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PubMed2001

Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy.

Three patients with progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) worsened clinically and radiologically. At the time of deterioration all three had reduced HIV viraemia and increased CD4 cell counts. Brain biopsy in all three disclosed PML and marked perivascular lymphoplasmacytic infiltration. We reviewed the slides of 28 brain biopsies diagnostic of PML. Inflammatory changes were observed in four out of nine patients on HAART and in one out of 19 patients not on HAART.

AIDS-Related Opportunistic Infections↗
PubMed2006

Conventional and diffusion-weighted MRI in progressive multifocal leukoencephalopathy: new elements for identification and follow-up.

PURPOSE: Progressive multifocal leukoencephalopathy (PML) is a serious disorder that primarily affects individuals with a suppressed immune system. Few semiological elements help clearly distinguish PML from other diseases included in the differential diagnosis. Moreover, the clinical course of disease may be chronic or rapidly progressive, with different magnetic resonance imaging (MRI) patterns. The purpose of this study was to confirm the diagnostic value of conventional MRI sequences combined with diffusion-weighted imaging (DWI) in PML to identify those patients with worst prognosis. MATERIALS AND METHODS: We used both conventional MRI sequences and DWI to monitor four male patients aged between 40 and 50 years affected by PML. In two patients, the disease rapidly led to death whereas the other two patients presented a chronic course. RESULTS: Conventional MRI sequences enable detection of the extension of white matter lesions. DWI permits more accurate differentiation of the disease progression front, which exhibits low signal intensity in apparent diffusion coefficient (ADC) maps, from the central gliotic area of demyelinisation, characterised by high ADC values. Patients with rapidly evolving PML have a clear progression front on DWI, which seems to be very tenuous, if not absent, during the quiescent phases of the disease. CONCLUSIONS: The addition of DWI sequences to conventional MRI seems to be a valid method for accurately diagnosing PML and establishing the degree of disease progression.

Adult↗
PubMed1982

Progressive multifocal leukoencephalopathy. A case report and review of the literature.

Progressive multifocal leukoencephalopathy developed in a 70-year-old man with hepatoma treated with oncostatica. The brain showed multiple demyelinated lesions in the upper half of the cerebral white matter. The lesions consisted of proliferation of hypertrophied astrocytes and glial cells with abnormally large nuclei. These nuclei were shown to be filled with DNA by DAPI staining and reacted specifically with anti-JC antibody by immunofluorescence. Papova-like virions were confirmed on both the sections and negatively-stained brain extract under electron microscopy. The sixteen cases so far reported in Japan were reviewed.

Aged↗
PubMed1981

Progressive multifocal leukoencephalopathy. Neuropathology and virus isolation.

Mechanism of demyelination in progressive multifocal leukoencephalopathy (PML) was elucidated by demonstrating ultrastructurally the relationship between the affected glial cells and myelin sheaths. The myelinating cells in the central nervous system, namely oligodendroglias, were specifically attacked by PML-virus with eventual primary destruction of myelin sheaths. An attempt to isolate PML-virus from the autopsy material was made. The presence of virus particles in the extracts from the brain, reactions of virions with antibodies and evidence of virus proliferation in the primary human fetal glial cell culture were shown by various techniques including negative staining, immunofluorescence, immunoelectron microscopy, and electron micrography. The isolated virus was antigenically identical with JC type of papovaviruses.

Brain↗
PubMed1989

Progressive multifocal leukoencephalopathy in patients with AIDS: appearance on MR images.

Progressive multifocal leukoencephalopathy (PML) is an uncommon demyelinating disease that occurs in immunocompromised patients. The authors evaluated magnetic resonance (MR) images of 10 patients with pathologically proved PML and clinically diagnosed acquired immunodeficiency syndrome (AIDS) to determine the MR characteristics of this disorder. All patients had asymmetric cerebral involvement. Lesions were distributed throughout the brain, including the brain stem and basal ganglia. White matter was affected in all 10 patients; gray matter was also involved in five. In one patient the lesion enlarged and crossed the corpus callosum and contained focal hemorrhage. The authors conclude that, contrary to reported findings on computed tomographic scans, PML in patients with AIDS has a variable appearance on MR images and has many characteristics that differ from those previously thought to be typical on imaging studies.

Acquired Immunodeficiency Syndrome↗
PubMed1983

[Utilization behavior during the course of progressive multifocal leukoencephalopathy].

