Early Magnetic Resonance Detection of Natalizumab-Related Progressive Multifocal Leukoencephalopathy in a Patient with Multiple Sclerosis (original) (raw)
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Frontiers in Neurology, 2013
Natalizumab (Tysabri(®)) is a monoclonal antibody that prevents inflammatory cells from binding to brain endothelial cells and passing into the brain parenchyma. Natalizumab is a highly effective treatment for relapsing-remitting multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain JC virus infection that has been shown to be associated with natalizumab treatment. We describe PML in a patient with MS after 44 monthly infusions of natalizumab. With the aid of a routine Magnetic resonance imaging (MRI) scan, PML was detected before any unambiguous clinical manifestations had emerged. PML was treated with plasma exchange to accelerate removal of natalizumab. Mirtazapine and mefloquine was promptly added and approximately 1 month after plasma exchange, when an immune-reconstitution-inflammatory-syndrome appeared, steroid treatment was initiated. Steroid treatment was then continued until no virus could be detected in the cerebrospinal fluid. The outcome was favorable. We believe that this case clearly illustrates the importance of an early, presymptomatic, detection of PML, and an adequate treatment. We also propose that surveillance with MRI scans, every 3 months after 24 months of treatment, should be performed in JC virus antibody positive natalizumab-treated MS patients in order to detect PML in an early phase.
Journal of Medical Cases, 2015
We report a natalizumab (NTZ)-treated relapsing-remitting multiple sclerosis (RRMS) patient evaluated for worsening of pyramidal and cerebellar dysfunction. MRI showed Gd + lesions in juxtacortical frontal areas and middle cerebellar peduncles indicative of progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) showed 47 JC virus (JCV) copies/mL, high CD8 + and plasmacytoid dendritic cells (pDCs) compared to peripheral blood (PB). MRI after NTZ discontinuation and plasma exchange revealed PML aggravation. CSF JCV increased to 475 as CD4 + , CD19 + and pDCs. CSF 8 months later showed high CD4 + , CD19 + , pDCS, not JCV. MRI showed severe focal cortical atrophy and axonal degeneration of pontocerebellar fibers. Specific immune-cell response in the central nervous system (CNS) may be essential for control of PML.
Annals of Neurology, 2012
Objective: Natalizumab is an effective treatment for patients with multiple sclerosis (MS) that is associated with a risk of progressive multifocal leukoencephalopathy (PML). Recommendations were published in 2006 to improve early diagnosis of PML using magnetic resonance imaging (MRI). However, due to the small number of MS patients initially diagnosed with PML, the imaging criteria could only be derived from PML lesions in patients with human immunodeficiency virus. Therefore, there is an urgent need to assess the MRI characteristics of PML in MS patients to update the existing recommendations. Methods: In this retrospective review, the first 40 natalizumab-treated MS patients diagnosed with PML in the postmarketing setting were identified, of whom 22 (10 with clinically diagnosed immune reconstitution inflammatory syndrome) fulfilled the inclusion criteria for this study. Magnetic resonance images were analyzed according to predefined criteria by 5 independent readers. Results: The most frequent lesion pattern in early scans from PML patients was that of large (>3 cm, 15 of 18), subcortical (18 of 18), T2 or fluid-attenuated inversion recovery hyperintense (18 of 18), T1-hypointense (17 of 18), and diffusion-hyperintense (15 of 15) lesions, with a sharp border toward the gray matter and an ill-defined border toward the white matter (18 of 18) on T2-weighted images. We could detect contrast enhancement in 41% (7 of 17) of the cases on the first scan at clinical presentation. Interpretation: Attention to characteristic MRI patterns, especially the presence of contrast enhancement, and the subcortical location may have utility in screening and early diagnosis of PML in natalizumab-treated MS patients. ANN NEUROL 2012;72:779-787 View this article online at wileyonlinelibrary.com.
PloS one, 2016
The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characterist...
Asymptomatic progressive multifocal leukoencephalopathy associated with natalizumab
Journal of Neurology, 2012
Background: We report the development of asymptomatic progressive multifocal leukoencephalopathy in a patient with multiple sclerosis on natalizumab therapy. Progressive multifocal leukoencephalopathy often presents with debilitating neurologic symptoms. Very few cases have documented a completely asymptomatic course of the disease. Case presentation: A 26-year-old white woman with multiple sclerosis was treated with natalizumab. She was diagnosed as having progressive multifocal leukoencephalopathy based on characteristic magnetic resonance imaging lesions after 27 infusions of natalizumab. She had no neurologic deficits at the time of diagnosis and John Cunningham virus in cerebrospinal fluid was detected at 15 copies/ml. She was initially treated with mefloquine and mirtazapine and remained asymptomatic for 3 months. She later developed worsening magnetic resonance imaging lesions related to immune reconstitution inflammatory syndrome. At that time, she received intravenously administered immunoglobulin and high-dose intravenously administered methylprednisolone with radiologic improvement of the lesions. Conclusions: Our case report illustrates that early detection of asymptomatic progressive multifocal leukoencephalopathy and its subsequent treatment resulted in a benign clinical course. In consideration of the additional small number of cases of asymptomatic progressive multifocal leukoencephalopathy that have been reported, we conclude that routine magnetic resonance imaging surveillance is important for patients with multiple sclerosis who are at high risk for developing natalizumab-associated progressive multifocal leukoencephalopathy.
