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May 17, 2011; 76 (20) Articles

Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy

P. Vermersch, L. Kappos, R. Gold, J.F. Foley, T. Olsson, D. Cadavid, C. Bozic, S. Richman
First published May 16, 2011, DOI: https://doi.org/10.1212/WNL.0b013e31821a446b
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Abstract

Objective:Natalizumab, a therapy for multiple sclerosis (MS), has been associated with progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS associated with the JC virus. We assessed clinical outcomes and identified variables associated with survival in 35 patients with natalizumab-associated PML.

Methods:Physicians provided Karnofsky scores and narrative descriptions of clinical status. Data were supplemented by the natalizumab global safety database.

Results:At the time of analysis, 25 patients (71%) had survived. Survivors were younger (median 40 vs 54 years) and had lower pre-PML Expanded Disability Status Scale scores (median 3.5 vs 5.5) and a shorter time from symptom onset to diagnosis (mean 44 vs 63 days) compared with individuals with fatal cases. Of patients with nonfatal cases, 86% had unilobar or multilobar disease on brain MRI at diagnosis, whereas 70% of those with fatal cases had widespread disease. Gender, MS duration, natalizumab exposure, prior immunosuppressant use, and CSF JC viral load at diagnosis were comparable. Most patients were treated with rapid removal of natalizumab from the circulation. The majority of patients developed immune reconstitution inflammatory syndrome and were treated with corticosteroids. Among survivors with at least 6 months follow-up, disability levels were evenly distributed among mild, moderate, and severe, based on physician-reported Karnofsky scores.

Conclusions:Natalizumab-associated PML has improved survival compared with PML in other populations. Disability in survivors ranged from mild to severe. A shorter time from symptom onset to diagnosis and localized disease on MRI at diagnosis were associated with improved survival. These data suggest that earlier diagnosis through enhanced clinical vigilance and aggressive management may improve outcomes.

Natalizumab was first approved by the US Food and Drug Administration in 2004 to treat relapsing forms of multiple sclerosis (MS) and is currently approved in more than 50 countries. As of July 2010, more than 71,000 patients have been treated. However, a small number of natalizumab-treated patients develop progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the CNS. PML probably results from a complex interaction between JC virus (JCV) infection, viral factors, and host factors such as immunosuppression. Two cases of PML were reported in natalizumab MS clinical trials in subjects treated with natalizumab in combination with interferon β-1a,1,2 and a third case was later identified in a natalizumab Crohn's disease clinical trial.3 At that time, the incidence of PML in natalizumab clinical trials was estimated to be 1 case per 1,000 (95% confidence interval [CI] 0.2%–2.8%).4

The first postmarketing case of natalizumab-associated PML occurred in 2008. As of September 2010, 68 cases of PML have been reported worldwide since market reintroduction. The incidence of PML increases with longer treatment duration (figure 1) but remains within the range observed in clinical trials.4 Data in patients exposed to natalizumab beyond 3 years are limited; all postmarketing cases of PML to date involve patients with MS, none of whom received fewer than 12 natalizumab infusions before diagnosis.

Figure 1
Figure 1 Estimated incidence of progressive multifocal leukoencephalopathy (PML) by natalizumab treatment epoch

Incidence estimates by treatment epoch were calculated based on natalizumab exposure through August 31, 2010, with 68 cases being confirmed as of September 2, 2010. The incidence for each epoch is calculated as the number of PML cases divided by the number of patients exposed to natalizumab (e.g., number of PML cases in patients who received 25–36 infusions is divided by the total number of patients who have ever been exposed to at least 25 infusions and therefore had the risk of developing PML during this time). The 95% confidence interval (CI) is an estimated range that is 95% likely to include the true rate of PML. The width of the CI is an indication of the precision of the estimate. Wider confidence intervals in relation to the point estimate indicate a higher level of uncertainty. Increasing the denominator of treated patients will increase the precision of the estimates and narrow the CI. There are limited data beyond 3 years of treatment.5

A recent publication reviewed the clinical presentation, diagnosis, and management of the first 28 patients with natalizumab-associated PML.5 Our analysis focuses on clinical outcomes and includes a critical evaluation of predictors of survival and assessment of disability status among natalizumab-associated PML survivors.