A particular semiologic feature of a case of progressive multifocal leukoencephalopathy was the existence of utilization behavior as described by Lhermitte. The affection developed in a patient with myeloid leukemia treated by cytotoxic drugs. Multifocal low density areas were shown by CT Scan examination. The course of the disease was not altered by isoprinozine therapy.

Adult↗
PubMed2001

Cidofovir treatment of progressive multifocal leukoencephalopathy in a patient receiving highly active antiretroviral therapy.

Progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating disease caused by JC virus, occurs as an opportunistic infection in patients with acquired immunodeficiency syndrome. Curative therapy has been elusive, but recent reports suggest its improvement after institution of highly active antiretroviral therapy (HAART). We describe a case of PML that developed 6 months after the patient, a 55-year-old man, began to receive HAART. The PML progressed despite good virologic and immunologic response to HAART. Substantial symptomatic and radiographic improvement occurred after the addition of cidofovir to the treatment regimen. We reviewed the scientific literature on this rare occurrence of PML after institution of HAART and describe the patient characteristics, potential pathogenesis, and therapeutic options, including the successful use of cidofovir as an adjunctive agent.

AIDS-Related Opportunistic Infections↗
PubMed1994

Integrative agnosia following progressive multifocal leukoencephalopathy.

A 43 year-old man with presumed progressive multifocal leukoencephalopathy developed difficulty recognizing objects and faces in the presence of adequate visual acuity and visual fields. His copying and matching of line drawings was intact, suggesting that his agnosia was associative. However, he had difficulty perceiving overlapping forms and drawings of single objects as integrated wholes. Unlike control subjects, he made fewer errors identifying silhouettes compared to line drawings with internal details. These alterations, together with his feature-by-feature descriptions of objects and copying, suggest that his agnosia was due to a disturbance in integrating local form features, as described by Riddoch and Humphreys (1987). This interpretation is supported by the findings that his tactile recognition and semantic and structural knowledge of the objects he could not identify visually were intact. Furthermore, his deficient performance in categorical matching of photographs to objects was dependent upon the perceptual complexity of the photographs. Similar deficits in early form processing described by other investigators are discussed.

AIDS Dementia Complex↗
PubMed1995

The natural history of progressive multifocal leukoencephalopathy in patients with AIDS. Canadian PML Study Group.

Progressive multifocal leukoencephalopathy (PML) is usually a fatal neurological disease. The natural history of PML in patients with human immunodeficiency virus infection was analyzed. The correlations between CD4+ lymphocyte count, previous diagnosis of AIDS, treatment with cytarabine, and survival time are reported for 28 individuals for whom the diagnosis of PML was confirmed by histopathologic examination. For 16 patients (57%), PML was the AIDS-defining illness. For these 16 patients, the mean (+/- SD) survival time after presentation was 7.5 +/- 7.6 months (range, 1-31 months), whereas that for the 12 patients (43%) for whom AIDS was previously diagnosed was 3.2 +/- 2.8 months (range, 1-11 months) (P = .01). The overall mean (+/- SD) CD4+ cell count was 85 +/- 82/mm3 (range, 12-349/mm3). The mean (+/- SD) survival time for patients with CD4+ cell counts of > or = 90/mm3 at the time of presentation was 9.4 +/- 8.7 months, while that for patients with CD4+ cell counts of < 90/mm3 at the time of presentation was 3.6 +/- 1.8 months (P = .03). The nine patients did not benefit from treatment with cytarabine.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Genetic analysis of JC virus and BK virus from a patient with progressive multifocal leukoencephalopathy with hyper IgM syndrome.

A case of acute progressive multifocal leukoencephalopathy (PML) with hyper IgM syndrome 1 is reported. Viral DNA and VP1 protein of JC virus (JCV) and BK virus (BKV) were detected by immunohistochemistry, in situ hybridization, semi-nested polymerase chain (PCR) and PCR-restriction enzyme analysis. JCV DNA and VP1 protein were found in the nuclei of oligodendrocytes. The non-coding control region (NCCR) and VP1 region of the JCV genome were sequenced; this revealed a novel rearrangement pattern of the NCCR in the brain tissue. The VP1 regions of brain and urine JCV were identical and of genotype type 2A. The BKV in the urine sample was genotype I. No BKV genome was found in the brain. The novel genomic rearrangement of the JCV NCCR in the brain tissue may have altered JCV pathogenesis to induce PML; the impaired immunity from hyper IgM syndrome 1 may have enabled the rearrangement. The JCV NCCR rearrangement in the brain may have originated from the archetypal form in the urine through deletion and duplication.

