Original Article
Brief Report
Treatment of Progressive Multifocal Leukoencephalopathy Associated with Natalizumab
N Engl J Med 2009; 361:1075-1080September 10, 2009
- Abstract
We describe the clinical and therapeutic course of a 52-year-old patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML) developed after 12 months of therapy with natalizumab. The patient was hospitalized 2 months after the onset of neurologic and psychiatric symptoms and was treated with plasma exchange and immunoadsorption to eliminate natalizumab. After a brief improvement, he became critically ill with an apparent episode of immune reconstitution inflammatory syndrome. Steroid-pulse therapy led to stabilization of the patient's condition and clinically significant recovery. This case illustrates that prompt diagnosis and treatment may improve the outcome in patients with severe PML associated with natalizumab therapy.
Media in This Article
Figure 1
Changes on Cranial MRI during the Clinical Course of Progressive Multifocal Leukoencephalopathy (PML).Figure 2
The Course of Disease According to Diagnostic Procedures, Including Longitudinal Testing of Cerebrospinal Fluid for JC Virus DNA, and Therapeutic Approaches.Article Activity
- Article
Natalizumab (Tysabri, Biogen Idec and Elan), a monoclonal antibody directed against the α4 chain of VLA-4, is approved by the U.S. Food and Drug Administration and the European Medicines Agency as monotherapy for highly active relapsing–remitting multiple sclerosis. As of June 2008, more than 40,000 patients had received natalizumab during participation in clinical studies or during open-label use; approximately 14,000 had taken the drug for at least 12 months, and 6600 for at least 18 months (www.fda.gov). Shortly after approval of the drug, three cases of PML associated with natalizumab therapy were reported — two in patients with multiple sclerosis during the phase 3 clinical trial (Safety and Efficacy of Natalizumab in Combination with Interferon-1a in Patients with Relapsing Remitting Multiple Sclerosis study [SENTINEL; ClinicalTrials.gov number, NCT00030966]), in which natalizumab was used in combination with interferon beta-1a (Avonex, Biogen Idec), and one in a patient with Crohn's disease who had received prior immunosuppressive therapy. Two of the patients died, and one of the patients with multiple sclerosis had persistent, severe neurologic deficits.1-4
PML is a rare demyelinating disease of the central nervous system caused by the JC virus, a polyomavirus that typically occurs in severely immunocompromised patients, often with a fatal outcome.5 The predisposing mechanism of PML when it is associated with natalizumab therapy remains elusive.6 However, current hypotheses include compromised brain immunosurveillance or the mobilization by natalizumab of bone marrow cells carrying JC virus.7 Here we describe a patient who survived after PML associated with natalizumab therapy was diagnosed and treated.
Case Report
A previously healthy 52-year-old man had the first symptoms of multiple sclerosis in 1987. Between 1987 and 1992, the patient was in complete remission. After a relapse in 1992, the diagnosis of clinically definite multiple sclerosis according to the Poser criteria8 was made. At that time, the patient had mild tetraparesis combined with gait ataxia. Immunosuppressive therapy with azathioprine (100 mg per day, taken orally) was stopped shortly after initiation, and no further therapy to prevent relapses was used until after the second and third relapses occurred in January 2001 and May 2001, respectively. These relapses resulted in mild spasticity, gait ataxia, and disturbance of fine motor skills in the left arm. Beginning in May 2001, the patient received several doses of interferon beta-1a (Avonex) at a dose of 30 μg once a week, administered intramuscularly, but flulike symptoms developed, and he stopped taking the drug. In December 2001, he began taking another interferon beta-1a drug (Rebif, Merck Serono and Pfizer) at a dose of 44 μg three times a week, administered subcutaneously; this therapy led to even more severe flulike symptoms than those with Avonex, and the therapy was discontinued. In early 2002, azathioprine therapy was reinstituted at a dose of 100 mg daily; the dose was subsequently reduced to 50 mg daily until the beginning of 2007.