METHODS

Between January and March 2010, treating physicians for the first 35 postmarketing cases of natalizumab-associated PML provided clinical status updates on their patients using the Karnofsky Performance Scale,6 a functional outcome measure validated in several disease states and patient populations7,–,11 (table e-1 on the Neurology® Web site at www.neurology.org). Treating physicians also provided descriptions of their patients' clinical status, with an emphasis on motor function, cognition, and ability to perform daily activities. These outcome data were supplemented with information from the Biogen Idec natalizumab global safety database. The characteristics of patients with nonfatal and fatal cases of PML were compared to identify variables associated with improved survival.

RESULTS

Patient demographics.

Baseline demographics are shown in table 1. Patients include 10 men and 25 women aged 27–59 years (mean 43.7 years; median 43 years), with a mean MS duration of 12.5 years. Age, gender, and duration of MS in patients with PML were similar to those of the general natalizumab-treated MS population. Eleven patients were from the United States, and 24 patients were from Europe. Natalizumab exposure at the time of PML diagnosis ranged from 12 to 44 infusions (mean 26.6 infusions; median 26 infusions), and 49% of patients received at least one immunosuppressant drug (e.g., mitoxantrone, methotrexate, azathioprine, cyclophosphamide, or mycophenolate) before starting natalizumab. Expanded Disability Status Scale (EDSS) scores before PML diagnosis ranged from 0.0 to 6.5 (mean 4.2; median 4.0). At the time of the analysis, 25 patients (71%) had survived (3 from the United States and 22 from Europe), with a mean and median follow-up time of 6.8 and 4.5 months, respectively; 10 patients (29%) had died (8 from the United States and 2 from Europe).

View this table:
Table 1

Demographics and clinical outcome status of patients with PML

Predictors of survival in natalizumab-associated PML.

As shown in table 1, patients with nonfatal cases were younger at the time of PML diagnosis compared with those with fatal cases (mean age 40.7 vs 51.1 years) and had less disability before diagnosis, as evidenced by lower EDSS scores while receiving natalizumab (mean 3.9, median 3.5 vs mean 4.9, median 5.5). Gender distribution, duration of MS, natalizumab exposure, and immunosuppressant use before natalizumab were similar among those with nonfatal and fatal cases.

Nonfatal cases had a shorter time between symptom onset and PML diagnosis (mean 44.2 days; median 31 days) compared with fatal cases (mean 62.8 days; median 40.5 days) (figure 2A). Brain MRI results at the time of diagnosis were available for 31 patients and are shown in table 2. The majority of patients with nonfatal cases (86%) had either unilobar or multilobar disease (2 or more contiguous lobes), whereas the majority of those with fatal cases (70%) had widespread disease (2 or more noncontiguous lobes or disease present in both hemispheres). Unilobar PML involved the frontal and occipital lobes in 60% and 40% of patients, respectively. PML involvement of the posterior fossa was very rare, occurring in one patient who presented with widespread disease and had a fatal outcome. Gadolinium enhancement on MRI was present at diagnosis in 60% of patients with nonfatal cases and 33% of those with fatal cases (Biogen Idec, data on file). This difference was not thought to be clinically meaningful. As shown in figure 2B, JCV concentration in CSF at the time of PML diagnosis was lower in patients with nonfatal cases (mean 121,000 copies/mL; median 626 copies/mL) compared with those with fatal cases (mean 412,000 copies/mL; median 2,350 copies/mL). Twenty-five patients (18 nonfatal and 7 fatal cases) had CSF JCV testing performed by the NIH, which uses an ultrasensitive quantitative real-time PCR. To account for interlaboratory variability, CSF JCV loads for patients tested in the NIH laboratory were reviewed separately; patients with nonfatal cases had lower CSF JCV loads at diagnosis (mean 78,000 copies/mL; median 247 copies/mL) than those with fatal cases (mean 568,000 copies/mL; median 322 copies/mL). However, the difference in median values was small and may not be clinically meaningful.