Adult↗
PubMed1992

Progressive multifocal leukoencephalopathy in patients with human immunodeficiency virus.

Lesions of progressive multifocal leukoencephalopathy (PML) in patients infected with the human immunodeficiency virus (HIV) often have mononuclear cell infiltrates so intense that they obscure the nature of the lesion. This response may be especially prominent in stereotactic biopsies of contrast-enhancing areas. Of 10 consecutive PML lesions biopsied stereotactically, three were markedly, two were moderately, and five were mildly inflamed. There were few to no enlarged oligodendrocytic nuclei with inclusions in the markedly and moderately inflamed lesions. We investigated all biopsies with immunoperoxidase, DNA in situ hybridization, polymerase chain reaction, and Southern immunoblot methodologies for toxoplasmosis and the following viruses: JC, cytomegalovirus, herpes simplex viruses I and II, and human T-cell lymphotropic viruses I, II, and III. We confirmed the presence of JC virus in each lesion; polymerase chain reaction revealed HIV genome only in one. Inflammatory PML lesions in HIV+ patients do not reflect co-infection with toxoplasmosis or viruses commonly seen in these patients. The mononuclear cells are primarily T lymphocytes. Patients with severely inflamed PML lesions, whether HIV+ or not, often show stabilization of symptoms with or without antiviral treatment and have longer lengths of survival than patients with less inflamed lesions.

Adult↗
PubMed2000

Progressive multifocal leukoencephalopathy following oral fludarabine treatment of chronic lymphocytic leukemia.

Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating disorder of the central nervous system usually affecting immunocompromised individuals and is due to infection of the oligodendrocytes by the JC virus. A case of PML in a chronic lymphocytic leukemia (CLL) patient treated with fludarabine is reported, representing the second such instance in which the diagnosis of the neurological disorder was established by brain biopsy. A 61-year-old man with a 14-year history of B-cell type CLL, for which he had received chlorambucil therapy 10 years earlier, developed progressive paresis of both left extremities at 7 months of receiving low doses of oral fludarabine, when his CD4 count has decreased to 0.08 x 10(9)/l. Cranial magnetic resonance imaging revealed a subcortical focal lesion at the right precentral gyrus and a focal lesion at the right thalamus, and a stereotactic brain biopsy showed pathological findings consistent with PML, namely severe myelin breakdown, reactive astrocytosis, and abnormal, huge glial cells with large bizarre nuclei showing granular basophilic inclusions, whereas the presence of the JC virus was demonstrated by in situ hybridization. The present case, in addition to a few previously reported, calls attention to the possibility that severe neurological side effects can be associated with the immunosuppression provoked by the use of fludarabine in CLL patients.

Administration, Oral↗
PubMed1998

Reappraisal of progressive multifocal leukoencephalopathy due to simian virus 40.

Several cases of progressive multifocal leukoencephalopathy (PML) have been associated with simian virus 40 (SV40), rather than with JC virus (JCV), the polyomavirus originally isolated from PML tissue. PML has, therefore, been defined as a demyelinating syndrome with possible multiple viral etiologies. Tissues from three of the cases thought to be associated with SV40 were available for reexamination. Monoclonal antibodies specific for SV40 capsid antigen VPI, virus-specific biotinylated DNA probes for in situ hybridization, and virus-specific primers in the polymerase chain reaction (PCR) were used. Macaque PML brain served as a positive control tissue for SV40 brain infection. Monoclonal antibodies to SV40 VPI failed to recognize viral antigen in lesions from all three human PML cases. The biotinylated DNA probe, which reacted with SV40 in macaque PML, failed to detect SV40 in human PML. However, JCV could be detected by in situ hybridization with a JCV-specific DNA probe. Moreover, JCV DNA sequences were amplified by PCR from the human PML tissues, whereas SV40 DNA sequences were amplified only from the macaque brain. Thus, we could not confirm the original reports that the demyelinating agent in these three cases of PML was SV40, rather than JCV. We conclude that SV40 infection of the central nervous system need not be ruled out in the differential diagnosis of PML.

