Improvement of Neuropsychological Function in Cognitively Impaired Multiple Sclerosis Patients Treated with Natalizumab. A Preliminary Study

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1 Improvement of Neuropsychological Function in Cognitively Impaired Multiple Sclerosis Patients Treated with Natalizumab A Preliminary Study Keith R. Edwards, MD; William A. Goodman, PsyD; Carl Y. Ma, PhD Treatment with natalizumab has been shown to reduce physical disability in people with multiple sclerosis (MS). However, its effect on neuropsychological dysfunction is not well understood. A singlecenter, open-label, retrospective study was conducted to evaluate the effect of natalizumab treatment on neuropsychological function in individuals with relapsing-remitting multiple sclerosis (RRMS) who had a measurable neuropsychological deficit prior to natalizumab treatment. A total of 40 MS patients (mean age, 48.5 years; 77.5% female) were evaluated on a neuropsychological battery of nine tests designed for MS patients before and after 6 or more months of treatment with natalizumab. Posttreatment neuropsychological testing results were compared to baseline results. The mean baseline Neuropsychological Impairment Index was 0.49, which improved to 0.41 after treatment (P =.0002) as analyzed using the Wilcoxon signed rank test. The mean Beck Depression Inventory II (BDI-II) score improved by 2.45 points (P =.001). The mean Expanded Disability Status Scale (EDSS) score improved by 0.30 (P =.02). A total of 52.5% of patients showed neuropsychological improvement, while 30.0% showed no change and 17.5% had worsening. Magnetic resonance imaging showed no changes. The specific prior disease-modifying therapy had no influence on the results for natalizumab effect. The results of this study show that natalizumab can stabilize or improve neuropsychological function in RRMS patients. The improvement was consistent with, but apparently independent of, improvement in depression and physical disability. Int J MS Care. 2012;14: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that causes progressive neurologic disability by a combination of inflammation, demyelination, and axonal degeneration. Axonal degeneration and permanent disability may occur even at early stages of the disease. 1-3 Several observational studies using the Expanded Disability Status Scale (EDSS) to measure change in functioning over time have revealed much about the natural history of MS disability. 4,5 Physical disability as From the MS Center of Northeastern New York, Latham, NY, USA (KRE, WAG); and PharmStats, Ltd, Escondido, CA, USA (CYM). Correspondence: Keith R. Edwards, MD, MS Center of Northeastern New York, 1205 Troy-Schenectady Rd., Ste. 105, Latham, NY 12110; kedwards@tristateneuro.com. measured by the EDSS has been shown to be reduced, compared to placebo, by several of the currently available disease-modifying treatments (DMTs) that have been approved by the US Food and Drug Administration (FDA) for relapsing forms of MS. However, 50% to 65% of MS patients may develop neuropsychological impairment during the course of the disease Because such impairment is a major cause of disability in MS patients, the importance of assessment of cognitive function in MS cannot be overestimated. 6-8 Neuropsychological symptoms in MS commonly involve attention span, processing speed, multitasking, and working memory Verbal fluency is typically spared, so that cognitive deficits may not be recognized in the absence of specific neuropsychological test- 100

2 Improved Neuropsychological Function with Natalizumab in MS Patients ing, which may not be performed until the deficits are advanced. Even in so-called benign MS, difficulty in the ability to process information may be great enough to prevent employment. 12 Neuropsychological deficits may be independent of physical disability. 6 Early cognitive impairment, however, may be associated with rapidly progressing physical disability as measured by the EDSS. 11,13 Treatment with some DMTs appears to reduce neuropsychological impairment as compared with placebo. Weekly intramuscular (IM) interferon beta-1a (IFNβ- 1a) has shown statistically significant neuropsychological benefit compared with placebo in a 2-year multicenter treatment trial using a comprehensive neuropsychological battery 14 and a computerized battery. 15 A 2-year trial with glatiramer acetate (GA) did not show any benefit over placebo with a comprehensive neuropsychological battery. 16 Other studies of patients treated with DMTs have shown some benefit in neuropsychological function as measured by the Paced Auditory Serial Addition Test (PASAT), but comprehensive neuropsychological testing was not performed. 