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PubMedDate not supplied

[Progressive multifocal leukoencephalopathy as a cause of neurologic symptoms in Sharp syndrome].

Progressive multifocal leukencephalopathy (PML) is a very rare complication of immunosuppressive or cytostatic treatment of rheumatic diseases. We describe a patient with a mixed connective tissue disease (MCTD) existing for more than 15 years, who had polyarthritis, myositis, scleroderma-like symptoms, pulmonary involvement, and psychosis of undetermined origin. After a 12-year low-dose corticosteroid therapy and a 4-year azathioprin therapy a quickly progressive PML developed; symptoms included: difficulty in urinating, bladder, articulation, spastic hemiplegia, eye movement malfunction. The patient died after after a few months. PML is an important consideration in the differential diagnosis when a patient with MCTD develops neurologic symptoms.

Adrenal Cortex Hormones↗

PubMed1997

Progressive multifocal leukoencephalopathy: molecular biology, pathogenesis and clinical impact.

The human polyomaviruses JC virus (JCV) and BK virus (BKV) have long been known as onco- and neurooncogenic. Interest in their oncogenic potential has reemerged with the discovery of simian virus 40 DNA in human brain tumors including the pituitary as well as in bone tumors and mesotheliomas. The only human disease caused by an infection with the human polyomavirus JCV is progressive multifocal leukoencephalopathy (PML) characterized by a lytic infection of oligodendrocytes with consecutive demyelination. Malignant transformation of cell lines appears to be caused by a complex interaction of the viral large T (tumor) antigen with several transcription factors and tumor suppressor proteins such as p53 and the retinoblastoma protein. PML, once an extremely rare disease, has become much more frequent in the western world owing to the AIDS pandemic. An exceedingly complicated, cell-, tissue- and species-specific pattern of protein-DNA interaction and negative as well as positive feedback regulation by at least a dozen proteins and possibly mutations in the JC viral promoter-enhancer region govern host range and development of PML. The intricate molecular and immunological prerequisites ultimately leading to PML in humans have not yet been completely elucidated.

Animals↗

PubMed1977

[Progressive multifocal leukoencephalopathy as a complication of immunosuppression in kidney transplantation].

The progressive multifocal leukencephalopathy is mostly observed as paraneoplastic complication of malignant lymphoproliferative systemic diseases. It may develop also under the influence of a long-term immunosuppressive therapy, as it is necessary in the rejection treatment of recipients or organ transplantations. It is reported on a 44-year-old man in whom a progressive multifocal leukencephalopathy with exitus letalis developed 6 months after a kidney transplantation and following immunosuppressive therapy. In the oligodendroglia of the marginal region of leukodystrophic foci in the centrum semiovale of the right cerebral hemisphere by means of electron microscopy paracrystalline situated virions of the type Papova were proved in most cases.

Azathioprine↗

PubMed2000

Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy.

After solid organ transplantation, signs and symptoms of the central nervous system may present a diagnostic challenge. A 43-year-old patient developed a decrease in vision 15 months after bilateral lung transplantation. The initial diagnosis was a left posterior cataract, but left eye cataract extraction did not improve his vision. Seizures led to investigation of a broader differential diagnosis (cyclosporine intoxication, post-transplant lymphoproliferative disorder, infectious disease, chronic lymphatic leukemia). The clinical diagnosis of progressive multifocal leukoencephalopathy (PML) was confirmed by demonstration of JC virus in the cerebrospinal fluid and by autopsy findings. Modulation of the immunosuppressive regimen was unsuccessful. This case illustrates that decreased vision in immunocompromised patients may be the first manifestation of PML.

Adult↗

PubMed1985

[Progressive multifocal leukoencephalopathy in hemophilia A. Is there a relation to AIDS?].

Progressive multifocal leukencephalopathy (PML) due to Papovavirus is usually combined with a cellular immunodeficiency as a consequence either of a neoproliferative disease or of medical treatment. In the first description of a case of PML in combination with substituted hemophilia A with no known cellular immunodeficiency, possible pathogenetic relations to factor VIII substitution as well as to AIDS, caused by HTLV-III virus, are discussed.

