Carrie M. Hersh, D.O., Robert Fox, M.D. Natalizumab-Related Progressive Multifocal Leukoencephalopathy: A Case Report Carrie M. Hersh, D.O., Robert Fox, M.D. Mellen Center for Multiple Sclerosis, Neurological Department, Cleveland Clinic, Cleveland, OH, USA Cleveland Clinic Introduction Imaging Imaging Discussion Natalizumab (Tysabri) is a humanized monoclonal antibody that is directed against the alpha 4 subunit of the adhesion molecule alpha 4 beta 1 integrin. By binding to the integrin on leukocytes, natalizumab reduces their ability to migrate across the blood-brain barrier. Natalizumab reduces relapse frequency, delays onset of disease progression, and improves disease outcome in relapsing-remitting multiple sclerosis (RRMS). However, natalizumab is associated with the development of progressive multifocal leukoencephalopathy (PML), a serious opportunistic CNS infection that is caused by the JC virus (JCV). During the course of PML, immune reconstitution inflammatory syndrome (IRIS) is defined as the sudden restoration of cellular immunity with associated worsening of neurological symptoms. IRIS has been shown to occur in those patients with effective removal of natalizumab either through discontinuation alone or with accelerated removal via plasmapheresis (PLEX) or immunoabsorption. PML is a rare complication of natalizumab therapy, with current estimates at 2.3 per 1000 treated MS patients. Clinical features include cognitive and behavioral abnormalities, motor deficits, dysphasias, visual complaints, ataxia, and seizures. MRI show hyperintense lesions on FLAIR/T2-weighted images and often hypointense lesions on T1-weighted sequences. The risk of natalizumab-related PML increases with Duration of therapy Prior immunosuppressive therapies Previous exposure to JCV, as detected through blood test There is no known treatment for PML. Immune reconstitution is thought to improve outcome. With natalizumab therapy, immune reconstitution involves cessation of therapy and removal of the therapy from the body through either plasma exchange (PLEX) and/or immunoabsorption. No anti-viral therapy has demonstrated efficacy in PML. IRIS is associated with a worsening clinical status and has been seen in all cases of natalizumab-related PML. Corticosteroid therapy, either high-dose pulse and/or prolonged oral treatment, is commonly used to treat IRIS, although optimal management of IRIS is unknown. Differentiating PML from IRIS and from return of MS disease activity is not straight-forward. A B H F E D I C 6 months prior Day of PML presentation 7 weeks after presentation J O N M L K R Q P 14 weeks after presentation 18 weeks after presentation 20 weeks after presentation Case Description Modified from Fox and Rudick, Neurol 2012 using 4/2012 PML data A 57 year-old Caucasian female with past medical history significant for relapsing-remitting multiple sclerosis (RRMS), treated with natalizumab (Tysabri) for over 4 years, presented with 2 weeks of cognitive decline, short-term memory loss, and word-finding difficulties. She previously exhibited JCV seropositivity, but continued treatment due to an aggressive disease course and previous inadequate treatment response to beta-interferon and glatiramer acetate. At the time of presentation, brain MRI revealed FLAIR and T2-weighted hyperintense and T1-weighted hypointense lesions in the left frontal juxtacortical region without gadolinium-enhancement, and CSF was positive for JCV, confirming the diagnosis of PML. She underwent 5 sessions of PLEX over the course of 1.5 weeks, subsequently developing worsening symptoms after 6 weeks. Repeat MRI Brain revealed new patchy gadolinium-enhancement within the PML lesions, concerning for IRIS. She then received a 5-day course of 1g IV methylprednisolone (IVMP) daily, followed by an oral prednisone taper. As maintenance therapy, she continued monthly pulse IV steroids (1g daily over 3 days) and oral prednisone on all other days, with subsequent improvement in her symptoms. Repeat MRI Brain revealed progression of the white matter lesions involving the corpus callosum and right frontal parietal lobes in addition to the left hemisphere. However, there was also interval eradication of gadolinium-enhancement, consistent with the resolution of IRIS. G Figure 1: (A-C) MRI prior to symptom-onset. FLAIR and T2 hyperintense lesions consistent with aggressive MS burden; absence of gadolinium enhancement on T1-weighted imaging. (D-F) MRI on day of presentation. FLAIR and T2-weighted hyperintense lesions in the left frontal lobe, consistent with PML; no evidence of gadolinium-enhancement with post-contrast imaging on T1-weighted imaging. (G-I) MRI 7 weeks after symptom onset. Mild progression in FLAIR and T2-weighted hyperintense lesions in the left frontal lobe with mild mass effect on the left lateral ventricle. Patchy gadolinium enhancement on T1-weighted imaging, consistent with IRIS. Figure 2: (J-L) MRI 14 weeks after symptom onset. Progression of white matter lesions seen on FLAIR and T2-weighted sequences, most dominant in the left frontal lobe, with interval involvement of the corpus callosum and right frontal lobe. Mild progression of increased mass effect; peripheral gadolinium enhancement of left frontal lesion. (M-O) MRI 18 weeks after symptom onset. Further progression of multifocal white matter lesions with further extension into the left parietal and occipital lobes. Resolution of gadolinium enhancement on T1-weighted imaging. (P-R) MRI 20 weeks after symptom onset. Grossly stable diffuse, non-enhancing white matter lesions in the bilateral hemispheres. References Fox R, Rudick R. Risk stratification and patient counseling for natalizumab in multiple sclerosis. Neurology, 2012; 78: 436-37. Hunt D, Giovannoni G. Natalizumab-associated progressive multifocal leukoencephalopathy: a practical approach to risk profiling and monitoring. Practical Neurology, 2012; 12: 25-35.