Original Article
Brief Report
Progressive Multifocal Leukoencephalopathy after Natalizumab Monotherapy
N Engl J Med 2009; 361:1081-1087September 10, 2009
- Abstract
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.
Media in This Article
Figure 1
Progression of MRI Changes in the Patient's Right Motor Cortex from January through September 2008.Figure 2
Initial, Subtle Cortical Changes on MRI of the Patient's Right Motor Cortex in January 2008, as Seen with Contrast Enhancement, with Subsequent Changes through September 2008.Article Activity
- Article
PML 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.
Pretreatment History
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 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.
Natalizumab Therapy
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 (Figure 1Figure 1
Progression of MRI Changes in the Patient's Right Motor Cortex from January through September 2008. and Figure 2Figure 2Initial, Subtle Cortical Changes on MRI of the Patient's Right Motor Cortex in January 2008, as Seen with Contrast Enhancement, with Subsequent Changes through September 2008.). 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 myoclonic 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 (Figure 1). A PCR assay of cerebrospinal fluid for JC virus DNA was negative (<200 copies of JC virus per milliliter), according to the criteria of the Swedish Institute for Infectious Disease Control (SMI). The patient then received his 16th natalizumab treatment. However, his symptoms continued to worsen, with increased weakness and twitching in his left arm. Another MRI scan showed enlargement of the lesion (Figure 1). Again, a PCR assay for JC virus DNA in the cerebrospinal fluid was negative. However, PML was suspected on the basis of the patient's clinical course and MRI findings.
Treatment of PML
Plasma exchange was initiated to remove natalizumab in order to restore immune function, with five treatments (four consisting of 1 plasma-volume exchange and one of 1.5 plasma-volume exchanges) every second day.11 After the last two plasma-exchange treatments, 1000 ml of extra plasma was added. The plasma-exchange treatments significantly decreased the concentration of natalizumab in the patient's serum, from 14.4 μg per milliliter before treatment to 8.7 μg per milliliter after the second treatment and 5.5 μg per milliliter after the third treatment.
During plasma exchange and the 5 weeks that followed, the patient's symptoms continued to worsen. Samples of the patient's cerebrospinal fluid that had been obtained in July 2008, before the initiation of plasma-exchange treatment, had been sent to the Laboratory of Molecular Medicine and Neuroscience at the National Institute of Neurological Disorders and Stroke (NINDS) for quantitative PCR testing for JC virus DNA. This assay has been validated through independent proficiency testing and certified under the Clinical Laboratory Improvement Amendments by on-site examination by an independent U.S. federal agency.
With the quantitative PCR method, which has been described previously, TaqMan probes are used to amplify the viral T-protein coding sequences, a highly conserved and essential region for viral replication.12,13 Viral DNA template is extracted from 200 mm3 of cerebrospinal fluid that has been concentrated to 25 mm3 with the use of the QIAamp MinElute column spin kit (Qiagen); of this concentrate, a 10-mm3 sample is used for 40 cycles of amplification. The range of sensitivity levels is 10 million to 100 million copies per milliliter on the basis of control viral-DNA standards run in each assay.