Journal of Neuropathology & Experimental Neurology, 2013
Natalizumab, a monoclonal antibody directed against > 4 integrins, has, to date, been associated with 399 cases of progressive multifocal leukoencephalopathy (PML) worldwide in patients receiving treatment for multiple sclerosis (MS). Because of the limited number of histologic studies, the possible interplay between MS and PML lesions has not been investigated. We report the clinical, radiologic, and histologic findings of an MS patient who developed PML after 32 months of natalizumab monotherapy. After withdrawal of natalizumab, she received plasma exchange, mefloquine, and mirtazapine but died soon thereafter. Postmortem examination was restricted to examination of the brain and spinal cord. Extensive PML lesions, characterized by the presence of JC virus DNA were found in the cerebral white matter and neocortex. Sharply demarcated areas of active PML lesions contained prominent inflammatory infiltrates composed of approximately equal numbers of CD4-positive and CD8-positive T cells, consistent with an immune reconstitution inflammatory syndrome. Conversely, all MS lesions identified were hypocellular, long-standing inactive plaques characterized by myelin loss, relative axonal preservation, and gliosis and, importantly, were devoid of JC virus DNA and active inflammation. Chronic inactive MS lesions were separate and distinct from nearby PML lesions. This case demonstrates the coexistence and apparent lack of interplay between chronic inactive MS and PML lesions, and that immune reconstitution inflammatory syndrome seems to affect the shape and appearance of PML but not MS lesions.
Molecular and cellular probes, 2015
Natalizumab is a humanized monoclonal antibody against the alpha4 chain of the alpha4beta1 and alpha4beta7 integrin heterodimers used with high effectiveness in the treatment of multiple sclerosis. The use of this drug can unfortunately be associated with the onset of progressive multifocal leukoencephalopathy, a possibly fatal infection of the central nervous system, caused by polyomavirus JC. To understand and quantify the risk of developing PML is important for patients who are about to start therapy with natalizumab and for patients who already are under treatment with this drug. In this review we describe and critique molecular diagnostic tests proposed in the last years to assess the risk of PML.
Journal of Investigative Medicine High Impact Case Reports, 2020
Progressive multifocal leukoencephalopathy (PML) is a serious infective disease of the central nervous system that may occur in case of severe immunosuppression or after some treatment for multiple sclerosis (MS) with natalizumab, dimethyl fumarate, and fingolimod. In these case reports, we highlight the importance of differential diagnosis between PML and MS lesions in order to provide rapidly the best treatment option, by discussing the finding of brain (magnetic resonance imaging) MRI suggestive for PML in 2 MS patients, one treated with dimethyl fumarate and the other during natalizumab withdrawal. In both cases, although brain MRI was highly suggestive for PML, the detection of John Cunningham virus-DNA copies in cerebrospinal fluid resulted in negative result. These case reports illustrate the diagnostic process in case of suspected PML, as both patients were diagnosed with suspected PML during a routine brain MRI control, and highlights the importance of providing a strict br...
Neuroimaging of Natalizumab Complications in Multiple Sclerosis: PML and Other Associated Entities
Multiple sclerosis international, 2015
Natalizumab (Tysabri) is a monoclonal antibody (α4 integrin antagonist) approved for treatment of multiple sclerosis, both for patients who fail therapy with other disease modifying agents and for patients with aggressive disease. Natalizumab is highly effective, resulting in significant decreases in rates of both relapse and disability accumulation, as well as marked decrease in MRI evidence of disease activity. As such, utilization of natalizumab is increasing, and the presentation of its associated complications is increasing accordingly. This review focuses on the clinical and neuroimaging features of the major complications associated with natalizumab therapy, focusing on the rare but devastating progressive multifocal leukoencephalopathy (PML). Associated entities including PML associated immune reconstitution inflammatory syndrome (PML-IRIS) and the emerging phenomenon of rebound of MS disease activity after natalizumab discontinuation are also discussed. Early recognition of...