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Predictors of psychosocial functioning in multiple sclerosis : cognitive impairment, depression and physical… Good, Kimberley Patricia 1992

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PREDICTORS OF PSYCHOSOCIAL FUNCTIONING IN MULTIPLE SCLEROSIS:COGNITIVE IMPAIRMENT, DEPRESSION AND PHYSICAL DISABILITYbyKIMBERLEY PATRICIA GOODB.Sc., University of New Brunswick, 1989A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFMASTER OF SCIENCEinTHE FACULTY OF GRADUATE STUDIES(Department of Neuroscience)We accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIASeptember, 1992© Kimberley Patricia Good, 1992In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature) Department of  NI,0 ) 17-1.3( ipne The University of British ColumbiaVancouver, CanadaDate  (wp-f- I 1 / C DE-6 (2/88)ABSTRACTA number of reports suggests that multiple sclerosis (MS)leads to certain changes in psychosocial functioning. Whetherthese changes are the direct result of specific symptoms of MSsuch as: physical impairments, depression or deficits incognitive function, is not yet clear. Few studies have examinedthe relative effects of each of these symptoms on variousmeasures of social and vocational activities. Therefore, thepurpose of this study was to determine: 1) in a sample of MSpatients in the early stages of a relapsing-remitting diseasecourse, the prevalence of cognitive impairment and depression; 2)whether these two dimensions were independent of physicaldisability; and 3) whether cognitive impairment, depression, orphysical disability was most predictive of the decline ofpsychosocial functioning.In order to discover whether each of the symptoms existedwithin the sample, the MS group was divided according to cuttingscores established by the performance of the normal controlgroup. First, a group of MS patients who were cognitivelyimpaired was identified by scoring lower than the fifthpercentile of the normals' scores on the Word Fluency Test.Thirty seven patients (20%) of the MS group scored in theimpaired range. Validation of this impairment was assessed byperformance on other neuropsychological tests. Neither disease-related nor demographic variables could account for the deficit.Similarly, a group of patients with a high level of depressivesymptoms was identified by using the ninety-fifth percentile ofiithe normals' scores on the Beck Depression Inventory (BDI) as acut-off. Thirty eight (21%) patients were classified asdepressed according to the above criterion. Finally, thosepatients with highest levels of physical disability (top 20%)were identified from their scores on the Kurtzke EDSS. Thirtyfour (19%) of the MS group were considered physically impaired.Of the total MS sample, only 11% were impaired on a combinationof two or more dimensions.The dependent variable for the final question, psychosocialfunctioning, was assessed by activity in the work force (employedvs unemployed), level of social/recreational activity, andoutlook for the future (either optimistic or pessimistic).The results of this investigation suggest four things.First, cognitive impairment does exist in the early stages of MSand is independent of disease-related or demographic variables.Second, evidence for depressed mood was also found in a portionof this sample. Third, these observed symptoms as well as degreeof physical disability are independent phenomena in the earlystages of the disease. Fourth, being cognitively impaired isrelated to both a decrease in vocational and recreationalactivities and a greater pessimism towards the future. If a MSpatient is depressed, it is more likely that he or she isunemployed and also less socially active. Interestingly, thedegree of physically disability does not seem to be related tothese three areas of psychosocial functioning.iiiTABLE OF CONTENTSpageABSTRACT^ iiTABLE OF CONTENTS^ ivLIST OF TABLES viLIST OF FIGURES^ viiACKNOWLEDGEMENT viiiCHAPTER ONE: INTRODUCTION AND OVERVIEWIntroduction^  1Cognitive Impairment^  2Depression  4Relation Between Cognitive Impairment andDepression^  4Motor/Sensory Effects on Cognitive Impairment^ 5Role of Cognitive Change, Depression andMotor/Sensory Losses on Social Disability^ 5Rationale^  7Overview of Research Design^  9Specific Questions  9Method  11Contributions and Significance^  12Overview of Subsequent Chapters  14CHAPTER TWO: BACKGROUND TO THE STUDYEarly Findings in MS Research^  16^Diagnosis and Symptoms   17Cognitive Impairment  18Emotional Symptoms: Mood and Personality Changes ^ 19Current Understanding of MS^  