Figure 2
Figure 2 Predictors of survival in natalizumab-associated progressive multifocal leukoencephalopathy (PML)

(A) A shorter time interval (mean number of days) between symptom onset and confirmed diagnosis of PML was observed in nonfatal cases than in fatal cases. (B) Median concentrations of JC virus (JCV) DNA in CSF tended to be lower in nonfatal than in fatal cases of natalizumab-associated PML.

View this table:
Table 2

PML extension by MRI at time of diagnosis

Initial treatment of PML was similar in both groups. Natalizumab treatment was withheld in all patients once PML was suspected. In the majority of patients with nonfatal cases (92%) and in all those with fatal cases, accelerated removal of natalizumab from the circulation was performed using plasma exchange (PLEX) or immunoadsorption (IA). Mefloquine or mirtazapine was prescribed in some patients on the basis of results of in vitro viral replication inhibition studies.12,13 Use of these 2 agents was similar, with 56% of patients with nonfatal cases and 80% of patients with fatal cases receiving mefloquine and 60% of those with nonfatal cases and 70% of those with fatal cases receiving mirtazapine.

Almost all patients with PML (32 of 35 [91%]) developed immune reconstitution inflammatory syndrome (IRIS), an enhanced intracerebral inflammatory antiviral reaction associated with restoration of immune surveillance (92% of patients with nonfatal cases and 90% of those with fatal cases). Diagnosis of IRIS was determined by the treating physician. IRIS presented as new or worsening neurologic symptoms, tended to be severe, and usually occurred within days or weeks after accelerated removal of natalizumab. The mean time from initiation of PLEX or IA to onset of IRIS symptoms was similar for patients with nonfatal and fatal cases (35.3 and 32.4 days, respectively). The 3 patients for whom IRIS was not reported included one patient who died 4 weeks after PML diagnosis (before onset of IRIS) and 2 patients in whom PML was diagnosed in January 2010 and for whom physicians had not yet reported the development of IRIS at the time of the analysis. Of the 35 patients, 30 (86%) were treated with corticosteroids. The majority (86% of patients with nonfatal cases and 75% of those with fatal cases) received high-dose corticosteroids (at least 3 g methylprednisolone or the equivalent). Although data are limited, the most common regimens were pulsed IV high-dose corticosteroids or IV high-dose corticosteroids followed by oral taper.

PML clinical outcomes.

Causes and timing of death in PML.

Ten of 35 patients with PML (29%) had died at the time of the analysis. Mean and median times from PML diagnosis to death were 3.1 and 1.8 months, respectively (range 1–10.5 months). Seven of 10 patients died within approximately 2 months of PML diagnosis, and 5 probably died of IRIS. In all 5 possible deaths associated with IRIS, further medical intervention was withheld at the request of the patient or patient's family because of severe clinical worsening. Other causes of death included aspiration pneumonia (2 patients), hypoventilation syndrome and respiratory failure after residual brainstem injury from PML (1 patient), and progressive clinical worsening, tetraplegia, and coma leading to death 4 months after PML diagnosis (1 patient). In addition, one patient developed seizures/status epilepticus and, in the setting of clinical worsening, requested that further medical intervention and nutrition be withheld; this patient died of dehydration and acute renal failure approximately 11 months after PML diagnosis.

Functional outcomes in PML survivors.

