533229

research-article2014

MSJ0010.1177/1352458514533229Multiple Sclerosis JournalRHB Benedict, S Morrow

MULTIPLE SCLEROSIS MSJ JOURNAL

Research Paper

Characterizing cognitive function during relapse in multiple sclerosis Ralph HB Benedict, Sarah Morrow, Jonathan Rodgers, David Hojnacki, Margaret A Bucello, Robert Zivadinov and Bianca Weinstock-Guttman

Multiple Sclerosis Journal 2014, Vol. 20(13) 1745­–1752 DOI: 10.1177/ 1352458514533229 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

Abstract Objective: To characterize neuropsychological (NP) test performance during multiple sclerosis (MS) relapse and recovery. Methods: Clinical status was assessed with NP testing and Expanded Disability Status Scale (EDSS) in 24 relapsing patients, and 24 individually-matched, stable controls. All presented with cognitive symptoms as indicated by patient, clinician or caregiver perceived decline, but were free of optic neuritis, ataxia and upper extremity weakness that could compromise NP testing. The presence of enhancing magnetic resonance imaging (MRI) lesions was considered confirmatory of relapse. Relapsing patients were treated with corticosteroids. NP testing and EDSS were compared to pre-relapse baseline levels, and three-month, post-relapse, follow-up. Results: Analyses revealed significant decline on the Symbol Digit Modalities Test (SDMT) (p=0.005) and worsening on EDSS (p=0.019). Impairment was observed at the point of relapse in cases but not controls. The groups were no longer different at three-month follow-up. The increment of decline on SDMT was 3.5 raw score points, or roughly 6%. Conclusions: This is the first study to assess NP status changes during MS relapse using well established, reliable metrics. The presence of a clinically meaningful event is substantiated by decline in NP testing, observed or reported cognitive change, and in a subset of patients, gadolinium-enhancing MRI lesions.

Keywords:  Multiple sclerosis, relapsing–remitting, outcome measurement Date received: 5 February 2014; revised: 31 March 2014; accepted: 3 April 2014

Introduction Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system which most commonly presents with a relapsing–remitting course.1 Relapses are diagnosed via neurological examination often quantified with the Expanded Disability Status Scale (EDSS),2 but the EDSS only cursorily assesses alteration in cognitive function.3 So-called “cognitive relapses” are hypothesized to occur4 and may be more common than is currently appreciated due to the lack of appropriate measurement tools. Unfortunately, few studies have quantified changes on neuropsychological (NP) tests during MS relapses, and none have employed NP tests widely acknowledged to be reliable and valid for this purpose.5,6 Thus, there are no widely accepted guidelines for treating patients who have cognitive complaints and active post-contrast

magnetic resonance imaging (MRI) lesions, but minimal sensory/motor deficits. In addition, studying cognition during relapses provides an opportunity to characterize clinically meaningful change on NP tests, a hotly debated issue.7–9 Clinically meaningful change is especially important when outcome measures are not necessarily face valid or easily translated into everyday life experiences, as in the case of commonly used NP tests. NP outcomes are the best tools available for assessing cognition in clinical trials, and statistical change is well understood. However, establishing thresholds for clinically relevant change is far more difficult. One recommended approach is to correlate increments of change with clearly discernible clinical states such as relapse,10 or meaningful anchors such as job loss.9

Correspondence to: Ralph HB Benedict Buffalo General Hospital, Suite E2, 100 High Street, Buffalo, New York, 14203, USA. [email protected] Jonathan Rodgers David Hojnacki Margaret A Bucello Bianca Weinstock-Guttman University at Buffalo, State University of New York, USA Sarah Morrow Western University, Canada Robert Zivadinov State University of New York, USA/Buffalo Neuroimaging Analysis Center, State University of New York, USA/MRI Clinical Translational Research Center, State University of New York, USA

http://msj.sagepub.com 1745

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

Multiple Sclerosis Journal 20(13)

Figure 1.  Study design is presented, showing two groups of patients, those undergoing clinical evaluation at the time of relapse - relapsing group (RG) and stable group (SG) patients matched to the RG on a case-by-case basis. All patients had a baseline assessment including Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and the Brief Visuospatial Memory Test Revised (BVMTR). Most patients also had baseline values for Timed 25 Foot Walk (T25FW), Nine Hole Peg Test (NHPT) and the MS Neuropsychological Screening Questionnaire (MSNQ). RG patients were assessed on the day of clinical assessment of relapse, prior to corticosteroid therapy. All returned to the clinic three months later for repeat examination.

