Multiple Sclerosis and Related Disorders (2014) 3, 335–340
Available online at www.sciencedirect.com
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Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America: Results of the RELACCEM study F. Caceresa,n, S. Vanottia, R.H.B. Benedictb, RELACCEM Work Group1 a
INEBA-Neurosciences Institute of Buenos Aires, Guardia Vieja 4435, C1192AAW Buenos Aires, Argentina Department of Neurology, State University of New York at Buffalo School of Medicine, United States
b
Received 19 June 2013; received in revised form 21 October 2013; accepted 28 October 2013
KEYWORDS Multiple sclerosis; Cognitive impairment; Psychiatric symptoms; Caregiver burden; Employment; Epidemiology
Abstract Background: Cognitive impairment and psychiatric symptoms impact many aspects of the lives of people with multiple sclerosis [MS]. This literature is based largely on North American and Western European samples, and little is known about these aspects of MS disability in Latin America. Objective: RELACCEM is a longitudinal, multicenter study including MS centers in Argentina, Chile, Columbia, Venezuela, Uruguay and Mexico. The goal is to determine the prevalence of cognitive impairment (two or more cognitive domains under the 5th percentile of healthy controls performance) and the full range of neuropsychiatric symptoms in these regions, and how these symptoms relate to caregiver burden and employment. Methods: Participants were 110 patients with relapsing-remitting [RR] course and less than five years of disease duration. Thirty-four healthy controls were also recruited. All participants were evaluated in one of 14 specialized centers. Results: In additional to overall neurological disability, both cognition and neuropsychiatric symptoms distinguished patients and controls. The prevalence of cognitive impairment was 34.5% and 20.9% presented with clinically significant neuropsychiatric symptomatology. Cognitive impairment was a significant predictor of employment status. Conclusions: This is the first multicenter epidemiological study of MS-associated cognitive and neuropsychiatric symptoms in Latin America. Results indicate that cognitive dysfunction and psychiatric decline symptoms, fatigue, depression and caregiver burden are already apparent at an early stage of the disease. The presence of neuropsychiatric abnormalities indicates the need for appropriate interventions as early as possible to mitigate psychosocial consequences of caregiver burden. & 2013 Elsevier B.V. All rights reserved.
n
Corresponding author. Tel.: +54 1148677700. E-mail address: [email protected] (F. Caceres). 1 RELACCEM Work Group: Argentina: Cristiano E., Patrucco L., Rojas JI., Fernández MC., Garcea O., Fernández Liguori N., Villa A., Piedrabuena R., Saladino MA., Allegri R., Gil Mariño C. Chile: Nogales-Gaete J., Aracena R. Colombia: García Bonitto J., Medina Salcedo M., Pradilla G. Mexico: Corona T., Flores Rivera J., González S., Macias-Islas MA., Nuñez Orozco L., Ordoñez L. Uruguay: Oehninger C., Alcántara JC. Venezuela: Soto A., Armas E., Argentina: Ussher C., Ciufia N., Cores E. Chile: Vannia F., González C. Colombia: Montañes P., Mendez L. Mexico: Martínez Rosas A., Aguayo Arelis A., Villa Rodríguez M. Uruguay: Bocos L., Venezuela: Paccione S. 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.10.007
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1.
F. Caceres et al.
Introduction
MS causes marked impairments in cognitive function as well as neuropsychiatric symptoms, both of which have adverse impact on quality of life (QoL) (Langdon, 2011). Epidemiological studies further show that these symptoms can appear in early stages of the disease and are greatly varied, including not only cognitive disorder, but also neurobehavioral signs, fatigue and depression (Amato et al., 2001; Benedict and Zivadinov, 2011). For the most part, these conclusions are based on many studies from North America and Western Europe. Few studies are available from other regions of the world, notably Latin America. An exception is the Cáceres et al. (2011) study showing significant cognitive impairment using a Spanish translation of conventional neuropsychological (NP) tests. This study was limited by inclusion of just a single country, Argentina, and restriction of outcomes to the domain of cognition. Little is known about cognitive and especially neuropsychiatric manifestations of MS in Latin America, more generally speaking. Herein we present the results of the first multicenter study of persons with MS from Argentina, Chile, Colombia, Mexico, Uruguay and Venezuela. The study was designed to be a longitudinal, prospective assessment of consecutively enrolled MS patients from clinics affiliated with the RELACCEM Study group (Spanish acronym for Cognitive and Behavioral Survey of MS patients from Latin America). Our goal was to widen the scope of assessment to the domains of cognition and neuropsychiatric symptoms, and then determine their impact of caregiver distress and employment.
2. 2.1.