Disability status measured by Karnofsky scores for the 25 PML survivors is provided in table 3. Four patients (16%) had mild disability (Karnofsky scores 80–90), 9 patients (36%) had moderate disability (Karnofsky scores 50–70), and 12 patients (48%) had severe disability (Karnofsky scores 10–40). These physician- reported clinical assessments were part of a cross-sectional review, and each patient was observed at a different time point in the course of PML. Therefore, the duration between time of PML diagnosis and clinical assessment was evaluated. In general, patients with mild disability seemed to have had more elapsed time since their PML diagnosis (mean 10.4 months; median 8 months) than patients with severe disability (mean 6 months; median 4 months) (table 3). Evaluation of disability after an acute event is best accomplished once the patient has reached a stable clinical state. In other neurologic conditions, such as acute stroke, the greatest improvements present within the first weeks to months, and neurologic deficits generally stabilize 3–6 months after the acute event.14 Therefore, clinical outcomes of patients with PML who had at least 6 months follow-up after their PML diagnosis were analyzed separately. Of the 25 PML survivors, 12 had at least 6 months follow-up between PML diagnosis and time of clinical assessment. Four of these 12 patients (33%) had mild disability, 4 (33%) had moderate disability, and 4 (33%) had severe disability.

View this table:
Table 3

Disability status for PML survivors based on Karnofsky scores

Qualitative assessments of functional outcomes.

The range of functional outcomes experienced by natalizumab-associated PML survivors is exemplified by the first 2 cases reported in the postmarketing period.15,16 In a more recent case report, a patient with natalizumab-associated PML was successfully treated and returned to baseline pre-PML EDSS.17 Further examples of PML case outcomes are described in the following.

Mild disability.

A 45-year-old woman from Europe previously treated with mitoxantrone and with a pre-PML EDSS of 4.0 while receiving natalizumab was diagnosed with PML after 34 months of natalizumab. CSF JCV load was 760 copies/mL, and MRI demonstrated unilobar PML. Treatment included PLEX. She also received a 3-day course of IV methylprednisolone (1 g daily) followed by a corticosteroid taper over 6 weeks to treat IRIS. At 9 months after the diagnosis of PML, the patient had a Karnofsky score of 90, was ambulatory, and had no cognitive impairment. The only clinical sequela from PML was a bilateral homonymous quadranopsia.

Moderate disability.

A 35-year-old woman from the United States with no prior immunosuppressant use and with a pre-PML EDSS of 2.0 while receiving natalizumab was diagnosed with PML after 24 doses of natalizumab. CSF JCV load was 1.2 million copies/mL, and MRI demonstrated multilobar PML. Treatment included PLEX, mefloquine, and mirtazapine. She also received a 4-day course of IV methylprednisolone (1 g daily) followed by a corticosteroid taper over 4 weeks to treat IRIS. At 9 months after the diagnosis of PML, the patient had a Karnofsky score of 50. She required assistance with most daily activities and was ambulatory with assistance. Despite marked improvement in her attention and neglect, she continued to have an impaired ability to communicate and plegia in her left arm.

Severe disability.

A 27-year-old man from Europe with no prior immunosuppressant use and with a pre-PML EDSS of 4.5 while receiving natalizumab was diagnosed with PML after 29 months of natalizumab. CSF JCV load was 325 copies/mL, and MRI demonstrated multilobar PML. Treatment included PLEX, mefloquine, mirtazapine, and IV methylprednisolone before development of IRIS. He subsequently received 3 additional courses of IV corticosteroids over the next 2 months for IRIS. At 8 months after the diagnosis of PML, the patient had a Karnofsky score of 40 and required assistance with all daily activities. His cognitive functions were largely intact, but he had severe right-sided hemiparesis, moderate left leg weakness, and slight expressive dysphasia.

DISCUSSION

Analysis of the first 35 postmarketing cases of natalizumab-associated PML revealed 71% survival, with mean and median follow-up times of 6.8 and 4.5 months, respectively. Comparison of patients with nonfatal and fatal cases identified several characteristics that seem to be associated with improved survival in natalizumab-associated PML: younger age at diagnosis, less disability (lower EDSS scores) before PML, more localized disease on MRI, and shorter time from symptom onset to PML diagnosis. There are several possible biologic mechanisms to explain how these characteristics relate to survival after PML. Disability progression (as measured by EDSS) has been shown to correlate with whole-brain atrophy progression,18 and patients with lower levels of disability may therefore have more brain reserve with which to sustain acute injuries such as PML. Conversely, identification of initial PML symptoms in patients with greater levels of disability may be confounded by the presence of severe MS symptoms and delay diagnosis. Earlier PML diagnosis limits irreversible brain damage that can occur before development of IRIS and is therefore likely to influence overall clinical outcome,5 as evidenced by the current analysis.