17,18 In an early study involving IFNβ-1b, all but one neuropsychological function failed to show any improvement with treatment. 19 Natalizumab has been shown to significantly reduce neurologic disability as measured by the EDSS in the AFFIRM and SENTINEL trials. 20,21 Additionally, improvements in PASAT scores in the AFFIRM and SENTINEL trials suggested a neuropsychological benefit compared with placebo. 18 To date, results from a comprehensive neuropsychological battery in patients assessed before and after treatment with natalizumab have not been published. Because cognitive dysfunction is a significant cause of disability in MS patients, members of our MS center have long had a special interest in it. 9,22 When appropriate, we perform not only yearly magnetic resonance imaging (MRI) studies to measure adequacy of a DMT but also a neuropsychological battery (Table 1) that is similar to the Minimal Assessment of Cognitive Functions in Multiple Sclerosis (MACFIMS). 23 Unlike the MACFIMS, our battery is designed to avoid the confounding issue of motor movements in the measurement of cognitive abilities. Although similar to the MACFIMS battery in scope and length, the battery does not include tasks requiring motor output and thus does not assess visual memory. Tests included in the battery reflect the most common neuropsychological deficits in Table 1. Cognitive assessment protocol for multiple sclerosis Digit Span Subtest of the Wechsler Adult Intelligence Scale IV Stroop Color Word Test Letter Number Sequencing Test of the Wechsler Adult Intelligence Scale IV Paced Auditory Serial Addition Test Revised (Rao version, 2 and 3 seconds) California Verbal Learning Test II Logical Memory Subtest of the Wechsler Memory Scale IV Controlled Oral Word Association Test North American Adult Reading Test Revised Symbol Digit Modalities Test (oral version only) MS: processing speed, working memory, word retrieval, and executive functions. Baseline and follow-up testing are performed, allowing the efficacy of a DMT in preventing disability to be measured not only by the EDSS but also by neuropsychological status. The current study was conducted to evaluate the effect of natalizumab treatment on neuropsychological function in individuals with relapsing-remitting multiple sclerosis (RRMS) who had a measurable neuropsychological deficit prior to the initiation of natalizumab. Patients and Methods This single-center, open-label, retrospective study involved 40 consecutive natalizumab-treated MS patients with a measurable neuropsychological deficit prior to natalizumab treatment. Male and female patients were eligible to participate if they had RRMS, were aged 18 to 60 years, had been administered a comprehensive neuropsychological evaluation prior to receiving natalizumab, and had received at least six treatments of natalizumab, with repeat neuropsychological testing. Posttreatment test results were compared with pretreatment results. None of the patients had significant concomitant illness, medication changes, or any other factor that might cause neuropsychological dysfunction. The study was approved by the BioMed Institutional Review Board. Because the analyses were retrospective and related to data used for routine treatment, no patient consent forms were necessary. Each subtest of the neuropsychological evaluation specific for MS (Table 1) was rated as normal or abnormal, defined as one or more standard deviations (SD) from the norm. Each of the nine subtests was assigned a value of zero if normal or 0.11 if abnormal. 15 Therefore, a patient with a score of zero showed 101

3 Edwards et al. no cognitive dysfunction, since no test scores were at or more than one SD from the norm. A score of 0.22 indicated mild cognitive dysfunction, a score of 0.44 indicated moderate cognitive dysfunction, and a score of above 0.66 to 0.99 indicated severe cognitive dysfunction. Those values were summed to create a total Neuropsychological Impairment Index, with lower scores indicating impairment in fewer domains. If the impairment index score was 0.22 or higher, the patient was considered neuropsychologically impaired and qualified for enrollment in the study. Our primary analysis compared the pre natalizumab treatment Neuropsychological Impairment Index score to the posttreatment score. We also assessed changes in the Beck Depression Inventory II (BDI-II) score, EDSS score, and MRI data, as well as prior DMT use. Treatment and Procedures Natalizumab, 300 mg, was given intravenously over 1 hour every 4 weeks, followed by a 1-hour observation period. Infusions were administered at the MS Center of Northeastern New York by an infusion nurse belonging to the International Organization of MS Nurse Specialists (IOMSNS). There were no changes in concomitant medications or illnesses that would affect neuropsychological