Methods Study design and participants
The RELACCEM study is in progress and herein we report on baseline data from 110 MS patients and 34 healthy controls (HCs). The study was approved by the local Ethics Committee of each center and the independent institutional review board. All participants provided signed informed consent. Enrollment commenced in February 2010 and was closed in October 2010. All patients had a confirmed diagnosis of MS and relapsingremitting course (Polman et al., 2005). Other inclusion criteria were Z18 years old, disease duration o5 years, patient stable on disease modifying treatment for at least 3 months, not in a relapsing phase or under corticosteroid therapy during or 2 months before the evaluation, and absence of any other neurological or psychiatric illness. Fatigue was assessed using the Fatigue Severity Scale (FSS) (Krupp et al., 1989) Self- and informant-report of overall neuropsychological status was quantified using the MS Neuropsychological Screening Questionnaire [MSNQ] (Benedict et al., 2004) validated in Spanish (Vanotti et al., 2009). Neurological disability was assessed with the Expanded Disability Status Scale (EDSS) (Kurtzke, 1983) and The Multiple Sclerosis Functional Composite (MSFC) (Fischer et al., 1999). The HCs group was well matched to the patient group except that they were on average five years younger. As a result, age was controlled statistically in subsequent
analyses. Exclusion criteria for this group were history of neurological illness, head trauma, or alcohol or drug abuse. At least 3 Hcs were enrolled in each center
2.2.
Measures
Cognitive status was assessed using a Spanish translation of the Rao Brief Repeatable Battery for MS, implemented in prior research (Rao, 1991; Cáceres et al., 2011). The Selective Reminding Test (SRT) (Buschke and Fuld, 1974) was used to measure verbal learning and memory, yielding a sum of recalled words on the learning trails and the number of words recalled after a 25 min delay. The 7/24 Spatial Recall Test (Barbizet and Cany, 1968) was employed to measure visual memory. The 7/24 also included a measure of total learning and delayed recall. The Brief Visuospatial Memory Test Revised [BVMTR] (Benedict, 1997) was also administered because it was more sensitive than an adapted version of the 7/24 called the 10/36 Spatial Recall Test (Strober et al., 2009), and we hypothesized that it may also be more sensitive than the 7/24 in this Spanish study. BVMTR scores were total recall over all learning trials and recall after a delay interval, similar to SRT and 7/24. The Paced Auditory Serial Addition Test (Gronwall, 1977) administered using the Rao adapted 2- (PASAT-2) and 3-second (PASAT-3) inter-stimulus interval (Rao, 1991) was applied. Likewise, the oral version of the Symbol Digit Modalities Test [SDMT] (Smith, 1982) was administered. Finally, a word list generation task (WLG) (Benton et al., 1994) was administered. The Beck Depression Inventory Second Edition (BDI2) (Beck et al., 1996) was employed to quantify depression symptoms. The Neuropsychiatric Inventory (NPI) (Cummings et al., 1994), an informant report structured interview, was used to evaluate a wide range of neuropsychiatric symptoms. The NPI has wellestablished reliability and validity, and has been employed in numerous studies of dementia of varying etiology (Litvan et al., 1996; Mega et al., 2000) including MS (Fishman et al., 2004). This structured interview yields a score for severity [0=mild to 3=severe] and the frequency [0=none to 4=daily] for each of 10 symptom domains [hallucinations, delusions, sleep disturbance, agitation, euphoria, depression, anxiety, disinhibition, lability, apathy]. Total scores for each domain are derived by multiplying severity frequency. We also used Zarit's Caregiver's Burden Scale (Martín et al., 1996) which has been used in Alzheimer's disease (Hébert et al., 2000) and MS studies (Rivera-Navarro et al., 2009). The Zarit Scale is a self-administered tool, which consists of 22 statements regarding stress and burden of care, with ratings from “never” (score 0) to “almost always” (score 4). The total sum is from 0 to 88, with higher totals reflecting greater burden. Employment status was coded in three categories: full and part time employment, unemployment or retired, and housekeepers and students. These data were reported by patients and confirmed via informant interview.
2.3.
Procedure
The project commenced with an investigator meeting including neurologists, neuropsychologists and psychiatrists from the diverse set of countries noted above. Consensus on
Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America a comprehensive battery of clinical measures with Spanish translations was achieved. Next, in the clinic, investigators randomly selected candidates for screening and asked them to undergo assessment in the cognitive and neuropsychiatric aspects of MS. Consecutive candidates were screened for inclusion/exclusion criteria. All were then evaluated by a clinical neurologist and clinical neuropsychologist. Tests were administered in the same order throughout the study. Each center evaluated at least 10 MS patients randomly selected from their patient base considered eligible for the study and three healthy controls with roughly similar age and educational level to the average of patients. All participants volunteered for the assessment and were not paid for their collaboration in accordance with the Latin American ethical regulation.
2.4.
Statistical analysis
Data analysis was performed using SPSS. To adjust for type one error we employed a conservative threshold of po0.01 to designate statistical significance. In order to determine the prevalence of cognitive impairment, the 5th percentiles of the NP tests were calculated for HC, according to the specifications published elsewhere (Rao et al., 1991). These percentiles were used as a cutoff to determine the number of MS patients with cognitive impairment. An MS patient was considered to have cognitive impairment when two or more domains (verbal memory – SRT, visual memory – BVMTR, verbal fluency – WLG, attention – PASAT 3 and 2 seconds) were below the fifth percentile. For the BDI2, we employed the customary cut-point of 15. As reported previously (Figved et al., 2008; Fishman et al., 2004), two factors were constructed: I Euphoria factor (containing agitation, euphoria, disinhibition, and irritability) and II Apathy factor (containing depression, anxiety, and apathy). A score of 4 in any NPI dimension was considered abnormally high (Fishman et al., 2004). There were two levels of parametric analysis. First, group comparisons were carried out to determine where MS differed from HCs, using analysis of covariance (ANCOVA), controlling for the effects of demographics that may distinguish the MS and HC groups, namely age. Second, we endeavored to determine which cognitive and neuropsychiatric factors account for MS patient employment (not including students and housekeepers) and caregiver distress. Regression analysis was pursued for this purpose, logistic for the binary employment/unemployment outcome, and linear regression for the Zarit caregiver distress. In these analyses age, education and gender were entered and retained in block one, followed by the cognitive and neuropsychiatric predictors in block 2, with a forward stepwise selection criterion. As there were only two models, we accepted a po0.05 threshold for significance to be retained in the models.
