575172
research-article2015
MSJ0010.1177/1352458515575172Multiple Sclerosis JournalBL Roberg and JM Bruce
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Reconsidering outdoor temperature and cognition in multiple sclerosis
Multiple Sclerosis Journal 1–4 DOI: 10.1177/ 1352458515575172 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Brandon L Roberg and Jared M Bruce
Abstract Background: Research in multiple sclerosis (MS) suggests warmer weather plays a role in disease manifestation. Objective: This work sought to replicate the finding that warmer outdoor temperatures are significantly associated with poorer cognition in MS. Methods: Associations between outdoor temperature and cognition were examined in three studies with a total of 263 patients with MS. Results: Contrary to previous research, no significant relationship was found between cognitive performance and outdoor temperature in MS. Conclusions: The results of the current work underscore the need to better understand if, when, and how cognitive performance may be influenced by seasonal variables in MS.
Correspondence to: Jared M. Bruce Department of Psychology, University of MissouriKansas City, 5030 Cherry St., Cherry Hall Room 324, Kansas City, MO 64110, USA. [email protected] Brandon L Roberg Jared M Bruce Department of Psychology, University of MissouriKansas City, USA
Keywords: Multiple sclerosis, neuropsychological functioning, cognitive testing, memory, attention, processing speed Date received: 24 October 2014; received: 5 January2015; accepted: 1 February 2015 Introduction Research in multiple sclerosis (MS) suggests warmer weather may play a role in disease manifestation.1–3 In a cross-sectional analysis, Leavitt and colleagues4 found that warmer outdoor temperatures were significantly associated with poorer cognition in MS. In a separate MS sample, longitudinal analysis confirmed that performance on cognitive tests declined as outdoor temperature increased.4 Using a subset of the cross-sectional sample,4 they also found that warmer outdoor temperatures were associated with greater blood oxygen level-dependent (BOLD) activation in the frontal lobe and inferior parietal lobule during a sustained attention task.5 The present work attempted to replicate and extend Leavitt and colleagues’ cross-sectional results4 in three samples of MS patients. We hypothesized that warmer outdoor temperatures would be significantly associated with poorer cognitive performance in each study. In Study 3, we also investigated the relationship between cognition, body temperature. and broader weather-related variables.
Methods Participants and procedures The sample in Study 1 was composed of MS patients recruited as part of studies examining visual functioning and cognition6 and psychological correlates of cognition and fatigue.7 Study 2 patients were recruited in a larger study examining adherence to disease-modifying medications.8 In Study 3, patients were recruited as part of an ongoing study examining mentalizing and cognition in MS. Diagnosis and disease course were confirmed by patients’ neurologists using established criteria (see study references for more details).6–8 All studies were approved by the institutional review board at the University of Missouri-Kansas City.
Cognitive tests and disease severity Information processing speed was assessed using the oral version of the Symbol Digit Modalities Test (SDMT) and verbal learning was assessed with the Auditory Verbal Learning Test (AVLT).9 The variables
http://msj.sagepub.com 1
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Multiple Sclerosis Journal of interest were total SDMT items correct in 90 seconds and the sum of correct responses from the AVLT learning trials. Study 1 used five learning trials while Studies 2 and 3 used three trials. These tests were selected to model those described by Leavitt and colleagues, which also used the SDMT and a measure of verbal learning, the Selective Reminding Test.4 Raw scores were converted to sample-based z scores. These z scores were averaged together ((z score SDMT+ z score AVLT)/2) to create a single indicator of cognition in which higher scores indicated better cognitive status. To measure disease severity, Study 1 used the Multiple Sclerosis Functional Composite (MSFC), Study 2 used the Expanded Disability Status Scale (EDSS), and patients in Study 3 were administered the Guy’s Neurological Disability Scale (GNDS).10 Outdoor temperature Daily average outdoor temperatures were determined by zip code using a historical weather database at www.wunderground.com/history. In Study 3, average daily humidity and hours of visible sunlight data were also obtained from the