In 2006, the patient's multiple sclerosis worsened, and azathioprine therapy was discontinued in January 2007. After another relapse in March 2007, he was treated with methylprednisolone pulse therapy (5×1000 mg), and natalizumab monotherapy (300 mg monthly) was initiated in May 2007. During treatment with natalizumab, he had one more relapse in November 2007 and was treated with methylprednisolone pulse therapy. In April 2008, the patient's wife first noticed symptoms of depression in him. In May 2008, disabling left hemiparesis developed, predominantly affecting the leg. A cranial magnetic resonance imaging (MRI) scan in June 2008 showed preexisting multiple sclerosis lesions, and a new right-sided thalamic lesion was interpreted as being probably of ischemic origin (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Under the assumption that the new signs were indicative of a relapse of multiple sclerosis, the patient's neurologist treated him with two cycles of methylprednisolone pulse therapies (5×1000 mg) and a total of 100 mg of dexamethasone, given orally. The patient received two more infusions of natalizumab, the latter one on June 6, 2008. On July 14, his neurologic status declined further, and he was hospitalized.
On admission, the patient appeared drowsy and inattentive and had severe flaccid left-sided hemiparesis; the Babinski sign was present on the left side. He was unable to stand or sit and tended to fall to the left side. Impaired cognition and mood alterations, which manifested as depressive symptoms and aggressive episodes, were noted, and he had dysarthric speech. The initial MRI scan with contrast medium, which was obtained immediately after admission, revealed two large areas of increased T2-weighted and decreased T1-weighted signal, including a right-sided subinsular band-shaped lesion with a faint gadolinium-enhancing margin and a right-sided thalamic lesion (Figure 1AFigure 1
Changes on Cranial MRI during the Clinical Course of Progressive Multifocal Leukoencephalopathy (PML).). These atypical lesions raised the suspicion of PML, and the diagnosis was supported by the detection on polymerase-chain-reaction (PCR) assay of JC virus in cerebrospinal fluid (Figure 2Figure 2The Course of Disease According to Diagnostic Procedures, Including Longitudinal Testing of Cerebrospinal Fluid for JC Virus DNA, and Therapeutic Approaches.).An analysis of a sample of cerebrospinal fluid obtained at admission showed a normal white-cell count (<1 cell per cubic millimeter), a protein level of 54 mg per deciliter, a glucose level of 57 mg per deciliter (3.2 mmol per liter), and a lactate level of 1.4 mmol per liter. There were no substantive abnormalities in the total white-cell count or in its components (white cells, 11,990 per cubic millimeter; lymphocytes, 2500 per cubic millimeter; CD4+ T cells, 1233 per cubic millimeter; CD8+ T cells, 680 per cubic millimeter; CD56+ natural killer cells, 302 per cubic millimeter; and CD19+ B cells, 277 per cubic millimeter). Additional laboratory investigations showed normal C-reactive protein levels (<0.7 mg per liter) and normal liver enzyme levels (aspartate aminotransferase, 18 U per liter; alanine aminotransferase, 18 U per liter). Serum testing, performed by an enzyme-linked immunosorbent assay (ELISA), did not reveal neutralizing antibodies against natalizumab.
Treatment with natalizumab was stopped, and on August 1, plasma exchange of 30 ml per kilogram of body weight (2.5 liters) was performed, followed by three cycles of immunoadsorption with a tryptophan column (TR350-L) on August 2, August 4, and August 6 in an effort to remove natalizumab. Serum samples obtained 4 days before plasma exchange and 2 days after plasma exchange with immunoadsorption were stored for determination of natalizumab concentration. Blinded assessment of natalizumab concentration in serum was performed with the use of an ELISA-based approach (lower detection level, 0.25 μg per milliliter; Biogen Idec). An analysis of serum obtained 4 days before plasma exchange revealed a natalizumab level of 10.8 μg per milliliter, and analysis of serum obtained 2 days after plasma exchange with immunoadsorption showed that the natalizumab concentration was below the detection level. In addition to the plasma-exchange treatment, mefloquine, an antimalarial drug reported to have anti–JC-virus activity in vitro, was administered orally, with a loading dose of 1500 mg.9 Mirtazapine, a 5-hydroxytryptamine 2a (5-HT2a)-receptor inhibitor, was given concurrently (60 mg per day, with therapy still ongoing), since the 5-HT2a receptor has been hypothesized to be the gate for JC virus in glial cells.10