In the current study we endeavored to (a) examine neurocognitive status along with other aspects of neurological disability during a MS relapse, and (b) enhance the understanding of the clinically meaningful changes on candidate NP outcomes for clinical trials that may occur as a result of neurological worsening or response to treatment. Methods Research design Using a mixed-factor, matched-pairs design, 48 patients with clinically definite MS11 were evaluated at a single outpatient clinic in Buffalo, New York, USA. There were three assessments: baseline, relapse and recovery (Figure 1). The study design was prospective, in so far as the relapse and recovery assessments were current, although the baseline predated the study. Patient selection Inclusion criteria were age 18–65 years, first language English, near visual acuity of ≤20/70, EDSS < 7.0, and prior NP testing within four years of study. Patients in the relapsing group (RG) were identified by neurologist clinicians in an outpatient clinic setting. RG patients were recruited consecutively, but

were required to present with clinical symptoms indicating a relapse, and mental status changes as indicated by patient report, caregiver report, or clinician observation. The patients had a range of motor/sensory symptoms and met commonly used standards for relapse as determined by clinical neurologists (DH, BWG). Corroborating evidence in the form of a new gadolinium-enhancing lesion on MRI was documented, but not necessary for inclusion in the study. All RG patients were treated with intravenous corticosteroid therapy. Exclusion criteria were history of other medical or psychiatric illness that could compromise cognitive function, current treatment known to have an adverse impact of cognitive function (e.g. anticonvulsants, narcotics, chemotherapy), and signs or symptoms at relapse implicating focal pathology in the spinal cord, brainstem, or optic nerve. No patient had optic neuritis or an upper extremity deficit that could compromise NP test performance. Control patients were recruited from an archival database including roughly 1200 patients who had undergone prior NP testing. Once an RG patient completed the study, the database was surveyed for candidate controls that were matched based on age, time from baseline assessment, and previous available cognitive performance. Candidate controls were thus identified and listed in random order to be contacted. The first patient from the list agreeing to participate was

1746 http://msj.sagepub.com

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

RHB Benedict, S Morrow et al. enrolled. These stable group (SG) patients denied changes in medical status and had no (a) gadoliniumenhancing lesions on most recent MRI (less than six months from the evaluation), (b) new cognitive complaints or reported mental status changes, (c) corticosteroid therapy or medication change within three months of study entry, or during the three-month follow-up period. There were no changes in disease modifying therapy for either the RG or SG groups between the relapse and follow-up visits. The study was approved by the Institutional Review Board of the State University of New York at Buffalo, and written informed consent was obtained from all participating subjects. Assessments On the same day the relapse was identified, RG patients underwent an EDSS performed by a clinical neurologist or nurse practitioner. Next, the following tests were performed by a research assistant, blinded to prior NP testing results and both prior and current EDSS results: Rao12 adaptations of the 3 s Paced Auditory Serial Addition Test (PASAT),13 oral-response Symbol Digit Modalities Test (SDMT),14 Brief Visuospatial Memory Test Revised (BVMTR),15 Timed 25 Foot Walk (T25FW),16 Nine-Hole Peg Test (NHPT),17 and the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ).18 The primary cognitive outcomes were the SDMT, PASAT and BVMTR, because they were available in the baseline NP assessment in all patients, and because they are widely recognized as reliable and valid in MS,5,6,19,20 and as such candidates for inclusion in future clinical trials.8 Alternate forms of the SDMT, PASAT and BVMTR were employed as in our prior work.21,22 Other metrics were utilized as available from the baseline assessment. MRI was obtained in patients based on clinician request, and scanner availability. These were clinician ordered scans deemed confirmatory of clinical impression but not considered necessary in all cases. All MRI scans were obtained on a 1.5T or 3T GE Signa Excite HD 12.0 Twin Speed 8-channel scanner with standardized MRI protocols. Therefore, the sequences always included a 2D multi-planar dual fast spin-echo (FSE) proton density (PD) image, and a T2-weighted image. In addition, fluid-attenuated inversion-recovery (FLAIR) and spin echo (SE) T1 images were acquired, both with and without a single dose intravenous bolus of 0.1 mmol/kg gadolinium-diethylenetriamine pentaacetic acid 5 min after injection. One average was used for all pulse sequences. All sequences were acquired with a 256×192 matrix (freq×phase), field-of-view