testing results during the observation and testing periods. Statistical Analyses Comparison of baseline with posttreatment data was performed using the Wilcoxon signed rank test to calculate P values. Exploratory analyses for possible interactions between neuropsychological changes and EDSS score or depression were performed using analysis of variance (ANOVA) adjusted for age and baseline values. Results Baseline Characteristics Of the 40 patients, there were 31 females (77.5%) and 9 males (22.5%). The mean (SD) age was 48.5 (6.87) years. The mean number of natalizumab infusions was Prior DMT use included most FDAapproved medications and some immunosuppressants (Table 2). The mean (SD) EDSS score at baseline was 4.59 (1.24). The mean (SD) BDI-II score at baseline was 13.3 (10.5). The mean (SD) neuropsychological impairment rating at baseline was 0.49 (0.21). Standard cranial MRI with and without contrast enhancement Table 2. Summary of prior individual DMT use Prior DMT No. (%) of patients Interferon beta-1a IM 32 (80.0) Interferon beta-1b SC 7 (17.5) Glatiramer actetate SC 19 (47.5) Cyclophosphamide 6 (15.0) IVIG 2 (5.0) Methotrexate 6 (15.0) Mitoxantrone 8 (20.0) Mycophenolate 2 (5.0) Interferon beta-1a SC 10 (25.0) Abbreviations: DMT, disease-modifying therapy; IM, intramuscular; IVIG, intravenous immunoglobulin; SC, subcutaneous. Note: A patient may have used more than one DMT. was performed on a 1.5-T magnet before initial treatment with natalizumab. Treatment Effects Comprehensive neuropsychological performance improved from a mean Neuropsychological Impairment Index score of 0.49 at baseline to a mean score of 0.41 at the time of retesting (P =.0002). Depression ratings on the BDI-II improved from a mean score of to a mean score of (P =.001). The mean EDSS score improved from 4.59 to 4.29 (P =.02). A total of 52.5% of patients showed neuropsychological improvement, while 30.0% showed no change and 17.5% had worsening. Although all three functional measures improved, there was greater improvement in cognition than in depression or disability rating. Analysis of variance adjusted for age and baseline values did not show any statistically significant correlations between cognition and depression or EDSS score with specified baseline conditions (Table 3). Safety There were no adverse events associated with natalizumab in any of the 40 patients during the treatment period. There were no serious infusion reactions, laboratory abnormalities, or cases of progressive multifocal leukoencephalopathy (PML). Discussion This is the first study that we know of to demonstrate an improvement in cognition as assessed by a comprehensive neuropsychological battery with natalizumab treatment for patients with RRMS within a single year. Previous studies using comprehensive neuropsychological batteries have not consistently demonstrated improvement following treatment with other DMTs 102

4 Table 3. Analysis of variance Improved Neuropsychological Function with Natalizumab in MS Patients Comparison groups Variable P value Baseline COG 0.4 vs. > 0.4 EDSS change from baseline a.9661 Baseline COG 0.4 vs. > 0.4 BDI-II change from baseline b.1666 Baseline EDSS 3 vs. > 3 BDI-II change from baseline b.2717 Baseline EDSS 3 vs. > 3 COG change from baseline a.3187 Baseline BDI-II 12 vs. > 12 EDSS change from baseline a.6534 Baseline BDI-II 12 vs. > 12 COG change from baseline a.1185 Abbreviations: COG, cognition; BDI-II, Beck Depression Inventory II; EDSS, Expanded Disability Status Scale. a Wilcoxon rank sum test. b Analysis of variance adjusted for age and baseline value. in MS. 19,24 The ability to detect neuropsychological changes in such a small cohort of patients, in contrast to the failure to do so in much larger phase 4 clinical trials, points to either a stronger effect of natalizumab on cognition or the superior sensitivity of the test battery employed here. Moreover, individuals in this study showed some degree of cognitive impairment at baseline, which may not have been the case in other studies. Thus, our patients may have been better positioned to show measurable change. Neuropsychological symptoms may be subtle, may be confused with depression or anxiety, or may be comorbid with mood disturbance. As shown by careful testing in other studies, cognitive impairment may be disabling even if the EDSS score is in the traditionally benign category. 