Rapid improvement in the patient's cognitive and motor abilities was observed within 1 week. The patient was able to walk a few steps with assistance, and his wife thought that his cognition and ability to communicate had returned to normal. At the end of August, there was a progressive worsening of his clinical state, including the development of flaccid tetraparesis involving respiratory muscles, dysarthria, and stupor. On September 26, the patient was transferred to an intensive medical care unit, where he received artificial ventilation and gastrostomy feeding. A follow-up cranial MRI scan 8 weeks after the initial scan showed a worsening of subcortical and thalamic lesions, with an increase in their size and gadolinium enhancement, as well as marked edema and swelling causing compression of the right-lateral ventricle and sylvian fissure (Figure 1B). A new left-sided contralateral cortical–subcortical gadolinium-enhancing lesion at the frontoparietal lobe appeared as well. The deterioration of the patient's clinical state and the evidence of worsening lesions on MRI were consistent with the immune reconstitution inflammatory syndrome (IRIS). Interestingly, an increase in JC virus titers from 1800 copies per milliliter of cerebrospinal fluid to 4000 per milliliter accompanied this IRIS reaction (Figure 2). Because of the brain swelling, two cycles of steroid-pulse therapy were administered. Within 4 weeks, neurologic improvement was evident, including increased alertness, improved ability to communicate, and the ability to move his left arm and right leg. The clinical improvement was associated with an absence of swelling and gadolinium enhancement on brain MRI (Figure 1C) and a 90% decrease in viral titers in the cerebrospinal fluid (Figure 2). The patient was transferred to an inpatient rehabilitation program in early November 2008 and was discharged to his home in late December 2008.
As of January 24, 2009 — 6 months after the initiation of plasma-exchange therapy — the patient is being cared for by his family at home. He has normal cognition, as evidenced by his ability to follow a conversation and respond appropriately, and his wife thinks that his cognitive state is the same as it was before PML developed. He is able to swallow liquids and pulp. The neurologic examination on January 24 revealed persistent, severe left-sided hemiparesis and mild dysarthria. He is able to move his right arm and leg. Motor symptoms continue to decrease. Treatment with mefloquine (250 mg once per week) and mirtazapine (30 mg per day) has continued.
Discussion
The case history of the patient described here and that of the Swedish patient described in another article in this issue of the Journal 11 show that PML may occur during natalizumab monotherapy, in contrast to the initial cases of PML in patients with multiple sclerosis, both of which occurred while the patients were taking concurrent interferon beta therapy. Since multiple sclerosis without treatment with natalizumab has never been associated with PML, the increased risk for PML seems to be related to natalizumab therapy. The duration of natalizumab therapy in our case was approximately 14 months; previous cases occurred after 8 to 37 months of therapy.2,3 The relationship of the risk of PML to the duration of natalizumab treatment remains unclear. The overall risk of this complication had been estimated from the earliest cases to be 1 in 1000, but estimates derived from experience with open-label use to date suggest that the overall risk might be lower.12 To our knowledge, in addition to the three previously reported cases and the two cases reported in this issue of the Journal, three other cases of PML in patients taking natalizumab have been identified. PML developed in two patients in Germany, both of whom were treated with plasma exchange and immunoadsorption; the condition of both of these patients was stable as of February 2009. One patient in the United States died during an apparent episode of IRIS.
PML remains a rare opportunistic disease that is most commonly associated with the acquired immunodeficiency syndrome. PML associated with the human immunodeficiency virus (HIV) accounts for approximately 80% of cases of PML and has continued to occur even after the advent of highly active antiretroviral therapy.13 PML in patients with multiple sclerosis who are being treated with natalizumab constitutes a novel presentation for this disease. Although the hypothesis that PML associated with natalizumab is due to reduced immunosurveillance remains a matter of speculation, this idea has received support by the findings in a recent work that JC virus DNA — but no viral proteins — are detectable in glial cells even in the brains of healthy persons, raising the possibility that the brain is a site of latent JC virus.14
In the case of the patient described in this article, the detection and diagnosis of PML were made after the identification of new focal neurologic abnormalities, MRI imaging showing lesions consistent with PML, and analysis of cerebrospinal fluid that showed JC virus DNA.12,15 Because the detection of JC virus DNA in cerebrospinal fluid is specific but only approximately 60 to 80% sensitive, a brain biopsy must still be considered to confirm unusual suspected cases of PML when no JC virus DNA is detected in the cerebrospinal fluid. As seen in our patient, the MRI scan shows lesions with irregular margins, which are not characteristic of multiple sclerosis lesions. Slight gadolinium enhancement within the lesion may occur in the early phase of PML and may be more prominent in the case of IRIS. Longitudinal cerebrospinal fluid samples, as were obtained from our patient, provide a sensitivity of 92% and a specificity of 100%.16 Thus, our patient fulfilled all the classic criteria for PML, and a brain biopsy was not necessary.