The result of the quantitative PCR assay, which showed 53 copies of JC virus DNA per milliliter, was received 1 week after the initiation of plasma exchange. The patient now had paresis on the left side. A new MRI scan showed a further increase in the lesion size with no gadolinium enhancement (Figure 1). The absence of contrast enhancement suggested continued viral replication, rather than the onset of an immune-reconstitution inflammatory syndrome. Indeed, even though the cerebrospinal fluid was negative for JC virus on PCR assay at SMI, it still showed borderline positivity, at 10 copies per milliliter, on quantitative PCR assay at NINDS. Treatment with mirtazapine (at a dose of 30 to 45 mg per day) was initiated to further inhibit viral spread by blocking the 5-HT2 receptor, the proposed viral coreceptor for cellular infection.14
Immune-Reconstitution Inflammatory Syndrome
Approximately 3 weeks after plasma exchange, fever and headache developed in the patient, but no systemic infectious focus could be found. MRI now showed gadolinium enhancement in the right motor cortex (Figure 2). For the first time, a sample of cerebrospinal fluid showed pleocytosis with 82 mononuclear cells; both PCR and quantitative PCR assays were negative for JC virus DNA. The patient's symptoms again worsened, and he was confined to a wheelchair (EDSS score, 8.0). The aggravation of symptoms was presumed to be related to an immune-reconstitution inflammatory syndrome. This condition is well known from observation of patients with human immunodeficiency virus (HIV) infection in whom PML develops in association with immune recovery after highly active antiretroviral therapy.15
Clinical Course
Approximately 5 weeks after plasma exchange, the patient's fever and headache disappeared, and dizziness developed. MRI showed three new multiple sclerosis–related cerebellar lesions that were consistent with his symptoms (Figure 2). Because of the relapse and the fact that MRI showed increased gadolinium enhancement in the motor cortex, he was given intravenous methylprednisolone for 3 consecutive days. Analysis of the patient's cerebrospinal fluid at that time showed 20 mononuclear cells and slightly increased protein content but again no detectable JC virus DNA. Six weeks after plasma exchange, MRI showed a signal in the right motor cortex on a T1-weighted image, which was suggestive of cortical laminar necrosis (Figure 2).
The clinical course was stable from week 6 to week 8 after plasma exchange. The patient was bedridden, with symptoms of fatigue and severe paresis of the left side but no overt cognitive impairment. Eight weeks after plasma exchange, his clinical condition improved. Three months after plasma exchange, the patient's condition had improved further, and he could walk 300 m with a crutch. The myoclonic jerking of the left arm had disappeared, and some strength had returned to the left arm and hand (EDSS score, 6.0). One year after plasma exchange, the patient could walk 500 m with a cane but still had partial paresis on the left side (EDSS score, 6.0). He had not had any relapses and was working part time. He had also started treatment with interferon beta.
Discussion
The new, highly effective therapies for inflammatory autoimmune diseases carry the risk of rare but potentially life-threatening infections. Thus, PML has been associated not only with natalizumab but also with other monoclonal antibodies that interfere with various aspects of immune function.16-18 We believe that this case illustrates many important points that have to be considered with regard to the risk of PML and its management.
First, there are no specific ways to predict which patients are at risk for PML. Tests for JC virus in blood or cerebrospinal fluid do not provide predictive information,9,19 and there are no defined immune abnormalities that can be used predictively, other than global immunosuppression, such as that associated with HIV infection and treatment with immunosuppressive agents, which confer a predisposition to the infection. Our patient had no overt laboratory abnormalities with regard to immune function or blood leukocytes. Combinations of drugs that interfere with immune surveillance of the central nervous system may confer an increased risk, and the three previous reports of PML after natalizumab therapy all involved patients who had undergone concurrent treatment with either interferon beta or other immunosuppressive agents.9 Our patient's history shows that PML may also develop as a consequence of natalizumab used as monotherapy.
Second, there are no methods for monitoring patients who are treated with natalizumab for the early detection of PML. Clinical vigilance for symptoms suggestive of PML, which to some extent overlap with those of multiple sclerosis, is required. Liberal use of MRI is recommended for detection of changes that are typical of PML, but the differentiation of PML lesions from those related to multiple sclerosis can be difficult, as illustrated by the findings in our patient, who initially had only a single lesion on MRI, as opposed to the typical multifocal presentation of PML. The diagnosis may be established by detecting JC virus in the cerebrospinal fluid, a finding that has been thought to have a specificity of nearly 100% but a sensitivity ranging from 60 to 80%, depending on the particular laboratory analyzing the sample and perhaps on changes in the spectrum of PML infections.20,21 The case we describe underscores the point that if the clinical course and MRI results remain suggestive of PML, despite an absence of detectable JC virus DNA in the cerebrospinal fluid, one should continue to monitor the patient for PML. As a further complication, samples of cerebrospinal fluid have in rare cases been positive for JC virus in the absence of PML, though at very low copy numbers.19 A definitive diagnosis may also be established by means of brain biopsy, which was not performed in our patient because of the location of the lesion in the motor cortex. Thus, a diagnosis of PML depends on the combination of a characteristic clinical course, MRI findings that are consistent with the diagnosis, and the detection of JC virus in the cerebrospinal fluid. The history of our patient fulfilled these requirements but not at the first presentation of clinical signs.