Acquired Immunodeficiency Syndrome↗

PubMedDate not supplied

Progressive multifocal leukoencephalopathy resembling central nervous system systemic lupus erythematosus.

A 21-year-old woman with a 6-year history of SLE presented with a speech disturbance and right hand clumsiness along with manifestations of active disease suggesting central nervous system SLE. Despite aggressive treatment for SLE, her neurological condition worsened. MRI demonstrated low intensity in T1-weighted images and high intensity in T2-weighted images in the white matter of the bilateral cerebrum and cerebellum, compatible with progressive multifocal leukoencephalopathy (PML). Intraspinal administration of interferon-beta seemed to slow the deterioration of her MRI and neurological findings. However, she eventually developed decerebrate rigidity and died due to candidemia. DNA of the JC virus was detected in the autopsied brain by the polymerase chain reaction technique. PML should always be borne in mind when examining patients with SLE showing neurological abnormalities.

Adult↗

PubMed2000

Expression of Bax, Bcl-2, and P53 in progressive multifocal leukoencephalopathy.

It has been shown in vitro that JC viral protein can form a complex with wild-type p53 protein, which is a key regulator of both cell proliferation and cell death. Cellular factors, Bax and Bcl-2, are two essential downstream elements involved in p53-dependent apoptosis. To determine whether association of JC virus with p53 protein affects the expression of Bax and Bcl-2 in viral-infected cells in progressive multifocal leukoencephalopathy (PML), we studied the expression of Bax, Bcl-2, and p53 in 14 cases from 13 PML patients by using paraffin immunohistochemistry. Seven of 13 patients were known to be HIV positive. Overexpression of p53 was found in viral-infected oligodendrocytes and some astrocytes in all 14 cases. Intense immunostaining of Bax was strongly expressed in viral-infected oligodendrocytes and astrocytes. Bax immunostaining was also found in macrophages in the demyelinating lesions. Bcl-2 was not detected in viral-infected glial cells. The expression pattern of Bax positive/Bcl-2 negative in viral-infected glial cells suggests that the oligodendrocyte may be undergoing apoptosis which may in turn contribute to the demyelinating process in PML. The coexpression of p53 and Bax in the infected glial cells suggests that p53 detected by immunohistochemistry may still maintain its wild-type function.

Adult↗

PubMed1996

Antibody against synthetic multiple antigen peptides (MAP) of JC virus capsid protein (VP1) without cross reaction to BK virus: a diagnostic tool for progressive multifocal leukoencephalopathy.

Antibody against JC virus (JCV) was raised in rabbits with the use of synthetic multiple antigen peptides. The peptide sequences were derived from three regions of JCV VP1 protein, which showed less similarity with BK virus (BKV) counterpart. The antibodies raised with these peptides were designated as JCAb1, 2 and 3. JCAb1 specifically reacted with JCV and not with BKV, while JCAb2 and 3 reacted both with JCV and BKV. All of these antibodies reacted with JCV antigen of formalin-fixed paraffin sections of progressive multifocal leukoencephalopathy (PML) brain tissue. As JCAb1 is JCV-specific and reacted with JCV in formalin-fixed paraffin sections, it will contribute not only to rapid and accurate immunohistochemical diagnoses of PML but also to clarification of the pathogenesis of JCV infection.

Amino Acid Sequence↗

PubMed2002

Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution.

Immune reconstitution resulting from use of highly active antiretroviral therapy in patients infected with human immunodeficiency virus type 1 (HIV-1) has been associated with a significant decrease in infectious morbidity and with improved survival. Occasionally, patients with quiescent disease due to human cytomegalovirus or nontuberculous mycobacteria may experience paradoxical worsening due to "dysregulated" restitution of the immune system (that is, immune restoration disease [IRD]). Acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy (PML) is uncommon and often improves with immune recovery. We describe 2 HIV-1-infected patients with PML that presented with paradoxical worsening after the patients had commenced active antiretroviral therapy. After they had a transient response to high-dose corticosteroid therapy, both patients died of progressive neurological deterioration. IRD in these patients with PML was unexpected and occurred soon after they had started receiving active antiretroviral therapy, during the period of improved antigen-specific T-helper cell function. Predictors of patients' proclivity for these adverse events are uncertain. Evaluation of targeted immunomodulatory therapy directed towards disease-specific IRD is critical and may play an important role in improved survival for patients who are at risk.