website. Study 3 also included average body temperature data derived from two oral thermometer (Walgreens Premium 8-Second Digital Thermometer) readings administered before and after testing. Pearson correlation between patients’ time 1 and time 2 oral thermometer readings showed acceptable reliability (r = 0.76, p < 0.001); the manufacturer’s reported accuracy was ±0.2 for temperatures between 98° and 102°F. Testing was conducted in the Kansas City metropolitan area. Statistical analyses Pearson correlations were used to investigate the relationship between cognitive performance and outdoor temperature, followed by partial correlations co-varying for disease and patient characteristics. Associations between cognitive performance, broader weather variables, and average body temperature were also examined in Study 3. Results Study characteristics Study 1 included patients with relapsing–remitting MS (RRMS, n = 85), secondary-progressive MS (SPMS, n = 22), and primary-progressive MS (PPMS, n = 11) who had an average MSFC T score of 49.06±9.92. In Study 2, 71 RRMS and eight SPMS patients had an average EDSS score of 2.67±1.47. There were 34 RRMS and 32 SPMS patients in Study
3 with an average GNDS total score of 13.26±7.33. Other study demographics and cognitive characteristics are reported in Table 1. Hypothesis testing As shown in Figure 1, there were no significant zeroorder correlations between outdoor temperature and cognition in Study 1 (r = 0.12, p = 0.20), Study 2 (r = 0.04, p = 0.74), or Study 3 (r = 0.03, p = 0.85). Partial correlations, co-varying for age, education, disease severity, and disease duration also revealed non-significant associations (Studies 1–3, p > 0.80). In addition, the association between outdoor temperature and cognition remained non-significant when all study participants were combined (N = 263, r = 0.07, p = 0.25) and when RRMS patients (n = 190, r = 0.04, p = 0.63) and progressive (i.e. SPMS or PPMS) patients (n = 73, r = 0.14, p = 0.23) were analyzed separately. Within Study 3, there were no significant associations between cognition and average daily humidity (r = 0.02, p = 0.86), a ratio of outdoor temperature to humidity (r = 0.02, p = 0.86), hours of visible sunlight (r = 0.11, p = 0.37), or average body temperature (r = 0.07, p = 0.61). Discussion The results of this work suggest that outdoor temperature is not associated with cognitive test performance in MS. Despite large sample sizes and adequate statistical power, the current work could not replicate a significant association between outdoor temperatures and cognition in MS. In the Leavitt and colleagues study (N = 40; female, n = 36), outdoor temperature (55.5±18.9°F), SDMT performance (53.8±12.6), age (45.0±7.2), and disease duration (9.9±6.7) were comparable to Studies 1–3 (See Table 1 for comparison). Of note, the Leavitt and colleagues study4 controlled for brain atrophy, which may have increased the sensitivity of their analyses and allowed for the detection of relatively small effects. Similarly, Leavitt and colleagues’ subsequent longitudinal analysis may have been sensitive to relatively small effects by measuring within-subject cognitive fluctuations. It is worth noting, however, that the present study found no significant relationship between outdoor temperature and cognition despite a large combined sample that was also powered to detect very small effects. The current work and the Leavitt study may also differ because of environmental variables, such as access to air-conditioning, time spent outside, seasonal allergies, or some undetermined factor. Elucidating the relationship between cognitive functioning and seasonal variables is important to better
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
BL Roberg and JM Bruce Table 1. Patient demographics and cognitive characteristics.
N Age Disease duration Sex Female Male Ethnicity Whites Non-White Black/African Americans Hispanic/Latino/as Education ⩾ 4-year degree Some college High school grad SDMT (SD) AVLT-5 trial AVLT-3 trial Outdoor temperature °F Min–Max °F
Study 1
Study 2
Study 3
118 47.00 (10.50) 9.67 (8.55)
79 47.10 (10.79) 10.96 (8.30)
66 51.38 (9.90) 13.67 (10.40) 52 14 62 4 (n=3) (n=1) 45 16 5 49.60 (13.45) – 25.73 (6.04) 55.8 (17.6) 11–88
94 24
71 8
105 13 (n=13)
71 8 (n=4) (n=4)
47 18 53 50.34 (12.02) 47.48 (10.72) – 52.0 (17.9) 15–85
36 34 9 51.13 (12.63) – 25.68 (6.18) 61.0 (15.8) 24–86
Data point averages and standard deviations (SD) are reported in mean (SD) format. Age and disease duration are reported in years. Mean raw scores for the Symbol Digit Modalities Test (SDMT) and the Auditory Verbal Learning Test (AVLT), 3 trial and 5 trial are included.