12 Just as changes in physical disability may prompt a change in DMT, a decline in neuropsychological function may warrant a change in treatment in order to limit progression. A comprehensive neuropsychological battery is needed to assess cognitive function in people with MS. The PASAT-3ʺ may be a useful screening test, but other evaluations are needed to achieve an understanding of overall neuropsychological function. The neuropsychological battery used in this study (Table 1) was adapted from the MACFIMS to avoid tasks requiring motor output. To ensure that not just one or two of the tests were significantly affecting the total Neuropsychological Impairment Index, an analysis of individual tests using the paired t test or Wilcoxon signed rank test was performed. The results indicated that there was no single individual test that influenced the impairment index as a whole. This limited, retrospective study suggests that natalizumab may stabilize or even improve neuropsychological status in some RRMS patients with pre-existing neuropsychological deficits, including those who have experi- enced progression of disease with prior trials of DMTs (Table 2). Multivariate analyses indicated that improvement in cognitive impairment was independent of improvement in depression or physical impairment. Prospective studies are needed to confirm this observation. Conclusion The results of this study indicate that natalizumab therapy can stabilize or improve neuropsychological performance in a substantial proportion of MS patients. This finding is clinically relevant to a population that is expected to have progressive decline in neuropsychological function over time. Changes in neuropsychological function can be detected even in the absence of disease progression as measured by the EDSS. These results support the effectiveness of natalizumab therapy in the treatment of both physical disease activity and cognitive impairment in patients with RRMS. Testing for neuropsychological performance is an important component of overall evaluation of the physical, cognitive, and mental health of MS patients. A prospective multicenter trial is needed to confirm the preliminary results of this PracticePoints Neuropsychological dysfunction is the most common cause of disability in individuals with MS, affecting up to 65% of patients. Despite its high prevalence in MS, neuropsychological dysfunction is often overlooked, and recognition of impairments requires vigilance by patients and physicians. Natalizumab can have a stabilizing effect on neuropsychological dysfunction in MS patients. Some patients may experience a measurable improvement in cognitive function, independent of mood or physical function, after 6 months of treatment with natalizumab. 103

5 From the Department of Biomedical Engineering and Department of Physical Medicine and Rehabilitation, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA (MP); and Department of Occupational Therapy, University of Illinois at Chicago, Chicago, IL, USA (MF). Correspondence: Matthew Plow, PhD, Department of Biomedical Engineering and Department of Physical Medicine and Rehabilitation, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave., ND-20, Cleveland, OH 44195; 21 Edwards et al. study. Because cognitive dysfunction is a major cause of disability in MS patients, the results of comprehensive neuropsychological testing should be a primary or at least a secondary outcome measure in future multicenter trials of DMTs for MS. o Acknowledgments: The authors wish to thank Vineetha Kamath for her excellent technical assistance in the preparation of this manuscript. Financial Disclosures: Dr. Edwards has received financial compensation from Novartis Pharmaceuticals and Biogen Idec for serving on their scientific advisory boards, as well as from Novartis Pharmaceuticals, Biogen Idec, Acorda, and EMD Serono for serving as a speaker. He has received financial support for research activities from Biogen Idec, Novartis, Actelion, Acorda, Genzyme, EMD Serono, Eli Lilly, Janssen, and Sanofi-Aventis. Drs. Goodman and Ma have no conflicts of interest to disclose. Funding/Support: This work was supported by funding from Biogen Idec. References 1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338: Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372: Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. 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Cognitive function in patients with multiple sclerosis. Arch Neurol. 1980;37: Patti F. Cognitive impairment in multiple sclerosis. Mult Scler. 2009;15: Deloire MS, Salort E, Bonnet M, et al. Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76: Rovaris M, Riccitelli G, Judica E, et al. Cognitive impairment and structural brain damage in benign multiple sclerosis. Neurology. 2008;71: Lynch SG, Parmenter BA, Denney DR. The association between cognitive impairment and physical disability in multiple sclerosis. Mult Scler. 2005;11: Fischer JS, Priore RL, Jacobs LD, et al.; Multiple Sclerosis Collaborative Research Group. Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Ann Neurol. 2000;48: Wilken JA, Kane R, Sullivan CL, et al. 