Adult↗

PubMed2002

Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin's lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy.

Nonmyeloablative allogeneic stem cell transplantation (NMASCT) can be used to exploit the graft-versus-tumor (GVT) potential of allogeneic donor cells in the setting of reduced conditioning regimen toxicity. This approach is particularly attractive for patients who have received extensive prior therapy and are poor candidates for traditional allogeneic stem cell transplantation. However, toxicity in heavily pretreated patients remains uncertain. Additional immunosuppression in already immunocompromised patients may result in unexpected toxicity. We report a case of probable progressive multifocal leukoencephalopathy (PML) responsive to interleukin-2 (IL-2) following a NMASCT in a 29-year-old woman with relapsed Hodgkin's lymphoma. The patient developed severe neurological symptoms approximately 6 weeks following NMASCT associated with low CD4+ cell counts and magnetic resonance imaging (MRI) was consistent with PML. IL-2 therapy resulted in increasing CD4+ counts and progressive resolution of neurological symptoms. Disruption of IL-2 therapy led to neurological deterioration, which responded to reinstitution of IL-2 therapy. The patient's lymphoma initially progressed following NMASCT, but has responded to donor leukocyte infusions (DLI). This case reiterates the potent GVT potential of NMASCT in patients with Hodgkin's disease. However, it demonstrates the potential for severe complications related to immunosuppression, especially in heavily pretreated patients. The toxicity after NMASCT should not be understated and will need to be explored further.

Adult↗

PubMed2006

[Progressive multifocal leukoencephalopathy in a patient following long-term immunosuppressive therapy for systemic lupus erythematosus].

A 41-year-old woman who had suffered from systemic lupus erythematosus (SLE) for 22 years presented with signs of neurological deficits. CT-scanning of the brain revealed hypodense lesions that suggested cerebral infarction due to vasculitis in SLE. However, in spite of intensified immunosuppressive therapy, she showed rapid neurological deterioration. After extensive, additional examinations and tests, the diagnosis was finally changed to progressive multifocal leukoencephalopathy, caused by an opportunistic infection by the JC polyomavirus. Neurological and psychiatric symptoms frequently occur in patients with SLE. The differential diagnosis of these symptoms in SLE is extensive and includes, on the one hand, primary neurological and psychiatric diseases related to direct involvement of the nervous system by SLE, and on the other hand, secondary syndromes arising as a result of complications of the SLE or the immunosuppressive treatment. Opportunistic infections are often an important secondary cause of neurological and psychiatric syndromes in patients with SLE. The clinical symptoms and radiological cerebral signs are non-specific and usually do not suffice to differentiate between the various syndromes. Since each syndrome requires its own specific clinical approach and treatment, extensive diagnostics are mandatory before the diagnosis 'cerebral lupus' can be made and immunosuppressive therapy can be started or intensified.

Adult↗

PubMed1992

[AIDS-related progressive multifocal leukoencephalopathy limited to U fibers, responsible for subacute encephalopathy with normal CT scan findings].

A 41-year-old male homosexual with AIDS was hospitalized for temperature elevation to 40 degrees C with confusion. Neurologic evaluation found psychomotor slowing and temporospatial disorientation with no focal signs. The CD4 count was 100/mm3. CSF analysis and the CT scan were normal. Despite antiviral treatment the patient died fifteen days after admission. Gross appearance of the brain was normal. Histologic examination disclosed multiple, small foci of demyelination characteristic of progressive multifocal leukoencephalopathy. These foci were disseminated among the U fibers. In situ hybridization and immunocytochemical studies demonstrated papovavirus particles in oligodendrocytes and a few astrocytes. This case shows that papovavirus infection in AIDS patients may be responsible for a diffuse febrile encephalopathy with normal CT scan findings and a rapidly progressive course.

