Progressive Multifocal Leukoencephalopathy after Natalizumab ...

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Jan 28, 2008 - We describe progressive multifocal leukoencephalopathy (PML) caused by ... PML is a rare, opportunistic, demyelinating viral infection of.


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Progressive Multifocal Leukoencephalopathy after Natalizumab Monotherapy Hans Lindå, M.D., Ph.D., Anders von Heijne, M.D., Eugene O. Major, Ph.D., Caroline Ryschkewitsch, B.S., Johan Berg, M.D., Tomas Olsson, M.D., Ph.D., and Claes Martin, M.D., Ph.D.

Sum m a r y We describe progressive multifocal leukoencephalopathy (PML) caused by infection with human polyomavirus JC virus in a patient with multiple sclerosis who was treated with natalizumab. The first PML symptoms appeared after 14 monthly infusions of the drug. Magnetic resonance imaging (MRI) showed a presumed multiple sclerosis lesion, and JC virus DNA was not detected on polymerase-chain-reaction (PCR) assay of cerebrospinal fluid. The patient’s symptoms worsened, and the diagnosis of PML was established with a more sensitive quantitative PCR assay after 16 infusions of natalizumab. Plasma exchange was used to accelerate clearance of natalizumab. Approximately 3 weeks after plasma exchange, an immune-reconstitution inflammatory syndrome appeared. JC virus DNA was no longer detectable on quantitative PCR assay, and the patient’s symptoms improved.


ML is a rare, opportunistic, demyelinating viral infection of the central nervous system caused by JC virus, a human polyomavirus. It usually occurs in patients with profound immunosuppression.1 Natalizumab, a monoclonal antibody against α4 integrins, reduces the extravasation of T lymphocytes, B lymphocytes, and plasma cells into the central nervous system.2 The drug effectively decreases the number of multiple sclerosis lesions on MRI and the number of clinical relapses.3,4 The use of antibodies against α4 integrins also impairs inflammatory responses in other tissues, such as pancreatic islets and gut.5,6 PML has been described in patients with multiple sclerosis who have undergone natalizumab treatment but only when natalizumab was combined with other immunomodulatory drugs.7-9 PML has also been described in a patient with Crohn’s disease after natalizumab monotherapy.10 We describe the development of PML in a patient with multiple sclerosis who had received natalizumab as monotherapy.

From the Neurology Unit, Division of Internal Medicine (H.L., J.B., C.M.), the Department of Radiology (A.H.), and the Neuroimmunology Unit, Department of Clinical Neuroscience (T.O.), Danderyd Hospital, Karolinska Institutet, Stockholm; and the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (E.O.M., C.R.). Address reprint requests to Dr. Lindå at the Division of Neurology, Department of Internal Medicine, Danderyd Hospital, SE-182 88 Stockholm, Sweden, or at [email protected] N Engl J Med 2009;361:1081-7. Copyright © 2009 Massachusetts Medical Society.

Pr e t r e atmen t His t or y In November 2006, a 35-year-old, left-handed man presented with a 1-year history of two episodes of numbness in both legs and a tingling sensation in his hands. At that time, MRI of the brain with the use of a Gyroscan Intera 1.5T (Philips) showed more than 50 lesions on T2-weighted images. The patient’s reflexes were exaggerated in both legs. Sensation of vibration was absent in his feet, and there was partial hypoesthesia on the left side. His only motor symptom was mild paresis in the right arm. Analysis of the cerebrospinal fluid showed oligoclonal IgG bands. The

n engl j med 361;11  september 10, 2009



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patient’s score on the Kurtzke Expanded Disability Status Scale (EDSS) was 3.5 (on a scale ranging from 0 to 10, with higher scores indicating greater disability). MRI of the brain and spinal cord in December 2006 showed results similar to those on the scan obtained in November, although approximately 10 lesions were also visible on the spinal cord on T2-weighted images (one with gadolinium enhancement). The patient was treated with intravenous methylprednisolone for 3 consecutive days.

Nata l i zum a b Ther a py Intravenous natalizumab therapy (at a dose of 300 mg every 4 weeks) was initiated in January 2007. After 4 months of treatment, the patient’s only neurologic symptom was a slight tingling sensation in his right hand, and the only finding on neurologic examination was exaggerated leg reflexes (EDSS score, 1.0). From April 2007 through March 2008, the patient had no relapses and had no side effects of natalizumab therapy. A routine MRI scan obtained in January 2008 was initially interpreted as showing no new multiple sclerosis lesions and no increase in lesion burden. In retrospect, when the diagnosis of PML had been established in July 2008, a new, small MRI signal change was evident in the right motor cortex (Fig. 1 and 2). This finding indicates that the JC virus infection was probably present in January 2008, approximately 3 months before the onset of symptoms. However, retrospective quantitative PCR analysis of saved plasma samples obtained before the initiation of natalizumab therapy and 6 and 12 months after the initiation of therapy did not show JC virus DNA. In April 2008, after 14 natalizumab infusions, the patient had very gentle, action-dependent myo­ clonic jerking in his left arm. After 3 weeks, this symptom was reported, and MRI was performed 10 days later. It showed a small lesion in the subcortical area of the right motor cortex, which was thought to be a multiple sclerosis lesion. He had his 15th natalizumab infusion. In the first weeks of June, his symptoms progressed, with more intense myoclonic jerking and mild weakness in his left arm. In mid-June, MRI showed an increase in the size of the lesion, which was still believed to be related to multiple sclerosis (Fig. 1). A PCR assay of cerebrospinal fluid for JC virus DNA was negative (

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