Third, there are no antiviral treatments that have proved to be effective against PML caused by JC virus infection. Among patients receiving natalizumab therapy, the goal is to remove the antibody and thus restore immune function of the central nervous system. Plasma exchange has been shown to accelerate the clearance of natalizumab in a study involving patients with multiple sclerosis who had no opportunistic infection while being treated with natalizumab.11 In this study, a regimen of three plasma exchanges was effective, with lymphocyte migratory capacity nearly regained in vitro after approximately 3 weeks,11 a finding that is consistent with our case (i.e., the onset of an immune-reconstitution inflammatory syndrome after approximately 3 weeks). Our findings are also consistent with those of a study reporting a shortened time to the restoration of immune function, by approximately 2 months, since an immune-reconstitution inflammatory syndrome developed in patients with PML 3 months after the cessation of natalizumab, as described previously.9 A potential complication of plasma exchange is the removal of antibodies against JC virus, which could weaken the immune defense against infection. However, in the previously described patients with PML, the antibody titer was high before the diagnosis of PML, with a titer of more than 1:163,840 in a patient with multiple sclerosis,7 a titer of 10,460 in another patient with multiple sclerosis,8 and a titer of 163,840 in a patient with Crohn's disease (as measured with the use of a certified enzyme-linked immunosorbent assay specific for JC virus).9,10,22 Consequently, the presence of antibody does not prevent the development of PML and apparently does not alter disease progression.
In our patient, it is likely that the increased local inflammation due to the immune-reconstitution inflammatory syndrome with a presumed immune attack against the JC virus initially increased the local damage, since his symptoms and MRI signs increased during this phase. The previously described patients in whom PML developed during natalizumab treatment did not undergo plasma exchange. Two of these patients died, and one had neurologic sequelae.9 As of June 2009, nine additional cases of PML have been reported in patients with multiple sclerosis receiving natalizumab therapy, but to our knowledge, detailed accounts of these cases have not yet been published. Our patient's history illustrates the potential importance of early diagnosis and intervention in PML associated with natalizumab therapy.
Supported by grants from the Swedish Research Council, the European Union's Sixth Framework Program (Neuropromise project, LSHM-CT-2005-018637), the Bibbi and Niels Jensens Foundation, and the Söderberg Foundation.
Drs. Lindå, von Heijne, and Berg report receiving lecture fees from Biogen Idec; Dr. Olsson, receiving consulting fees from Biogen Idec, Merck Serono, and AstraZeneca, lecture fees from Novartis, and unrestricted grants from Biogen Idec, Sanofi Aventis, Bayer Schering Pharma, and Merck Serono; and Dr. Martin, serving on paid advisory boards for Biogen Idec.
No other potential conflict of interest relevant to this article was reported.
We thank David B. Clifford, M.D., of the Department of Neurology and Medicine, School of Medicine, Washington University, St. Louis, for valuable discussions regarding the treatment of PML; and Anna-Lena Hammarin of SMI, Stockholm, for diagnostic discussions.
Source Information
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 hans.linda@ki.se.
