Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection caused by the JC virus, which can become active in people with weakened immune systems. In multiple sclerosis (MS) treatment, certain disease-modifying therapies (DMTs), especially immunosuppressive or immunomodulatory drugs, carry a risk of triggering PML because they alter the immune system’s ability to control latent viruses like JC virus.
The risk of PML varies depending on the specific MS treatment used. Natalizumab (brand name Tysabri), one of the most effective DMTs for relapsing-remitting MS, is well-known for its association with PML. The likelihood of developing PML while on natalizumab depends mainly on three factors: whether a person has antibodies against JC virus indicating prior exposure; how long they have been treated with natalizumab; and whether they have previously used other immunosuppressants. Patients who are positive for JC virus antibodies and have been on natalizumab for more than two years face an increased risk compared to those without these factors.
To reduce this risk, extended interval dosing (EID) strategies—giving natalizumab every 6 to 8 weeks instead of every 4 weeks—have been adopted in some cases. While EID may lower PML incidence overall, it does not completely eliminate it and may be less effective in populations with high prevalence or high antibody levels against JC virus, such as reported in Japanese patients.
Other MS treatments also carry varying degrees of PML risk but generally lower than natalizumab. Fingolimod and dimethyl fumarate are examples where rare cases of PML have occurred mostly in patients who had additional immune suppression or lymphopenia (low white blood cell counts). Alemtuzumab has also been linked to opportunistic infections including very rare instances of PML due to its profound immune depletion effects.
Because there is no definitive cure for PML once it develops, prevention through careful patient selection and monitoring is critical during MS therapy. Regular testing for JC virus antibodies helps stratify patients’ risks before starting drugs like natalizumab. If a patient tests positive or shows rising antibody levels during treatment, clinicians may consider switching therapies or adjusting dosing intervals.
If suspected early enough after symptoms appear—such as new neurological deficits or cognitive changes—diagnostic tests including MRI scans and cerebrospinal fluid analysis can confirm PML by detecting viral DNA from the JC virus. Experimental treatments such as pembrolizumab—a drug that boosts immune response by blocking PD-1 receptors—and mirtazapine—a medication thought to block viral entry into brain cells—have shown some promise but remain investigational without established protocols.
In summary, while several highly effective MS treatments improve disease outcomes significantly, their use requires balancing benefits against risks like progressive multifocal leukoencephalopathy. Careful screening for JC virus status before and during therapy along with vigilant clinical monitoring remains essential strategies to minimize this potentially devastating complication associated primarily with certain immunomodulatory agents such as natalizumab.
