Progressive multifocal leukoencephalopathy: epidemiology and spectrum of predisposing conditions

Abstract

Population-based data on the epidemiology of progressive multifocal leukoencephalopathy, its predisposing conditions and mortality rate are lacking, although such data are crucial to raise awareness among clinicians and to lay foundations for future therapeutic trials in immunomodulating therapies. In our study, patients were identified by interrogating the French national healthcare reimbursement database from January 1st, 2008 to December 31st, 2017, using progressive multifocal leukoencephalopathy International Classification of Diseases code and a patient’s selection algorithm. Overall incidence rate, one-year all-cause mortality rate and survival patterns were calculated, and factors associated with death were identified using a multivariate Cox proportional hazards regression model. Our cohort is the largest to date, comprising 584 patients with incident progressive multifocal leukoencephalopathy. The overall incidence in France from 2010 to 2017 was stable during the study period at 0.11 per 100,000 person-years, 95% confidence interval [0.10-0.12]. Predisposing diseases were HIV infection (43.7%), followed by haematological malignancies (21.9%), chronic inflammatory diseases (20.2%), solid organ transplantation (4.3%), solid neoplasm (4.1%), and primary immune deficiency (1.5%). The one-year mortality rate was 38.2%, 95% confidence interval [34.2-42.2]. In multivariate analysis, factors independently associated with death were older age (adjusted hazard ratio 0.33 [0.20-0.53] for patients aged 20 to 40 compared with patients aged over 60), male gender (adjusted hazard ratio 0.73 [0.54-0.99] for females compared with males), and predisposing immunosuppressive disease, with the highest risk for solid neoplasms (adjusted hazard ratio 4.34 [2.25-8.37]), followed by haematological malignancies (adjusted hazard ratio 3.13 [1.85-5.30]) and HIV infection (adjusted hazard ratio 1.83 [1.12-3.00]), compared with chronic inflammatory diseases. Immune reconstitution inflammatory syndrome was notified in 7.0% of patients. In conclusion, incidence of progressive multifocal leukoencephalopathy is stable in France, and HIV infection remains the main predisposing disease. This large size cohort uncovers a higher risk of mortality for male patients compared to females, and the worst prognosis for patients with solid neoplasm, while prognosis in patients with haematological malignancies appeared less dismal than in previous studies.

Progressive Multifocal Leukoencephalopathy Treated by Immune Checkpoint Inhibitors

“…However, it is also possible that survival of "historical controls" underestimates current survival rates, as suggested by a recent nationwide study in France that found 1‐year survival following PML diagnosis of patients with hematological malignancies and primary immune deficiencies was respectively of 39.2 and 55.6%. 19 Of note, the significantly longer delay between ICI initiation and death in patients with primary immune deficiencies as compared to the other categories is an interesting observation; although the molecular heterogeneity of this subcohort precludes generalizable conclusions, further investigation into this finding may provide greater insight into mechanisms contributing to immune exhaustion and susceptibility to rescue using ICIs. The low numbers of patients in this study with underlying chronic inflammatory disease, solid neoplasm, and kidney transplantation limit interpretation in these groups.…”

“…In this study, survival of patients with hematological malignancy (50%) and primary immunodeficiency (57.1%) was greater than historically reported, suggesting a potential benefit of ICI add‐on to standard of care. However, it is also possible that survival of "historical controls" underestimates current survival rates, as suggested by a recent nationwide study in France that found 1‐year survival following PML diagnosis of patients with hematological malignancies and primary immune deficiencies was respectively of 39.2 and 55.6% 19 . Of note, the significantly longer delay between ICI initiation and death in patients with primary immune deficiencies as compared to the other categories is an interesting observation; although the molecular heterogeneity of this subcohort precludes generalizable conclusions, further investigation into this finding may provide greater insight into mechanisms contributing to immune exhaustion and susceptibility to rescue using ICIs.…”

Progressive multifocal leukoencephalopathy in an HIV patient: A case report and literature review

“…Primary JCV infection mainly occurs in childhood and is asymptomatic, after which the virus remains latent, possibly in the lymphoid organs, neuronal tissues, and/or kidneys 8 . However, in cases of cellular immune deficiency, such as HIV/AIDS, viral reactivation can result in demyelination of the central nervous system (CNS) 9 . The clinical presentation of PML varies depending on the affected cerebral areas and is nonspecific.…”

Progressive Multifocal Leukoencephalopathy

“…19 JCV transmission and the route of primary infection are not well understood; however, this most likely occurs through a fecal-oral route during childhood. 1,4,6 It has been assumed that following a period of asymptomatic viremia, JCV establishes latent and/or persistent infection in the kidney, lymphoid organs, bone marrow, and possibly the brain and elsewhere in the body. In association with immunosuppression, JCV can reactivate from sites of latency or persistency, undergoing viral genetic changes to become a pathogenic neurotropic virus.…”

“…The mortality rate can be high, ranging from 20% to 90%, depending on the underlying condition. 1 Although no Class I evidence for JCV-specific therapy is yet available, 2 the recent encouraging application of a variety of immunotherapeutic approaches, including virus-directed T-cell therapies and checkpoint inhibitors, creates the justified hope that the development of such therapies may advance to formal testing in clinical trials. 3 This review provides a brief overview of the current understanding of PML and its clinical variants.…”