(FOV) of 25.6×19.2 cm (256×256 matrix with Phase FOV=0.75), for an in-plane resolution of 1 mm ×1 mm. For all 2D scans 48 slices were collected, using a thickness of 3 mm, and no gap between slices. All scans were acquired in an axial-oblique orientation, parallel to the sub-callosal line. Other relevant parameters were as follows: for dual FSE PD/T2, echo and repetition times (TE and TR) TE1/TE2/TR=9/98/5300 ms, flip angle (FA)=90, echo train length (ETL)=14; for FLAIR, TE/TI/TR=120/2100/8500 ms (TI-inversion time), FA=90, ETL=24; for SE T1-WI, TE/TR=16/600 ms, FA=90 and for 3D HIRES T1-WI, TE/TI/TR=2.8/900/5.9 ms, FA=10. The gadolinium number and lesion volumes (LVs) were measured using a semi-automated edge detection contouring/ thresholding technique previously described.23 Territorial analysis of lesion localization was performed manually using standard anatomical landmarks. Statistical analysis The data were largely analyzed with parametric statistics with the exception of nonparametric tests as indicated for some demographics and the EDSS. The RG and SG groups were compared using conventional t tests and chi-square analyses. For the primary hypotheses, we utilized a mixed-factor, analysis of variance (ANOVA) model, whereby the RG and SG betweengroup factor was coupled with the within-subjects factor of time (baseline, enrollment/relapse, recovery). The general hypothesis, that the dependent variable would be impacted at the point of relapse in the RG but not SG, was assessed by the group×time interaction. As there is no mixed model analog for ordinal data, EDSS was analyzed as if the interaction was significant: the study groups were compared at each time point using the Mann-Whitney U Test. In addition, each group was assessed over time using the Friedman Test, and if significant the Wilcoxon Test was calculated comparing baseline to acute testing, and acute to recovery testing. Results The groups were well matched on demographics, disease characteristics, and the test-retest interval (Table 1). There were no significant differences between RG and SG patients. The RG and SG groups were well matched on baseline SDMT, with scores approximating a raw value of 53 (stable 53.1±11.9; relapsing 53.6±11.3, p=0.882). However, the groups diverged at the relapse assessment such that the RG group declined

http://msj.sagepub.com 1747

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

Multiple Sclerosis Journal 20(13) Table 1.  Demographic and disease characteristics in relapsing and stable multiple sclerosis (MS) patients. Relapsing mean Age Education Male/female Caucasian/other Disease duration in years Disease course: RR/RP EDSS MSNQ SDMT PASAT BVMTR Time from baseline in days

43.3 14.5  06/18  23/1 11.8  22/2 2.6 26.5 53.6 44.2 22.6 975.8

SD 8.1 2.1

8.0 1.2 12.8 11.3 10.2 7.8 705.4

Stable mean 43.5 13.5  04/20  22/2 9.1  24/0 2.9 25.2 53.1 42.0 22.4 836.3

SD 7.6 1.9

6.8 1.6 12.7 11.9 11.9 5.9 626.2

p 0.898 0.100 0.362 0.600 0.220 0.149 0.442 0.519 0.882 0.803 0.802 0.473

BVMTR: Brief Visuospatial Memory Test Revised; EDSS: Expanded Disability Status Scale; MSNQ: MS Neuropsychological Screening Questionnaire; PASAT: Paced Auditory Serial Addition Test; RP: relapsing progressive; RR: relapsing–remitting; SD: standard deviation; SDMT: Symbol Digit Modalities Test.