21Diagnostic Criteria  21Motor/Sensory Losses  23Cognitive Impairment  24Relation Between Motor/Sensory Loss and Cognition ^ 29Depression^  33Interaction Between Depression and CognitiveImpairment  36Social Disability^  38Rationale and Motivation for the Current Study^ 44ivSummary^  46CHAPTER THREE: METHODSHypotheses and Predictions^  47Questions^  47Predictions  48Sampling Procedures  50Subjects  51Assessment Techniques^  52Neuropsychological Tests of Interest:Administration  52Demographic and Neurological data^  57Data Collection and Entry^  58Analyses^  59Analysis I^  59Analysis II  61Analysis III  64CHAPTER FOUR: RESULTSSample Demographics^  69Analyses^  71Analysis I  71Analysis II  76Analysis III^  81CHAPTER FIVE: DISCUSSIONS AND CONCLUSIONSPrecautions Interpreting the Results of This Study^ 90Significance^  96Findings  96Cardinal Findings^  101Implications  102Neuropsychological Assessment and Levelof Depression  103Independence of the Phenomena^  105Differential Effects on Social Ability^ 106Ideas for Future Research^  107REFERENCES^  110vLIST OF TABLESpageTABLE 2.1^Literature review of the effects ofcognitive impairment, depression andphysical disability on vocational andrecreational activity in MS^  43TABLE 3.1^Predicted results of the effects of cognitiveimpairment, depression, and physicaldisability on vocational and recreationalactivities^  49TABLE 4.1^Demographics of original sample: MSversus control  70TABLE 4.2^Demographics for the three groups.Cognitively impaired MS, Normal MS, andNormal controls^  72TABLE 4.3^Disease-related variables for the cognitivelyimpaired MS and the Normal MS^ 74TABLE 4.4^Neuropsychological variables for theCognitively impaired MS, Normal MS and theNormal Controls^  75TABLE 4.5^Vocational/recreational variables for theCognitively impaired MS, Normal MS and NormalControls. Analysis II^  79TABLE 4.6^Vocational/recreational variables for theCognitively impaired MS, Cognitively NormalMS, Depressed MS, Non-Depressed MS,Physically Disabled MS, and Non-physicallydisabled MS. Analysis III^  82TABLE 4.7 Predicted and observed results of theeffects of cognitive impairment, depression,and physical disability on vocational andrecreational activities. Analysis III^ 83Group membership^  84Mean scores on criterion measures for theCognitively impaired MS, Depressed MS,Physically disabled MS and Normal Controls.. 86TABLE 4.8TABLE 4.9viLIST OF FIGURESpageFIGURE 1^Neuropsychological performance^ 77viiACKNOWLEDGEMENTMy sincere appreciation is extended to the members of mysupervisory committee: Dr. Peter Graf, Dr. Athanasios Zis, and inparticular, to my advisor, Dr. Campbell Clark. Without theirhelp and patience, this thesis could never have been completed.The technical assistance provided by Sally Adams is gratefullyacknowledged as is help from: Dana Sair for support and help withthe final product; Eleanor Boyle, for her editorial assistanceand kind listening ear; and finally, Greg Stewart, for beingthere.I am indebted to the staff of the UBC MS clinic as well asto all the MS patients (and controls) who gave their time andeffort so that this project could be.viiiCHAPTER IINTRODUCTION AND OVERVIEWIntroductionA number of studies suggest that multiple sclerosis (MS)leads to changes in psychosocial functioning. Whether thesechanges are a direct result of deficits in certain symptoms of MSsuch as: cognitive impairment, depression or physical disability,is not yet clear.^Simply, there are no published investigationsexamining the relative effects of each of these three symptoms onvarious measures of quality of life. The literature on thissubject is limited to studies which assess the effects of onlyone of the symptoms on social and vocational outcome measures.A possible explanation for the limited focus in the socialfunctioning literature is a debate concerning the relationships(or lack thereof) among the three symptoms. For example, someresearchers have argued for the role of depression (Weingartner &Silberman, 1982) as well as motor/sensory losses (Beatty & Gange,1977) in the manifestation of cognitive change. While otherinvestigators have disagreed, arguing for the independence of thethree (Rao, Leo, Bernardin, & Unverzagt, 1991a; Reitan, Reed, &Dyken, 1971). Similarly, depression has been reported to be agrief reaction to the loss of physical functions (Vanderplate,1984) and is thus intimately linked to the physical symptoms.Here too, controversy has prevailed (Minden, Orav & Reich, 1987).1Each of the three symptoms (cognitive impairment, depressionand physical disability), whether interacting