Progressive multifocal leukoencephalopathy associated with prolonged hemodialysis treatment

Summary The association of progressive multifocal leukoencephalopathy (PML) with prolonged hemodialysis treatment (PHT), not previously reported, was observed in a 56-year-old Japanese man who received PHT for 11 years. He suffered from recurrent bouts of fever and progressive neurological signs, such as irritability, speech disturbance, gait disturbance and dysphagia for seven months, and finally fell into a deep coma and died. Clinical signs and symptoms were highly suggestive of progressive dialysis encephalopathy. Necropsy revealed that the PML mainly involved the brainstem and cerebellar white matter. The aluminium content of the brain tissue was lower than that of controls. Possibly the virus causing PML is one of the causes of progressive dialysis encephalopathy, since clinically PML is not easily distinguished from progressive dialysis encephalopathy. It is essential to differentiate PML of viral etiology from progressive dialysis encephalopathy of unknown cause.     

T cell deficiencies as a common risk factor for drug associated progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a disease of the central nervous system caused by neuropathogenic prototypes of ubiquitous community-acquired JC virus (JCV). The disease became of particular concern following its association with certain therapies that modulate immune system function without heavy immunosuppression. Due to lack of prophylactic/treatment options and poor outcomes, which often include severe disability or death, PML is a considerable concern for development of new drugs that interfere with immune system functions. In this review of clinical and research findings, we discuss the evidence that deficiencies in CD4⁺ T helper cells, cytotoxic CD8⁺ T cells, and interferon gamma are of crucial importance for development of PML under a variety of circumstances, including those associated with use of various drugs, regardless of differences in their mechanisms of action. These deficiencies apparently enable transformation of the harmless JCV archetype into neuropathogenic prototypes, but the site(s), and the mechanisms, of this transformation are yet to be elucidated. Here we discuss the evidence for brain as one of the sites of this transformation, and propose a model of PML pathogenesis that emphasizes the central role of T cell deficiencies in the two life cycles of the JCV, one non-pathogenic and one neuropathogenic. Finally, we conclude that the development of clinical grade T cell functional tests and more consistent use of already available laboratory tests for T cell subset analysis would greatly aid the effort to more accurately predict and assess the magnitude of PML risk for concerned therapeutic interventions.     

Diagnostic assays for polyomavirus JC and progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a devastating and often fatal demyelinating disease of the central nervous system for which effective therapies are lacking. It is caused by the replication of polyomavirus JC (JCV) in the oligodendrocytes and astrocytes leading to their cytolytic death and loss of myelin from the subcortical white matter. While the virus is very common in human populations worldwide, the incidence of the disease is very low and confined almost exclusively to individuals with some form of immunological dysfunction. However, the number of people who constitute the at‐risk population is growing larger and includes individuals with HIV‐1/AIDS and patients receiving immunomodulatory therapies such as multiple sclerosis patients treated with natalizumab. Further adding to the public health significance of this disease are the difficulties encountered in the diagnosis of PML and the lack of useful biomarkers for PML progression. In this review, we examine the diagnostic assays that are available for different aspects of the JCV life cycle, their usefulness and drawbacks, and the prospects for improvements. Copyright © 2015 John Wiley & Sons, Ltd.     

JC virus, a human polyomavirus associated with progressive multifocal leukoencephalopathy: additional biological characteristics and antigenic relationships.

JC virus, a human polyomavirus, failed to grow or produce cytopathic effects in any of a variety of cells tested other than primary human fetal glial (PHFG) cells. Cells tested included other primary human cells and glial cells from other animals. Only a rare cell in inoculated insusceptible human cell cultures produced T or virion antigen. In PHFG cell cultures JC virus produced subtle cytopathic effects, and the majority of progeny remained cell associated. Only a few cells in the heterogenous PHFG cell cultures contained T antigen at 24 h postinoculation, and virion antigen was not detected until 48 h postinoculation. The infectivity of JC virus was resistant to inactivation by ether and by heating at 50 degrees C for 1 h. A three-way minor antigenic relationship was demonstrated among the virion antigens of JC virus, BK virus, and simian virus 40 by neurtralization and/or hemagglutination inhibition tests. Serological evidence is presented for the existence of JC virus as a distinct entity before the use of simian virus 40-contaminated poliovirus vaccines and for the nonexistence of an animal reservoir for JC virus infection.     