The 71% survival rate for natalizumab-associated PML in this analysis is higher than survival rates reported for PML in other populations such as patients with HIV infection before the era of highly active antiretroviral therapy (HAART) and transplant recipients. A survival rate of 29% has been reported in transplant recipients with PML (17 of 24 died). The median duration of PML in these patients was 2.5 months (range 0.5–15 months).19 In a separate report of renal transplant recipients with PML, survival was 31% (9 of 13 died); 8 patients died within 5 months of PML diagnosis (range 2–13 months). Survivors were more likely to have undergone immunosuppressant reduction or discontinuation.20 In the HIV infection–associated PML population, 1-year survival rates of 10% before the HAART era and 50% survival rates after the introduction of HAART have been reported.21 A 26% survival rate has been reported among patients with PML within the Danish HIV Cohort Study (35 of 47 died).22 Thirteen patients with PML diagnosed before the HAART era had a median survival of approximately 5 months, whereas 34 patients with PML diagnosed after the introduction of HAART had a median survival of 1.8 years.22 Patients with PML who have immune systems capable of reconstitution have a higher survival rate than patients with immune systems that cannot be reconstituted.5,19,23,24 Therefore, a possible reason for the improved survival seen in natalizumab-associated PML is that these patients have intact, functional immune systems that can be reconstituted. Removal of natalizumab from the circulation by withholding of treatment, PLEX, or IA results in restoration of immune surveillance to the CNS.25 Another factor possibly contributing to improved survival in natalizumab-associated PML is earlier detection of PML. The extensive education on PML that is provided to prescribers, patients, and relatives as part of global risk-management programs for natalizumab has probably resulted in earlier detection of PML, and prompt restoration of immune surveillance has contributed to better clinical outcomes.26

Natalizumab-associated PML survivors exhibit various levels of disability, ranging from mild to severe. Limited information describing the clinical status of PML survivors in other populations is available in the literature. One study evaluated clinical outcomes in 118 patients with HIV infection treated with HAART and PML.27 Of the 118 patients, 75 (63.6%) survived for a median of 114 weeks (2.2 years). For the 73 survivors with available follow-up, neurologic function was “cured” (resolution of symptoms and signs of PML) or “improved” (reduction of symptoms and signs of PML) in 33 patients (44%) and “stabilized” (no change in symptoms and signs of PML) or “worsened” (progression of symptoms and signs of PML) in 40 patients (53%).27 The assessment tool used by investigators in that study differed from the Karnofsky Performance Scale used in our analysis, making a direct comparison of clinical outcomes between natalizumab-associated PML survivors and this particular group of PML survivors with HIV infection difficult. A more recent report of 24 long-term (>5 years) PML survivors (23 HIV-positive and one HIV-negative with non-Hodgkin lymphoma)28 used the modified Rankin disability scale (mRDS).29 This validated, quantitative measure of functional status may be more comparable to the Karnofsky Performance Scale. After an average observation period of 94.2 months, 8 of 24 patients (33%) had no significant disability despite persistent symptoms (mRDS score = 1), 6 of 24 patients (25%) were living independently with slight disability (mRDS score = 2), 5 of 24 patients (21%) were moderately disabled, requiring some help with activities of daily living (mRDS score = 3), and 5 of 24 patients (21%) had moderately severe disability, requiring constant help or institutionalization (mRDS score = 4).28

One of the limitations of our analysis is the lack of long-term follow-up of PML survivors. From the time that the first postmarketing case of natalizumab-associated PML was reported in 2008 to the time of the current analysis, the proportion of patients who survive has remained near 70%. Because most deaths of PML occurred within 2 months of diagnosis, it appears likely that this survival rate will be maintained. However, the number of patients with long-term follow-up is still limited; only 12 of 25 PML survivors had follow-up beyond 6 months at the time of this analysis. More detailed and standardized long-term data collection on PML survivors is needed to better characterize functional status and to reassess predictors of disability. Obtaining these long-term data will require a collaborative effort among treating physicians, Biogen Idec, and Elan. Another limitation of the current analysis is that our attempt to characterize the clinical status of PML survivors was probably confounded by disability attributable to underlying MS. Therefore, interpretation of residual disability after PML should be made cautiously.