or actingindependently, may have detrimental effects on an individual'sability to cope in every day life situations. Separating out theindependent effects of each is of clinical importance.Therefore, reflecting the nature of the issues, the purposes ofthis study were threefold. The first purpose was to determine,in a sample of mild relapsing-remitting (R/R) MS patients,whether cognitive problems and depression exist. Given thatthese two dimensions exist, the second purpose will be to findout whether they are independent of each other, and of physicaldisability. The final purpose was to discover whether cognitiveimpairment, depression or physical disability is most predictiveof the decline of psychosocial functioning. Psychosocialfunctioning was measured by the patient's activity in the workforce, the number and type of social/recreational activitiesundertaken by the patient and whether the patient has apessimistic future outlook.Cognitive ImpairmentAlthough the frequency and patterns of cognitive problems inMS are still unresolved, there is general agreement thatcognitive impairment is a feature of the disease (reviewed inRao, 1986). Early investigations of MS suggest that cognitiveimpairment does occur (Charcot, 1877; Ombredane, 1929; Cottrell &Wilson, 1926) but there was no agreement in terms of the2prevalence rate or specific features. These prevalence ratesranged from 2 to 72% but in general cognitive impairment wasconfined to the later stages of the disease. More recentresearch has suggested that cognitive problems do exist inapproximately 50% of patients (Sandford & Petajan, 1990) but bearno relation to disease duration (Rao et al., 1991a) or level ofphysical disability (Franklin, Nelson, Filley & Heaton, 1989).Moreover, Canter (1951b) argued that cognitive problemscould be observed early in the disease, and this fact has beensubsequently validated by other investigators (Klonoff, Clark,Oger, Paty & Li, 1991; Beatty, Goodkin, Monson, & Beatty, 1989).Not only did Klonoff et al. (1991) and Beatty et al. (1989)indicate that cognitive impairment can be an early stage effect,they also argue that it can occur in some patients withrelapsing-remitting (R/R) course while in remission.The cognitive problems that have been reported in MS arechanges in memory function, in abstract conceptual reasoning, inword fluency, and in speed of information processing (Minden,Moes, Orav, Kaplan & Reich, 1990). Primary language abilitiesand recall of overlearned material, on the other hand, seem to bespared (reviewed in Rao, 1986; Peyser & Poser, 1986).3DepressionIn addition to problems with cognition, emotional problemsare common in MS. The prevalence of depression has beenestimated between 27-54% (Minden & Schiffer, 1990). The reportedprevalence has been variable from study to study perhaps due tothe lack of standardized terminology and assessment tools.Depression has been postulated as being of the reactive typeearly in the disease course due to the problems of adjusting tothe diagnosis of a progressively disabling disease (VanderPlate,1984), whereas depression seen in the later stage is presumed tobe organic, reflecting lesions in the cerebrum (Schiffer, Caine,Bamford & Levy, 1983).Relation Between Cognitive Impairment and DepressionThe relationship of cognitive impairment and depression hasnot been clearly established. Some researchers have argued thatthe poorer performance by MS patients on neuropsychological testswas a secondary reaction to depression (Weingartner & Silberman,1982, Goldstein & Shelly, 1974). Moreover, it is conceivable thatcausation could run in the opposite direction with cognitiveimpairment being a precipitating factor in the appearance ofdepressive symptoms. Schiffer et al. (1983) and Rao, Leo,Ellington, Nauertz, Bernardin, Unverzagt,(1991b) have argued thatcognitive impairment and depression might bear no relation to oneanother.4Motor/Sensory Effects on Cognitive ImpairmentThere is a further complicating issue to the debateconcerning the underlying causes of cognitive impairment. Theissue is that motor/sensory deficits, the cardinal symptoms ofMS, have been proposed to be a possible contributing factor(Beatty & Gange, 1977; Rao, 1986). There are numerous reports inthe literature indicating that tests of motor/sensory functionare performed less efficiently by MS patients (Klonoff et al.,1991; Minden et al., 1990). However, physical impairment can notaccount for poorer performance on other tests which havevirtually no motor/sensory component. Reitan et al. (1971) haveindicated that MS patients perform