Study 2 (N=79)
2
2.5
1
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0
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Cognition
Cognition
Study 1 (N=118)
-1 -2 -3 25
50
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-1.5 -2.5
100
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100
Outdoor Temperature °F
Outdoor Temperature °F
Study 3 (N=66)
Combined MS Samples (N=263)
2.5
2.5
1.5
1.5
0.5
0.5
Cognition
Cognition
0
-0.5
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-0.5 -1.5 -2.5
0
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Outdoor Temperature °F
Figure 1. Scatter plots between cognition and outdoor temperature. Cognition is reported as z scores, with higher scores representing better cognitive performance. Pearson correlations between daily average outdoor temperature and cognition were: for Study 1 (r = 0.12, p = 0.20), Study 2 (r = 0.04, p = 0.74), Study 3 (r = 0.03, p = 0.85), and for combined multiple sclerosis (MS) samples (r = 0.07, p = 0.25). http://msj.sagepub.com 3
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
Multiple Sclerosis Journal inform patient feedback and clinical research investigations spanning different seasons.4 Research in this area can be conducted retrospectively with archival weather data. This research is encouraged to be performed by investigators in a broad range of climates as regional/seasonal differences may influence study results.2 The results of the current work underscore the need to better understand if, when, and how cognitive performance may be influenced by seasonal variables in MS. Acknowledgements Study 2 was partially funded by a pilot grant from the National MS Society to the corresponding author (PP1506). Study 3 was funded by a University of Missouri-Kansas City School of Graduate Studies grant awarded to Brandon Roberg. Conflicts of interest Dr Bruce is a member of the Novartis Unbranded Speakers Bureau and the Novartis MS and Cognition Medical Advisory Board. He has also received funding from Cephalon and is a paid consultant to the National Hockey League. Mr. Roberg has nothing to declare. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
2. Bamford CR, Sibley WA and Thies C. Seasonal variation of multiple sclerosis exacerbations in Arizona. Neurology 1983; 33: 697–701. 3. Simmons RD, Ponsonby AL, van der Mei IAF, et al. What affects your MS? Responses to an anonymous, Internet-based epidemiological survey. Mult Scler 2004; 10: 202–211. 4. Leavitt VM, Sumowski JF, Chiaravalloti N, et al. Warmer outdoor temperature is associated with worse cognitive status in multiple sclerosis. Neurology 2012; 78: 964–968. 5. Leavitt VM, Wylie G, Chiaravalloti N, et al. Warmer outdoor temperature is associated with task-related increased BOLD activation in patients with multiple sclerosis. Brain Imaging Behav 2014; 8: 128–132. 6. Feaster HT and Bruce JM. Visual acuity is associated with performance on visual and non-visual neuropsychological tests in multiple sclerosis. Clin Neuropsychol 2011; 25: 640–651. 7. Roberg BL, Bruce JM, Lovelace CT, et al. How patients with multiple sclerosis perceive cognitive slowing. Clin Neuropsychol 2012; 26: 1278–1295. 8. Bruce JM, Hancock LM, Arnett P, et al. Treatment adherence in multiple sclerosis: Association with emotional status, personality, and cognition. J Behav Med 2010; 33: 219–227. 9. Lezak MD, Howieson DB, Bigler ED, et al. Neuropsychological assessment. 5th ed. New York, New York: Oxford University Press; 2012.
References Visit SAGE journals online http://msj.sagepub.com
SAGE journals
1. Meier DS, Balashov KE, Healy B, et al. Seasonal prevalence of MS disease activity. Neurology 2010; 75: 799–806.
10. Sharrack B and Hughes RA. The Guy’s Neurological Disability Scale (GNDS): A new disability measure for multiple sclerosis. Mult Scler 1999; 5: 223–233.
