Original Paper Eur Neurol 2004;52:92–95 DOI: 10.1159/000079937
Received: January 27, 2004 Accepted: May 14, 2004 Published online: July 22, 2004
Cognitive, but Not Mood Dysfunction Develops in Multiple Sclerosis during 7 Years of Follow-Up C.G. Haase a, d M. Tinnefeld b, c I. Daum c R.E. Ganz e M. Haupts d P.M. Faustmann a, b a Department
of Neurology, University Hospital Essen, Essen, b Department of Neuroanatomy/Molecular Brain Research, of Cognitive Neurosciences and d Department of Neurology, Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, and e Swiss Epilepsy Center, Zurich, Switzerland c Institute
Key Words Multiple sclerosis W Cognition W Mood W Depression W Follow-up
Abstract Long-term development of psychological deficits in disability-free early multiple sclerosis (MS) was evaluated in 27 female patients over a period of 7 years and compared with healthy controls. Physical and cognitive parameters deteriorated significantly but not depression scores. In particular, the self-assessed somatic complaints remained non-similar between patients and controls. This indicates that although depression is clinically relevant and frequent in MS, in contrast to cognition it is not related to physical disease progression. Copyright © 2004 S. Karger AG, Basel
Introduction
Impairment of neuropsychological functions, including memory and mood, has been well recognized in multiple sclerosis (MS) [1]. However, cognitive changes vary with respect to severity and affected domains [2]. Disease
ABC
© 2004 S. Karger AG, Basel 0014–3022/04/0522–0092$21.00/0
Fax + 41 61 306 12 34 E-Mail
[email protected] www.karger.com
Accessible online at: www.karger.com/ene
duration of less than 3 years was found to be associated with cognitive and physical dysfunction, including visual (e.g. facial recognition), verbal and short-term memory deficits, which steadily increased after 5 and more years [1, 3]. However, executive functions as used in IQ measurements often lack sensitivity with respect to increased cognitive dysfunction in MS patients, in particular as physical disability hampers the cognitive assessment [4]. Little is still known with respect to long-term effects on memory performance, in particular short-term memory, including abstract reasoning and affective variables, although those have been found to appear early in the course of disease [5–9]. Few cross-sectional studies in disabled MS patients (Expanded Disability Status Scale, EDSS, 12) have been performed, and their results were limited either by large drop-out rates or fast progression due to the nature of the underlying disease, resulting in considerable heterogeneity of the findings [1, 3]. Cognitive decline appeared to be related to physical disease progression at several stages and with respect to morphological parameter changes and were often combined with visual disturbances [8, 10, 11]. As life-time prevalence of depression and depressive symptoms has been accounted to about 50% of all MS patients, mood alterations, emotional symptoms, signs of depression and anxiety dis-
Claus G. Haase, MD Department of Neurology, University Hospital In der Schornau 23–25 DE–44892 Bochum (Germany) Tel. +49 234 993700, Fax +49 234 2993709, E-Mail
[email protected]
orders have frequently been assessed and were found to influence significantly the cognitive function and quality of life in patients [5, 9–14]. In the present study, we report on a homogeneous group of female MS patients without physical disability (EDSS !2) who have been followed up for 7 years with regard to their cognitive and affective status.
Table 1. Baseline demographics and cognitive and affective test
results in patients and controls
Age, years IQ DS BL BFS BDT NETGEOM NETNONS NET
MS patients (n = 27)
Control subjects (n = 27)
31.41 (5.49) 101.46 (9.66) 10.76 (9.25) 24.33 (14.37) 15.56 (11.79) 107.33 (15.01) 16.33 (5.47) 6.11 (4.36) 22.44 (7.25)
31.37 (5.64) 105.07 (5.26) 3.65 (4.08) 14.11 (9.81) 10.70 (7.94) 116.57 (13.93) 18.89 (2.93) 9.36 (5.03) 28.25 (7.19)
p value
0.981 0.132 !0.0011 0.0041 0.08 0.0341 0.0371 0.0141 0.0051
Values are numbers or means, with standard deviations in parentheses. IQ = Intelligence quotient; DS = global depression, Zerssen score; BL = somatic complaints, Zerssen score; BFS = actual mood, Zerssen score; BDT = block design test; NETGEOM = geometric recurrent figure score; NETNONS = nonsense recurrent figure score; NET = total visual memory score. 1 Significantly different with p ! 0.05; italics indicate significant trend.
