JNS-13032; No of Pages 5 Journal of the Neurological Sciences xxx (2014) xxx–xxx
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Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical trial Naghmeh Mokhber a,1, Amir Azarpazhooh b,c,d,1, Elias Orouji e, Stephen M. Rao f, Bita Khorram g, Mohammad Ali Sahraian h, Mohsen Foroghipoor e, Morteza Modares Gharavi i, Sorayya Kakhi j, Karim Nikkhah e,⁎, Mahmoud Reza Azarpazhooh e a
Department of Psychiatry, Avicenna Hospital, Mashhad University of Medical Sciences, Mashhad, Iran Department of Biological and Diagnostic Sciences, Faculty of Dentistry, University of Toronto, Canada c Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto, Canada d Toronto Health Economics and Technology Assessment Collaborative, University of Toronto, Canada e Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad, Iran f Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA g Toronto, Canada h Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran i Department of Psychology, Avicenna Hospital, Mashhad University of Medical Sciences, Mashhad, Iran j Mashhad University of Medical Sciences, Mashhad, Iran b
a r t i c l e
i n f o
Article history: Received 9 June 2013 Received in revised form 13 January 2014 Accepted 27 January 2014 Available online xxxx Keywords: Multiple sclerosis Cognitive dysfunction Disease-modifying therapies Memory Processing speed Clinical trial
a b s t r a c t Background: Multiple sclerosis (MS) is a chronic autoimmune disease that can deteriorate cognitive function in at least 50% of patients even in the early stages. Objective: We conducted a three-arm parallel study with balanced randomization to evaluate the effect of various disease-modifying therapies (DMTs) on cognitive function in MS. Methods: Ninety newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran, were enrolled into this study between 2006 and 2009. They were randomly categorized into three DMT groups; Avonex, Rebif and Betaferon. Cognition status was assessed in MS patients at baseline and 12 months after treatment with DMTs using the 5 tests of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). Results: The Symbol Digit Modalities Test scores improved in all groups at 12 month vs. baseline (Avonex: 34.50 vs. 38.95, p = 0.011; Rebif: 35.30 vs. 40.13, p = 0.001; Betaferon: 26.18 vs. 29.32, p = 0.029). The Selective Reminding Test (SRT)-Total, the 10/36-Delay, and the Paced Auditory Serial Addition Test-Easy were improved in Avonex and Rebif but not in Betaferon group. The SRT-Delay and Word List Generation were improved only in the Avonex group. There was no significant difference in other components of the BRB-N among these three treatment groups. Conclusions: Different types of DMTs may improve some aspects of cognitive function in patients with MS. Treatment with Avonex and Rebif (Interferon beta-1a preparations) were more helpful in resolving the cognitive impairments in MS patients compared to Betaferon (Interferon beta-1b) as investigated in this study. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Multiple Sclerosis (MS) is a chronic autoimmune disease that affects at least 2.5 million people worldwide [1]. Traditionally, MS is defined as recurrent exacerbations due to central nervous system (CNS) involvement, which leads to physical disability. However, MS can also deteriorate cognitive function even in the early stages [2]. The frequency of cognitive dysfunction was formerly underestimated. Recent studies have shown that at least half of MS patients will develop cognitive dysfunction, which can significantly influence their daily functional skills [3–5]. By improving ⁎ Corresponding author. Tel.: +98 511 606 7489; fax: +98 511 842 9828. E-mail address: [email protected] (K. Nikkhah). 1 These authors contributed equally to the paper.
cognitive evaluation techniques, it has been possible to identify mild and early changes in cognitive functions as well as specific aspects such as memory, attention, visual–spatial abilities, executive functions, and processing speed in MS [6–11]. For this purpose, the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) [12] was constructed to test different domains of cognition which are frequently impaired in MS [13–17]. This group of tests explores most of the cognitive functions while minimizing the overlap between them [18–21]. The BRB-N is sensitive to early cognitive impairment in patients with MS [22–24] and several studies have consistently indicated that MS patients perform significantly worse than controls on this test [25,26]. The cognitive dysfunction may be related to lesion burden, brain atrophy, and physical disability [27,28]. However, the exact mechanism remains a matter of debate.