- References
References
1
Koralnik IJ . New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 2004;17:365-370
CrossRef | Web of Science | Medline2
Stuve O ,Marra CM ,Jerome KR , et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006;59:743-747
CrossRef | Web of Science | Medline3
Miller DH ,Khan OA ,Sheremata WA , et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003;348:15-23
Full Text | Web of Science | Medline4
Polman CH ,O'Connor PW ,Havrdova E , et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006;354:899-910
Full Text | Web of Science | Medline5
Yang XD ,Michie SA ,Tisch R ,Karin N ,Steinman L ,McDevitt HO . A predominant role of integrin alpha 4 in the spontaneous development of autoimmune diabetes in nonobese diabetic mice. Proc Natl Acad Sci U S A 1994;91:12604-12608
CrossRef | Web of Science | Medline6
Sandborn WJ ,Colombel JF ,Enns R , et al. Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 2005;353:1912-1925
Full Text | Web of Science | Medline7
Langer-Gould A ,Atlas SW ,Green AJ ,Bollen AW ,Pelletier D . Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-381
Full Text | Web of Science | Medline8
Kleinschmidt-DeMasters BK ,Tyler KL . Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353:369-374
Full Text | Web of Science | Medline9
Yousry TA ,Major EO ,Ryschkewitsch C , et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006;354:924-933
Full Text | Web of Science | Medline10
Van Assche G ,Van Ranst M ,Sciot R , et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005;353:362-368
Full Text | Web of Science | Medline11
Khatri BO ,Man S ,Giovannoni G , et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009;72:402-409
CrossRef | Web of Science | Medline12
Ryschkewitsch C ,Jensen P ,Hou J ,Fahle G ,Fischer S ,Major EO . Comparison of PCR-Southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods 2004;121:217-221
CrossRef | Web of Science | Medline13
Landry ML ,Eld T ,Bannykh S ,Major EO . False negative PCR despite high levels of JC virus DNA in spinal fluid: implications for diagnostic testing. J Clin Virol 2008;43:247-249
CrossRef | Web of Science | Medline14
Aksamit AJ . Progressive multifocal leukoencephalopathy. Curr Treat Options Neurol 2008;10:178-185
CrossRef | Medline15
Venkataramana A ,Pardo CA ,McArthur JC , et al. Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients. Neurology 2006;67:383-388
CrossRef | Web of Science | Medline16
Hemmer B ,Frohmann E ,Hartung HP ,Stuve O . Central nervous system infections -- a potential complication of systemic immunotherapy. Curr Opin Neurol 2006;19:271-276
CrossRef | Web of Science | Medline17
Martin SI ,Marty FM ,Fuimara K ,Treon SP ,Gribben JG ,Baden LR . Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis 2006;43:16-24
CrossRef | Web of Science | Medline18
Pelosini M ,Focosi D ,Rita F , et al. Progressive multifocal leukoencephalopathy: report of three cases in HIV-negative hematological patients and review of the literature. Ann Hematol 2008;87:405-412
CrossRef | Web of Science | Medline19
Iacobaeus E ,Ryschkewitsch C ,Gravell M , et al. Analysis of cerebrospinal fluid and cerebrospinal fluid cells from patients with multiple sclerosis for detection of JC virus DNA. Mult Scler 2009;15:28-35
CrossRef | Web of Science | Medline20
Falco V ,Olmo M ,del Saz SV , et al. Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study. J Acquir Immune Defic Syndr 2008;49:26-31
CrossRef | Web of Science | Medline21
Marzocchetti A ,Di Giambenedetto S ,Cingolani A ,Ammassari A ,Cauda R ,De Luca A . Reduced rate of diagnostic detection of JC virus DNA in cerebrospinal fluid in cases of suspected progressive multifocal leukoencephalopathy in the era of potent antiretroviral therapy. J Clin Microbiol 2005;43:4175-4177
CrossRef | Web of Science | Medline22
Hamilton RS ,Gravell M ,Major EO . Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus. J Clin Microbiol 2000;38:105-109
Web of Science | Medline
- Citing Articles (51)
Citing Articles
1
I. Ayzenberg, C. Lukas, N. Trampe, R. Gold, K. Hellwig. (2012) Value of MRI as a surrogate marker for PML in natalizumab long-term therapy. Journal of Neurology
CrossRef2
Daniel L. Barber, Bruno B. Andrade, Irini Sereti, Alan Sher. (2012) Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. Nature Reviews Microbiology
CrossRef3
