By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College; Assistant Attending Neurologist, New York-Presbyterian Hospital
In this population-based cohort study of 584 cases of progressive multifocal leukoencephalopathy (PML), predisposing conditions with the highest risk of PML were human immunodeficiency virus (HIV) infection, hematological malignancies, chronic inflammatory disease, solid organ transplantation, solid malignancies, and primary immune deficiency. The one-year mortality rate was 38.2% for all cases of PML. Factors independently associated with higher mortality rate were older age, male gender, and immunosuppressive diseases, such as hematological malignancies, solid neoplasms, and HIV.
Joly M, Conte C, Cazanave C, et al. Progressive multifocal leukoencephalopathy: Epidemiology and spectrum of predisposing conditions. Brain 2023;146:349-358.
Progressive multifocal leukoencephalopathy (PML) is a rare central nervous system demyelinating disease, which is an opportunistic infection caused by reactivation of John Cunningham virus in immunocompromised patients. It has a high mortality rate and often severe neurologic deficits in those who survive.
The most effective therapeutic strategy for PML is rapid reconstitution of the immune system. However, this comes at the price of immune-reconstitution inflammatory syndrome (IRIS) that will occur in a significant percentage of patients, with its own detrimental effects.
The association of PML with immunocompromised conditions, such as human immunodeficiency virus (HIV), malignancies, and immune-suppressive treatments increasingly used in the treatment of neurological diseases, particularly multiple sclerosis, makes it imperative that clinicians are well informed about the risk factors influencing prognosis in PML.
This nationwide population-based cohort study from France prospectively collected anonymized health data for all insured individuals from the French health insurance system database and public and private hospital discharge database, covering 98% of the French population. The subjects were identified by ICD-10 codes. Data from Jan. 1, 2008, to Dec. 31, 2017, were used for the study.
A total of 584 patients were diagnosed with incident PML and included in the study. The median age at the time of PML diagnosis was 52 years, and 58.0% were male. Predisposing conditions were HIV infection (43.7%), hematological malignancies (21.9%), chronic inflammatory diseases (20.2%), solid organ transplantation (4.3%), and primary immune deficiency (1.5%). Twenty-five (4.3%) of the patients had two or three predisposing conditions. Multiple sclerosis was the most common chronic inflammatory condition (76.7%), followed by sarcoidosis (9.2%), systematic lupus erythematosus (SLE) (3.3%), rheumatoid arthritis (2.5%), and psoriasis (2.5%).
The one-year mortality rate was 38.2% for all cases of PML. The median time from diagnosis to death was 63 days. Demographic factors independently associated with death were older age and male gender. Regarding predisposing conditions, patients with immunosuppressive diseases, malignancies, and HIV infection fared worse than patients with chronic inflammatory conditions who were on immunosuppressive treatments.
On analysis of specific immunosuppressive treatment, 13.7% of the patients were being treated with natalizumab within 24 months of PML diagnosis, and 85.9% of those had a diagnosis of multiple sclerosis. Among other disease-modifying treatments for multiple sclerosis, two patients were taking mycophenolate mofetil, one was taking dimethyl fumarate, and one was taking azathioprine. Among the entire PML cohort, 13.9% had received rituximab.
The incidence of IRIS within 12 months of PML diagnosis was 7.0%. Median time between PML diagnosis and IRIS was 26 days. The main conditions associated with IRIS were HIV infection and a chronic inflammatory condition.
The limitations of this study include the lack of magnetic resonance imaging features or detailed clinical status, the absence of data regarding the duration of the immune-suppressive treatment, and an absence of patients from rural community hospitals who are not entered into the database.
The authors concluded that HIV infection remains the most common predisposing condition for PML, but hematological malignances remain a strong risk factor. Chronic inflammatory conditions were found to be a significant risk, primarily influenced by patients with multiple sclerosis who were treated with natalizumab. Recently, PML risk has declined with better risk stratification for patients starting natalizumab. Regarding mortality from PML, patients with chronic inflammatory conditions had the best survival rates.
COMMENTARY
For a relatively rare entity that affects specific populations, this study of PML on a population-based cohort helps our understanding of disease risks and characteristics. This study provides valuable insights into the relative risks of the predisposing conditions and the factors that determine outcome.
Although some of the immune-suppressive conditions associated with PML, such as HIV infection, are well known, with the increasing use of immunosuppressive medications for the treatment of chronic inflammatory conditions such as multiple sclerosis, clinicians need to be well informed about the potential risk of PML so that a better benefit/risk assessment can be made prior to the initiation of therapy. This study gives us meaningful data that will result in better understanding of this disease and will be helpful in designing therapeutic trials.