4 http://msj.sagepub.com
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
research-article2015
MSJ0010.1177/1352458515575172Multiple Sclerosis JournalBL Roberg and JM Bruce
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Reconsidering outdoor temperature and cognition in multiple sclerosis
Multiple Sclerosis Journal 1–4 DOI: 10.1177/ 1352458515575172 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Brandon L Roberg and Jared M Bruce
Abstract Background: Research in multiple sclerosis (MS) suggests warmer weather plays a role in disease manifestation. Objective: This work sought to replicate the finding that warmer outdoor temperatures are significantly associated with poorer cognition in MS. Methods: Associations between outdoor temperature and cognition were examined in three studies with a total of 263 patients with MS. Results: Contrary to previous research, no significant relationship was found between cognitive performance and outdoor temperature in MS. Conclusions: The results of the current work underscore the need to better understand if, when, and how cognitive performance may be influenced by seasonal variables in MS.
Correspondence to: Jared M. Bruce Department of Psychology, University of MissouriKansas City, 5030 Cherry St., Cherry Hall Room 324, Kansas City, MO 64110, USA. [email protected] Brandon L Roberg Jared M Bruce Department of Psychology, University of MissouriKansas City, USA
Keywords: Multiple sclerosis, neuropsychological functioning, cognitive testing, memory, attention, processing speed Date received: 24 October 2014; received: 5 January2015; accepted: 1 February 2015 Introduction Research in multiple sclerosis (MS) suggests warmer weather may play a role in disease manifestation.1–3 In a cross-sectional analysis, Leavitt and colleagues4 found that warmer outdoor temperatures were significantly associated with poorer cognition in MS. In a separate MS sample, longitudinal analysis confirmed that performance on cognitive tests declined as outdoor temperature increased.4 Using a subset of the cross-sectional sample,4 they also found that warmer outdoor temperatures were associated with greater blood oxygen level-dependent (BOLD) activation in the frontal lobe and inferior parietal lobule during a sustained attention task.5 The present work attempted to replicate and extend Leavitt and colleagues’ cross-sectional results4 in three samples of MS patients. We hypothesized that warmer outdoor temperatures would be significantly associated with poorer cognitive performance in each study. In Study 3, we also investigated the relationship between cognition, body temperature. and broader weather-related variables.
Methods Participants and procedures The sample in Study 1 was composed of MS patients recruited as part of studies examining visual functioning and cognition6 and psychological correlates of cognition and fatigue.7 Study 2 patients were recruited in a larger study examining adherence to disease-modifying medications.8 In Study 3, patients were recruited as part of an ongoing study examining mentalizing and cognition in MS. Diagnosis and disease course were confirmed by patients’ neurologists using established criteria (see study references for more details).6–8 All studies were approved by the institutional review board at the University of Missouri-Kansas City.
Cognitive tests and disease severity Information processing speed was assessed using the oral version of the Symbol Digit Modalities Test (SDMT) and verbal learning was assessed with the Auditory Verbal Learning Test (AVLT).9 The variables
http://msj.sagepub.com 1
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
Multiple Sclerosis Journal of interest were total SDMT items correct in 90 seconds and the sum of correct responses from the AVLT learning trials. Study 1 used five learning trials while Studies 2 and 3 used three trials. These tests were selected to model those described by Leavitt and colleagues, which also used the SDMT and a measure of verbal learning, the Selective Reminding Test.4 Raw scores were converted to sample-based z scores. These z scores were averaged together ((z score SDMT+ z score AVLT)/2) to create a single indicator of cognition in which higher scores indicated better cognitive status. To measure disease severity, Study 1 used the Multiple Sclerosis Functional Composite (MSFC), Study 2 used the Expanded Disability Status Scale (EDSS), and patients in Study 3 were administered the Guy’s Neurological Disability Scale (GNDS).10 Outdoor temperature Daily average outdoor temperatures were determined by zip code using a historical weather database at www.wunderground.com/history. In Study 3, average daily humidity and hours of visible