more poorly than normalcontrols on tests of motor function, but also did poorly on testsnot requiring motor functions.Role of Cognitive Changes, Depression, and Motor/Sensory Losses on Social DisabilityMS, with its debilitating symptoms and fluctuating course,can interfere with the ability of MS patients to perform everydayactivities. Sandford and Petajan (1990) review the impact of MSon daily life activities. They indicate that MS patients areless proficient at managing the household, less apt to undertakerecreational activities, and have more difficulty with their jobs(if they are still working). Sandford and Petajan (1990) do notspeculate on the underlying basis of the reduced ability to5function in social settings, but they do indicate that cognitiveand affective problems may be partly to blame.Clearly, the physical symptoms of MS (motor/sensory losses)may contribute to social disability in MS patients. However, itis possible that the accompanying depression may be more sociallydisabling for the patient. Furthermore, cognitive impairment mayalso give rise to social disability. This question warrantsinvestigation. Specifically, which of the three manifestations ofthe disease (motor/sensory losses, depression, or cognitiveimpairment) is most social disabling for the MS patient.A study was undertaken by Rao et al. (1991b) to determinethe effects of cognitive impairment on the psychosocialfunctioning in MS patients. They identified a subgroup of MSpatients who were cognitively impaired according to theircriteria. The impaired group was compared with a cognitivelyintact group on measures of social functioning indicated byemployment status and level of recreational activity. Thecognitive impaired group was more likely to be unemployed andless likely to partake in recreational activities. Furthermore,the two groups did not differ in terms of level of depression.Their results suggest that cognitive impairment is a major factordetermining life satisfaction for the MS patient in terms ofremaining socially active and in the work force.6The Rao et al. (1991b) study was instrumental in motivatingthe present study. Although similar in methodology, the currentstudy differs from the Rao et al. (1991b) investigation in manyrespects. In the Rao et al. (1991b) study, patients wereselected who represented differing disease courses. In addition,these patients were at various stages of the disease. Finally,the patients were older and more physically disabled than thosepatients in the current study. The subjects in the presentinvestigation were young, early stage R/R MS patients with mildphysical disability. The strict entry criteria provided a samplefree from potentially confounding variables that have beenproblematic in other research (for example, severe physicaldisability or relentless disease course). The research questionwas to determine whether cognitive impairment (if it exists)interferes with the daily life activities of MS patients who areat most mildly physically disabled early in the disease course.RationaleThe relationship between cognitive impairment and depressionhas been addressed in the literature in many different ways. Forexample, DePaulo and Folstein (1978), using a cross sectionaldesign, presented evidence in support of the independence of thetwo phenomena. However, only 6 of the 126 neurological patientswere MS patients. Their research method consisted of using twotests known to screen for cognitive impairment and emotionaldisturbance and to determine whether poor performance on one test7necessarily means poor performance on the other. Only 13% oftheir sample were impaired on both tests. Another approach,which was taken by Peyser, Edwards, Poser, and Filskov (1980)involved correlating the extent of cognitive impairment with thelevel of depression and finding no significant relation betweenthe two. The current study will use a unique approach. Thesample will be divided into two groups based on cognitiveperformance and subsequently, the level of psychosocialfunctioning will be compared. This approach will be used becauseprevious studies have suggested that cognitive impairment isconfined to a sub-sample of MS patients (Rao, Hammeke, McQuillen,Khatri & Lloyd, 1984). Similarly, a group of depressed patientswill be identified by their scores on the Beck DepressionInventory as compared to the similar normal controls and assessedon psychosocial outcome measures. A group of patients with thehighest levels of physical disability will also be identified andcompared on psychosocial measures.This particular research