Table 2. Comparison of baseline and
follow-up demographics and cognitive and affective results in patients with MS Age, years Mean Range EDSS IQ DS BL BFS BDT NETGEOM NETNONS NET
Patients and Methods Twenty-seven female patients (mean age at baseline 31, range 17– 39 years) with relapsing-remitting clinically definite MS and EDSS ! 2 were included into the study. Details are displayed in table 1. Reexamination was performed after 7 years; data are depicted in table 2. At times of testing, all patients were in a relapse-free stage of the disease and were free of any other disease. An IQ-matched healthy female control group was formed to compare the neuropsychological test results at baseline. None of the control subjects had a history of psychiatric or neurological disorder or was on medication at the time of testing. All subjects had normal or corrected visual acuity. Patients had been free of drugs affecting the central nervous system for at least 4 weeks prior to the examination, excluding immunosuppressive medication. At baseline, 8 patients received azathioprine, the others were untreated. At re-testing patients, 13 received either ß-interferon (n = 7), azathioprine (n = 4) or glatiramer acetate (n = 2); 9 were untreated. They had experienced 0–8 relapses (median 4). All subjects had at least secondary school education and gave informed consent to participate in this study. For intelligence assessment, all subjects completed a modified short version of the German Wechsler Intelligence Performance scales, based on performance of the subtests on general knowledge, similarities and picture completion. These subtests were chosen and motor executive parts like the block design test (BDT) and two-digit test excluded, since they put patients with MS at a disadvantage due to motor speed demands [5, 9, 13]. There were no differences between patients and healthy controls with regard to age and IQ. For the assessment of the affective status, Zerssen scales were used, which are self-rating scales with two parallel forms. We preferred the Zerssen scales [15] over Beck’s Depression Inventory, in order to cover 3 different aspects: global depression status, somatic/physical complaints and the actual mood at the time of testing [12]. Visuospatial/visuoconstructive functions were assessed by the BDT; visuospatial short-term memory was assessed by non-verbal Kimura’s recurring figures test, with two sorts of abstract (geometric and nonsense) drawings. Three variables were extracted: NETGEOM, NETNONS and NET. NETGEOM
Baseline MS patients (n = 27)
Follow-up MS patients (n = 22)
31B5 17U39 1.07 (1.11) 101.46 (9.66) 10.76 (9.25) 24.33 (14.37) 15.56 (11.79) 107.33 (15.01) 16.33 (5.47) 6.11 (4.36) 22.44 (7.25)
38B6 24U46 2.09 (1.85) 104.36 (7.81) 11.84 (6.94) 26.77 (12.39) 15.75 (11.95) 104.68 (15.86) 12.00 (4.85) 3.68 (7.24) 15.68 (10.98)
p value (repeated measures)
0.0031 0.089 0.411 0.159 0.873 0.073 !0.0031 0.126 !0.0141
Values are numbers or means, with standard deviations in parentheses; for abbreviations used, refer to table 1. 1 Significantly different with p ! 0.05; italics indicate trend.
Cognition in MS
Eur Neurol 2004;52:92–95
93
Fig. 1. Results of cognitive data of MS patients at baseline and at follow-up compared to healthy female controls. Mean values with standard deviation are displayed for BDT, NETGEOM (geometric recurrent figure score), NETNONS (nonsense recurrent figure score) and NET (total visual memory score).
(NETNON) was the difference of correct and misleadingly remembered geometric (nonsense) recurrent figures. The performance of the visuospatial short-term memory, NET, was the sum of NETGEOM and NETNONS, therefore the difference of all correct and misleadingly remembered recurrent figures [5, 16]. Statistical analyses were performed using SPSS version 10. Group differences were evaluated by analysis of variance (ANOVA). If there were significant group differences in variances, non-parametric tests (Kruskal-Wallis ANOVA) were used. Post-hoc paired group comparisons were carried out using the strict Bonferroni’s alpha correction or Mann-Whitney U tests, respectively. Significance was considered if p ! 0.05.