http://dx.doi.org/10.1016/j.jns.2014.01.038 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Mokhber N, et al, Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical t..., J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.01.038
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N. Mokhber et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
In spite of the correlation between cognitive dysfunction and MS, there are still limited data considering the management of the developed dysfunction. Treatment is crucial since it can improve the functional level of daily activities and quality of life. During the past decade, several disease-modifying therapies (DMTs) have become available for the treatment of MS and have altered the long-term course of the disease [29]. These agents are generally safe and well tolerated, can reduce the risk of physical disability, and can diminish the number of active brain lesions visible on magnetic resonance imaging images [30]. It is believed that treatment with interferon beta-1a exerts its neuropsychological effects via both short-term mechanisms by inhibiting inflammation, and also long-term mechanisms by slowing or preventing further CNS tissue damage [31]. However, very few studies have examined the effect of treatment on cognition. Several clinical trials have shown beneficial effects of DMTs on longterm cognitive measures which may even reduce cognitive deficits in MS patients [22–24,32–35]. Animal models of MS, along with assessments of the clinical response to DMTs, suggest the disease is mediated immunologically [36]. The immune system effects of Interferon beta, relevant to its therapeutic mechanisms in MS, are not well understood but are believed to include decrease in T-cell activation, induction of cytokine shifts in favor of an anti-inflammatory effect, prevention of T-cell adhesion and extravasation across the blood brain barrier, as well as induction of T-regulatory cells [37]. Besides such anti-inflammatory actions, MS-related changes in cortical matter play a critical role in the development of cognitive symptoms [38] and since interferon beta can decrease the volume of brain lesion [39], it can have a protective effect against cognitive decline. Given the high incidence and the importance of cognitive dysfunction in MS, we designed this clinical trial to evaluate, using the BRB-N, the effect of various DMTs on the cognitive function of patients with MS. We hypothesized that although all DMTs have positive effects on cognition in MS patients, various preparations of Interferon beta
treatment could improve the cognitive status in these patients at different levels. 2. Method 2.1. Trial design and protocol This study is a double blind three-arm parallel study, with balanced randomization conducted in the Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran, between May 2006 and June 2009. The flow of the study is presented in Fig. 1. All subjects gave their consent to the study in accordance with the informed consent regulations of the Ethics Committee of Mashhad University of Medical Sciences, Mashhad, Iran (protocol number: 84393-1). Eligible participants were all new cases of definite MS according to the revised McDonald criteria, which include magnetic resonance imaging, detailed neurological history and examination, and paraclinical laboratory tests of cerebrospinal fluid findings and visual-evoked potential [40]. Patients were excluded if they had a history of substance abuse or prior treatment with any type of DMTs. Patients were also excluded if they showed any signs of depression. For this purpose, the study neuropsychiatrist performed semi-structural psychiatric interviews using the Beck Depression Inventory to assess symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and decrease in libido [41]. The study neurologist (MRA) enrolled the participants and allocated the subjects using a computer-generated list of random numbers to the 3 treatment groups of three distinct commercially available forms of interferon beta. Avonex was administered 30 mcg once per week via intramuscular injection; Rebif was administered 44 mcg three times per week via subcutaneous injection; and Betaferon was administered 0.25 mg every other day via subcutaneous injection. Injections were
Fig. 1. Flow diagram of the three-arm parallel study to investigate cognition in MS patients.
Please cite this article as: Mokhber N, et al, Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical t..., J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.01.038
N. Mokhber et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
performed by either the patients themselves or their caregivers after being trained by the study neurologists (MRA or MF). 2.2. Outcome measures During initial psychiatric and neurological assessment as well as administration of the BRB-N, participants and all those assessing outcomes were blinded to the treatment groups. Demographic data including age and gender were extracted from the study questionnaire. Cognition status was the primary outcome measure. The study psychologist (MMG) and neuropsychiatrist (NM), both blinded to the treatment groups, evaluated the cognitive function before treatment, and 12 months after treatment. For this purpose, the following five tests included in the BRB-N were used [12]: 1) The Selective Reminding Test (SRT) measures verbal learning through the presentation of a list of 12 words and 5 subsequent learning trials. Delayed recall (SRTD) was assessed after an 11minute delay. 