AIDS-Related Opportunistic Infections↗

PubMed2002

Unusual viral infections (progressive multifocal leukoencephalopathy and cytomegalovirus disease) after high-dose chemotherapy with autologous blood stem cell rescue and peritransplantation rituximab.

Efforts to reduce relapse of non-Hodgkin lymphoma after autologous transplantation have included ex vivo stem cell selection and/or peritransplantation immunotherapy. The late infectious and immunologic consequences of these maneuvers are not well understood, although an increase in early cytomegaloviral disease after CD34(+) stem cell selection and an alteration in immunoglobulin and T-cell recovery after peritransplantation rituximab has been noted. We report the first 2 cases of progressive multifocal leukoencephalopathy caused by JC papovavirus after autologous peripheral blood stem cell transplantation and a case each of cytomegalovirus retinitis and pneumonitis. All 4 patients experienced significant impairment of CD4 T-cell recovery, placing them at risk for these unusual viral infections. The clustering of cases is concerning because all occurred shortly after the introduction of peritransplantation rituximab into treatment protocols (4 of 62 immunotherapy recipients compared with 0 of 276 without; z = 3.595; P <.001), although a direct association with this CD20 B-cell-directed therapy remains speculative.

Adult↗

PubMed2001

Clinical and magnetic resonance imaging regression of progressive multifocal leukoencephalopathy in an AIDS patient after intensive antiretroviral therapy.

A 36-year-old homosexual man with 6 months of visual symptoms and headaches had right homonymous hemianopia, mild new learning impairment, and alexia with agraphia. The initial brain magnetic resonance imaging (MRI) scan was reported consistent with left occipital infarction. Subsequent MRI demonstrated abnormal demyelination in subcortical white matter and deep parieto-occipital white matter bilaterally, but primarily left. Human immunodeficiency virus testing and cerebrospinal fluid polymerase chain reaction for JC virus DNA were both positive, consistent with progressive multifocal leukoencephalopathy (PML) with AIDS. His clinical status steadily deteriorated, and MRI white matter abnormalities worsened despite high-dose antiretroviral therapy. After the antiretroviral regimen was intensified by the addition of a protease inhibitor, rapid clinical and radiographic improvement occurred with subsequent MRI studies revealing only residual left parieto-occipital encephalomalacia. PML in AIDS patients has been associated with a nearly uniformly poor prognosis until recent reports of improved outcomes after highly active antiretroviral therapy. This patient with PML and AIDS similarly showed a robust clinical and MRI response to intensive antiretroviral combination therapy, which has been maintained for more than 3 years.

AIDS-Related Opportunistic Infections↗

PubMed1988

A monoclonal antibody to SV40 large T-antigen labels a nuclear antigen in JC virus-transformed cells and in progressive multifocal leukoencephalopathy (PML) brain infected with JC virus.

Thirty monoclonal antibodies to SV40 large T-antigen were tested for reactivity on the JC virus-transformed hamster glial cell line known as HJC-15. Two of them (PAb 416 and PAb 108) detected a nuclear antigen in both SV40-transformed CCL 75.1 cells and in HJC-15 cells, but not in control cells lacking T-antigen. These same antibodies also labeled a nuclear antigen in hamster tumor tissue derived from HJC-15 cells. In addition, the monoclonal antibody PAb 416 detected a nuclear antigen in progressive multifocal leukoencephalopathy (PML) tissue infected with JC virus, but not in normal brain tissue or tissue from other neurological diseases. Staining by PAb 416 was reduced by prior incubation with hamster anti-JCV tumor serum, suggesting that the polyclonal antiserum to JCV T-antigen may compete for an epitope at or near the PAb 416 binding site.

Animals↗

PubMed1996

Progressive multifocal leukoencephalopathy during cyclosporine treatment. A case report.