Maria Chiara G Monaco, Eugene O Major. (2012) The link between VLA-4 and JC virus reactivation. Expert Review of Clinical Immunology 8:1, 63-72
CrossRef4
M. A. Sahraian, E.-W. Radue, A. Eshaghi, S. Besliu, A. Minagar. (2011) Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. European Journal of Neurologyno-no
CrossRef5
M. Pallin, C. O'sullivan, J. D. Dodd, K. McCreery, F. Brett, M. Farrell, D. O'brien, W. W. Hall, N. J. Tubridy, M. P. Keane. (2011) A case of progressive multifocal leukoencephalopathy in a patient with sarcoidosis. QJM
CrossRef6
Gert Van Assche, James D Lewis, Gary R Lichtenstein, Edward V Loftus, Qin Ouyang, Julian Panes, Corey A Siegel, William J Sandborn, Simon P L Travis, Jean-Frederic Colombel. (2011) The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organisation: Safety. The American Journal of Gastroenterology 106:9, 1594-1602
CrossRef7
Daniel M. Harrison, Scott D. Newsome, Richard L. Skolasky, Justin C. McArthur, Avindra Nath. (2011) Immune reconstitution is not a prognostic factor in progressive multifocal leukoencephalopathy. Journal of Neuroimmunology 238:1-2, 81-86
CrossRef8
Namita Kothary, Ida-Lina Diak, Allen Brinker, Shewit Bezabeh, Mark Avigan, Gerald Dal Pan. (2011) Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients. Journal of the American Academy of Dermatology 65:3, 546-551
CrossRef9
Joachim Havla, Lisa Ann Gerdes, Ingrid Meinl, Markus Krumbholz, Hans Faber, Frank Weber, Hannah Luise Pellkofer, Reinhard Hohlfeld, Tania Kümpfel. (2011) De-escalation from natalizumab in multiple sclerosis: recurrence of disease activity despite switching to glatiramer acetate. Journal of Neurology 258:9, 1665-1669
CrossRef10
Gillian M. Bell, Gary Reynolds, John D. Isaacs. (2011) Biologic therapies in non-rheumatic diseases: lessons for rheumatologists?. Nature Reviews Rheumatology 7:9, 507-516
CrossRef11
Ludwig Kappos, David Bates, Gilles Edan, Mefkûre Eraksoy, Antonio Garcia-Merino, Nikolaos Grigoriadis, Hans-Peter Hartung, Eva Havrdová, Jan Hillert, Reinhard Hohlfeld, Marcelo Kremenchutzky, Olivier Lyon-Caen, Ariel Miller, Carlo Pozzilli, Mads Ravnborg, Takahiko Saida, Christian Sindic, Karl Vass, David B Clifford, Stephen Hauser, Eugene O Major, Paul W O'Connor, Howard L Weiner, Michel Clanet, Ralf Gold, Hans H Hirsch, Ernst-Wilhelm Radü, Per Soelberg Sørensen, John King. (2011) Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. The Lancet Neurology 10:8, 745-758
CrossRef12
D Sean Riminton, Hans-Peter Hartung, Stephen W Reddel. (2011) Managing the risks of immunosuppression. Current Opinion in Neurology 24:3, 217-223
CrossRef13
Israel F. Charo, Rebecca Taub. (2011) Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nature Reviews Drug Discovery 10:5, 365-376
CrossRef14
C. Warnke, O. Adams, R. Gold, H.-P. Hartung, R. Hohlfeld, H. Wiendl, B.C. Kieseier. (2011) Progressive multifokale Leukenzephalopathie unter Natalizumab. Der Nervenarzt 82:4, 475-480
CrossRef15
Martin Duddy, Aiden Haghikia, Eleonora Cocco, Christian Eggers, Jelena Drulovic, Olga Carmona, Helene Zéphir, Ralf Gold. (2011) Managing MS in a changing treatment landscape. Journal of Neurology
CrossRef16
S. A. Ryan, P. MacEneaney, S. P. O’Reilly, E. J. Moylan, D. G. Power. (2011) Reversible posterior leukoencephalopathy induced by carboplatin and etoposide. Medical Oncology
CrossRef17
Derek G. Power, Nancy E. Kemeny. (2011) Nasal septum perforation and bevacizumab. Medical Oncology 28:1, 89-93
CrossRef18
Joy Derwenskus. (2011) Current Disease-Modifying Treatment of Multiple Sclerosis. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 78:2, 161-175
CrossRef19
Robert Weissert. (2011) Progressive multifocal leukoencephalopathy. Journal of Neuroimmunology 231:1-2, 73-77
CrossRef20
Annette Baumgartner, Oliver Stich, Sebastian Rauer. (2011) Clinical and radiological disease reactivation after cessation of long term therapy with natalizumab. International Journal of Neuroscience1
CrossRef21
Peter Wipfler, Andrea Harrer, Georg Pilz, Katrin Oppermann, Eugen Trinka, Jörg Kraus. (2011) Recent developments in approved and oral multiple sclerosis treatment and an update on future treatment options. Drug Discovery Today 16:1-2, 8-21
CrossRef22
Fredrik Piehl, C. Holmén, J. Hillert, T. Olsson. (2011) Swedish natalizumab (Tysabri) multiple sclerosis surveillance study. Neurological Sciences 31:S3, 289-293