2) The 10/36 Spatial Recall Test (SPART) was used to assess visual learning and recall by asking the subjects to recreate a pattern of 10 checkers on a 6 × 6 checkerboard viewed for 10 s. 3) The Symbol Digit Modalities Test (SDMT) was used to measure complex attention and concentration by asking the subjects to pair symbols with numbers and quickly generate the number when shown the symbol for 90 s. 4) The Paced Auditory Serial Addition Test (PASAT) was used to evaluate sustained attention and information processing speed by asking the subjects to add each number to the one immediately preceding it. The numbers were presented every two seconds (Easy Module) and every three seconds (Hard Module). 5) The Word List Generation (WLG) test was used to measure semantic verbal fluency, evaluating the spontaneous production of words beginning with a particular letter for 60 s. The Expanded Disability Status Scale (EDSS) was the secondary outcome measure which was investigated at baseline and after 12 months. The EDSS is a method of quantifying disability in MS in eight Functional Systems (FS) and provides a functional system score. The EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory. The EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation [42]. 2.3. Statistical analyses To investigate the effect of the treatment protocols on cognition, we computed several sample sizes for each of outcome measures and treatment groups. We then selected the largest calculated sample size for the study. Hence, a minimum sample size of 18 patients per group would provide 80% power to detect the differences in SRT total in Avonex and Rebif groups using two independent means t-test. Statistical analysis was performed using the Statistical Package for the Social Sciences software (SPSS version 18, Chicago, IL). Lilliefors (Kolmogorov– Smirnov) test was applied to assure the normal distribution of the data. We used Paired T Test for comparing the statistical significance of the before–after continuous variables. Analysis of variance (ANOVA) with post-hoc analysis using Tukey's Honestly Significant Difference was used to assess the statistical significance of the continuous variables. A value of P ≤ 0.05 was used as a criterion for statistical significance. 3. Results 3.1. Demographic data From May 2006 to June 2009, a total of 90 definite MS patients were screened for eligibility. From this original pool, 14 patients were excluded due to previous treatment with DMTs, 3 were excluded due to a
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positive history of substance abuse and 4 were excluded due to positive signs of depression. The remaining 69 patients were randomly allocated into the 3 treatment groups of 23 patients. Three patients in the Avonex group and 1 patient in the Betaferon group did not attend the follow-up sessions. Therefore, we managed to evaluate and follow up 65 new cases of definite MS by the end of the trial. The study group included 23 males (35.4%) and 42 females (64.6%) with a mean age of 29.1 ± 7.9 years (Supplementary Table S1). 3.2. BRB-N and EDSS scores Table 1 presents the data on the BRB-N components and EDSS measured at baseline and after 12 months follow-up in the three groups. 3.3. Assessment within the treatment groups Within the Avonex treatment group, we observed significant improvements in the following BRB-N components at baseline vs. the 12-month follow up: SRT Total (42.25 vs. 47.20), SRT Delay (7.05 vs. 8.05), 10/36 Delay (4.30 vs. 5.30), PASAT Easy (23.68 vs. 29.15), SDMT (34.50 vs. 38.95), and WLG (12.85 vs. 15.65). The EDSS did not show any improvement in the Avonex group after 12 months of treatment. Within the Rebif treatment group, significant improvements in the following BRB-N components were observed at baseline vs. the 12month follow up: SRT Total (44.35 vs. 51.57), 10/36 Delay (4.43 vs. 5.39), PASAT Easy (33.17 vs. 38.47), SDMT (35.30 vs. 40.13). Similarly, in this group, the EDSS was significantly improved after treatment (2.32 vs. 1.37). Within the Betaferon treatment group, we observed significant improvement only in the SDMT from 26.18 at baseline to 29.32 in the 12-month follow up. The EDSS was also significantly improved after treatment (2.16 vs. 1.57). 3.4. Assessment among the three treatment groups Comparison of the BRB-N components at baseline and after 12 months of treatment using ANOVA test revealed a significant difference in the PASAT Easy, PASAT Hard, SDMT, and WLG. Further, the posthoc analysis using Tukey's Honestly Significant Difference showed a significant difference between Avonex and Rebif (− 9.32) and between Rebif and Betaferon (9.04) in the PASAT Easy component after treatment. There was also a significant mean difference at baseline between Avonex and Rebif (−16.71) and Rebif and Betaferon (17.76) and after treatment between Rebif and Betaferon (9.2). For the SDMT component, a significant mean difference was noted at baseline between Rebif and Betaferon (9.12) and after treatment between Avonex and Betaferon (9.63) and Rebif and Betaferon (10.81). The WLG test showed significant mean difference at baseline between Avonex and Betaferon (−16.65) and Avonex and Rebif (−14.75) and after treatment between Avonex and Betaferon (−16.75) and Avonex and Rebif (−18.26). The EDSS did not have significant difference at baseline and posttreatment among treatment groups. 4. Discussion Several studies have provided evidence of cognitive impairment in a substantial number of patients with MS [43–47]. Although the cognitive deficiencies usually go unnoticed by physicians and may not be recognized by the patients themselves, they have considerable effects on the lives of the patients and their family members. The most common cognitive impairments include recent memory, attention, informationprocessing speed, executive functions, and visual–spatial perception [47]. Cognitive impairment can be poorly predicted on the basis of clinical indicators as well as neurologic disability; therefore, it is crucial to evaluate the cognitive function using valid testing. Hence, our study evaluated the effect of Avonex, Rebif and Betaferon on the cognitive function of patients with MS.