A 45-year-old patient suffering from chronic renal insufficiency developed dermatopolymyositis. Since the patient did not respond to treatment with high doses of prednisone and immunoglobulin, concomitant cyclosporine A was added. Four months later, worsening signs of bilateral pyramidal disorder and an altered state of consciousness appeared. Serial computed tomography (CT) and magnetic resonance imaging (MRI) revealed multiple alterations of the cerebral white matter. Cyclosporine was then discontinued. One month later, exitus occurred. Microscopic examination of the brain showed diffuse tumescence; histological examination revealed perivascular and diffuse lymphomonocyte infiltrations, areas of demyelination, astrocytes with bizarre nuclei, and oligodendrocytes with enlarged nuclei due to hyperchromatic inclusion. Morphological examination confirmed the presence of intranuclear icosahedral viral bodies. Progressive multifocal leukoencephalopathy was diagnosed. The literature contains only one report of an analogous case observed during a course of cyclosporine treatment for Wegener's granulomatosis.

Brain↗

PubMedDate not supplied

Ultrastructural studies in the lytic phase of progressive multifocal leukoencephalopathy in AIDS patients.

Brain fragments from eight cases (four autopsies and four biopsies) of patients with acquired immune deficiency syndrome (AIDS) with JC virus (JCV) lytic infections were examined ultrastructurally. Particular efforts were made to look for virions and their subcellular distribution in cells not usually involved by papovavirus infection. The cellular and subcellular distribution of virions was investigated with emphasis on cell types not normally associated with papovavirus infection. The pattern of JCV infection was as follows: 1) oligodendrocytes; nucleus only, 7 cases; cytoplasm only, no cases; 2) astrocytes (normal and "bizarre"); nucleus and cytoplasm, two cases; cytoplasm only, four cases; 3) macrophages; nucleus and cytoplasm, one case; cytoplasm only, four cases; and 4) neurons; nucleus and cytoplasm, two cases; cytoplasm only, three cases. Perivascular, endothelial, ependymal, and microglial cells were never infected. Our ultrastructural data indicate that cell types other than oligodendrocytes can be involved productively by JCV in the lytic phase of progressive multifocal leukoencephalopathy (PML) in AIDS patients. Neuronal cells, especially, can be infected productively by the JCV, and this should be considered in clinical interpretation of cortical symptoms and signs in suspected or proven cases of PML.

AIDS-Related Opportunistic Infections↗

PubMed2000

[Diffuse large B-cell lymphoma showing CNS invasion by CD30-positive multinuclear giant cells mimicking the clinical features of progressive multifocal leukoencephalopathy].

We report a 55-year-old woman with diffuse large B-cell lymphoma showing central nervous system (CNS) infiltration by CD30-positive lymphoma cells. The patient was admitted with pleural effusion, ascites and a large mass in the abdominal cavity. Southern blot analysis of DNA extracted from the ascites revealed IgJH rearrangement, and therefore she was initially diagnosed as B-cell neoplasia. She received combined chemotherapy (DICE and CHOP regimens), and achieved a transient clinical response. Three months later, she developed various neurological abnormalities, and brain magnetic resonance imaging revealed diffuse infiltration of the cerebral white matter. We considered the possibility of CNS involvement by the lymphoma or progressive multifocal leukoencephalopathy (PML), and began a course of anti-virus therapy and radiation therapy. Because multiple lumbar punctures demonstrated large multinuclear lymphoma cells in the cerebrospinal fluid, a diagnosis of metastatic CNS lymphoma was made. Immunohistochemistry revealed that these lymphoma cells were reactive with anti-CD30 antibody. Although the radiation therapy was temporarily effective against the CNS involvement, the patient died of systemic invasion of the lymphoma cells. The final diagnosis was diffuse large B-cell lymphoma on the basis of pathologic findings, immunohistochemistry, and Southern blot analysis using a mesenteric lymph node obtained at autopsy. Cytospin preparations and immunohistochemistry of specimens obtained from frequent lumbar punctures were useful for differentiating CNS lymphoma from PML.

Brain Neoplasms↗