CrossRef23
D. Spoerl, Andreas J. Bircher. 2011. Drugs that act on the immune system. , 769-814.
CrossRef24
Edward J Fox. (2010) Alemtuzumab in the treatment of relapsing–remitting multiple sclerosis. Expert Review of Neurotherapeutics 10:12, 1789-1797
CrossRef25
Joseph R. Berger. (2010) Progressive Multifocal Leukoencephalopathy and Newer Biological Agents. Drug Safety 33:11, 969-983
CrossRef26
Irini Sereti, Alison J Rodger, Martyn A French. (2010) Biomarkers in immune reconstitution inflammatory syndrome: signals from pathogenesis. Current Opinion in HIV and AIDS 5:6, 504-510
CrossRef27
Eilhard Mix, Hans Meyer-Rienecker, Hans-Peter Hartung, Uwe K. Zettl. (2010) Animal models of multiple sclerosis—Potentials and limitations. Progress in Neurobiology 92:3, 386-404
CrossRef28
A Balduzzi, G Lucchini, H H Hirsch, S Basso, M Cioni, A Rovelli, A Zincone, M Grimaldi, P Corti, S Bonanomi, A Biondi, F Locatelli, E Biagi, P Comoli. (2010) Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplantation
CrossRef29
D Jing, U Oelschlaegel, R Ordemann, K Hölig, G Ehninger, H Reichmann, T Ziemssen, M Bornhäuser. (2010) CD49d blockade by natalizumab in patients with multiple sclerosis affects steady-state hematopoiesis and mobilizes progenitors with a distinct phenotype and function. Bone Marrow Transplantation 45:10, 1489-1496
CrossRef30
Ursula Neu, Melissa S. Maginnis, Angelina S. Palma, Luisa J. Ströh, Christian D.S. Nelson, Ten Feizi, Walter J. Atwood, Thilo Stehle. (2010) Structure-Function Analysis of the Human JC Polyomavirus Establishes the LSTc Pentasaccharide as a Functional Receptor Motif. Cell Host & Microbe 8:4, 309-319
CrossRef31
Leonid Gorelik, Michaela Lerner, Sarah Bixler, Mary Crossman, Brian Schlain, Kenneth Simon, Amy Pace, Anne Cheung, Ling Ling Chen, Melissa Berman, Fairuz Zein, Ewa Wilson, Ted Yednock, Alfred Sandrock, Susan E. Goelz, Meena Subramanyam. (2010) Anti-JC virus antibodies: Implications for PML Risk Stratification. Annals of Neurology 68:3, 295-303
CrossRef32
Leslie J. Marshall, Eugene O. Major. (2010) Molecular Regulation of JC Virus Tropism: Insights into Potential Therapeutic Targets for Progressive Multifocal Leukoencephalopathy. Journal of Neuroimmune Pharmacology 5:3, 404-417
CrossRef33
Alexandra Schröder, Ralf A. Linker, Ralf Gold. (2010) Plasmapheresis for neuroinflammatory disorders. Clinical and Experimental Neuroimmunology 1:3, 95-102
CrossRef34
Jakob Paues, Magnus Vrethem. (2010) Fatal progressive multifocal leukoencephalopathy in a patient with non-Hodgkin lymphoma treated with rituximab. Journal of Clinical Virology 48:4, 291-293
CrossRef35
Peter O Behan. (2010) Futility of the autoimmune orthodoxy in multiple sclerosis research. Expert Review of Neurotherapeutics 10:7, 1023-1025
CrossRef36
Andreas P Lysandropoulos, Renaud A Du Pasquier. (2010) Demyelination as a complication of new immunomodulatory treatments. Current Opinion in Neurology 23:3, 226-233
CrossRef37
Saud A. Sadiq, Lauren M. Puccio, Edward W. A. Brydon. (2010) JCV detection in multiple sclerosis patients treated with natalizumab. Journal of Neurology 257:6, 954-958