Please cite this article as: Mokhber N, et al, Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical t..., J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.01.038
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N. Mokhber et al. / Journal of the Neurological Sciences xxx (2014) xxx–xxx
Table 1 Comparison of BRB-N components and EDSS measured at baseline and after 12 months follow-up within Avonex, Rebif and Betaferon groups. BRB-N
Avonex
Rebif
Baseline –SRT Total –SRT Delay –10/36 Total –10/36 Delay –PASAT Easy –PASAT Hard –SDMT –WLG EDSS
42.25 7.05 15.15 4.30 23.68 27.88 34.50 12.85 1.5
± ± ± ± ± ± ± ± ±
After 12 m 18.51 2.91 5.19 2.05 9.83 11.09 15.05 4.68 1.0
47.20 8.05 16.70 5.30 29.15 34.75 38.95 15.65 1.5
± ± ± ± ± ± ± ± ±
14.12 2.11 5.29 1.68 11.85 11.94 13.70 4.22 0.6
p
Betaferon
Baseline b
0.015 0.029b 0.076b 0.005b 0.013b 0.916b 0.011b 0.015b 0.548a
44.35 8.39 15.30 4.43 33.17 44.60 35.30 27.61 2.3
± ± ± ± ± ± ± ± ±
After 12 m 18.62 3.20 5.40 1.87 14.61 8.83 11.70 10.60 1.5
51.57 7.87 16.65 5.39 38.47 42.84 40.13 33.91 1.3
± ± ± ± ± ± ± ± ±
17.79 2.49 4.69 1.58 12.56 9.63 10.70 8.48 0.9
p
Baseline b
0.028 0.531b 0.139b 0.034b 0.016b 0.985b 0.001b 0.000b 0.001a
53.05 ± 7.82 ± 13.645.16 4.09 ± 24.40 ± 26.83 ± 26.18 ± 29.50 ± 2.1 ±
15.88 2.71 1.54 13.50 13.08 10.41 8.83 1.0
After 12 m
p
53.50 8.50 14.55 4.77 29.42 33.57 29.32 32.41 1.5
0.893b 0.333b 0.357b 0.87b 0.141b 0.153b 0.029b 0.067b 0.028a
± ± ± ± ± ± ± ± ±
10.95 1.89 4.67 1.71 12.31 8.12 8.83 7.67 1.0
Baseline EDSS p value between treatment groups: 0.065 (Kruskal–Wallis test). After 12 m EDSS p value between treatment groups: 0.508 (Kruskal–Wallis test). Bold text indicate p b 0.05. a Wilcoxon Signed Ranks test. b t-test.
The results revealed a significant improvement in the cognitive function of new cases of MS twelve months after initiation of these DMTs. In particular, SDMT was improved in all three treatment groups and SRT, 10/36 Delay and PASAT Easy improved in patients treated with Avonex and Rebif, although not with Betaferon. WLG and SRT Delay were also improved in the Avonex group. Some studies have shown the importance of the SDMT as the most sensitive measure of cerebral integrity, which can calculate the reduced speed of processing. Hence, the observed development in all treatment groups could be explained by the DMTs' effects on this function in the brain [15,48,49]. In 2000, Fischer et al. showed the positive effect of interferon beta-1a (Avonex) on cognitive function in patients with relapsing MS. Patients treated with Avonex had a 47% reduction in the risk of experiencing cognitive deterioration versus those treated with placebo in a 2-year neuropsychological follow up [31]. Barak and Achiron, in a relatively small sample size study (n = 23), showed significant deterioration of cognitive function in the control group in comparison with patients treated with interferon beta-1a [50]. In spite of several studies evaluating cognitive function in MS patients [3,4,13,14,16,44,46,51], there are still insufficient data regarding the treatment of cognitive dysfunction and the prevention of cognitive impairment [31,50]. The BRB-N was also used by Lincoln et al. to evaluate the benefits of providing a psychology service on the cognition of MS patients. Their results showed no effect on intervention of cognitive impairment or independence [52]. In spite of the relatively small sample size, we managed to compare the effect of the three different DMTs on cognition. In contrast to previous studies, patients uninitiated to DMT treatment and new cases of definite MS were recruited in our study. Therefore, we were able to measure the effect of treatment independent from the duration of the disease. Considering the early decline in the cognitive impairment of MS patients [3], and since DMTs may improve some important aspects of cognitive performance, it is recommended to diagnose the MS accurately and start DMTs as early as possible. In conclusion, in our sample of 65 MS patients with different preparations of DMTs, we found Interferon beta-1a (Avonex and Rebif) resolved or diminished more aspects of cognitive impairment after 12 months of treatment than did Interferon beta1-b (Betaferon). Consequently, we recommend Interferon beta-1a in conditions where administration of either of these drugs is of equal benefit to the patient.
Conflict of interest None to be declared.
Acknowledgment The study was supported by the Vice Chancellor of Research at Mashhad University of Medical Sciences in Iran (Grant number: 84393). The authors would like to thank Saeed Akhlaghi and Mojtaba Meshkat for their assistance with data analysis and Sharareh Shahraki for performing the neuropsychological tests.
Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2014.01.038.