3.
Results
Median EDSS value of 2.07 [range 0.0–6.5] representing mild disability. Mean MSFC was 0.42, also suggesting mild neurological disability. The fatigue was higher in MS, p= 0.001,
337
the FSS revealed mild degrees of fatigue relative to HCs. Demographic and clinical data are presented in Table 1. Significant differences, controlling for age, were found between MS and HCs on all cognitive tests (Table 2). Patients and informants both reported cognitive difficulties in MS patients more than their HC counterparts, leading to higher MSNQ scores, p =0.001. In the domain of cognition, the effect sizes ranged from d of 0.6 for 7/24 Total Learning
Table 1
Demographic and clinical data.
Age Education Gender MSNQ Self-Report MSNQ Informant FSS MSFC Total Z Score EDSS
MS, N =110
HC, N= 34
M
M
SD
36.6 14.7 67.3% 17.6 12.5 33.5 0.42 2.07
10.6 3.4 women 11.3 10.6 16.9 0.98 1.3
31.5 14.0 61.8% 9.6 6.2 24.5 0.82
p
SD 10.8 4.0 women 7.5 6.3 12.7 0.78
0.017 0.366 0.543 0.001 0.001 0.001 0.017
Notes: MSNQ: MS Neuropsychological Screening Questionnaire. FSS: Fatigue Severity Scale. MSFC: Multiple Sclerosis Functional Composite. EDSS: Expanded Disability Status Scale.
Table 2 Comparison between groups on cognitive and neuropsychiatric outcomes. MS M
HC SD
Cognitive function WLG 32.3 10.7 SDMT 44.1 13.5 PASAT-3 39.2 15.1 PASAT-2 32.1 13.9 SRT TL 47.9 10.1 SRT DR 7.7 2.9 7/24 TL 28.3 5.9 7/24 DR 5.7 1.7 BVMTR TL 18.5 7.5 BVMTR DR 7.1 2.6
M
p
d
% MS Impaired
SD
39.4 10.0 0.003 0.7 17.3 57.9 12.8 0.000 1.0 21.8 48.1 9.8 0.004 0.7 12.7 42.3 11.4 0.001 0.9 14.5 58.2 6.4 0.000 1.3 33.6 10.4 1.7 0.000 1.9 23.6 31.4 5.4 0.001 0.6 3.6 6.3 1.2 0.000 1.0 5.5 25.3 6.1 0.000 1.1 27.3 10.0 1.5 0.000 1.9 30.9
Neuropsychiatric symptoms BDI-II 10.9 8.4 5.4 NPI 7.8 15.8 0.6 Factor I. 2.8 6.4 0.1 Euphoria Factor II. 2.7 5.3 0.2 Apathy
5.3 0.001 0.7 1.0 0.001 0.7 0.6 0.000 7.7 0.4 0.000 7.0
Notes: All comparisons control for the effects of age. Abbreviations: PASAT=Paced Auditory Serial Addition Test, SRT=Selective Reminding Test, WLG=Word List Generation, SDMT=Symbol Digit Modalities Test, BVMTR=Brief Visuospatial Memory Test Revised, TL =Total Learning, DR=Delayed Recall.
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F. Caceres et al.
Table 3
*
Comparison between groups on NPI domains.
NPI Domain
MS
p**
HC
Absent Present Absent Present N
%
N
%
N %
Delusions 104 94 6 6 34 100 Hallucinations 105 95 5 5 34 100 Agitation 87 79 23 21 32 94 Depression 66 60 44 40 30 88 Anxiety 74 67 36 33 32 94 Euphoria 95 86 15 14 33 97 Apathy 85 77 25 23 33 97 Disinhibition 95 86 15 14 33 97 Irritability 75 68 35 32 33 97 Aberrant Motor 107 97 3 3 34 100 Behavior
N
%
0 0 2 4 2 1 1 1 1 0
0 0 6 12 6 3 3 3 3 0
0.192 0.254 0.032 0.001 0.001 0.068 0.005 0.068 0.000 0.443
n
The table presents the number of patients and percentage of sample with positive endorsement for each NPI symptom using a cut-off total score (frequency severity) of 1 or higher. nn Alfa level correspond to Chi Square analysis.