(50.3±12.1, p=0.005), whereas the SG group gained slightly, although not significantly (55.3±9.9, p=0.15). The mixed factor ANOVA (Figure 2(a)) revealed a significant interaction (F=6.0 (1,46), p=0.004). Analysis of within-subjects main effects revealed no significance for the SG, but the withingroup change for the RG was statistically significant (p=0.002). The within-subjects simple effects were significant only for the baseline vs acute (p=0.005), and acute vs recovery (p=0.001) comparisons. The groups were also balanced on baseline PASAT and BVMTR, but ANOVA models were not significant for either test. For EDSS, the between-group effect by Mann-Whitney test was significant only at the relapse assessment (p=0.019) where the median value for RG was 3.25 and for SG 2.5 (Figure 2(b)). In the SG condition, the median EDSS remained 2.5 at each time point, whereas in the RG the median scores moved from 2.5, to 3.25 to 2.75. The Friedman test measuring the within-group effect was not significant for the SG (p=0.787), but the test was significant for the RG (p=0.001). As was the case for SDMT, the within-subjects paired comparisons for the RG group were significant only for the comparison of baseline and acute (p=0.002), and acute and recovery (p=0.033) comparisons. Clinical MRI scans were obtained within 21 days of the clinical visit in 15 RG patients (six on 1.5T, nine on 3T scanner). One patient’s gadolinium enhancement scan could not be quantified due to motion

artifact. All but one of the 14 remaining scans revealed gadolinium enhancement, with lesion counts ranging from 0– 43 (in nine patients, the scan prompted an urgent clinical visit that revealed a relapse meeting inclusion criteria). The mean gadolinium lesion volume was 530.8±1456.3 mm3 with a range of 0–5580.5. All of the lesions were supratentorial, and mostly in the frontal, periventricular white matter. In three patients the enhancing lesions were in the right hemisphere, in seven patients the lesions were in the left hemisphere, and the remaining four patients had bilateral involvement. All scans revealed FLAIR T2 lesions (mean volume 16,183.4±16,754.7 mm3, range 224.9–63,012.4). There was no significant correlation between T2 or gadolinium lesion number or volume and change in SDMT or EDSS. There were no significant interaction effects for the subgroups with complete T25FW (n=20) and NHPT (n=22) data. The MSNQ model with 19 matched cases revealed a trend toward significant interaction (p=0.088). This ANOVA model was under-powered considering a 21% reduction in the sample size. We therefore elected to test the within-groups main effects which were significant only in the RG (baseline 26.5±12.8, relapse 29.2±12.5, recovery 24.3±10.8; p=0.019). Discussion This is the first prospective study documenting cognitive abilities, before, during and after MS relapse

1748 http://msj.sagepub.com

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

RHB Benedict, S Morrow et al.

Figure 2.  Relapsing and stable patient scores. (a) Raw scores from the Symbol Digit Modalities Test obtained from relapsing and stable multiple sclerosis patients. The mixed factor analysis of variance (ANOVA) reveals a significant interaction, with significant drop in performance among relapsing patients, but no significant changes in the stable group. (b) Scatterplots of Expanded Disability Status Scale scores for each group at each time point. Data are shown for baseline, relapse, and three-month recovery. The horizontal bar bar within the distribution indicates the median for that distribution. Nonparametric tests reveal a significant difference between the groups only at time 2, where the EDSS is higher for relapsing group patients versus controls.

using NP tests with excellent psychometric validity.5,19,22,24,25 We have previously shown that the SDMT is sensitive to mental status changes during MS relapses.10 However, in that study, relapses were documented during a large clinical trial and the specific symptoms were not described – relapsing patients may have had optic neuritis, severe ataxia, upper extremity paresis, or other non-cognitive symptoms that could impact NP test scores. Moreover, there was no clinical appraisal of mental status in that study. Here, we endeavored to control for sensory/

motor symptoms and in addition, only recruited patients exhibiting signs of cognitive disorder while excluding optic neuritis, upper extremity ataxia or spinal cord involvement in order to avoid interference with the cognitive assessment. We found that during such cognitive relapses, cognitive function did indeed decline from baseline, and subsequently normalize after corticosteroid treatment. Our review of the literature reveals only three other studies26–28 assessing cognition in MS patients during