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Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical trial Naghmeh Mokhber a,1, Amir Azarpazhooh b,c,d,1, Elias Orouji e, Stephen M. Rao f, Bita Khorram g, Mohammad Ali Sahraian h, Mohsen Foroghipoor e, Morteza Modares Gharavi i, Sorayya Kakhi j, Karim Nikkhah e,⁎, Mahmoud Reza Azarpazhooh e a
Department of Psychiatry, Avicenna Hospital, Mashhad University of Medical Sciences, Mashhad, Iran Department of Biological and Diagnostic Sciences, Faculty of Dentistry, University of Toronto, Canada c Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto, Canada d Toronto Health Economics and Technology Assessment Collaborative, University of Toronto, Canada e Department of Neurology, Ghaem Medical Center, Mashhad University of Medical Sciences, Mashhad, Iran f Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA g Toronto, Canada h Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran i Department of Psychology, Avicenna Hospital, Mashhad University of Medical Sciences, Mashhad, Iran j Mashhad University of Medical Sciences, Mashhad, Iran b
a r t i c l e
i n f o
Article history: Received 9 June 2013 Received in revised form 13 January 2014 Accepted 27 January 2014 Available online xxxx Keywords: Multiple sclerosis Cognitive dysfunction Disease-modifying therapies Memory Processing speed Clinical trial
a b s t r a c t Background: Multiple sclerosis (MS) is a chronic autoimmune disease that can deteriorate cognitive function in at least 50% of patients even in the early stages. Objective: We conducted a three-arm parallel study with balanced randomization to evaluate the effect of various disease-modifying therapies (DMTs) on cognitive function in MS. Methods: Ninety newly diagnosed, definite MS subjects referred to Ghaem Medical Center, Mashhad, Iran, were enrolled into this study between 2006 and 2009. They were randomly categorized into three DMT groups; Avonex, Rebif and Betaferon. Cognition status was assessed in MS patients at baseline and 12 months after treatment with DMTs using the 5 tests of the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). Results: The Symbol Digit Modalities Test scores improved in all groups at 12 month vs. baseline (Avonex: 34.50 vs. 38.95, p = 0.011; Rebif: 35.30 vs. 40.13, p = 0.001; Betaferon: 26.18 vs. 29.32, p = 0.029). The Selective Reminding Test (SRT)-Total, the 10/36-Delay, and the Paced Auditory Serial Addition Test-Easy were improved in Avonex and Rebif but not in Betaferon group. The SRT-Delay and Word List Generation were improved only in the Avonex group. There was no significant difference in other components of the BRB-N among these three treatment groups. Conclusions: Different types of DMTs may improve some aspects of cognitive function in patients with MS. Treatment with Avonex and Rebif (Interferon beta-1a preparations) were more helpful in resolving the cognitive impairments in MS patients compared to Betaferon (Interferon beta-1b) as investigated in this study. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Multiple Sclerosis (MS) is a chronic autoimmune disease that affects at least 2.5 million people worldwide [1]. Traditionally, MS is defined as recurrent exacerbations due to central nervous system (CNS) involvement, which leads to physical disability. However, MS can also deteriorate cognitive function even in the early stages [2]. The frequency of cognitive dysfunction was formerly underestimated. Recent studies have shown that at least half of MS patients will develop cognitive dysfunction, which can significantly influence their daily functional skills [3–5]. By improving ⁎ Corresponding author. Tel.: +98 511 606 7489; fax: +98 511 842 9828. E-mail address: [email protected] (K. Nikkhah). 1 These authors contributed equally to the paper.
cognitive evaluation techniques, it has been possible to identify mild and early changes in cognitive functions as well as specific aspects such as memory, attention, visual–spatial abilities, executive functions, and processing speed in MS [6–11]. For this purpose, the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) [12] was constructed to test different domains of cognition which are frequently impaired in MS [13–17]. This group of tests explores most of the cognitive functions while minimizing the overlap between them [18–21]. The BRB-N is sensitive to early cognitive impairment in patients with MS [22–24] and several studies have consistently indicated that MS patients perform significantly worse than controls on this test [25,26]. The cognitive dysfunction may be related to lesion burden, brain atrophy, and physical disability [27,28]. However, the exact mechanism remains a matter of debate.