Immune reconstitution is the only known effective therapy for PML at this time. To speed this response, natalizumab therapy must be stopped, but its long duration of action may delay immune reconstitution. To accomplish more rapid elimination of natalizumab, plasma exchange and immunoadsorption have been advocated, since recent reports suggest that the biologic half-life of natalizumab may be several times longer than its pharmacokinetics would suggest.17-19 Khatri and colleagues found that rapid elimination of natalizumab by plasma exchange leads to desaturation of the α4-integrin and restoration of immune function in peripheral-blood cells.19 The levels of natalizumab before and after plasma exchange and immunoabsorption support these findings. On the other hand, abrupt immune reconstitution may precipitate severe IRIS, a condition that is life-threatening and that requires treatment of the inflammatory brain infiltrate that involves multinucleated cells and lymphocytes, as was recently shown by histopathological analysis of PML associated with HIV.20 Additional research is required to prove that our proposed therapeutic algorithm is indeed superior to the natural course of reconstitution.
Various antiviral drugs, including cidofovir, have been used in addition to highly active antiretroviral therapy for the treatment of PML in patients with HIV but have not been effective.21 Mefloquine, a drug approved for malaria therapy, has recently been shown to have an effect on the activity of JC virus in a screening bioassay when it is applied on a human glial cell line infected with JC virus.9 In the case of our patient, we also administered mirtazapine, an inhibitor of 5-HT2a-receptor, which may be used by JC virus for cell entry and has been shown to inhibit the infection of a human astroglial cell line.10 Recently, an anecdotal report has shown the efficacy of mirtazapine in a patient with PML, although many experts doubt that this therapeutic agent has substantial efficacy.22
In conclusion, our case underscores the importance of vigilance for new neurologic symptoms during the course of natalizumab therapy. Optimal management of the immune reconstitution syndrome can improve survival and reduce the severity of this often fatal complication.
Dr. Wenning reports receiving lecture fees from Biogen Idec; Dr. Clifford, consulting fees from Biogen Idec and Elan and grant support from Biogen (Protocol 111 JC 101) as per-patient reimbursement for costs; Dr. Chan, lecture fees from Biogen Idec, Bayer–Schering, Merck Serono, and Teva–Sanofi-Aventis and grant support from Biogen Idec; and Dr. Gold, lecture and consulting fees from Biogen Idec, Bayer–Schering, Merck Serono, and Teva–Sanofi-Aventis and grant support from Biogen Idec and Teva.
No other potential conflict of interest relevant to this article was reported.
We thank Dr. Susan Goelz of Biogen Idec for support with the measurement of natalizumab serum levels.
Source Information
From the Neurological Clinic (W.W., P.F.B.) and the Radiological Clinic (J.L.), Ortenau-Klinikum, Offenburg; and the Department of Neurology, Ruhr University Bochum, St. Josef-Hospital Bochum, Bochum (A.H., A.C., R.G.) — both in Germany; and Washington University, St. Louis (D.B.C.).
Address reprint requests to Dr. Gold at the Department of Neurology, Ruhr University Bochum, St. Josef-Hospital Bochum, Gudrunstr. 56, 44791 Bochum, Germany, or at ralf.gold@rub.de.