http://msj.sagepub.com 1749

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

Multiple Sclerosis Journal 20(13) an acute relapse. None of these studies limited recruitment to patients with cognitive symptoms, included non-relapsing MS controls, or assessed patients prior to relapse. In Foong et al.’s study of 13 patients,27 a trend for improvement on some tests of attention (or processing speed) after relapse was observed in a subgroup showing reduction in gadolinium enhancement on MRI. Of note, there was no gain in the domain of memory as observed in the current study. The remaining studies used the PASAT as part of the Multiple Sclerosis Functional Composite. Patzold et al.26 and Ozakbas et al.28 employed similar methodology, with 27 and 36 patients respectively, excluding patients with optic neuritis. The PASAT was administered prior to treatment and 20–30 days post-treatment. Significant improvement was observed in one study,26 but not the other,28 but in this latter case, improvement was observed on EDSS. While these studies included healthy controls, none employed mixed factor ANOVA to account for the effects of practice among patients in the same statistical model. Nevertheless, there are some findings in common with our study. These early studies also reported improvement on cognitive testing after relapse, but only in the domain of information processing speed. While this is certainly a new area of research, at this time, it would seem that slowed mental processing may be a key deficit during MS cognitive relapses. There is a distinction to be drawn between statistical and clinically meaningful change in cognitive performance.9 The former is easily quantified and understood as a magnitude of change that exceeds statistical error variance.29 In contrast, understanding clinical meaning of raw score changes requires associating increments of change to relevant anchors such as vocational disability or clinical states where a patient’s impairment is clearly discernible to patients, clinicians or caregivers.9 In this study we emphasized the latter approach, showing that decline on SDMT was associated with mental status changes either reported by patients or observed by clinicians. In a retrospective, nested case-control study of the STRATA database comparing patients with and without relapses, analyses also showed significant SDMT worsening during relapse that improved on subsequent testing.30 While this study did not distinguish between relapses with or without cognitive symptoms, a raw score change of 3–4 points, or a change of 5%, was suggested as a threshold for clinical meaningfulness. Similar results were found here, with relapsing patients dropping by 3–4 points or 6% on SDMT, and showing recovery of the same magnitude three months later. Similar results were obtained using a

vocational status anchor. Morrow et al. retrospectively compared the NP scores of 97 MS patients with cognitive testing at baseline and three years. In those reporting reduced responsibility at work and/or unemployment, worsening on SDMT approximated four points.31 Thus, overall, there seems to be an emerging consensus that a score change of 3–4 points on SDMT is clinically meaningful. It is noteworthy that this degree of change is well within the confidence interval of statistical error variance. There are some notable limitations to our research design. First, the neurologist clinicians evaluating patients at relapse were aware of the study hypothesis and therefore bias may have entered into their appraisal of patients with regard to cognitive problems. While we acknowledge this point, we also note that the neurologists were blind to clinical testing results. We followed strictly standardized test manuals in applying neurological and cognitive tests, but the test administrators were not blinded to patient clinical status (they were blind to baseline test values). As these were relapsing patients, and as such symptomatic, it is difficult to envisage how this limitation could be overcome. Second, we studied only patients with overt cognitive involvement. Therefore we cannot estimate the prevalence of cognitive dysfunction in all relapsing MS patients. With more resources, it would be better to study a large sample of relapsing patients, determine the frequency of cognitive impairment, and then relate that to the clinician appraisals of cognitive status. Third, we did not include a measure of fatigue. While subjective reports of fatigue are not consistently correlated with NP test performance in MS,32 it is nevertheless possible that fatigue could account for some additional variance in the observed decline in NP performance. Fourth, while the study was prospective in the sense that the relapse and recovery testing followed enrollment, the baselines were retrospective and remote. While a lot can happen in four years that could influence cognition and EDSS, this same confound was just as potentially influential for the stable control group. Nevertheless, a more recent baseline and uniform baseline-to-relapse interval would no doubt enhance statistical power and validity. Finally, it would also be ideal to improve the MRI component in future studies. We would have preferred to obtain research MRI scans in both relapsing and stable control patients at both the acute and recovered stages. This would enhance statistical power and also permit correlation between clinical improvement and presumably partial vs full MRI-based recovery patterns. Our failure to detect such correlation is likely related to our use of multiple scanners in only a subset of 14 patients.