Neuropathology of JC virus infection in progressive multifocal leukoencephalopathy in remission

AIM: To investigate the neuropathology of the brain in a rare case of remission following diagnosis of progressive multifocal leukoencephalopathy (PML).METHODS: Consent from the family for an autopsy was obtained, clinical records and radiograms were retrieved. A complete autopsy was performed, with brain examination after fixation and coronal sectioning at 1 cm intervals. Fourteen regions were collected for paraffin embedding and staining for microscopic analysis. Histologic sections were stained with Luxol blue, hematoxylin/eosin, and immunostained for myelin basic protein, neurofilament, SV40 T antigen and p53. The biopsy material was also retrieved and sections were stained with hematoxylin/eosin and immunostained for SV40 and p53. Sections were examined by American Board of Pathology certified pathologists and images captured digitally.RESULTS: Review of the clinical records was notable for a history of ulcerative colitis resulting in total colectomy in 1977 and a liver transplant in 1998 followed by immune-suppressive therapy. Neurological symptoms presented immediately, therefore a biopsy was obtained which was diagnosed as PML. Immunotherapy was adjusted and clinical improvement was noted. No subsequent progression was reported. Review of the biopsy demonstrated atypical astrocytes and enlarged hyperchromatic oligodendroglial cells consistent with JC virus infection. Strong SV40 and p53 staining was found in glial cells and regions of dense macrophage infiltration were present. On gross examination of the post-mortem brain, a lesion in the same site as the original biopsy in the cerebellum was identified but no other lesions in the brain were found. Microscopic analysis of this cerebellar lesion revealed a loss of myelin and axons, and evidence of axonal damage. This single burned-out lesion was equivocally positive for SV40 antigen with little p53 staining. Examination of thirteen other brain regions found no other occult sites.CONCLUSION: Our study reveals residual damage, rare macrophages or other inflammation and minimal evidence of persistent virus. This case demonstrates the possibility of complete remission of PML.     

Isolation of a SV40-like virus from a patient with progressive multifocal leukoencephalopathy

A SV40-like virus was isolated from the brain of a patient with progressive multifocal leukoencephalopathy. The virus was antigenically and serologically indistinguishable from SV40 wild type. A unique difference from SV40 was its ability to grow on human glial and CV-I monkey cells. The molecular weight of the viral DNA was very similar to that of SV40 DNA and the DNA cleavage patterns obtained after digestion with Hind II and Hind III restriction endonucleases were indistinguishable from those of SV40.     

The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases

Progressive multifocal leukoencephalopathy (PML) is a rare and devastating neurological disease with areas of demyelination in the central nervous system classically associated with profound imunosuppression. PML is caused by reactivation of latent JC virus, leading to the death of myelin-producing oligodendrocytes typically with a rapidly fatal outcome. Once seen primarily in severely immunosuppressed states including lymphoma, solid organ malignancies, and organ transplant recipients, PML became an AIDS-defining illness in the 1980s. PML has now emerged as a catastrophic illness in multiple sclerosis with biologic drug therapy (natalizumab) and reported in rheumatic diseases with and without biologic therapeutic agents. With current and future treatments that suppress and manipulate the immune system, there is risk for severe acute infections and reactivation of latent infections, such as JC virus reactivation leading to PML. It is critical, therefore, to proceed cautiously when immune system modification strategies are being evaluated for fear of unleashing undesirable or even fatal diseases. Fortunately this complication remains a rare event.