Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences.

In this issue of the Journal, there are reports describing in detail three patients in whom progressive multifocal leukoencephalopathy (PML) developed during treatment with natalizumab, a humanized monoclonal antibody against a 4 integrins. 1-3 These patients were among 3000 who had participated in clinical trials of natalizumab for the treatment of multiple sclerosis or Crohn’s disease. PML is a deadly opportunistic infection of the central nervous system (CNS) for which there is no specific treatment. It is caused by reactivation of a clinically latent JC polyomavirus infection. This virus infects and destroys oligodendrocytes, leading to multifocal areas of demyelination and associated neurologic dysfunction. The occurrence of PML in this setting was totally unexpected, since it almost invariably occurs in the context of profoundly impaired cell-mediated immunity in patients with AIDS or leukemia or in organ-transplant recipients. In retrospect, can we retrace the events that led to the surprising development of PML in these three patients? Seropositivity rates for JC virus, the etiologic agent of PML, increase with age and vary in different populations. After infection, the virus remains quiescent in the kidneys and in lymphoid organs of people with immunocompetence. The virus is often present in the urine but is generally not found in the blood. However, JC viremia can be detected in persons with immunosuppression, and hematogenous dissemination is the likely route of entry into the CNS. 4