What is Progressive Multifocal Leukoencephalopathy (PML)?
Progressive Multifocal Leukoencephalopathy, or PML, is a rare and life-threatening demyelinating disease of the central nervous system [1.10.2]. It is caused by the reactivation of the John Cunningham (JC) virus, a common polyomavirus that infects a majority of the adult population, with seroprevalence rates estimated between 66% to 92% [1.9.1, 1.9.3]. In most individuals, the JC virus remains latent and asymptomatic, often in the kidneys and lymphoid tissues [1.10.2]. However, in people with weakened immune systems, the virus can reactivate, travel to the brain, and destroy the cells that produce myelin—the protective sheath that covers nerve fibers [1.10.2]. This damage disrupts nerve communication, leading to a variety of severe neurological symptoms [1.9.2].
Symptoms of PML can develop over weeks to months and vary depending on the location of the brain lesions [1.11.3]. Common signs include:
- Progressive weakness and clumsiness [1.11.3]
- Vision changes, such as vision loss in half the visual field (hemianopia) [1.9.1]
- Speech and language difficulties [1.11.3]
- Cognitive and personality changes [1.11.3]
- Lack of coordination (ataxia) [1.9.1]
Diagnosis involves a combination of clinical evaluation, characteristic findings on a brain MRI, and the detection of JC virus DNA in the cerebrospinal fluid (CSF) via polymerase chain reaction (PCR) [1.11.1].
The Link Between Medications and PML Risk
The primary trigger for JC virus reactivation is a compromised immune system [1.10.2]. While this was historically most associated with conditions like HIV/AIDS and certain cancers, a significant number of cases are now iatrogenic, meaning they are caused by medical treatment [1.9.2, 1.10.2]. Certain medications, particularly those that suppress or modulate the immune system, lower the body's ability to keep the JC virus in its latent state [1.8.1]. These drugs are often used to treat autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis, as well as cancers and to prevent organ transplant rejection [1.9.2].
The mechanism involves disrupting immune surveillance. For example, some drugs prevent immune cells (lymphocytes) from entering the central nervous system, which impairs the body's ability to fight off the reactivated virus within the brain [1.8.3]. Other medications deplete specific types of immune cells, such as B-cells, which are also believed to play a role in controlling the JC virus [1.8.3].
Medications with Established PML Risk
A number of drugs, particularly monoclonal antibodies and other immunosuppressants, have been identified as carrying a risk of PML. The risk level varies significantly between these medications. Three key risk factors have been identified for some drugs, particularly natalizumab: presence of anti-JCV antibodies, prior use of immunosuppressants, and duration of therapy (especially over two years) [1.3.1].
High-Risk Medications
- Natalizumab (Tysabri): This monoclonal antibody is used to treat multiple sclerosis and Crohn's disease. It has one of the highest associated risks of PML [1.8.1, 1.8.3]. As of February 2024, the overall global incidence of natalizumab-associated PML was reported as 3.43 per 1,000 patients [1.4.2]. The risk increases significantly with the number of infusions, prior use of immunosuppressants, and a positive, high-titer result on a JC virus antibody test [1.3.1, 1.4.1]. Due to this risk, it is only available through a restricted distribution program [1.2.2].
Moderate to Low-Risk Medications
- Rituximab (Rituxan): An anti-CD20 monoclonal antibody used for hematologic cancers and autoimmune diseases like rheumatoid arthritis [1.5.2, 1.5.3]. It is associated with an increased PML risk, although many patients receiving it have underlying conditions that are also risk factors [1.8.3]. One study in veterans with chronic lymphocytic leukemia found rituximab use was associated with a nearly 20-fold increased relative risk of developing PML [1.5.1].
- Dimethyl Fumarate (Tecfidera): An oral medication for MS. While the risk is considered much lower than with natalizumab, cases have been confirmed [1.3.1, 1.6.2]. The estimated incidence is about 0.02 per 1,000 patients [1.6.2]. Major risk factors for PML in patients taking DMF appear to be older age and prolonged, severe lymphopenia (low lymphocyte counts) [1.6.2].
- Fingolimod (Gilenya): Another oral MS therapy. The risk of PML is low, with an estimated incidence rate of 3.12 per 100,000 patient-years [1.7.1, 1.7.2]. Risk appears to increase with age (over 45) and longer treatment duration (over 2 years) [1.7.2, 1.7.3].
- Ocrelizumab (Ocrevus): An anti-CD20 antibody for MS. PML cases have been reported, though many were considered "carry-over" cases from a prior therapy known to have a PML risk [1.13.1, 1.13.2]. The drug's label was updated to include a specific warning for PML [1.13.1].
- Brentuximab Vedotin (Adcetris): Used to treat certain lymphomas. A black box warning for PML risk has been added to its label [1.14.2, 1.14.3]. Onset can be rapid, sometimes after only a few doses [1.14.1].
Comparison of Select Drugs and PML Risk
| Drug (Brand Name) | Primary Use(s) | PML Risk Level | Key Risk Factors |
|---|---|---|---|
| Natalizumab (Tysabri) | Multiple Sclerosis, Crohn's Disease | High | JCV antibody status, duration of use (>2 years), prior immunosuppressant use [1.3.1]. |
| Rituximab (Rituxan) | Lymphomas, Autoimmune Diseases | Moderate | Underlying malignancy, other immunosuppressive therapies [1.8.3]. |
| Dimethyl Fumarate (Tecfidera) | Multiple Sclerosis | Low | Prolonged severe lymphopenia, older age [1.6.2]. |
| Fingolimod (Gilenya) | Multiple Sclerosis | Low | Age >45 years, treatment duration >2 years [1.7.2]. |
| Ocrelizumab (Ocrevus) | Multiple Sclerosis | Low/Emerging | Many cases linked to prior high-risk drug use ("carry-over") [1.13.1, 1.13.2]. |
Other drugs with warnings or reported associations include alemtuzumab (Lemtrada), mycophenolate mofetil (CellCept), and pomalidomide (Pomalyst) [1.2.1, 1.15.2, 1.16.1].
Risk Mitigation and Monitoring
There is no cure for PML, and treatment focuses on restoring immune function, primarily by stopping the offending drug [1.10.2]. Therefore, prevention and early detection are critical.
- Risk Stratification: Before starting high-risk therapies like natalizumab, patients are often tested for JC virus antibodies to stratify their risk [1.4.2]. A positive test, especially with a high index value, indicates a greater risk [1.4.2].
- Regular Monitoring: Patients on associated medications require vigilant monitoring for any new or worsening neurological symptoms [1.12.1]. This includes regular clinical check-ups and, in some cases, periodic brain MRIs to screen for asymptomatic lesions [1.12.1].
- Patient Education: Patients must be educated about the early signs and symptoms of PML and instructed to report them immediately. These can include new clumsiness, weakness, or changes in vision or thinking [1.11.3].
Conclusion
While a variety of powerful immunomodulating drugs can significantly improve outcomes for patients with cancer and autoimmune diseases, they carry the rare but serious risk of enabling the JC virus to cause PML. The risk is highest with natalizumab but is present to a lesser degree with a growing list of other agents, including rituximab, dimethyl fumarate, and fingolimod [1.2.1]. Understanding this risk involves a careful discussion between doctor and patient, weighing the benefits of the medication against the potential danger. For patients on these therapies, vigilant monitoring and immediate reporting of any neurological changes are the most crucial tools for ensuring safety and enabling early diagnosis, which is key to a better outcome [1.7.1].
For more information, you can visit the National Institute of Neurological Disorders and Stroke (NINDS) page on PML. [1.9.2]