http://dx.doi.org/10.1016/j.jns.2014.01.038 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Mokhber N, et al, Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical t..., J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.01.038
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In spite of the correlation between cognitive dysfunction and MS, there are still limited data considering the management of the developed dysfunction. Treatment is crucial since it can improve the functional level of daily activities and quality of life. During the past decade, several disease-modifying therapies (DMTs) have become available for the treatment of MS and have altered the long-term course of the disease [29]. These agents are generally safe and well tolerated, can reduce the risk of physical disability, and can diminish the number of active brain lesions visible on magnetic resonance imaging images [30]. It is believed that treatment with interferon beta-1a exerts its neuropsychological effects via both short-term mechanisms by inhibiting inflammation, and also long-term mechanisms by slowing or preventing further CNS tissue damage [31]. However, very few studies have examined the effect of treatment on cognition. Several clinical trials have shown beneficial effects of DMTs on longterm cognitive measures which may even reduce cognitive deficits in MS patients [22–24,32–35]. Animal models of MS, along with assessments of the clinical response to DMTs, suggest the disease is mediated immunologically [36]. The immune system effects of Interferon beta, relevant to its therapeutic mechanisms in MS, are not well understood but are believed to include decrease in T-cell activation, induction of cytokine shifts in favor of an anti-inflammatory effect, prevention of T-cell adhesion and extravasation across the blood brain barrier, as well as induction of T-regulatory cells [37]. Besides such anti-inflammatory actions, MS-related changes in cortical matter play a critical role in the development of cognitive symptoms [38] and since interferon beta can decrease the volume of brain lesion [39], it can have a protective effect against cognitive decline. Given the high incidence and the importance of cognitive dysfunction in MS, we designed this clinical trial to evaluate, using the BRB-N, the effect of various DMTs on the cognitive function of patients with MS. We hypothesized that although all DMTs have positive effects on cognition in MS patients, various preparations of Interferon beta
treatment could improve the cognitive status in these patients at different levels. 2. Method 2.1. Trial design and protocol This study is a double blind three-arm parallel study, with balanced randomization conducted in the Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran, between May 2006 and June 2009. The flow of the study is presented in Fig. 1. All subjects gave their consent to the study in accordance with the informed consent regulations of the Ethics Committee of Mashhad University of Medical Sciences, Mashhad, Iran (protocol number: 84393-1). Eligible participants were all new cases of definite MS according to the revised McDonald criteria, which include magnetic resonance imaging, detailed neurological history and examination, and paraclinical laboratory tests of cerebrospinal fluid findings and visual-evoked potential [40]. Patients were excluded if they had a history of substance abuse or prior treatment with any type of DMTs. Patients were also excluded if they showed any signs of depression. For this purpose, the study neuropsychiatrist performed semi-structural psychiatric interviews using the Beck Depression Inventory to assess symptoms of depression such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as well as physical symptoms such as fatigue, weight loss, and decrease in libido [41]. The study neurologist (MRA) enrolled the participants and allocated the subjects using a computer-generated list of random numbers to the 3 treatment groups of three distinct commercially available forms of interferon beta. Avonex was administered 30 mcg once per week via intramuscular injection; Rebif was administered 44 mcg three times per week via subcutaneous injection; and Betaferon was administered 0.25 mg every other day via subcutaneous injection. Injections were
Fig. 1. Flow diagram of the three-arm parallel study to investigate cognition in MS patients.
Please cite this article as: Mokhber N, et al, Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical t..., J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.01.038
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performed by either the patients themselves or their caregivers after being trained by the study neurologists (MRA or MF). 2.2. Outcome measures During initial psychiatric and neurological assessment as well as administration of the BRB-N, participants and all those assessing outcomes were blinded to the treatment groups. Demographic data including age and gender were extracted from the study questionnaire. Cognition status was the primary outcome measure. The study psychologist (MMG) and neuropsychiatrist (NM), both blinded to the treatment groups, evaluated the cognitive function before treatment, and 12 months after treatment. For this purpose, the following five tests included in the BRB-N were used [12]: 1) The Selective Reminding Test (SRT) measures verbal learning through the presentation of a list of 12 words and 5 subsequent learning trials. Delayed recall (SRTD) was assessed after an 11minute delay. 