (4) the prognosis is slightly better in transplant recipients.

Adult↗

PubMed1997

Magnetization transfer study of HIV encephalitis and progressive multifocal leukoencephalopathy. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine.

PURPOSE: To ascertain whether the use of magnetization transfer (MT) in MR imaging can characterize tissue destruction in human immunodeficiency virus (HIV)-positive patients with presumed progressive multifocal leukoencephalopathy (PML) or HIV encephalitis. METHODS: Brain MR studies that included MT were obtained in three groups: 11 healthy control subjects, 10 HIV-positive patients with clinical and radiologic findings of PML, and 13 HIV-positive patients with HIV encephalitis. MT ratios (MTRs) were calculated in PML and HIV encephalitis lesions and in normal-appearing white matter in the patients and control subjects. RESULTS: PML lesions revealed a dramatic decrease in MTR (22% +/- 2.3). HIV encephalitis lesions had statistically significantly higher MTR values (40% +/- 3.8) than PML lesions. The MTR of normal-appearing white matter was significantly higher in the control subjects (47% +/- 2.3) than in the PML group (46% +/- 3.3) or the HIV encephalitis group (44% +/- 2.6). CONCLUSION: MTR determinations suggest the possibility of distinguishing PML from HIV encephalitis and of indicating whether HIV encephalitis is involved in white matter that appears normal on conventional MR images.

Adult↗

PubMed1999

Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus.

We describe a patient with longstanding systemic lupus erythematosus (SLE) in remission who presented with recent onset neurological symptoms. Magnetic resonance imaging, followed by a brain biopsy and in situ hybridization, confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML). The clinical findings in this patient emphasize the importance of considering PML in an individual with SLE and neurological abnormalities.

Adult↗

PubMed1990

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.

Twenty-five brains with definite, and three brains with possible, progressive multifocal leukoencephalopathy (PML), including six brains of AIDS patients, were studied with special regard to the detection of papovaviruses. Formalin-fixed serial paraffin sections were immunostained with monospecific anti-JC virus (JCV) and genus-specific anti-simian virus (SV) 40 antisera, and hybridized in situ with DNA probes for JCV and SV 40, respectively. Immunocytochemistry (ICC) and in situ hybridization (ISH) were similarly sensitive in detecting virus in classical PML lesions. In all but one definite PML cases at least one method detected virus (96%). Possible PML tissue was never labeled. Labeling patterns were generally similar in ICC and ISH: mainly oligodendroglia and, less frequently, astroglia harbored virus, whereas labeling of neurons and endothelia was absent. Bizarre giant astrocytes were occasionally labeled by ICC and ISH. Burnt-out lesions harbored JCV DNA but not virus antigens. SV 40 DNA was never detectable. PML morphology in AIDS cases did not usually differ from the disease process seen in the pre-AIDS era. However, two AIDS brains presented extremely extended and, in one case, unusually necrotizing PML damage; in the latter case, PML lesions contained large amounts not only of JCV, but also of human immunodeficiency virus (HIV) antigens. We conclude that ICC and ISH are methods of comparable sensitivity for detection of papovavirus in fluorishing PML lesions. In burnt-out PML lesions only ISH may detect virus. The possibility of an exceptional non-JCV (e.g., SV 40) etiology of PML could be neither confirmed nor disproved. In AIDS, massive coinfection by HIV of PML lesions may increase damage to tissue, resulting in unusually extended and necrotizing PML.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Origin of JC polyomavirus variants associated with progressive multifocal leukoencephalopathy.

JC polyomavirus (JCV) DNAs from the urine of nonimmunocompromised individuals (designated archetypal isolates) regularly contain a regulatory sequence that may have generated various regulatory sequences of JCV isolates derived from the brain of patients with progressive multifocal leukoencephalopathy (PML). In this report, we constructed a phylogenetic tree for 14 isolates (7 archetypes and 7 PML types) from DNA sequence data on the VP1 (major capsid protein) gene. According to the phylogenetic tree, the 14 isolates diverged into types A and B, each of which contained archetypal and PML-type isolates. Each type further diverged into several groups containing archetypal and PML-type isolates. We conclude that PML-type isolates are polyphyletic in their origin and do not constitute a unique lineage. This conclusion suggests that PML-type JCV isolates are generated from archetypal strains during persistence in the hosts. Furthermore, the present phylogenetic analysis indicates that an ancestral JCV carried the archetypal regulatory sequence and that this structure has been conserved in the course of JCV evolution.