Although PML has traditionally been considered a fatal disease, current data for natalizumab-associated PML challenge this belief. Improved survival is probably the result of earlier diagnosis through enhanced clinical vigilance and aggressive treatment of both the primary PML process and secondary IRIS in the setting of underlying normal immune function. PML remains a serious and sometimes fatal complication of natalizumab therapy, but the majority of patients with natalizumab-associated PML have survived with various levels of disability. Delineation of premorbid risk factors, better understanding of the natural history and epidemiology of natalizumab-associated PML, earlier diagnosis, and further refinement and development of therapeutic modalities for treatment of both PML and IRIS should continue to improve clinical outcomes.

AUTHOR CONTRIBUTIONS

Statistical analysis was conducted by Dr. Sandra Richman. Dr. Vermersch, Dr. Kappos, Dr. Gold, Dr. Foley, and Dr. Olsson are representatives of the PML Outcomes Working Group.

DISCLOSURE

Prof. Vermersch serves on scientific advisory boards for Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Teva Pharmaceutical Industries Ltd., and sanofi-aventis; has received funding for travel and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Novartis, Teva Pharmaceutical Industries Ltd., sanofi-aventis, and Merck Serono; and receives research support from Biogen Idec, Merck Serono, sanofi-aventis, Teva Pharmaceutical Industries Ltd., and Bayer Schering Pharma. Prof. Kappos serves on the editorial board of the International MS Journal and Multiple Sclerosis Journal; receives research support from the Swiss National Research Foundation, the Swiss MS Society, and the Gianni Rubatto Foundation (Zurich); his department at the University Hospital Basel has received research support from Actelion, Advancell, Allozyne, BaroFold, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, CLC Behring, Elan, Genmab, Genmark, GeNeuro SA, GlaxoSmithKline, Lilly, Merck Serono, MediciNova, Novartis, Novonordisk, Peptimmune, Sanofi-aventis, Santhera, Roche, Teva, UCB, and Wyeth. LK has been principal investigator, member, or chair of steering committees or advisory boards in multiple sclerosis clinical trials sponsored by these companies, and has received lecture fees from one or more of these companies. Payments and consultancy fees were exclusively used for the support of research activities. Prof. Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of American Journal of Pathology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Merck Serono, and Novartis. Dr. Foley serves on scientific advisory boards for Biogen Idec and Genzyme Corporation; has received funding for travel and speaker honoraria from Biogen Idec and Teva Pharmaceutical Industries Ltd.; serves as a consultant for Novartis, Biogen Idec, Teva Pharmaceutical Industries Ltd., and Genzyme Corporation; and serves on the speakers' bureau for Novartis, Biogen Idec, and Teva Pharmaceutical Industries Ltd. Prof. Olsson has served on scientific advisory boards for Merck Serono, Biogen Idec, sanofi-aventis, and Novartis; serves as Co-Editor for Current Opinion in Immunology; has received speaker honoraria from Novartis, Biogen Idec, sanofi-aventis, and Merck Serono; and receives research support from Merck Serono, Biogen Idec, sanofi-aventis, Bayer Schering Pharma, Novartis, The Swedish Research Council (07488), the European Union, EURATools, the Söderbergs Foundation, Bibbi and Nils Jensens Foundation, the Montel Williams Foundation, and the Swedish Brain Foundation. Dr. Cadavid is a full-time employee of and owns stock and stock options in Biogen Idec and has received research support from the NIH. Dr. Bozic is a full-time employee of and owns stock in Biogen Idec. Dr. Richman is a full-time employee of and owns stock in Biogen Idec.

