Elsevier

The Lancet Neurology

Volume 9, Issue 4, April 2010, Pages 425-437
The Lancet Neurology

Review
Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis

https://doi.org/10.1016/S1474-4422(10)70040-5Get rights and content

Summary

Progressive multifocal leukoencephalopathy (PML) is a rare but often fatal brain disease caused by reactivation of the polyomavirus JC. Knowledge of the characteristics of PML has substantially expanded since the introduction of combination antiretroviral therapy during the HIV epidemic and the development of immune reconstitution inflammatory syndrome (IRIS) in patients with PML. Recently, the monoclonal antibodies natalizumab, efalizumab, and rituximab—used for the treatment of multiple sclerosis, psoriasis, haematological malignancies, Crohn's disease, and rheumatic diseases—have been associated with PML. Additionally, the JC virus can also lead to novel neurological disorders such as JC virus granule cell neuronopathy and JC virus encephalopathy, and might also cause meningitis. The increasingly diverse populations at risk and the recent discovery of the presence of the JC virus in the grey matter invite us to reappraise the pathogenesis of this virus in the CNS.

Introduction

Progressive multifocal leukoencephalopathy (PML) is caused by the human polyomavirus JC.1 PML is a disease of the brain resulting from lytic infection of glial cells in severely immunosuppressed patients and is often fatal.

PML is a demyelinating disease of the CNS that can occur in patients with severe immunosuppression. Before the HIV epidemic, PML was a rare disease, seen in only a few immunosuppressed patients, including individuals with haematological malignancies, organ transplant recipients, and patients with chronic inflammatory disorders. The prevalence of PML in the general population was estimated at 4·4 cases per 100 000 individuals, according to data from a medical service and outpatient prescription claims database.2 However, prevalence of PML increased substantially during the HIV epidemic, in which up to 5% of patients with AIDS developed the disease. Mortality related to PML has also increased from 1·5 per 10 million individuals in the pre-HIV era in 1979 to 6·1 deaths per 10 million individuals in the post-HIV era in 1987.3 In case records from the Massachusetts General Hospital, MA, USA, of 61 patients with PML, 48 had AIDS and 11 had haematological diseases, including three recipients of bone marrow transplants, one with history of thymoma, and one with dermatomyositis.4 More recently, a study based on national US inpatient diagnosis codes analysed 9675 cases of PML from 1998 to 2005, including 7934 (82%) patients with HIV, 813 (8%) patients with haematological cancers, 274 (3%) patients with solid organ cancers, and 43 (0·44%) patients with rheumatological diseases.5

Several classes of medications that suppress the host cellular immune response are associated with PML. Recently, immunomodulatory medications for autoimmune diseases have emerged as a new category of drugs associated with PML, including natalizumab for multiple sclerosis and Crohn's disease,6, 7, 8 rituximab for lupus,9 and efalizumab for psoriasis.10, 11

In this Review, we discuss the clinical features of PML and outline the recently discovered clinical syndromes that result from neuronal infection by the JC virus.

Section snippets

Virology and host immune response

The JC virus is a neurotropic virus that infects only human beings. Therefore, research on JC virus pathogenesis has been hampered by the absence of an animal model. An N-linked glycoprotein with an α-(2,6)-linked sialic acid, present on many human cells, is one of the cellular receptors for the JC virus.12 Additionally, the JC virus can bind to the serotoninergic 5-HT2a receptor to infect astroglial cells in culture.13 This receptor is present in several cell types, including kidney epithelial

Clinical presentation

Typically, PML is caused by productive infection of oligodendrocytes and, to a lesser extent, astrocytes. Therefore, neurological deficits are associated with the areas of demyelination in the brain. The presenting symptoms can vary and include muscle weakness, sensory deficit, hemianopsia, cognitive dysfunction, aphasia, and/or coordination and gait difficulties. The disease does not usually involve the optic nerves or the spinal cord. However, incidental spinal cord demyelination has been

PML-IRIS

Although a cellular immune response directed against the JC virus is beneficial in classic PML, a rapid global recovery of the immune system might not always be favourable. Such a recovery can trigger an immune reconstitution inflammatory syndrome (IRIS). This syndrome is an inflammatory response to clinically apparent or subclinical pathogens associated with recovery of the immune system after a period of immunosuppression. This immune reconstitution is inferred by an increase in T-lymphocyte

PML associated with monoclonal antibodies

Over the past few years, therapeutic monoclonal antibodies have been associated with cases of PML in patients with autoimmune diseases, including multiple sclerosis, Crohn's disease, psoriasis, and lupus, none of which have been previously included among populations at risk for PML.

JC virus granule cell neuronopathy

Whereas PML results from JC virus infection of glial cells in the brain, JC virus granule cell neuronopathy is caused by JC virus infection of granule cell neurons in the cerebellum. Areas of cell loss in the granule cell layer were first described in up to 5% of patients with PML before the HIV epidemic.101 Granule cells with hypochromatic and enlarged nuclei were also seen in AIDS patients with PML,102 and JC virus DNA was detected by PCR in the cerebellar biopsy sample of an AIDS patient

Conclusions

There have been major changes in the epidemiology and clinical presentation of PML since its initial description in 1958. Novel clinical disorders caused by JC virus infection of cerebellar and cortical pyramidal neurons have been discovered. These findings have expanded the knowledge of clinical features of JC virus infection in the CNS (table). Examples of the associated histopathological findings are shown in figure 5. These new features of JC virus infection provide further challenges for

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the terms “progressive multifocal leukoencephalopathy” and “JC virus”. Only papers in English were reviewed. We focused on papers published in the past 20 years up to October, 2009, but also included earlier papers that made definitive contributions to the field. For the latest updates on the patients with multiple sclerosis, we accessed the MedWatch websites up to February, 2010.

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