- References
References
1
Rudick RA ,Stuart WH ,Calabresi PA , et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354:911-923
Full Text | Web of Science | Medline2
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 | Medline3
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 | Medline4
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 | Medline5
Thurnher MM ,Post MJ ,Rieger A ,Kleibl-Popov C ,Loewe C ,Schindler E . Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol 2001;22:977-984
Web of Science | Medline6
Steinman L . Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 2005;4:510-518
CrossRef | Web of Science | Medline7
del Pilar Martin M ,Cravens PD ,Winger R , et al. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol 2008;65:1596-1603
CrossRef | Web of Science | Medline8
Poser CM ,Paty DW ,Scheinberg L , et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231
CrossRef | Web of Science | Medline9
Brickelmaier M ,Allaire N ,Gorelik L . Identification and characterization of mefloquine efficacy against JC virus in vitro. Mult Scler 2008;14:Suppl 1:S44-S44
Web of Science10
O'Hara BA ,Atwood WJ . Interferon beta1-a and selective anti-5HT(2a) receptor antagonists inhibit infection of human glial cells by JC virus. Virus Res 2008;132:97-103
CrossRef | Web of Science | Medline11
Linda H ,von Heijne A ,Major ED , et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009;361:1081-1087
Full Text | Web of Science | Medline12
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 | Medline13
Gray F ,Chretien F ,Vallat-Decouvelaere AV ,Scaravilli F . The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 2003;62:429-440
Web of Science | Medline14
Perez-Liz G ,Del Valle L ,Gentilella A ,Croul S ,Khalili K . Detection of JC virus DNA fragments but not proteins in normal brain tissue. Ann Neurol 2008;64:379-387
CrossRef | Web of Science | Medline15
Kappos L ,Bates D ,Hartung HP , et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 2007;6:431-441
CrossRef | Web of Science | Medline16
Delbue S ,Tremolada S ,Ferrante P . Application of molecular tools for the diagnosis of central nervous system infections. Neurol Sci 2008;29:Suppl 2:S283-S285
CrossRef | Web of Science | Medline17
Stuve O ,Marra CM ,Bar-Or A , et al. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 2006;63:1383-1387
CrossRef | Web of Science | Medline18
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 | Medline19
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 | Medline20
Gonzalez-Duarte A ,Sullivan S ,Sips GJ , et al. Inflammatory pseudotumor associated with HIV, JCV, and immune reconstitution syndrome. Neurology 2009;72:289-290
CrossRef | Web of Science | Medline21
De Luca A ,Ammassari A ,Pezzotti P , et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 2008;22:1759-1767
CrossRef | Web of Science | Medline22
Verma S ,Cikurel K ,Koralnik IJ , et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 2007;196:709-711
CrossRef | Web of Science | Medline
- Citing Articles (45)
Citing Articles
1
Imke Metz, Ernst-Wilhelm Radue, Agustin Oterino, Tania Kümpfel, Heinz Wiendl, Sven Schippling, Jens Kuhle, Mohammad Ali Sahraian, Francoise Gray, Veronika Jakl, Darius Häusler, Wolfgang Brück. (2012) Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy. Acta Neuropathologica 123:2, 235-245
CrossRef2
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
CrossRef3
Vishesh Chhibber, Robert Weinstein. (2012) Evidence-Based Review of Therapeutic Plasma Exchange in Neurological Disorders. Seminars in Dialysisno-no
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
Kerstin Hellwig, Ralf Gold. (2011) Progressive multifocal leukoencephalopathy and natalizumab. Journal of Neurology 258:11, 1920-1928
CrossRef6
Eugenio Pucci, Giorgio Giuliani, Alessandra Solari, Silvana Simi, Silvia Minozzi, Carlo Di Pietrantonj, Ian Galea, Eugenio Pucci. 2011. Natalizumab for relapsing remitting multiple sclerosis. .