CrossRef38
L. Steinman. (2010) Inverse vaccination, the opposite of Jenner’s concept, for therapy of autoimmunity. Journal of Internal Medicine 267:5, 441-451
CrossRef39
Mathias Buttmann. (2010) Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Review of Neurotherapeutics 10:5, 791-809
CrossRef40
T. Weber, W. Köhler. (2010) Entmarkungserkrankungen. Der Nervenarzt 81:4, 471-496
CrossRef41
Trevor T. Hansel, Harald Kropshofer, Thomas Singer, Jane A. Mitchell, Andrew J. T. George. (2010) The safety and side effects of monoclonal antibodies. Nature Reviews Drug Discovery 9:4, 325-338
CrossRef42
Chen S Tan, Igor J Koralnik. (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. The Lancet Neurology 9:4, 425-437
CrossRef43
Cary Twyman, Joseph R. Berger. (2010) A giant MS plaque mimicking PML during natalizumab treatment. Journal of the Neurological Sciences 291:1-2, 110-113
CrossRef44
David B Clifford, Andrea DeLuca, David M Simpson, Gabriele Arendt, Gavin Giovannoni, Avindra Nath. (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. The Lancet Neurology 9:4, 438-446
CrossRef45
Richard M Ransohoff. (2010) PML risk and natalizumab: more questions than answers. The Lancet Neurology 9:3, 231-233
CrossRef46
Zbigniew M. Szczepiorkowski, Jeffrey L. Winters, Nicholas Bandarenko, Haewon C. Kim, Michael L. Linenberger, Marisa B. Marques, Ravindra Sarode, Joseph Schwartz, Robert Weinstein, Beth H. Shaz. (2010) Guidelines on the use of therapeutic apheresis in clinical practice-Evidence-based approach from the apheresis applications committee of the American Society for Apheresis. Journal of Clinical Apheresis 25:3, 83-177
CrossRef47
M. Jagodic, C. Colacios, R. Nohra, A. S. Dejean, A. D. Beyeen, M. Khademi, A. Casemayou, L. Lamouroux, C. Duthoit, O. Papapietro, L. Sjoholm, I. Bernard, D. Lagrange, I. Dahlman, F. Lundmark, A. B. Oturai, H. B. Soendergaard, A. Kemppinen, J. Saarela, P. J. Tienari, H. F. Harbo, A. Spurkland, S. V. Ramagopalan, D. A. Sadovnick, G. C. Ebers, M. Seddighzadeh, L. Klareskog, L. Alfredsson, L. Padyukov, J. Hillert, M. Clanet, G. Edan, B. Fontaine, G. J. Fournie, I. Kockum, A. Saoudi, T. Olsson. (2009) A Role for VAV1 in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Science Translational Medicine 1:10, 10ra21-10ra21
CrossRef48
JAMIE TALAN. (2009) MS Specialists Question Company Disclosure of Natalizumab-Associated PML. Neurology Today 9:20, 5-7
CrossRef49
Major, Eugene O., . (2009) Reemergence of PML in Natalizumab-Treated Patients — New Cases, Same Concerns. New England Journal of Medicine 361:11, 1041-1043
Full Text50
Wenning, Werner, Haghikia, Aiden, Laubenberger, Jörg, Clifford, David B., Behrens, Peter F., Chan, Andrew, Gold, Ralf, . (2009) Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab. New England Journal of Medicine 361:11, 1075-1080
Full Text51
Laurie J. Barten, Douglas R. Allington, Kendra A. Procacci, Michael P. Rivey. (2009) Natalizumab update: a story of benefit and risk. Drug Discovery Today: Therapeutic Strategies 6:1, 21-31
CrossRef