2) The 10/36 Spatial Recall Test (SPART) was used to assess visual learning and recall by asking the subjects to recreate a pattern of 10 checkers on a 6 × 6 checkerboard viewed for 10 s. 3) The Symbol Digit Modalities Test (SDMT) was used to measure complex attention and concentration by asking the subjects to pair symbols with numbers and quickly generate the number when shown the symbol for 90 s. 4) The Paced Auditory Serial Addition Test (PASAT) was used to evaluate sustained attention and information processing speed by asking the subjects to add each number to the one immediately preceding it. The numbers were presented every two seconds (Easy Module) and every three seconds (Hard Module). 5) The Word List Generation (WLG) test was used to measure semantic verbal fluency, evaluating the spontaneous production of words beginning with a particular letter for 60 s. The Expanded Disability Status Scale (EDSS) was the secondary outcome measure which was investigated at baseline and after 12 months. The EDSS is a method of quantifying disability in MS in eight Functional Systems (FS) and provides a functional system score. The EDSS steps 1.0 to 4.5 refer to people with MS who are fully ambulatory. The EDSS steps 5.0 to 9.5 are defined by the impairment to ambulation [42]. 2.3. Statistical analyses To investigate the effect of the treatment protocols on cognition, we computed several sample sizes for each of outcome measures and treatment groups. We then selected the largest calculated sample size for the study. Hence, a minimum sample size of 18 patients per group would provide 80% power to detect the differences in SRT total in Avonex and Rebif groups using two independent means t-test. Statistical analysis was performed using the Statistical Package for the Social Sciences software (SPSS version 18, Chicago, IL). Lilliefors (Kolmogorov– Smirnov) test was applied to assure the normal distribution of the data. We used Paired T Test for comparing the statistical significance of the before–after continuous variables. Analysis of variance (ANOVA) with post-hoc analysis using Tukey's Honestly Significant Difference was used to assess the statistical significance of the continuous variables. A value of P ≤ 0.05 was used as a criterion for statistical significance. 3. Results 3.1. Demographic data From May 2006 to June 2009, a total of 90 definite MS patients were screened for eligibility. From this original pool, 14 patients were excluded due to previous treatment with DMTs, 3 were excluded due to a
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positive history of substance abuse and 4 were excluded due to positive signs of depression. The remaining 69 patients were randomly allocated into the 3 treatment groups of 23 patients. Three patients in the Avonex group and 1 patient in the Betaferon group did not attend the follow-up sessions. Therefore, we managed to evaluate and follow up 65 new cases of definite MS by the end of the trial. The study group included 23 males (35.4%) and 42 females (64.6%) with a mean age of 29.1 ± 7.9 years (Supplementary Table S1). 3.2. BRB-N and EDSS scores Table 1 presents the data on the BRB-N components and EDSS measured at baseline and after 12 months follow-up in the three groups. 3.3. Assessment within the treatment groups Within the Avonex treatment group, we observed significant improvements in the following BRB-N components at baseline vs. the 12-month follow up: SRT Total (42.25 vs. 47.20), SRT Delay (7.05 vs. 8.05), 10/36 Delay (4.30 vs. 5.30), PASAT Easy (23.68 vs. 29.15), SDMT (34.50 vs. 38.95), and WLG (12.85 vs. 15.65). The EDSS did not show any improvement in the Avonex group after 12 months of treatment. Within the Rebif treatment group, significant improvements in the following BRB-N components were observed at baseline vs. the 12month follow up: SRT Total (44.35 vs. 51.57), 10/36 Delay (4.43 vs. 5.39), PASAT Easy (33.17 vs. 38.47), SDMT (35.30 vs. 40.13). Similarly, in this group, the EDSS was significantly improved after treatment (2.32 vs. 1.37). Within the Betaferon treatment group, we observed significant improvement only in the SDMT from 26.18 at baseline to 29.32 in the 12-month follow up. The EDSS was also significantly improved after treatment (2.16 vs. 1.57). 3.4. Assessment among the three treatment groups Comparison of the BRB-N components at baseline and after 12 months of treatment using ANOVA test revealed a significant difference in the PASAT Easy, PASAT Hard, SDMT, and WLG. Further, the posthoc analysis using Tukey's Honestly Significant Difference showed a significant difference between Avonex and Rebif (− 9.32) and between Rebif and Betaferon (9.04) in the PASAT Easy component after treatment. There was also a significant mean difference at baseline between Avonex and Rebif (−16.71) and Rebif and Betaferon (17.76) and after treatment between Rebif and Betaferon (9.2). For the SDMT component, a significant mean difference was noted at baseline between Rebif and Betaferon (9.12) and after treatment between Avonex and Betaferon (9.63) and Rebif and Betaferon (10.81). The WLG test showed significant mean difference at baseline between Avonex and Betaferon (−16.65) and Avonex and Rebif (−14.75) and after treatment between Avonex and Betaferon (−16.75) and Avonex and Rebif (−18.26). The EDSS did not have significant difference at baseline and posttreatment among treatment groups. 4. Discussion Several studies have provided evidence of cognitive impairment in a substantial number of patients with MS [43–47]. Although the cognitive deficiencies usually go unnoticed by physicians and may not be recognized by the patients themselves, they have considerable effects on the lives of the patients and their family members. The most common cognitive impairments include recent memory, attention, informationprocessing speed, executive functions, and visual–spatial perception [47]. Cognitive impairment can be poorly predicted on the basis of clinical indicators as well as neurologic disability; therefore, it is crucial to evaluate the cognitive function using valid testing. Hence, our study evaluated the effect of Avonex, Rebif and Betaferon on the cognitive function of patients with MS.