Animals↗
PubMed1997

Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy.

OBJECTIVE: To evaluate progressive multifocal leukoencephalopathy (PML) lesions using proton magnetic resonance spectroscopy (1H MRS). DESIGN: CSF polymerase chain reaction (PCR) detection for JC viral (JCV) DNA; MRI and localized 1H MRS in the PML lesions, normal-appearing contralateral brain regions (CONTRA), and in matched brain regions of normal subjects. SETTING: University-affiliated medical center. PATIENTS OR PARTICIPANTS: 20 AIDS patients with clinical diagnosis of PML, 16 had tissue and/or CSF evidence of JCV infection; 20 age-matched normal subjects. MAIN OUTCOME MEASURES: Metabolites from 1H MRS: N-acetyl aspartate (NA), creatine (CR), choline-containing compounds (CHO), myoinositol (MI), glutamine/glutamate (GLX), lactate, and lipids. RESULTS: CSF PCR for JCV DNA showed 86% sensitivity. MRI showed characteristic demyelinating lesions; commonest locations were frontal lobe and cerebellum. 1H MRS in the lesions showed decreased NA (-35%; p < 0.0001) and CR (-18%; p = 0.003), increased CHO (+28%; p = 0.0005), occasional increased MI, and excess lactate (15/20 lesions) and lipids (18/20). In the CONTRA, MRS showed trends for increased CR (+15%), CHO (+15%), MI (+13%), and lower GLX (-9%; p = 0.02). Six patients, studied longitudinally (4-18 months), showed progressive spectroscopic changes; two patients with longest survival showed the highest MI. CONCLUSIONS: These MRS findings are consistent with neuropathologic observations of neuronal loss, cell membrane and myelin breakdown, and increased glial activity in PML lesions. The CONTRA abnormalities may be due to remote effects of PML or direct HIV-1 infection. 1H MRS may be useful for characterization and follow-up evaluation of PML lesions.

Adult↗
PubMed2006

Progressive multifocal leukoencephalopathy and multiple sclerosis: lessons from natalizumab.

Three patients have developed progressive multifocal leukoencephalopathy while being treated with natalizumab for their autoimmune diseases. One patient had relapsing-remitting multiple sclerosis (RRMS), one had Crohn's disease, and one (who had been enrolled in an RRMS phase III trial) had no evidence of multiple sclerosis on autopsy. The patient with RRMS now has severe, permanent neurologic damage and the other two patients died. In this article, we recommend revised entry and diagnostic criteria to prevent enrollment of RRMS patients with a favorable prognosis or questionable diagnosis into trials of drugs with unknown safety profiles. In light of the risk of progressive multifocal leukoencephalopathy, we strongly recommend that RRMS patients who are at low risk of disability not be treated with natalizumab. Finally, we discuss what additional natalizumab efficacy data need to be presented before any decisions should be made about treating RRMS patients with a high risk of developing long-term disability.

Antibodies, Monoclonal↗
PubMed1998

Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team.

BACKGROUND: Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. METHODS: In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. RESULTS: At the time of the last analysis, 14 patients in each treatment group had died, and there were no significant differences in survival among the three groups (P=0.85 by the log-rank test). The median survival times (11, 8, and 15 weeks, respectively) were similar to those in previous studies. Only seven patients completed the 24 weeks of treatment. Anemia and thrombocytopenia were more frequent in patients who received antiretroviral therapy in combination with intravenous cytarabine than in the other groups. CONCLUSIONS: Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents we used, nor does high-dose antiretroviral therapy alone appear to improve survival over that reported in untreated patients.

AIDS-Related Opportunistic Infections↗
PubMed1993

Stereotactic brain biopsy for diagnosis of progressive multifocal leukoencephalopathy.

We describe three patients in whom the diagnosis of progressive multifocal leukoencephalopathy (PML) was made by stereotactic biopsy. All three patients had a rapidly progressive clinical course pathologically characterized by demyelination, Alzheimer I astrocytes, and basophilic intranuclear inclusions in oligodendrocytes. In each case, the diagnosis was confirmed with immunohistochemical staining of oligodendrocytes for the JC virus and in one case by electron microscopy. Determination of the adequacy of tissue received at the time of frozen section is critical and can direct the appropriate submission of tissue to maximize available diagnostic procedures.

Adult↗