Review
Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned

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Summary

Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab points to a role for this drug in the pathophysiology of PML. Emerging knowledge of the cellular and molecular biology of JCV infection and the pathogenesis of PML—including interplay of this common virus with the human immune system and features of natalizumab that might contribute to PML pathogenesis—provides new opportunities to monitor viral status and predict risk of JCV-associated disease. In the absence of an effective treatment for PML, early detection of the disease in patients with multiple sclerosis who are receiving natalizumab or other immunomodulatory treatments is vital to minimize CNS injury and avoid severe disability. Frequent MRI, stratified along a clinical and virus-specific immune risk profile, can be used to detect presymptomatic PML. Improved approaches to PML risk stratification are needed to guide treatment choices and surveillance of patients with multiple sclerosis.

Introduction

More than a decade has passed since the first reports of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis who were taking natalizumab in phase 3 clinical trials.1, 2, 3 Natalizumab is a monoclonal antibody to α4β1 and α4β7 integrins that blocks inflammatory cell entry into the brain and can prevent multiple sclerosis-related clinical relapses. The co-occurrence of PML and multiple sclerosis was unanticipated, because these disorders have little in common except for the destruction of myelin: PML is a JC virus (JCV)-induced lytic brain infection, whereas relapsing-remitting multiple sclerosis is an autoimmune disorder. PML was quickly associated with natalizumab treatment because patients with multiple sclerosis had been treated with other immune therapies for decades without reports of PML.1, 2, 3, 4 The initial prevalence of natalizumab-associated PML in patients with multiple sclerosis was estimated to be one in 1000.4 More than 750 PML cases have now been confirmed among natalizumab-treated patients, with a fatality rate higher than 20% and substantial morbidity in survivors.5 The prevalence of PML among patients treated with natalizumab for more than 24 months, with antibody evidence of JCV and previous immunosuppressant exposure, has reached at least one in 70—much higher than the prevalence of any other opportunistic infection in this setting.6, 7 Risk-profiling analyses of patients who are positive for anti-JCV antibody gave an estimated cumulative PML probability over 6 years of 1·7% (95% CI 1·4–2·1).8 A few reports of PML in patients taking other treatments for multiple sclerosis, such as dimethyl fumarate and fingolimod, have been published.9, 10, 11, 12, 13 However, the prevalence of PML in patients with multiple sclerosis who are taking other immune-modulating therapies is much lower than that associated with natalizumab, perhaps one in 10 000 to one in 100 000. Although outcomes for patients with PML have improved with early detection and initiation of immune reconstitution,5 PML is a serious and sometimes lethal disorder, and the clinical management of patients with multiple sclerosis—including PML risk assessment and surveillance—remains challenging.

Investigations in patients with multiple sclerosis have contributed to improved understanding of the pathogenesis of PML. This knowledge is crucial in recognising therapy-associated risks of PML, establishing evidence-based monitoring strategies for patients, and informing the selection of effective treatments for individuals with multiple sclerosis. In this Review, we explore several areas of progress. First, we discuss molecular aspects of PML pathogenesis and the cell-specific involvement of JCV infection leading to PML, which are generally applicable to all cases of PML regardless of underlying diseases. Second, we consider the central role of MRI in the diagnosis of PML and outline how treated patients can be monitored to minimise morbidity and advance our understanding of aspects of pathophysiology. Third, we highlight new insights of clinical value in early PML detection.

Section snippets

JCV infection and PML pathogenesis

PML is usually characterised as a rare disease caused by JCV, a common polyomavirus named from the initials of the first patient from whom the virus was isolated.14 PML develops almost exclusively in patients with a compromised immune system, particularly when cell-mediated immune responses are involved. For example, PML was initially reported in patients with underlying neoplastic diseases, mostly lymphoproliferative diseases, and in patients with organ transplants who had undergone immune

Early detection, diagnosis, and management of PML

Brain imaging makes a vital contribution to the diagnosis of PML, which also routinely requires the identification of active CNS pathology and JCV in the brain.63 Indeed, PML diagnosis cannot be verified without an MRI lesion. The sensitivity of MRI in identifying PML lesions has made it the modality of choice in monitoring natalizumab-treated patients with multiple sclerosis for early detection of PML. MRI has also contributed to our understanding of the clinical stages of PML, which depend on

Towards successful risk-mitigation strategies

A risk-mitigation strategy was developed with the aim of protecting patients from PML in the setting of natalizumab therapy.103 The fundamentals have been actively discussed and variably applied.6, 7, 104, 105, 106, 107, 108 However, the ideal of witnessing plummeting incidence of PML cases has not yet materialised.109 We summarise our own suggestions, which are based on a recent algorithm79 and a review of available data (table 3). We propose that surveillance be guided by estimated

Conclusion and future directions

Substantial progress in understanding JCV and PML has been made in the past decade. Close observation of patients with natalizumab-associated PML and additional cases of PML seen in patients with multiple sclerosis have provided an opportunity to learn more about the molecular biology of JCV and to make some progress in understanding the evolution of risk and invasion of the brain. Enhanced identification of high-risk patients has allowed the use of MRI to evolve such that detection of PML

Search strategy and selection criteria

We searched PubMed for articles published between Jan 1, 2005, and Dec 31, 2017, using the search terms “PML”, “progressive multifocal leukoencephalopathy”, “JCV”, “human polyomavirus”, “antiviral antibodies”, “PML IRIS”, and “natalizumab”. Articles were also identified by searches of the authors' own files and the reference lists of selected papers. There were no language restrictions. The final reference list was generated on the basis of relevance to the topic of the Review, with a focus on

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