ACKNOWLEDGMENT

The authors thank the following contributors and members of the PML Outcomes Working Group who provided patient information (in alphabetical order): Dr. Zdenek Ambler, Professor Gabriele Arendt, Professor Bruno Brochet, Professor Renaud Du Pasquier, Dr. John Foley, Professor Ralf Gold, Dr. Kerstin Hellwig, Dr. Karin Hoehn, Professor Michael Hutchinson, Dr. Mark Janicki, Dr. Ilijas Jelcic, Professor Ludwig Kappos, Dr. Klimentini Karageorgiou, Dr. Charles Kaufman, Professor Bernd Kieseier, Dr. Christoph Klawe, Dr. Ingo Kleiter, Dr. Roderick Kriekaart, Dr. Lauren Krupp, Dr. Jens Kuhle, Dr. Chris Laganke, Dr. Hans Linda, Professor Alfred Lindner, Professor Michael Linnebank, Dr. K. Alvin Lloyd, Dr. Jochen Machetanz, Dr. Blair Marsteller, Dr. Claes Martin, Dr. Michael Marvi, Professor Mathias Maschke, Professor Erich Mauch, Dr. Roy Meckler, Dr. Martin-Andreas Müller, Dr. Erik van Munster, Dr. Kevin Murphy, Professor Tomas Olsson, Dr. Agustín Oterino, Dr. Jean-Christophe Ouallet, Dr. Olivier Outteryck, Dr. Fredrik Piehl, Professor Ernst-Wilhelm Radue, Dr. Alexandra Schröder, Professor Klaus V. Toyka, Professor Patrick Vermersch, Professor Sandra Vukusic, Dr. Randall Webb, Dr. Anna Weidlich, Dr. Bianca Weinstock-Guttman, Dr. Gary Weiss, Dr. Werner Wenning, Professor Heinz Wiendl, Dr. Hélène Zephir, and Professor Uwe Zettl. Members of the PML Outcomes Working Group participated in the Biogen Idec/Elan–sponsored PML Outcomes Meeting held in London, UK, on February 27–28, 2010, and completed a PML Standardized Data Collection Form with clinical outcome data for their PML patients. The authors thank the following groups of people for their contribution to this manuscript: Biogen Idec Drug Safety and Risk Management (United States and International) for collecting and processing all natalizumab PML cases globally; Biogen Idec Affiliate Medical Directors, Staff, and Distributors for help in contacting PML physicians in their regions and assisting with the collection of PML Standardized Data Collection Forms/Clinical Outcome Data; Biogen Idec US Medical Affairs Representatives/Medical Science Liaisons for help in contacting US PML physicians and assisting with the collection of PML Standardized Data Collection Forms/Clinical Outcome Data; Eugene O. Major, PhD, and the NIH laboratory for performing ultrasensitive quantitative real-time PCR testing for JCV DNA on many of the CSF samples from patients included in this analysis; and Dr. Frederick Munschauer, Dr. Tuan Dong-Si, Dr. Glyn Belcher, Dr. Mariska Kooijmans, Dr. Christophe Hotermans, Dr. Grainne Quinn, and Susan Goelz, PhD, from Biogen Idec and Elan who participated in the PML Outcomes Meeting in London, UK. The authors also thank Dr. Petra Duda for her input to the content of the PML Data Collection Tool and Bill Aschenbach, PhD, for reviewing, copyediting, and providing graphic assistance with this manuscript.

Footnotes

  • Editorial, page 1688

  • Supplemental data at www.neurology.org

  • CI
    confidence interval
    EDSS
    Expanded Disability Status Scale
    HAART
    highly active antiretroviral therapy
    IA
    immunoadsorption
    IRIS
    immune reconstitution inflammatory syndrome
    JCV
    JC virus
    mRDS
    modified Rankin disability scale
    MS
    multiple sclerosis
    PLEX
    plasma exchange
    PML
    progressive multifocal leukoencephalopathy

  • Received August 10, 2010.
  • Accepted November 23, 2010.

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