1750 http://msj.sagepub.com

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

RHB Benedict, S Morrow et al. These concerns notwithstanding, we believe that our study has characterized cognition during relapses that involve mental status changes but not optic neuritis or severe ataxia. We also tentatively propose that a raw score change of four points on SDMT is clinically meaningful in MS patients. Acknowledgements The authors gratefully acknowledge R Kininger and N Emmert for assistance with data management. The authors were involved in the production of this article as follows. RHBB: Study concept or design, analysis and interpretation of data, drafting/revising the manuscript for content, statistical analysis, obtaining funding; SM: Study concept or design, Revising the manuscript for content, including medical writing for content, interpretation of data; JR: Revising the manuscript for content, statistical analysis, interpretation of data; DH: Revising the manuscript for content, administrative, technical, material support; MAB: Revising the manuscript for content, administrative, technical, material support; RZ: Revising the manuscript for content, interpretation of data, administrative, technical, material support; BWG: Revising the manuscript for content, administrative, technical, material support. Conflict of interest RHB Benedict has been funded by the National MS Society, Accorda, Questcor, Novartis and Genzyme to pursue projects unrelated to the current study. He provides consultancies for Novartis, Genzyme, and Genentech, and serves on the speaker’s bureau for EMD Serono. S Morrow has received speaker and/or consulting fees from Biogen Idec, Teva Neurosciences, Novartis, EMD Serono and Genzyme. She has received investigator initiated grants from Biogen Idec and Novartis. J Rodgers has no competing interests. D Hojnacki provides consultancies for Biogen Idec, Teva Neurosciences, EMD Serono, and Genzyme. MA Bucello serves on the speaker bureau for Biogen Idec, Teva Neuroscience, and Genzyme. R Zivadinov received personal compensation from Teva Pharmacuticals, Biogen Idec, EMD Serono, Novartis and Sanofi-Genzyme for speaking and consultant fees. Dr. Zivadinov received financial support for research activities from Biogen Idec, Teva Pharmacuticals, EMD Serono, Novartis and SanofiGenzyme. B Weinstock-Guttman has participated in speaker’s bureaus and served as a consultant for Biogen Idec, Teva Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme and Sanofi, Mylan and Accorda. She also has received grant/research support from the agencies listed above as well as ITN-Cyclon, Questcor and Shire.

Funding This research was supported by Biogen Idec, via an investigator-initiated study to enhance the understanding of clinically meaningful change in multiple sclerosis.

References 1. Benedict RHB Murray TJ. Diagnosis and treatment of multiple sclerosis. Brit Med J 2006; 332: 525–527. 2. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Ann Neurol 1983; 13: 227–231. 3. Marrie RA and Goldman M. Validity of performance scales for disability assessment in multiple sclerosis. Mult Scler 2007; 13: 1176–1182. 4. Prado FM, Kosac VA and Dib JG. Cognitive relapse in multiple sclerosis: Report of 3 cases. Mult Scler2012; 18: 1830–1831. 5. Langdon DW, Amato MP, Boringa J, et al. Recommendations for a brief international cognitive assessment for multiple sclerosis (BICAMS). Mult Scler 2012; 18: 891–898. 6. Benedict RHB, Fischer JS, Archibald CJ, et al. Minimal neuropsychological assessment of MS Patients: A consensus approach. Clin Neuropsychol 2002; 16: 381–397. 7. Cohen JA, Reingold SC, Polman CH, et al. and MS IACoCTi. Disability outcome measures in multiple sclerosis clinical trials: Current status and future prospects. Lancet Neurology 2012; 11: 467–476. 8. Ontaneda D, LaRocca N, Coetzee T, et al. Revisiting the multiple sclerosis functional composite: Proceedings from the National Multiple Sclerosis Society (NMSS) Task Force on Clinical Disability Measures. Mult Scler 2012; 18: 1074–1080. 9. Morrow SA, Drake, A, Zivadinov R, et al. Predicting loss of employment over three years in multiple sclerosis: Clinically meaningful cognitive decline. Clinical Neuropsychologist, 2010; 24: 1131–1145. 10. Morrow SA, Jurgensen S, Forrestal F, et al. Effects of acute relapses on neuropsychological status in multiple sclerosis patients. J Neurol. 2011; 258: 1603–1608. 11. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 Revisions to the “McDonald Criteria”. Ann Neurol 2005; 58: 840–846. 12. Rao SM. A manual for the brief, repeatable battery of neuropsychological tests in multiple sclerosis. New York: National Multiple Sclerosis Society, 1991.