sunlight data were also obtained from the website. Study 3 also included average body temperature data derived from two oral thermometer (Walgreens Premium 8-Second Digital Thermometer) readings administered before and after testing. Pearson correlation between patients’ time 1 and time 2 oral thermometer readings showed acceptable reliability (r = 0.76, p < 0.001); the manufacturer’s reported accuracy was ±0.2 for temperatures between 98° and 102°F. Testing was conducted in the Kansas City metropolitan area. Statistical analyses Pearson correlations were used to investigate the relationship between cognitive performance and outdoor temperature, followed by partial correlations co-varying for disease and patient characteristics. Associations between cognitive performance, broader weather variables, and average body temperature were also examined in Study 3. Results Study characteristics Study 1 included patients with relapsing–remitting MS (RRMS, n = 85), secondary-progressive MS (SPMS, n = 22), and primary-progressive MS (PPMS, n = 11) who had an average MSFC T score of 49.06±9.92. In Study 2, 71 RRMS and eight SPMS patients had an average EDSS score of 2.67±1.47. There were 34 RRMS and 32 SPMS patients in Study
3 with an average GNDS total score of 13.26±7.33. Other study demographics and cognitive characteristics are reported in Table 1. Hypothesis testing As shown in Figure 1, there were no significant zeroorder correlations between outdoor temperature and cognition in Study 1 (r = 0.12, p = 0.20), Study 2 (r = 0.04, p = 0.74), or Study 3 (r = 0.03, p = 0.85). Partial correlations, co-varying for age, education, disease severity, and disease duration also revealed non-significant associations (Studies 1–3, p > 0.80). In addition, the association between outdoor temperature and cognition remained non-significant when all study participants were combined (N = 263, r = 0.07, p = 0.25) and when RRMS patients (n = 190, r = 0.04, p = 0.63) and progressive (i.e. SPMS or PPMS) patients (n = 73, r = 0.14, p = 0.23) were analyzed separately. Within Study 3, there were no significant associations between cognition and average daily humidity (r = 0.02, p = 0.86), a ratio of outdoor temperature to humidity (r = 0.02, p = 0.86), hours of visible sunlight (r = 0.11, p = 0.37), or average body temperature (r = 0.07, p = 0.61). Discussion The results of this work suggest that outdoor temperature is not associated with cognitive test performance in MS. Despite large sample sizes and adequate statistical power, the current work could not replicate a significant association between outdoor temperatures and cognition in MS. In the Leavitt and colleagues study (N = 40; female, n = 36), outdoor temperature (55.5±18.9°F), SDMT performance (53.8±12.6), age (45.0±7.2), and disease duration (9.9±6.7) were comparable to Studies 1–3 (See Table 1 for comparison). Of note, the Leavitt and colleagues study4 controlled for brain atrophy, which may have increased the sensitivity of their analyses and allowed for the detection of relatively small effects. Similarly, Leavitt and colleagues’ subsequent longitudinal analysis may have been sensitive to relatively small effects by measuring within-subject cognitive fluctuations. It is worth noting, however, that the present study found no significant relationship between outdoor temperature and cognition despite a large combined sample that was also powered to detect very small effects. The current work and the Leavitt study may also differ because of environmental variables, such as access to air-conditioning, time spent outside, seasonal allergies, or some undetermined factor. Elucidating the relationship between cognitive functioning and seasonal variables is important to better
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
BL Roberg and JM Bruce Table 1. Patient demographics and cognitive characteristics.
N Age Disease duration Sex Female Male Ethnicity Whites Non-White Black/African Americans Hispanic/Latino/as Education ⩾ 4-year degree Some college High school grad SDMT (SD) AVLT-5 trial AVLT-3 trial Outdoor temperature °F Min–Max °F
Study 1
Study 2
Study 3
118 47.00 (10.50) 9.67 (8.55)
79 47.10 (10.79) 10.96 (8.30)
66 51.38 (9.90) 13.67 (10.40) 52 14 62 4 (n=3) (n=1) 45 16 5 49.60 (13.45) – 25.73 (6.04) 55.8 (17.6) 11–88
94 24
71 8
105 13 (n=13)
71 8 (n=4) (n=4)
47 18 53 50.34 (12.02) 47.48 (10.72) – 52.0 (17.9) 15–85
36 34 9 51.13 (12.63) – 25.68 (6.18) 61.0 (15.8) 24–86
Data point averages and standard deviations (SD) are reported in mean (SD) format. Age and disease duration are reported in years. Mean raw scores for the Symbol Digit Modalities Test (SDMT) and the Auditory Verbal Learning Test (AVLT), 3 trial and 5 trial are included.