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A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354: Edwards K, Goodman W, Wilken J, et al. Computerized testing to screen for cognitive impairments in MS. Mult Scler. 2009;15:S Benedict RH, Fischer JS, Archibald CJ, et al. Minimal neuropsychological assessment of MS patients: a consensus approach. Clin Neuropsychol. 2002;16: Galetta SL, Markowitz C, Lee AG. Immunomodulatory agents for the treatment of relapsing multiple sclerosis: a systematic review. Arch Intern Med. 2002;162: HERNDON AWARD FOR OUTSTANDING IJMSC ARTICLE The Consortium of Multiple Sclerosis Centers (CMSC) presents an annual award, the Herndon Award for Outstanding IJMSC Article, for the best article published in the during a given calendar year. Preference is given to articles that are based on data presented at an annual CMSC meeting. The winners of the 2011 award are Matthew Plow (Cleveland Clinic Lerner Research Institute) and Marcia Finlayson (University of Illinois at Chicago), for their article Potential Benefits of Nintendo Wii Fit Among People with Multiple Sclerosis: A Longitudinal Pilot Study, published in the Spring 2011 issue of IJMSC. The award carries a $1000 stipend. Robert M. Herndon was the founding editor of IJMSC and currently serves as Editor Emeritus. Potential Benefits of Nintendo Wii Fit Among People with Multiple Sclerosis A Longitudinal Pilot Study Matthew Plow, PhD; Marcia Finlayson, PhD, OT(C), OTR/L We examined the potential of Nintendo Wii Fit (Nintendo Co, Ltd, Kyoto, Japan) to increase physical activity (PA) behavior and health among people with multiple sclerosis (MS). The study consisted of a repeated-measures design with a baseline control period and involved 30 people with MS who had the ability to walk 25 feet with or without a cane (26 individuals were included in the analyses). Nintendo Wii was set up in the homes of participants, who were prescribed a Wii Fit exercise program lasting 14 weeks, 3 days a week. The Physical Activity and Disability Survey, Modified Fatigue Impact Scale, and 36-item Short Form Health Status Survey were administered three times before participants gained access to Wii Fit (control period, at 2-week intervals), and three times after they received Wii Fit (posttest 1: immediately after; posttest 2: 7 weeks after; posttest 3: 14 weeks after). Mobility, balance, strength, and weight were assessed at the first pretest, immediately prior to obtaining access to Wii Fit, and 7 weeks after obtaining access to Wii Fit. Results from the questionnaires indicated that PA significantly improved at week 7, but at week 14, PA levels declined relative to week 7 and the difference was no longer significant compared with the control period. Physical assessments indicated that balance and strength significantly improved at week 7. One adverse event was reported (repetitive knee injury). Physical assessments indicated that people with MS may be able to improve their fitness levels by using Wii Fit. Future studies should incorporate behavior change strategies to promote long-term use of Wii Fit, and explore whether individuals with more severe symptoms of MS can safely use Wii Fit. Int J MS Care. 2011;13: egular physical activity (PA) has established program resulted in improved health perception and benefits among people with mild-to-moderate reduced fatigue among MS patients. R 5 Nevertheless, a multiple sclerosis (MS). 1 It has been shown meta-analysis found that, in general, people with MS are that regular PA over a 5-year period has a positive effect inactive. 6 Furthermore, few clinical trials have identified on quality of life and physical function in people with intervention strategies to promote routine participation MS. 2 A 15-week aerobic training program was found in PA and/or exercise programs. The low rates of PA among people with MS may to reduce fatigue and body fat percentage as well as be due to the personal and environmental barriers to improve strength in individuals with MS. 3 Romberg et routine PA faced by this population. Symptoms related al. 4 found that a home-based resistance strength training to MS, such as fatigue, pain, and depression, as well as program resulted in improved walking speed in people mobility impairments, can reduce motivation and capacity to engage in PA Furthermore, social obligations with MS. Even regular participation in a 4-week exercise (eg, domestic roles), reactions to the social environment (eg, stress), and accessibility of health clubs can all interfere with PA. 11,12 Given these numerous barriers, innovative intervention strategies are needed to promote PA in people with MS. One such innovative strategy may be the use of interactive video game technology. Advances in gaming technology now allow individuals to exert 104