Please cite this article as: Mokhber N, et al, Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: A randomized clinical t..., J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.01.038
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Table 1 Comparison of BRB-N components and EDSS measured at baseline and after 12 months follow-up within Avonex, Rebif and Betaferon groups. BRB-N
Avonex
Rebif
Baseline –SRT Total –SRT Delay –10/36 Total –10/36 Delay –PASAT Easy –PASAT Hard –SDMT –WLG EDSS
42.25 7.05 15.15 4.30 23.68 27.88 34.50 12.85 1.5
± ± ± ± ± ± ± ± ±
After 12 m 18.51 2.91 5.19 2.05 9.83 11.09 15.05 4.68 1.0
47.20 8.05 16.70 5.30 29.15 34.75 38.95 15.65 1.5
± ± ± ± ± ± ± ± ±
14.12 2.11 5.29 1.68 11.85 11.94 13.70 4.22 0.6
p
Betaferon
Baseline b
0.015 0.029b 0.076b 0.005b 0.013b 0.916b 0.011b 0.015b 0.548a
44.35 8.39 15.30 4.43 33.17 44.60 35.30 27.61 2.3
± ± ± ± ± ± ± ± ±
After 12 m 18.62 3.20 5.40 1.87 14.61 8.83 11.70 10.60 1.5
51.57 7.87 16.65 5.39 38.47 42.84 40.13 33.91 1.3
± ± ± ± ± ± ± ± ±
17.79 2.49 4.69 1.58 12.56 9.63 10.70 8.48 0.9
p
Baseline b
0.028 0.531b 0.139b 0.034b 0.016b 0.985b 0.001b 0.000b 0.001a
53.05 ± 7.82 ± 13.645.16 4.09 ± 24.40 ± 26.83 ± 26.18 ± 29.50 ± 2.1 ±
15.88 2.71 1.54 13.50 13.08 10.41 8.83 1.0
After 12 m
p
53.50 8.50 14.55 4.77 29.42 33.57 29.32 32.41 1.5
0.893b 0.333b 0.357b 0.87b 0.141b 0.153b 0.029b 0.067b 0.028a
± ± ± ± ± ± ± ± ±
10.95 1.89 4.67 1.71 12.31 8.12 8.83 7.67 1.0
Baseline EDSS p value between treatment groups: 0.065 (Kruskal–Wallis test). After 12 m EDSS p value between treatment groups: 0.508 (Kruskal–Wallis test). Bold text indicate p b 0.05. a Wilcoxon Signed Ranks test. b t-test.
The results revealed a significant improvement in the cognitive function of new cases of MS twelve months after initiation of these DMTs. In particular, SDMT was improved in all three treatment groups and SRT, 10/36 Delay and PASAT Easy improved in patients treated with Avonex and Rebif, although not with Betaferon. WLG and SRT Delay were also improved in the Avonex group. Some studies have shown the importance of the SDMT as the most sensitive measure of cerebral integrity, which can calculate the reduced speed of processing. Hence, the observed development in all treatment groups could be explained by the DMTs' effects on this function in the brain [15,48,49]. In 2000, Fischer et al. showed the positive effect of interferon beta-1a (Avonex) on cognitive function in patients with relapsing MS. Patients treated with Avonex had a 47% reduction in the risk of experiencing cognitive deterioration versus those treated with placebo in a 2-year neuropsychological follow up [31]. Barak and Achiron, in a relatively small sample size study (n = 23), showed significant deterioration of cognitive function in the control group in comparison with patients treated with interferon beta-1a [50]. In spite of several studies evaluating cognitive function in MS patients [3,4,13,14,16,44,46,51], there are still insufficient data regarding the treatment of cognitive dysfunction and the prevention of cognitive impairment [31,50]. The BRB-N was also used by Lincoln et al. to evaluate the benefits of providing a psychology service on the cognition of MS patients. Their results showed no effect on intervention of cognitive impairment or independence [52]. In spite of the relatively small sample size, we managed to compare the effect of the three different DMTs on cognition. In contrast to previous studies, patients uninitiated to DMT treatment and new cases of definite MS were recruited in our study. Therefore, we were able to measure the effect of treatment independent from the duration of the disease. Considering the early decline in the cognitive impairment of MS patients [3], and since DMTs may improve some important aspects of cognitive performance, it is recommended to diagnose the MS accurately and start DMTs as early as possible. In conclusion, in our sample of 65 MS patients with different preparations of DMTs, we found Interferon beta-1a (Avonex and Rebif) resolved or diminished more aspects of cognitive impairment after 12 months of treatment than did Interferon beta1-b (Betaferon). Consequently, we recommend Interferon beta-1a in conditions where administration of either of these drugs is of equal benefit to the patient.
Conflict of interest None to be declared.
Acknowledgment The study was supported by the Vice Chancellor of Research at Mashhad University of Medical Sciences in Iran (Grant number: 84393). The authors would like to thank Saeed Akhlaghi and Mojtaba Meshkat for their assistance with data analysis and Sharareh Shahraki for performing the neuropsychological tests.
Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2014.01.038.
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