Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis

Abstract

A 46-year-old woman with relapsing-remitting multiple sclerosis died from progressive multifocal leukoencephalopathy (PML) after having received 37 doses of natalizumab (300 mg every four weeks) as part of a clinical trial of natalizumab and interferon beta-1a.PML was diagnosed on the basis of the finding of JC viral DNA in cerebrospinal fluid on polymerase-chain-reaction assay and was confirmed at autopsy.Nearly every tissue section from bilateral cerebral hemispheres contained either macroscopic or microscopic PML lesions.There was extensive tissue destruction and cavitation in the left frontoparietal area, large numbers of bizarre astrocytes, and inclusion-bearing oligodendrocytes, which were positive for JC virus DNA on in situ hybridization.rogressive multifocal leukoencephalopathy (pml), a demyelinating disease of the central nervous system (CNS), is associated with high rates of morbidity and mortality and occurs almost exclusively in immunocompromised patients.1 We describe a patient with multiple sclerosis who died of PML after receiving natalizumab (Tysabri, Biogen Idec) as part of a clinical trial conducted to test the safety and efficacy of natalizumab in combination with interferon beta-1a (Avonex, Biogen Idec) in the treatment of relapsing-remitting multiple sclerosis.To our knowledge, there have been no prior reports of the concomitant association of multiple sclerosis and PML.Natalizumab is a humanized monoclonal antibody against a 4 integrins that was recently introduced for the treatment of multiple sclerosis.The drug was withdrawn from the market after reports of the development of PML in two patients with multiple sclerosis who were receiving natalizumab and interferon beta-1a in clinical trials.An additional case of PML, in a patient receiving natalizumab for the treatment of Crohn's disease, is described elsewhere in this issue of the Journal . 2 A 41-year-old, right-handed woman began to have numbness and burning pain in her right foot and leg and tingling numbness and clumsiness in her right hand in June 1999.She had a history of migraine and transient numbness of the left hand.A neurologic examination revealed increased tone on her right side and generalized hyperreflexia (3+) with normal plantar responses.In September 1999, magnetic resonance imaging (MRI) with contrast medium showed four small, nonenhancing foci of increased signal in the summary p case report