Base Sequence↗

PubMed2005

[A case of progressive multifocal leukoencephalopathy presenting white matter MRI lesions extending over the cerebral cortex and a marked decrease in cerebral blood flow on SPECT, and associated with HTLV-I infection].

We report a 47-year-old woman with progressive multifocal leukoencephalopathy (PML). She was a carrier of HTLV-I virus, and developed subacute right hemiparesis and marked motor aphasia. She had a malignant lymphoma in the left neck and basal cell carcinoma in the right inguinal region. Three months after the onset, she became unable to walk because of the right leg weakness or to speak because of motor aphasia. Magnetic resonance imaging (MRI) revealed multifocal T2-high lesions in the white matter of the left frontal lobe, and a brain biopsy revealed demyelinating pathology. A biopsy of the left parotid gland revealed a diffuse pleomorphic type large B cell lymphoma. Although anti-HTLV-I antibody was positive in the serum and cerebrospinal fluid (CSF), no adult T-cell leukemia (ATL) cells were found in the blood or CSF. The patient was then admitted to our hospital. Neurological examinations revealed severe motor aphasia, mild sensory aphasia/cognitive impairment, right hemiplegia, mild right hemihypesthesia, limb-kinetic apraxia in the left hand, idiomotor apraxia, agraphia, perseveration, marked spasticity and brisk tendon reflex in four extremities, and positive bilateral pathological reflexes. MRI showed multifocal T2-high lesions mainly in the cerebral white matter, predominantly in the left hemisphere, and partly in the cerebral cortex. No gadolinium enhancement was found. In addition, 99mTcECD-SPECT showed a broad decrease in cerebral blood flow (CBF) in the cortex. Anti-HTLV-I antibody was positive but anti-HIV antibody was negative in serum. ATL cells were found in 1-3% of the peripheral white blood cells after admission. CSF examination revealed that the cell count (1/microl), protein level (24 mg/dl), and IgG index (0.4) were all normal. However, the myelin basic protein level (321 pg/ml; normal < 102) was increased, JC virus DNA was detected by PCR, and anti-HTLV-I antibody (x 8) was detected in CSF. The regulatory region of the JC virus DNA in the CSF was partly deleted; immunostaining with anti-JC virus protein antibodies revealed the existence of JC virus in biopsied brain specimens, and these findings were consistent with PML. Her symptoms such as motor aphasia, cognitive dysfunction and left hemiparesis were subacutely progressive, and she developed akinetic mutism two weeks after admission. Since the efficacy of cytosine arabinoside for PML has been reported, she was administered 80 mg/day of the drug for five days. After treatment, her communication function was mildly improved but the efficacy was transient. Since it has been reported that HTLV-I, as well as HIV, activates the JC virus promoter and its proliferation, the latent infection of HTLV-I in the central nervous system (CNS) in this case might have stimulated the JC virus proliferation, promoting lesion extension over the cerebral cortex. There have been only a few reports of broad decreases in CBF by SPECT in PML patients. Further MRI and SPECT studies on PML patients are therefore necessary to evaluate the significance of HTLV-I in promoting the JC virus infiltration into the CNS.

Aphasia, Broca↗

PubMed2005

Progressive multifocal leukoencephalopathy in an HTLV-I carrier.

This report describes a previously 28-year-old healthy woman, identified as an asymptomatic human T-lymphotropic virus type I (HTLV-I) carrier, who developed both progressive multifocal leukoencephalopathy (PML) and Pneumocystis jiroveci pneumonia. For diagnostic confirmation of PML, stereotactic brain biopsy demonstrated multiple demyelinating lesions with the presence of JC viral antigen. Intramuscular alpha-interferon therapy for 2 weeks brought considerable neurologic improvement. Three years later, the patient developed lymphoma-type of adult T-cell leukemia, suggesting that HTLV-I carrier might be one of the underlying diseases of PML.

Adult↗

PubMed1995

Capsid protein VP1 deletions in JC virus from two AIDS patients with progressive multifocal leukoencephalopathy.

PCR on 52 cerebrospinal fluid (CSF) specimens and 33 brain biopsies obtained from HIV-1 positive patients utilized pairs of primers from both the early region (JTP) and late region (JLP). In these patients, in whom progressive multifocal leukoencephalopathy (PML) was suspected on the basis of clinical symptoms and magnetic resonance imaging (MRI) studies, eight CSFs (15%) and 14 brain biopsy specimens (42%) contained JCV DNA sequences. In two patients' samples, the CSFs were positive for JCV DNA in the VP1 region using the primer pair for the VP1 region (JLP), but the fragment amplified migrated more rapidly than the 129-bp product obtained from prototype JCV(Mad-1) or the fragment amplified from the antigenic variant of JCV known as Mad-11. These patients died 3-4 months after onset of progressive neurological symptoms. Cycle sequencing of the fragments revealed overlapping deletions of 24 and 27 nucleotides. These strains were of different genotypes, designated strain 107 and strain 206. Computer analysis of the VP1 amino acid sequence predicts that the eight or nine amino acid residue deletions represent a surface loop with a high antigenic index. These naturally occurring deletion mutants are the first examples of a phenomenon observed experimentally in the mouse polyoma virus capsid protein VP2.