to 1.9 for the BVMTR Delayed Recall. Indeed, for visual memory in general, we observed larger effect sizes for BMVTR than 7/24, and in subsequent analyses we incorporated the former rather than the latter. Regarding neuropsychiatric symptoms, BDI2 scores were significantly elevated from HCs in MS patients [p=0.001]. On the NPI, the overall score distinguished the groups, as did total scores for anxiety [p=0.001], depression [p=0.001], apathy [p=0.008], irritability [p=0.001] [Table 3], Factor I (Euphoria) [po0.001] and Factor II (Apathy) [po0.001]. In the MS group, 35% (n=38) were determined to be cognitively impaired. 32 patients (29%) were abnormal on the BDI2. On the NPI, the prevalence of abnormally high scores (4 points or more in at least one dimension) was 20.9%. The MS and HC groups differed in caregiver burden as quantified with the Zarit scale [po0.001]. MS caregivers responses led to a mean Zarit score of 32.9711.6, compared to 22.272.8 for HCs. Within the MS sample, linear regression controlling for demographics was used to determine the most important cognitive and neuropsychiatric predictors of caregiver burden. The model retained NPI Disinhibition and BDI2, the final model having an R2 of 0.326 [p=0.003]. Contrary to expectation, there was no significant difference between employment rate in MS vs HCs [p= 0.274]. Specifically, 12 patients and 1 HC were unemployed or retired, whereas 74 patients and 27 HCs were employed. The logistic regression model predicting employment in MS retained two cognitive tests, PASAT-3 and WLG. The R2 was 0.411 [po0.0001] and 86% of patients were correctly classified.
4.
Discussion
For the first time we report on the prevalence and clinical significance of cognitive and neuropsychiatric alterations in
a Latin-American MS sample. As in prior North American and European studies, we found large effects in all cognitive domains and in some neuropsychiatric symptoms, especially depression and anxiety. The prevalence of cognitive impairment, being 35%, is generally consistent with other early disease MS samples (Patti et al., 2009). We also replicate the frequently noted observation that cognitive tests are significantly predictive of employment status. These findings are noteworthy considering the cross-cultural implications and that our patients were comparatively young, and early in their disease. Thus, although our sample was at an early stage of the disease and had a low level of physical disability, there was considerable cognitive impairment, neuropsychiatric disorder, and caregiver burden. To the best of our knowledge MS neuropsychiatric symptoms have been studied using the NPI in the USA (Fishman et al., 2004), Mexico (Diaz-Olavarrieta et al., 1999) and Norway (Figved et al., 2008). In all of these studies, depression, anxiety and irritability were more commonly observed in MS, but euphoria and disinhibition, when seen, tended to be especially detrimental to family functioning and caregiver stability (Benedict et al., 2001). In part, we have replicated this observation in this sample spanning six different Spanish speaking countries. In particular, we found that NPI Disinhibition loaded on the second step of a linear regression model predicting Zarit caregiver burden. Selfreport depression, as measured by the BDI2, also loaded in the model after NPI Disinhibition, suggesting that the combined influence of disinhibition and expression of negative affect is particularly distressing to caregivers. We have replicated the common observation that higher cognitive ability as measured by neuropsychological testing is associated with preserved employment status. There are some unique results here that are somewhat difficult to reconcile with prior research. First and foremost, we found that employment status did not differ between MS patients and HCs. In the present study PASAT was retained in the model, as reported in a large sample USA study (Benedict et al., 2006). However, the lack of a memory test predictor is somewhat unusual for this literature. Whether or not this observation is related to unique aspects of work in South America, or some other unknown factor, will require further research. Our study confirms the high frequency of depression and anxiety in MS, despite possible cultural effects. Similar results were found in previous studies of incipient population using the same technique (Jonsson et al., 2006). In this study, using the NPI, it has been found that 20.9% had neuropsychiatric disorders. This symptomatology has also been reported in other studies of later stages but not in initial stages (Figved et al., 2007; Fishman et al., 2004). The presence of neuropsychiatric abnormalities indicates the need for appropriate interventions as early as possible to mitigate psychosocial consequences of caregiver burden. Our caregivers are showing signs of burden from early diagnosis. The state of burden has also previously been detected with the same scale (Rivera-Navarro et al., 2009), but not in early stages. Regarding visual memory, it is important to highlight that BVMTR prove to be more sensitive to this difference than 7/24 Visuoespacial Recall. This finding is in agreement with Strober et al. (2009). Moreover, among cognitive tests, the
Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America BVMTR allowed obtaining the greater difference between groups. This is the first study to validate BVMTR in Spanish, a test that is incorporated in the Brief International Cognitive Assessment for MS [BICAMS] (Benedict et al., 2012). The limitations of this study include its cross-sectional design and small number of HCs. The sampling of controls was not randomized and was not matched individually to MS patients on a case–control basis. Although multivariate adjustments were made, the significant difference between patients and controls in Age could affect the conclusions. Nevertheless, the results found in this research are consistent with the international literature. This leads us to conduct further research to corroborate our data. While the MS sample was sufficient in total, we did not have sufficient power to compare performance across countries involved in the study. Future work will also need to investigate further the unexpected finding of similar employment rates in MS and HCs. These concerns notwithstanding, this is the first multicenter study of MS associated cognitive and neuropsychiatric symptoms in Latin America. The outcome measures employed were valid and correctly applied. The data obtained will improve the therapeutic tools considering neuropsychiatric aspects and their impact on the environment, even when dealing with patients with sociocultural variables typical of that of developed countries.
Conflict of interest The authors have no conflict of interests in relationship with this work.
Acknowledgments This study is an Investigator Initiated Trial (IIT) supported by Biogen Idec International. The funds have been used to pay transportation costs and accommodations for the training and the coordination meeting of neurologists and neuropsychologists. Economic support also served to pay for the shipping materials and the statistician fees. We thank Claudio Gonzalez for his comments in the study.