CrossRef7
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
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
Noelia Pontello, Ezequiel Gleichgerrcht, Manes Facundo, Vladimiro Sinay. (2011) Criptococosis meníngea en inmunosuprimidos: rol del síndrome inflamatorio de reconstitución inmune. Neurología Argentina
CrossRef10
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
CrossRef11
Sundarapandian Thangapandian, Shalini John, Sugunadevi Sakkiah, Keun Woo Lee. (2011) Discovery of Potential Integrin VLA-4 Antagonists Using Pharmacophore Modeling, Virtual Screening and Molecular Docking Studies. Chemical Biology & Drug Design 78:2, 289-300
CrossRef12
A. Horga, M. Tintoré. (2011) Natalizumab para la esclerosis múltiple remitente-recurrente. Neurología 26:6, 357-368
CrossRef13
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. (2011) Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplantation 46:7, 987-992
CrossRef14
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 258:5, 728-739
CrossRef15
, A. Ghezzi, L. M. E. Grimaldi, M. G. Marrosu, C. Pozzilli, G. Comi, A. Bertolotto, M. Trojano, P. Gallo, R. Capra, D. Centonze, E. Millefiorini, S. Sotgiu, V. Brescia Morra, M. P. Amato, A. Lugaresi, G. Mancardi, D. Caputo, E. Montanari, L. Provinciali, L. Durelli, R. Bergamaschi, P. Bellantonio, M. R. Tola, S. Cottone, G. Savettieri, G. Tedeschi. (2011) Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group—Italian Neurological Society. Neurological Sciences 32:2, 351-358
CrossRef16
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
CrossRef17
Xavier Bosch, Albert Saiz, Manuel Ramos-Casals. (2011) Monoclonal antibody therapy-associated neurological disorders. Nature Reviews Neurology 7:3, 165-172
CrossRef18
L.P. Kihm, V. Schwenger. (2011) Plasmapherese und Immunadsorption auf der Intensivstation. Der Nephrologe 6:2, 149-154
CrossRef19
Robert Weissert. (2011) Progressive multifocal leukoencephalopathy. Journal of Neuroimmunology 231:1-2, 73-77
CrossRef20
D. Spoerl, Andreas J. Bircher. 2011. Drugs that act on the immune system. , 769-814.
CrossRef21
A. Horga, M. Tintoré. (2011) Natalizumab for relapsing-remitting multiple sclerosis. Neurología (English Edition) 26:6, 357-368
CrossRef22
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
CrossRef23
Joseph R. Berger. (2010) Progressive Multifocal Leukoencephalopathy and Newer Biological Agents. Drug Safety 33:11, 969-983
CrossRef24
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
CrossRef25
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
CrossRef26
Michael Hutchinson. (2010) Natalizumab Therapy of Multiple Sclerosis. Journal of Interferon & Cytokine Research 30:10, 787-789
CrossRef27
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
CrossRef28
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
CrossRef29
Alexandra Schröder, Ralf A. Linker, Ralf Gold. (2010) Plasmapheresis for neuroinflammatory disorders. Clinical and Experimental Neuroimmunology 1:3, 95-102
CrossRef30
G.F. Hamann, M. Dieterich. (2010) Bericht vom 2. NeuroUpdate der MedUpdate-Reihe in Wiesbaden. Der Nervenarzt 81:8, 998-1002
CrossRef31
Andreas P Lysandropoulos, Renaud A Du Pasquier. (2010) Demyelination as a complication of new immunomodulatory treatments. Current Opinion in Neurology 23:3, 226-233
CrossRef32
R. Shah, A.K. Bag, P.R. Chapman, J.K. Curé. (2010) Imaging manifestations of progressive multifocal leukoencephalopathy. Clinical Radiology 65:6, 431-439
CrossRef33
Mathias Buttmann. (2010) Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Review of Neurotherapeutics 10:5, 791-809
CrossRef34
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
CrossRef35
T. Weber, W. Köhler. (2010) Entmarkungserkrankungen. Der Nervenarzt 81:4, 471-496
CrossRef36
Juan C. Gea-Banacloche. (2010) Rituximab-Associated Infections. Seminars in Hematology 47:2, 187-198
CrossRef37
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
CrossRef38
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
CrossRef39
Richard M Ransohoff. (2010) PML risk and natalizumab: more questions than answers. The Lancet Neurology 9:3, 231-233
CrossRef40
James Woodworth, Meena Subramanyam, Mark Rogge. (2010) Reply. Annals of Neurology 67:2, 272-272
CrossRef41
Daniele Focosi. (2010) Concerns on unpredictable pharmacokinetics and pharmacodynamics of natalizumab. Annals of Neurology 67:2, 270-270
CrossRef42
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
CrossRef43
JAMIE TALAN. (2009) MS Specialists Question Company Disclosure of Natalizumab-Associated PML. Neurology Today 9:20, 5-7
CrossRef44
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 Text45
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