AIDS-Related Opportunistic Infections↗

PubMed2005

Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease.

The prior diagnosis of fatal astrocytoma in a 60-year-old man with Crohn's disease treated with natalizumab, a monoclonal antibody against alpha4 integrins, was reclassified as JC virus-related progressive multifocal leukoencephalopathy (PML). Analysis of frozen serum samples showed that JC virus DNA had appeared in the serum three months after the initiation of open-label natalizumab monotherapy and two months before the appearance of symptomatic PML. There was staining of the brain lesion for polyomavirus. This case report, along with two others, suggests that anti-alpha4-integrin therapy can result in JC virus-induced PML.

Antibodies, Monoclonal↗

PubMed1993

Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation.

The authors investigated the spectrum of radiologic findings in a large series (n = 47) of patients seropositive to human immunodeficiency virus (HIV) 1 and with pathologically proved progressive multifocal leukoencephalopathy, to determine the characteristic imaging pattern of the disease. Thirty-six computed tomographic (CT) scans and 29 magnetic resonance (MR) imaging studies obtained in the 47 patients were retrospectively reviewed and correlated with pathologic and clinical findings. Contrast agents were used in 32 CT procedures and 13 MR imaging studies. Lesions typically were hypoattenuating on CT scans and were characterized by areas of increased signal intensity without mass effect on dual-echo MR images. Lesions most often involved periventricular and subcortical white matter in parietooccipital or frontal lobes. Fifteen patients had posterior fossa lesions, and disease was limited to the posterior fossa in two. Lesions were also in the corpus callosum (seven patients), thalamus (eight patients), and basal ganglia (seven patients). In comparison with CT, MR imaging demonstrated greater sensitivity for the extent and number of lesions.

Adolescent↗

PubMed2004

Detection of polyoma virus in brain tissue of patients with progressive multifocal leukoencephalopathy by real-time PCR and pyrosequencing.

We evaluated 2 methods, a LightCycler PCR assay and pyrosequencing for the detection of the JC polyoma virus (JCV) in fixed brain tissue of 10 patients with and 3 control patients without progressive multifocal leukoencephalopathy (PML). Nucleic acid extraction was performed after deparaffinization and proteinase K digestion. The LightCycler assay differentiates the BK virus (BKV), JCV, and SV40 using melt curve analysis. Conventional PCR was used with the same primers to generate products for pyrosequencing. Two sequencing primers were used that differentiate the polyoma viruses. Seven of 11 biopsies (1 patient had 2 biopsies) with PML were positive for JCV by real-time PCR and/or PCR/pyrosequencing. Three of 4 remaining biopsies were positive by real-time PCR but had melting points between JCV and SV40. The 4 specimens that were negative or atypical by LightCycler PCR were positive by traditional PCR, but 1 had an amplicon of lower molecular weight by gel electrophoresis. These were shown to represent JCV by at least 1 of the 2 pyrosequencing primers. The biopsies from patients without PML were PCR negative. Both the LightCycler and pyrosequencing assays are useful for confirming JCV in brain biopsies from patients with PML, but variant JCVs may require supplementary methods to confirm JCV infection.

BK Virus↗

PubMed2002

Progressive multifocal leukoencephalopathy after fludarabine therapy for low-grade lymphoproliferative disease.

Fludarabine is becoming the initial therapy for low-grade lymphoproliferative malignancies, such as CLL and follicular lymphoma. Fludarabine is highly immunosuppressive in addition to being myelosuppressive and has been associated with neurotoxicity. Progressive multifocal leukoencephalopathy (PML) is an infection with JC virus of the white matter of the central nervous system seen mostly in immunosuppressed patients. We describe two patients treated with fludarabine who developed PML. Immunolabeling was positive for JCV in both patients, but PCR was repeatedly negative in one of them. We suggest that fludarabine may increase the risk of PML in patients with lymphoproliferative diseases.

Aged↗

PubMed2001

Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: a monocenter observational study with clinical and JC virus load monitoring.