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Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America: Results of the RELACCEM study F. Caceresa,n, S. Vanottia, R.H.B. Benedictb, RELACCEM Work Group1 a
INEBA-Neurosciences Institute of Buenos Aires, Guardia Vieja 4435, C1192AAW Buenos Aires, Argentina Department of Neurology, State University of New York at Buffalo School of Medicine, United States
b
Received 19 June 2013; received in revised form 21 October 2013; accepted 28 October 2013
KEYWORDS Multiple sclerosis; Cognitive impairment; Psychiatric symptoms; Caregiver burden; Employment; Epidemiology
Abstract Background: Cognitive impairment and psychiatric symptoms impact many aspects of the lives of people with multiple sclerosis [MS]. This literature is based largely on North American and Western European samples, and little is known about these aspects of MS disability in Latin America. Objective: RELACCEM is a longitudinal, multicenter study including MS centers in Argentina, Chile, Columbia, Venezuela, Uruguay and Mexico. The goal is to determine the prevalence of cognitive impairment (two or more cognitive domains under the 5th percentile of healthy controls performance) and the full range of neuropsychiatric symptoms in these regions, and how these symptoms relate to caregiver burden and employment. Methods: Participants were 110 patients with relapsing-remitting [RR] course and less than five years of disease duration. Thirty-four healthy controls were also recruited. All participants were evaluated in one of 14 specialized centers. Results: In additional to overall neurological disability, both cognition and neuropsychiatric symptoms distinguished patients and controls. The prevalence of cognitive impairment was 34.5% and 20.9% presented with clinically significant neuropsychiatric symptomatology. Cognitive impairment was a significant predictor of employment status. Conclusions: This is the first multicenter epidemiological study of MS-associated cognitive and neuropsychiatric symptoms in Latin America. Results indicate that cognitive dysfunction and psychiatric decline symptoms, fatigue, depression and caregiver burden are already apparent at an early stage of the disease. The presence of neuropsychiatric abnormalities indicates the need for appropriate interventions as early as possible to mitigate psychosocial consequences of caregiver burden. & 2013 Elsevier B.V. All rights reserved.
n
Corresponding author. Tel.: +54 1148677700. E-mail address: [email protected] (F. Caceres). 1 RELACCEM Work Group: Argentina: Cristiano E., Patrucco L., Rojas JI., Fernández MC., Garcea O., Fernández Liguori N., Villa A., Piedrabuena R., Saladino MA., Allegri R., Gil Mariño C. Chile: Nogales-Gaete J., Aracena R. Colombia: García Bonitto J., Medina Salcedo M., Pradilla G. Mexico: Corona T., Flores Rivera J., González S., Macias-Islas MA., Nuñez Orozco L., Ordoñez L. Uruguay: Oehninger C., Alcántara JC. Venezuela: Soto A., Armas E., Argentina: Ussher C., Ciufia N., Cores E. Chile: Vannia F., González C. Colombia: Montañes P., Mendez L. Mexico: Martínez Rosas A., Aguayo Arelis A., Villa Rodríguez M. Uruguay: Bocos L., Venezuela: Paccione S. 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.10.007
336
1.
F. Caceres et al.
Introduction
MS causes marked impairments in cognitive function as well as neuropsychiatric symptoms, both of which have adverse impact on quality of life (QoL) (Langdon, 2011). Epidemiological studies further show that these symptoms can appear in early stages of the disease and are greatly varied, including not only cognitive disorder, but also neurobehavioral signs, fatigue and depression (Amato et al., 2001; Benedict and Zivadinov, 2011). For the most part, these conclusions are based on many studies from North America and Western Europe. Few studies are available from other regions of the world, notably Latin America. An exception is the Cáceres et al. (2011) study showing significant cognitive impairment using a Spanish translation of conventional neuropsychological (NP) tests. This study was limited by inclusion of just a single country, Argentina, and restriction of outcomes to the domain of cognition. Little is known about cognitive and especially neuropsychiatric manifestations of MS in Latin America, more generally speaking. Herein we present the results of the first multicenter study of persons with MS from Argentina, Chile, Colombia, Mexico, Uruguay and Venezuela. The study was designed to be a longitudinal, prospective assessment of consecutively enrolled MS patients from clinics affiliated with the RELACCEM Study group (Spanish acronym for Cognitive and Behavioral Survey of MS patients from Latin America). Our goal was to widen the scope of assessment to the domains of cognition and neuropsychiatric symptoms, and then determine their impact of caregiver distress and employment.
2. 2.1.
Methods Study design and participants
The RELACCEM study is in progress and herein we report on baseline data from 110 MS patients and 34 healthy controls (HCs). The study was approved by the local Ethics Committee of each center and the independent institutional review board. All participants provided signed informed consent. Enrollment commenced in February 2010 and was closed in October 2010. All patients had a confirmed diagnosis of MS and relapsingremitting course (Polman et al., 2005). Other inclusion criteria were Z18 years old, disease duration o5 years, patient stable on disease modifying treatment for at least 3 months, not in a relapsing phase or under corticosteroid therapy during or 2 months before the evaluation, and absence of any other neurological or psychiatric illness. Fatigue was assessed using the Fatigue Severity Scale (FSS) (Krupp et al., 1989) Self- and informant-report of overall neuropsychological status was quantified using the MS Neuropsychological Screening Questionnaire [MSNQ] (Benedict et al., 2004) validated in Spanish (Vanotti et al., 2009). Neurological disability was assessed with the Expanded Disability Status Scale (EDSS) (Kurtzke, 1983) and The Multiple Sclerosis Functional Composite (MSFC) (Fischer et al., 1999). The HCs group was well matched to the patient group except that they were on average five years younger. As a result, age was controlled statistically in subsequent
analyses. Exclusion criteria for this group were history of neurological illness, head trauma, or alcohol or drug abuse. At least 3 Hcs were enrolled in each center
2.2.