design will also overcome anotherpotential problem. Many of the neuropsychological tests used toassess intellectual functioning have some degree of motorinvolvement. In the current study, subjects with possibleimpairment will be identified by performance on the Word FluencyTest. This test requires the subject to produce words startingwith a specific letter (F,A,S). The Word Fluency Test was chosenas it has very little motor component and is thus a relativelypure measure of cognitive function. The assertion that this8group has cognitive impairment will be validated by examiningperformance on other cognitive tests. Moreover, the performanceof the two groups will be compared in terms of motor sensorytests.The current study will attempt to minimize the kinds ofmethodological problems which have been criticized (Rao 1986;Heaton, Nelson, Thompson, Burks & Franklin, 1985; Peyser, Rao,LaRocca, & Kaplan, 1990) in earlier papers. As 181 MS and 90normal controls have been assessed, the resulting estimatesshould be stable. Since all subjects were recruited during theirannual visit to a Hospital MS clinic and are by definition "mild"(Kurtzke EDSS less than or equal to 6), this avoided a potentialproblem of preselecting hospitalized individuals (who are likelyto be more seriously ill). Finally, the effects of acuteexacerbations and medication are avoided by testing only thosepatients who are in remission at time of testing and arerelatively drug free (having had at least one week drug holiday).Overview of Research DesignSpecific OuestionsThree questions will be examined in this study.9Question one. Given that cognitive dysfunction does existin a sample of early relapsing remitting MS patients with mildphysical disease course (Good et al., in Press), what is itsrelation to depression or physical disability.Question two. Does the decline of intellectual functionsrelate to a decrease in psychosocial functioning? Psychosocialfunctioning will be measured in terms of activity in the workforce, number and type (for example active sports vs. hobbies) ofleisure activities in which the patient engages per week, andtheir level of optimism for the future.Question three. What is the relative effect of cognitiveimpairment on psychosocial functioning in comparison tophysical disability and depression. Specifically, this analysiswill try to determine whether depression can interfere with thenumber of leisure activities, the employment status and level ofoptimism for the future. Furthermore, the same questions will beasked with respect to physical disability.The above analyses will be performed in order to answer thelarger question: Are the three symptoms independent of eachother, and which of these symptoms is associated most stronglywith a decline in psychosocial functioning.10MethodSample description. The data was drawn from an existingdatabase. The subjects were considered for inclusion into alarger study at their annual visit to the UBC MS clinic.Subjects were included if they met the criteria of being in theearly/mild stage of a relapsing-remitting disease course, and inremission at time of testing; diagnosed as clinically definite;young, aged less that 50 years and having been diagnosed beforethe age of 40 years.^The MS patients must not have had anypsychiatric diagnosis predating the onset of the disease, nor anycomplicating medical problem or drug regimen concurrent with MS.Each MS patient was asked to recruit a same-sex, educationallyand socio-economically matched non-relative who met the samecriteria where applicable to act as a control.Measures and design. Data collected on each subject (bothMS and controls) included scores from an extensiveneuropsychological battery, interview data, an MRI (magneticresonance imaging) scan, and in the case of the MS patients,disease related information including their level of physicaldisability from the Expanded Disability Status Scale (EDSS). Theneuropsychological battery included 23 tests which assessed awide range of functions. The Word Fluency Test was administeredand it will be used as a screening device in order to detectpatients with possible cognitive impairment.1 1To ensure that these patients will not be selected solelybecause of lower premorbid ability, subjects will then becompared on highest level of vocational achievement, andeducational status.