Study 2 (N=79)
2
2.5
1
1.5
0
0.5
Cognition
Cognition
Study 1 (N=118)
-1 -2 -3 25
50
75
-1.5 -2.5
100
0
25
50
75
100
Outdoor Temperature °F
Outdoor Temperature °F
Study 3 (N=66)
Combined MS Samples (N=263)
2.5
2.5
1.5
1.5
0.5
0.5
Cognition
Cognition
0
-0.5
-0.5 -1.5 -2.5
-0.5 -1.5 -2.5
0
25
50
75
Outdoor Temperature °F
100
0
25
50
75
100
Outdoor Temperature °F
Figure 1. Scatter plots between cognition and outdoor temperature. Cognition is reported as z scores, with higher scores representing better cognitive performance. Pearson correlations between daily average outdoor temperature and cognition were: for Study 1 (r = 0.12, p = 0.20), Study 2 (r = 0.04, p = 0.74), Study 3 (r = 0.03, p = 0.85), and for combined multiple sclerosis (MS) samples (r = 0.07, p = 0.25). http://msj.sagepub.com 3
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
Multiple Sclerosis Journal inform patient feedback and clinical research investigations spanning different seasons.4 Research in this area can be conducted retrospectively with archival weather data. This research is encouraged to be performed by investigators in a broad range of climates as regional/seasonal differences may influence study results.2 The results of the current work underscore the need to better understand if, when, and how cognitive performance may be influenced by seasonal variables in MS. Acknowledgements Study 2 was partially funded by a pilot grant from the National MS Society to the corresponding author (PP1506). Study 3 was funded by a University of Missouri-Kansas City School of Graduate Studies grant awarded to Brandon Roberg. Conflicts of interest Dr Bruce is a member of the Novartis Unbranded Speakers Bureau and the Novartis MS and Cognition Medical Advisory Board. He has also received funding from Cephalon and is a paid consultant to the National Hockey League. Mr. Roberg has nothing to declare. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
2. Bamford CR, Sibley WA and Thies C. Seasonal variation of multiple sclerosis exacerbations in Arizona. Neurology 1983; 33: 697–701. 3. Simmons RD, Ponsonby AL, van der Mei IAF, et al. What affects your MS? Responses to an anonymous, Internet-based epidemiological survey. Mult Scler 2004; 10: 202–211. 4. Leavitt VM, Sumowski JF, Chiaravalloti N, et al. Warmer outdoor temperature is associated with worse cognitive status in multiple sclerosis. Neurology 2012; 78: 964–968. 5. Leavitt VM, Wylie G, Chiaravalloti N, et al. Warmer outdoor temperature is associated with task-related increased BOLD activation in patients with multiple sclerosis. Brain Imaging Behav 2014; 8: 128–132. 6. Feaster HT and Bruce JM. Visual acuity is associated with performance on visual and non-visual neuropsychological tests in multiple sclerosis. Clin Neuropsychol 2011; 25: 640–651. 7. Roberg BL, Bruce JM, Lovelace CT, et al. How patients with multiple sclerosis perceive cognitive slowing. Clin Neuropsychol 2012; 26: 1278–1295. 8. Bruce JM, Hancock LM, Arnett P, et al. Treatment adherence in multiple sclerosis: Association with emotional status, personality, and cognition. J Behav Med 2010; 33: 219–227. 9. Lezak MD, Howieson DB, Bigler ED, et al. Neuropsychological assessment. 5th ed. New York, New York: Oxford University Press; 2012.
References Visit SAGE journals online http://msj.sagepub.com
SAGE journals
1. Meier DS, Balashov KE, Healy B, et al. Seasonal prevalence of MS disease activity. Neurology 2010; 75: 799–806.
10. Sharrack B and Hughes RA. The Guy’s Neurological Disability Scale (GNDS): A new disability measure for multiple sclerosis. Mult Scler 1999; 5: 223–233.
4 http://msj.sagepub.com
Downloaded from msj.sagepub.com at University of Leeds on October 4, 2015