Measures
Cognitive status was assessed using a Spanish translation of the Rao Brief Repeatable Battery for MS, implemented in prior research (Rao, 1991; Cáceres et al., 2011). The Selective Reminding Test (SRT) (Buschke and Fuld, 1974) was used to measure verbal learning and memory, yielding a sum of recalled words on the learning trails and the number of words recalled after a 25 min delay. The 7/24 Spatial Recall Test (Barbizet and Cany, 1968) was employed to measure visual memory. The 7/24 also included a measure of total learning and delayed recall. The Brief Visuospatial Memory Test Revised [BVMTR] (Benedict, 1997) was also administered because it was more sensitive than an adapted version of the 7/24 called the 10/36 Spatial Recall Test (Strober et al., 2009), and we hypothesized that it may also be more sensitive than the 7/24 in this Spanish study. BVMTR scores were total recall over all learning trials and recall after a delay interval, similar to SRT and 7/24. The Paced Auditory Serial Addition Test (Gronwall, 1977) administered using the Rao adapted 2- (PASAT-2) and 3-second (PASAT-3) inter-stimulus interval (Rao, 1991) was applied. Likewise, the oral version of the Symbol Digit Modalities Test [SDMT] (Smith, 1982) was administered. Finally, a word list generation task (WLG) (Benton et al., 1994) was administered. The Beck Depression Inventory Second Edition (BDI2) (Beck et al., 1996) was employed to quantify depression symptoms. The Neuropsychiatric Inventory (NPI) (Cummings et al., 1994), an informant report structured interview, was used to evaluate a wide range of neuropsychiatric symptoms. The NPI has wellestablished reliability and validity, and has been employed in numerous studies of dementia of varying etiology (Litvan et al., 1996; Mega et al., 2000) including MS (Fishman et al., 2004). This structured interview yields a score for severity [0=mild to 3=severe] and the frequency [0=none to 4=daily] for each of 10 symptom domains [hallucinations, delusions, sleep disturbance, agitation, euphoria, depression, anxiety, disinhibition, lability, apathy]. Total scores for each domain are derived by multiplying severity frequency. We also used Zarit's Caregiver's Burden Scale (Martín et al., 1996) which has been used in Alzheimer's disease (Hébert et al., 2000) and MS studies (Rivera-Navarro et al., 2009). The Zarit Scale is a self-administered tool, which consists of 22 statements regarding stress and burden of care, with ratings from “never” (score 0) to “almost always” (score 4). The total sum is from 0 to 88, with higher totals reflecting greater burden. Employment status was coded in three categories: full and part time employment, unemployment or retired, and housekeepers and students. These data were reported by patients and confirmed via informant interview.
2.3.
Procedure
The project commenced with an investigator meeting including neurologists, neuropsychologists and psychiatrists from the diverse set of countries noted above. Consensus on
Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America a comprehensive battery of clinical measures with Spanish translations was achieved. Next, in the clinic, investigators randomly selected candidates for screening and asked them to undergo assessment in the cognitive and neuropsychiatric aspects of MS. Consecutive candidates were screened for inclusion/exclusion criteria. All were then evaluated by a clinical neurologist and clinical neuropsychologist. Tests were administered in the same order throughout the study. Each center evaluated at least 10 MS patients randomly selected from their patient base considered eligible for the study and three healthy controls with roughly similar age and educational level to the average of patients. All participants volunteered for the assessment and were not paid for their collaboration in accordance with the Latin American ethical regulation.
2.4.
Statistical analysis
Data analysis was performed using SPSS. To adjust for type one error we employed a conservative threshold of po0.01 to designate statistical significance. In order to determine the prevalence of cognitive impairment, the 5th percentiles of the NP tests were calculated for HC, according to the specifications published elsewhere (Rao et al., 1991). These percentiles were used as a cutoff to determine the number of MS patients with cognitive impairment. An MS patient was considered to have cognitive impairment when two or more domains (verbal memory – SRT, visual memory – BVMTR, verbal fluency – WLG, attention – PASAT 3 and 2 seconds) were below the fifth percentile. For the BDI2, we employed the customary cut-point of 15. As reported previously (Figved et al., 2008; Fishman et al., 2004), two factors were constructed: I Euphoria factor (containing agitation, euphoria, disinhibition, and irritability) and II Apathy factor (containing depression, anxiety, and apathy). A score of 4 in any NPI dimension was considered abnormally high (Fishman et al., 2004). There were two levels of parametric analysis. First, group comparisons were carried out to determine where MS differed from HCs, using analysis of covariance (ANCOVA), controlling for the effects of demographics that may distinguish the MS and HC groups, namely age. Second, we endeavored to determine which cognitive and neuropsychiatric factors account for MS patient employment (not including students and housekeepers) and caregiver distress. Regression analysis was pursued for this purpose, logistic for the binary employment/unemployment outcome, and linear regression for the Zarit caregiver distress. In these analyses age, education and gender were entered and retained in block one, followed by the cognitive and neuropsychiatric predictors in block 2, with a forward stepwise selection criterion. As there were only two models, we accepted a po0.05 threshold for significance to be retained in the models.