A monocenter observational study was conducted to determine the clinical and virological effects of cidofovir added to highly active anti-retroviral therapy (HAART) in AIDS-associated progressive multifocal leukoencephalopathy (PML). Exposure to other anti-viral drugs or late initiation of cidofovir were exclusion criteria. Of the 53 consecutive patients with virologically proven PML admitted at the NeuroAIDS Unit of Bicêtre Hospital between May 1996 and July 2000 and having received HAART with or without cidofovir, 46 met the inclusion criteria. Cidofovir was initiated in most cases on compassionate grounds. The 22 patients treated with HAART only (HAART group) were compared to the 24 patients treated with HAART and cidofovir (CDV group). Survival, neurological outcome assessed by the expanded disability status scale (EDSS), and monitoring of the JC virus (JCV) load in CSF were investigated prospectively. At baseline (date of initiation or intensification of HAART), both groups were similar regarding CD4 cell count, plasma HIV load, CSF JCV load, EDSS, and demographic features. Both groups had similar response to HAART in terms of plasma HIV load and CD4 cell count. At month 6, CSF-JCV load was below the detection level in 8 out of 24 (33%) patients from the CDV group and 7 out of 18 (39%) patients from the HAART group (P = 0.71). One-year cumulative probability of being alive was 62% in the CDV group and 53% in the HAART group (P = 0.72). However, an additional benefit with respect to survival was observed in patients who were given cidofovir after adjustment to the following baseline variables (CSF-JCV load, CD4 cell count, and EDSS). Despite the addition of cidofovir to HAART, no significant benefit had been observed in neurological outcome, particularly in patients with an early worsening.

AIDS-Related Opportunistic Infections↗

PubMed2002

Overview of the cellular immunity against JC virus in progressive multifocal leukoencephalopathy.

The human polyomavirus JC (JCV) infects most healthy adults without causing any disease. In the setting of severe deficit of cell-mediated immunity, such as in acquired immunodeficiency syndrome (AIDS), malignancies or in organ transplant recipients, JCV can reactivate and cause progressive multifocal leukoencephalopathy (PML), a deadly demyelinating disease of the central nervous system. The humoral immune response, measured by the presence of virus-specific immunoglobulin G (IgG) in the blood or by intrathecal synthesis of IgG in the cerebrospinal fluid (CSF), is unable to contain the progression of PML. CD4+ T lymphocytes recognize extracellular viral proteins that have been degraded into peptides through the exogenous pathway and presented on major histocompatibility complex (MHC) class II molecules at the surface of antigen-presenting cells. Consistent with their underlying immunosuppression, the proliferative response of CD4+ T lymphocytes to mitogens or JCV antigens is reduced in PML patients. CD8+ cytotoxic T lymphocytes recognize intracellularly synthesized viral proteins that have been degraded into peptides through the endogenous pathway, and presented on MHC class I molecules at the surface of virus-infected cells. One of such JCV peptide, the VP1(p100) ILMWEAVTL, has been characterized as a cytotoxic T lymphocyte (CTL) epitope in HLA-A *0201 + PML survivors. Staining with the corresponding A *0201/JCV VP1(p100) tetrameric complex showed that VP1(p100)-stimulated peripheral blood mononuclear cells (PBMCs) of 5/7 (71%) PML survivors had JCV-specific CTL, versus none of 6 PML progressors (P = .02). This cellular immune response may therefore be crucial in the prevention of PML disease progression and the tetramer staining assay may be used as a prognostic marker in the clinical management of these patients.

Humans↗

PubMed2006

Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name?

Nothing is more disappointing for patients than when a promising new treatment hits a roadblock because of unexpected side effects. This is what happened when natalizumab (Tysabri) was associated with a few cases of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis and Crohn's disease patients, caused by the reactivation of the polyomavirus JC. These dramatic events drew PML squarely into the spotlight and generated considerable interest from the medical community, the pharmaceutical industry, financial markets, and regulatory agencies alike. This scrutiny, in turn, helped crystallize areas of consensus and expose gaps in our understanding of PML pathogenesis. Indeed, since its initial description, there has been a considerable evolution in both the epidemiology and clinical presentations of this disease, and new manifestations of central nervous system infection by polyomavirus JC have been characterized. To keep pace with this opportunistic pathogen, we are therefore forced to reexamine the foundations of our knowledge of virus-host interactions, reappraise our investigational approaches, and in short, rethink PML down to its very name. Hopefully, this crisis will be instrumental in helping us define novel avenues of research, develop predictive tests for PML in populations at risk, and challenge us to find a treatment for this deadly disease.

Biomarkers↗