http://msj.sagepub.com 1751

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

Multiple Sclerosis Journal 20(13) 13. Gronwall DMA. Paced auditory serial addition task: A measure of recovery from concussion. Percept Mot Skills 1977; 44: 367–373. 14. Smith A. Symbol Digit Modalities test: Manual. Los Angeles: Western Psychological Services, 1982. 15. Benedict RHB. Brief Visuospatial Memory Test - Revised: Professional manual. Odessa, Florida: Psychological Assessment Resources, 1997. 16. Schwid SR, Goodman AD, Mattson DH, et al. The measurement of ambulatory impairment in multiple sclerosis. Neurology. 1997; 49: 1419–1424. 17. Mathiowetz V, Weber K, Kashman N, et al. Adult norms for the Nine Hole Peg Test of finger dexterity. OTJR (Thorofare N J) 1985; 5: 24–38. 18. Benedict RHB, Cox D, Thompson LL, et al. Reliable screening for neuropsychological impairment in MS. Mult Scler 2004; 10: 675–678.

26. Patzold T, Schwengelbeck M, Ossege LM, et al. Changes of the MS functional composite and EDSS during and after treatment of relapses with methylprednisolone in patients with multiple sclerosis. Acta Neurol Scand 2002; 105: 164–168. 27. Foong J, Rozewicz L, Quaghebeur G, et al. Neuropsychological deficits in multiple sclerosis after acute relapse. J Neurol Neurosurg Psychiatry 1998; 64: 529–532. 28. Ozakbas S, Cagiran I, Ormeci B, et al.Correlations between multiple sclerosis functional composite, expanded disability status scale and health-related quality of life during and after treatment of relapses in patients with multiple sclerosis. J Neurol Sci 2004; 218: 3–7.

20. Benedict RHB, Amato MP, Boringa J, et al. Brief international cognitive assessment for MS (BICAMS): International standards for validation. BMC Neurol 2012; 12: 55.

29. Temkin NR. Standard error in the Jacobson and Truax Reliable Change Index: The “classical approach” leads to poor estimates. J Int Neuropsychol Soc 2004; 10: 899–903.

22. Benedict RHB. Effects of using same vs. alternate form memory tests in short-interval, repeated assessment in multiple sclerosis. J Int Neuropsychol Soc 2005; 11: 727–736.

 SAGE journals

25. Benedict RHB, Smerbeck A, Parikh R, et al. Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: Implications for multiple sclerosis clinical trials. Mult Scler 2012; 18: 1320–1325.

19. Benedict RHB, Krupp L, Francis G, et al. NINDS common data elements, multiple sclerosis, neuropsychology/cognition recommendations. In: Group MCW (ed) Washington: National Institute for Neurological Diseases and Stroke, 2012.

21. Benedict RHB, Smerbeck A, Parikh R, et al. Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: Implications for multiple sclerosis clinical trials. Mult Scler 2012; 18: 1320–1325.

Visit SAGE journals online http://msj.sagepub.com

Multiple Sclerosis (MACFIMS). J Int Neuropsychol Soc 2006; 12: 549–558.

23. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing– remitting MS. Neurology 2001; 57: 1239–1247. 24. Benedict RHB, Cookfair D, Gavett R, et al. Validity of the Minimal Assessment of Cognitive Function in

30. Morrow SA, Jurgensen S, Forrestal F. Effects of acute relapses on neuropsychological status in multiple sclerosis patients. J Neurol 258: 1603– 1608. 31. Morrow SA, Drake A, Zivadinov R, et al. Predicting loss of employment over three years in multiple sclerosis: Clinically meaningful cognitive decline. Clin Neuropsychol 24: 1131–1145. 32. Morrow SA, Weinstock-Guttman B, Munschauer F, et al. Subjective fatigue is not associated with cognitive impairment in multiple sclerosis: Crosssectional and longitudinal analysis. Mult Scler 2009; 15: 998–1005.

1752 http://msj.sagepub.com

Downloaded from msj.sagepub.com at Universiteit Leiden \ LUMC on April 17, 2015

Characterizing cognitive function during relapse in multiple sclerosis.

To characterize neuropsychological (NP) test performance during multiple sclerosis (MS) relapse and recovery...
521KB Sizes 6 Downloads 4 Views