3.
Results
Median EDSS value of 2.07 [range 0.0–6.5] representing mild disability. Mean MSFC was 0.42, also suggesting mild neurological disability. The fatigue was higher in MS, p= 0.001,
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the FSS revealed mild degrees of fatigue relative to HCs. Demographic and clinical data are presented in Table 1. Significant differences, controlling for age, were found between MS and HCs on all cognitive tests (Table 2). Patients and informants both reported cognitive difficulties in MS patients more than their HC counterparts, leading to higher MSNQ scores, p =0.001. In the domain of cognition, the effect sizes ranged from d of 0.6 for 7/24 Total Learning
Table 1
Demographic and clinical data.
Age Education Gender MSNQ Self-Report MSNQ Informant FSS MSFC Total Z Score EDSS
MS, N =110
HC, N= 34
M
M
SD
36.6 14.7 67.3% 17.6 12.5 33.5 0.42 2.07
10.6 3.4 women 11.3 10.6 16.9 0.98 1.3
31.5 14.0 61.8% 9.6 6.2 24.5 0.82
p
SD 10.8 4.0 women 7.5 6.3 12.7 0.78
0.017 0.366 0.543 0.001 0.001 0.001 0.017
Notes: MSNQ: MS Neuropsychological Screening Questionnaire. FSS: Fatigue Severity Scale. MSFC: Multiple Sclerosis Functional Composite. EDSS: Expanded Disability Status Scale.
Table 2 Comparison between groups on cognitive and neuropsychiatric outcomes. MS M
HC SD
Cognitive function WLG 32.3 10.7 SDMT 44.1 13.5 PASAT-3 39.2 15.1 PASAT-2 32.1 13.9 SRT TL 47.9 10.1 SRT DR 7.7 2.9 7/24 TL 28.3 5.9 7/24 DR 5.7 1.7 BVMTR TL 18.5 7.5 BVMTR DR 7.1 2.6
M
p
d
% MS Impaired
SD
39.4 10.0 0.003 0.7 17.3 57.9 12.8 0.000 1.0 21.8 48.1 9.8 0.004 0.7 12.7 42.3 11.4 0.001 0.9 14.5 58.2 6.4 0.000 1.3 33.6 10.4 1.7 0.000 1.9 23.6 31.4 5.4 0.001 0.6 3.6 6.3 1.2 0.000 1.0 5.5 25.3 6.1 0.000 1.1 27.3 10.0 1.5 0.000 1.9 30.9
Neuropsychiatric symptoms BDI-II 10.9 8.4 5.4 NPI 7.8 15.8 0.6 Factor I. 2.8 6.4 0.1 Euphoria Factor II. 2.7 5.3 0.2 Apathy
5.3 0.001 0.7 1.0 0.001 0.7 0.6 0.000 7.7 0.4 0.000 7.0
Notes: All comparisons control for the effects of age. Abbreviations: PASAT=Paced Auditory Serial Addition Test, SRT=Selective Reminding Test, WLG=Word List Generation, SDMT=Symbol Digit Modalities Test, BVMTR=Brief Visuospatial Memory Test Revised, TL =Total Learning, DR=Delayed Recall.
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F. Caceres et al.
Table 3
*
Comparison between groups on NPI domains.
NPI Domain
MS
p**
HC
Absent Present Absent Present N
%
N
%
N %
Delusions 104 94 6 6 34 100 Hallucinations 105 95 5 5 34 100 Agitation 87 79 23 21 32 94 Depression 66 60 44 40 30 88 Anxiety 74 67 36 33 32 94 Euphoria 95 86 15 14 33 97 Apathy 85 77 25 23 33 97 Disinhibition 95 86 15 14 33 97 Irritability 75 68 35 32 33 97 Aberrant Motor 107 97 3 3 34 100 Behavior
N
%
0 0 2 4 2 1 1 1 1 0
0 0 6 12 6 3 3 3 3 0
0.192 0.254 0.032 0.001 0.001 0.068 0.005 0.068 0.000 0.443
n
The table presents the number of patients and percentage of sample with positive endorsement for each NPI symptom using a cut-off total score (frequency severity) of 1 or higher. nn Alfa level correspond to Chi Square analysis.