Results
Discussion
From 27 patients included into the study at baseline, 22 (82%) could be followed up for 7 years. EDSS worsened significantly over time, as anticipated. No significant correlation could be found between changes of EDSS and development of depression expressed as changes in the depression rating scales (r !0.359, p 1 0.101). Baseline demographics and cognitive and affective test results are displayed in table 1. MS patients differed significantly from controls in all cognitive and affective variables, with the exception of IQ and actual mood. In the patient group, visuoconstructive performance, derived from the BDT, but not IQ tended to decrease (p = 0.073 and p = 0.089, respectively) over the 7 years of assessment. Kimura’s recurring figures test showed a significant decrease in visuospatial short-term memory, using geometric figures (NETGEOM and NET; p ! 0.014), but not if nonsense figures (NETNONS) were used (p = 0.126).
94
Comparison of baseline and follow-up demographics and cognitive and affective results are displayed in table 2. An increase in EDSS at follow-up correlated significantly with a decrease in BDT scores (r ! –0.456, p ! 0.033), which as well correlated significantly with NETNONS (r = 0.559, p = 0.002) and NET (r 10.468, p = 0.014), but not with NETGEOM (r 10.3196, p = 0.068). Results of cognitive data of MS patients at baseline and at follow-up compared to healthy female controls are illustrated in figure 1.
Eur Neurol 2004;52:92–95
The present study compared cognitive and affective variables in a homogeneous group of young female patients with stable MS. Clinical data apart from the course in these patients resulting in relatively low EDSS are in keeping with the average female patients with benign MS [1, 5, 6, 8, 11]; however, EDSS at the end of our study was lower (table 2) than previously reported in follow-up studies (3.48 B 2.55 [1] or 5.5 B 1.3 [3]). Affective variables remained stable for the period of 7 consecutive years in our patients, and although depression scores were increased in these patients compared to healthy women, depression remained a constant, however fluctuating symptom. Interim assessment of Zerssen scales after 4 years revealed lower but non-similar depression rates compared to baseline or after 7 years (data not shown). This supports earlier findings that depression does not seem to be associated with physical deterioration, as it was observed for cognitive variables [3, 8, 10]. In contrast
Haase/Tinnefeld/Daum/Ganz/Haupts/ Faustmann
to others [1, 3], we focused in the present study on nonverbal, visual-spatial memory. And contrary to our earlier findings regarding patients with early MS [5, 6, 9], shortterm memory of geometric recurrent figures seemed to be more severely affected than that of nonsense items, which could be due to the clinically mild disturbances, challenging the sensitivity of the tests used. The overall findings are in keeping with other studies on cognition, and memory in particular, which reported impaired recall, a reliable and robust phenomenon in early MS [2, 3, 5, 9]. Those results in long-lasting disease were supported by morphological changes which appeared more frequently and correlated negatively with cognitive performance [1, 3]. In particular, MS lesion volumes in frontal and parietal regions lead to impaired memory as well as deficits in attention and processing speed [9, 10, 13]. As visuospatial and short-term memory of recurrent figures could not be attributed to disturbed visual acuity in our patients, an involvement of the right temporal lobe plays most likely a role in disturbed visual memory performance in our patients, although serial MRI scans could not be performed [10]. While in contrast to cognitive deterioration, total lesion load was not generally correlated with depression, in patients with higher EDSS, higher levels of depression correlated with lesions in the temporal lobe [14, 16]. However, in our study, we did not find a significant correlation between depression and recurrent figures findings, which may be due to the relatively small number of patients. With respect to affective changes, our results corroborated the findings from earlier studies [5–9]. Coping with the diagnosis of MS, the cause of the illness and
therapies, MS puts a high emotional strain on young female patients. While many advanced patients showed symptoms of major depression, patients in early stages of MS had more subtle complaints, which were well assessed using Zerssen’s scales [12]. Our study was designed to exclude effects of somatic symptoms of MS including effects of steroid therapy (such as influences on cognition, sleep disturbances or changes of body weight) as possible causes of depression in MS patients. However, to assess the contribution of immunosuppressive treatments the number of patients appeared too small. As in our study, others [12] tried to differentiate between reactive effects on the quality of life and mood dysfunction. Their findings as well as ours supported a relative stability of mood changes in MS patients up to 7 years. This suggests a rather reactive than organic pattern as origin of their mood variability; however, detailed neuroimaging or reliable surrogate/biomarker testing could not be performed to support these hypotheses. Our results indicate that cognitive parameters, in particular, should be followed closely from the earliest time of diagnosis and need to be followed over the whole course of disease, taking into account the potential interfering changes in mood and/or depressive states in this group of patients [9].