to 1.9 for the BVMTR Delayed Recall. Indeed, for visual memory in general, we observed larger effect sizes for BMVTR than 7/24, and in subsequent analyses we incorporated the former rather than the latter. Regarding neuropsychiatric symptoms, BDI2 scores were significantly elevated from HCs in MS patients [p=0.001]. On the NPI, the overall score distinguished the groups, as did total scores for anxiety [p=0.001], depression [p=0.001], apathy [p=0.008], irritability [p=0.001] [Table 3], Factor I (Euphoria) [po0.001] and Factor II (Apathy) [po0.001]. In the MS group, 35% (n=38) were determined to be cognitively impaired. 32 patients (29%) were abnormal on the BDI2. On the NPI, the prevalence of abnormally high scores (4 points or more in at least one dimension) was 20.9%. The MS and HC groups differed in caregiver burden as quantified with the Zarit scale [po0.001]. MS caregivers responses led to a mean Zarit score of 32.9711.6, compared to 22.272.8 for HCs. Within the MS sample, linear regression controlling for demographics was used to determine the most important cognitive and neuropsychiatric predictors of caregiver burden. The model retained NPI Disinhibition and BDI2, the final model having an R2 of 0.326 [p=0.003]. Contrary to expectation, there was no significant difference between employment rate in MS vs HCs [p= 0.274]. Specifically, 12 patients and 1 HC were unemployed or retired, whereas 74 patients and 27 HCs were employed. The logistic regression model predicting employment in MS retained two cognitive tests, PASAT-3 and WLG. The R2 was 0.411 [po0.0001] and 86% of patients were correctly classified.
4.
Discussion
For the first time we report on the prevalence and clinical significance of cognitive and neuropsychiatric alterations in
a Latin-American MS sample. As in prior North American and European studies, we found large effects in all cognitive domains and in some neuropsychiatric symptoms, especially depression and anxiety. The prevalence of cognitive impairment, being 35%, is generally consistent with other early disease MS samples (Patti et al., 2009). We also replicate the frequently noted observation that cognitive tests are significantly predictive of employment status. These findings are noteworthy considering the cross-cultural implications and that our patients were comparatively young, and early in their disease. Thus, although our sample was at an early stage of the disease and had a low level of physical disability, there was considerable cognitive impairment, neuropsychiatric disorder, and caregiver burden. To the best of our knowledge MS neuropsychiatric symptoms have been studied using the NPI in the USA (Fishman et al., 2004), Mexico (Diaz-Olavarrieta et al., 1999) and Norway (Figved et al., 2008). In all of these studies, depression, anxiety and irritability were more commonly observed in MS, but euphoria and disinhibition, when seen, tended to be especially detrimental to family functioning and caregiver stability (Benedict et al., 2001). In part, we have replicated this observation in this sample spanning six different Spanish speaking countries. In particular, we found that NPI Disinhibition loaded on the second step of a linear regression model predicting Zarit caregiver burden. Selfreport depression, as measured by the BDI2, also loaded in the model after NPI Disinhibition, suggesting that the combined influence of disinhibition and expression of negative affect is particularly distressing to caregivers. We have replicated the common observation that higher cognitive ability as measured by neuropsychological testing is associated with preserved employment status. There are some unique results here that are somewhat difficult to reconcile with prior research. First and foremost, we found that employment status did not differ between MS patients and HCs. In the present study PASAT was retained in the model, as reported in a large sample USA study (Benedict et al., 2006). However, the lack of a memory test predictor is somewhat unusual for this literature. Whether or not this observation is related to unique aspects of work in South America, or some other unknown factor, will require further research. Our study confirms the high frequency of depression and anxiety in MS, despite possible cultural effects. Similar results were found in previous studies of incipient population using the same technique (Jonsson et al., 2006). In this study, using the NPI, it has been found that 20.9% had neuropsychiatric disorders. This symptomatology has also been reported in other studies of later stages but not in initial stages (Figved et al., 2007; Fishman et al., 2004). The presence of neuropsychiatric abnormalities indicates the need for appropriate interventions as early as possible to mitigate psychosocial consequences of caregiver burden. Our caregivers are showing signs of burden from early diagnosis. The state of burden has also previously been detected with the same scale (Rivera-Navarro et al., 2009), but not in early stages. Regarding visual memory, it is important to highlight that BVMTR prove to be more sensitive to this difference than 7/24 Visuoespacial Recall. This finding is in agreement with Strober et al. (2009). Moreover, among cognitive tests, the
Cognitive and neuropsychiatric disorders among multiple sclerosis patients from Latin America BVMTR allowed obtaining the greater difference between groups. This is the first study to validate BVMTR in Spanish, a test that is incorporated in the Brief International Cognitive Assessment for MS [BICAMS] (Benedict et al., 2012). The limitations of this study include its cross-sectional design and small number of HCs. The sampling of controls was not randomized and was not matched individually to MS patients on a case–control basis. Although multivariate adjustments were made, the significant difference between patients and controls in Age could affect the conclusions. Nevertheless, the results found in this research are consistent with the international literature. This leads us to conduct further research to corroborate our data. While the MS sample was sufficient in total, we did not have sufficient power to compare performance across countries involved in the study. Future work will also need to investigate further the unexpected finding of similar employment rates in MS and HCs. These concerns notwithstanding, this is the first multicenter study of MS associated cognitive and neuropsychiatric symptoms in Latin America. The outcome measures employed were valid and correctly applied. The data obtained will improve the therapeutic tools considering neuropsychiatric aspects and their impact on the environment, even when dealing with patients with sociocultural variables typical of that of developed countries.
Conflict of interest The authors have no conflict of interests in relationship with this work.
Acknowledgments This study is an Investigator Initiated Trial (IIT) supported by Biogen Idec International. The funds have been used to pay transportation costs and accommodations for the training and the coordination meeting of neurologists and neuropsychologists. Economic support also served to pay for the shipping materials and the statistician fees. We thank Claudio Gonzalez for his comments in the study.
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