Acknowledgement This study was supported by a grant of the Gemeinnützige Hertie-Stiftung, Frankfurt (GHS 274/93).
References 1 Amato MP, Ponziani G, Siracusa G, Sorbi S: Cognitive dysfunction in early-onset multiple sclerosis. Arch Neurol 2001;58:1602–1606. 2 Hämäläinen P, Ruutiainen J: Cognitive decline in multiple sclerosis. Int Mult Scler J 1999;6: 51–57. 3 Kujala P, Portin R, Ruutiainen J: The progress of cognitive decline in multiple sclerosis: A controlled 3-year follow-up. Brain 1997;120: 289–297. 4 Rao SM: Neuropsychology of multiple sclerosis. Curr Opin Neurol 1995;8:216–220. 5 Haase CG, Tinnefeld M, Lienemann M, et al: Depression and cognitive impairment in disability-free early multiple sclerosis. Behav Neurol 2003;14:39–45. 6 Landro NI, Sletvold H, Gulowsen Celius E: Memory functioning and emotional changes in early phase multiple sclerosis. Arch Clin Neuropsychol 2000;15:37–46.
Cognition in MS
7 Faustmann PM, Ganz RE: Depressiveness and memory impairment prior to significant physical disability in early multiple sclerosis. J Neurol 1997;244:S75. 8 Ruggieri RM, Palermo R, Vitello G, Genusso M, Settipani N, Piccoli F: Cognitive impairment in patients suffering from relapsing-remitting multiple sclerosis with EDSS ! or = 3.5. Acta Neurol Scand 2003;108:323–326. 9 Landro NI, Celius EG, Sletvold H: Depressive symptoms account for deficient information processing speed but not for impaired working memory in early phase multiple sclerosis. J Neurol Sci 2004;15:211–216. 10 Berg D, Supprian T, Thomae J, et al: Lesion pattern in patients with multiple sclerosis and depression. Mult Scler 2000;6:156–162. 11 Hawkins SA, McDonnell GV: Benign multiple sclerosis? Clinical course, long term follow-up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry 1999;67:148–152.
Eur Neurol 2004;52:92–95
12 Fruhwald S, Loffler-Statska H, Eher R, Saletu B, Baumhackl U: Relationship between symptoms of depression and anxiety and the quality of life in multiple sclerosis. Wien Klin Wochenschr 2001;113:333–338. 13 Randolph JJ, Arnett PA, Freska P: Metamemory in multiple sclerosis: Exploring affective and executive contributors. Arch Clin Neuropsychol 2004;19:259–279. 14 Sadovnick AD, Remick RA, Allen J, et al: Depression and multiple sclerosis. Neurology 1996;46:628–632. 15 von Zerssen D, Strian F, Schwarz D: Evaluation of depressive states, especially in longitudinal studies; in Pichot P, Olivier-Martin R (eds): Psychological Measurements in Psychopharmacology. Modern Problems in Pharmacopsychiatry. Basel, Karger, 1974, vol 7, pp 189–202. 16 Kimura D: Right temporal lobe damage. Arch Neurol 1963;8:264–271.
95