^In order to be certain that the loweredcognitive efficiency is not a result of poor sensory/motorskills, performance on the tests of sensory/motor function(Grooved Pegboard, a test of motor speed and coordination) willbe examined.The cognitively impaired subgroup will then be compared withthe cognitively intact group on such measures as employmentstatus, amount and type of social/recreational activity in whichthe patients engage and patients' level of pessimism towards thefuture. Finally, the relative effects of cognitive impairment,depression, and physical disability will be examined. It washypothesized that cognitive impairment might have an effect oneach of these areas, but level of physical disability ordepression may also play a role. Therefore, these variable willbe examined in order to determine which variable is able topredict the social disability that these patients face.Contributions and SignificanceThe motor/sensory deficits associated with MS and theirdebilitating effects are well recognized in the literature andusually used to explain subsequent problems in adaptation innormal living. However, if cognitive changes occur in the early12stages of the disease, the recognition of these changes and theirresultant effects on the individual clearly has a direct bearingon treatment planing.This study should contribute to our understanding of theeffects of various MS related symptoms on psychosocialfunctioning, specifically whether cognitive change may be themost socially disabling. The results of this study mayunderscore the need for timely and accurate neuropsychologicalassessment. Cognitive deficits can interfere with theperformance of normal daily activities and in particular can leadto cessation of employment, regardless of level of physicaldisability. Neuropsychological assessment can give informationthat may be beneficial to family members, friends, employers sothat adaptations can then be made in working and livingconditions. With respect to working conditions, cognitiveretraining programs could be beneficial for the MS patient tomake use of mental processes spared by the disease. Alternately,retraining to take on a new less mentally challenging positionwhich minimizes the cognitive component needed for jobperformance. In terms of leisure activities, changes can be madein order to lessen the impact of impaired cognitive functioningon ultimate life satisfaction. Should depression be found to besocially disabling, recognizing and treating the cause might leadto favorable outcomes in terms of social and vocationallife-style.13A detailed neuropsychological battery which covers a widerange of functions, including an assessment for the level ofdepression, should be used in assessing cognitive functions earlyin the course of the disease, and information from thisassessment should be used in planning realistic life goals forthe MS patient and his/her family.Overview of Subsequent ChaptersThis thesis has been divided into five chapters. Thefollowing section provides a rough overview of the chapters tofollow.Chapter two serves as a review of the literature, examiningissues which are pertinent to the research question. It has beenbroken down into two sections: 1) early findings in MS, and 2)the current status of our knowledge. The second section has beenfurther subdivided into seven sections. These are: 1)diagnostic criteria; 2) physical disability; 3) cognitiveimpairment; 4) interaction of cognitive impairment and physicalchanges; 5) depression; 6) interaction of cognitive impairmentand depression; 7) social disability.Chapter three provides a detailed methodological sectionoutlining subject selection, assessment techniques, methodology,and analyses. Chapter four reviews the obtained results of theanalyses.14Chapter five provides a detailed discussion of the findingsand draws conclusions based on the obtained results.Furthermore, implications of these results on the everyday livesof the MS patients are discussed as well as presenting ideas forfuture research.15CHAPTER IIBACKGROUND TO THE STUDYThe purpose of this study is to determine the relativeeffects of motor/sensory impairment, cognitive deficits anddepressed mood in multiple sclerosis, on the individual'sability to live a normal life. Therefore, this chapter willfirst review the reported cognitive and mood changes in multiplesclerosis with specific reference to the early or mild stages ofthe disease. Subsequently, our current understanding of thesocial impact of this disease will be outlined. To date,however, there are few studies attempting to delineate therelative effects of impairment in these three spheres(motor/sensory, cognitive or mood) on daily function althoughclear recognition of the potential effects of such impairment isevident in the literature.Early Findings in MS ResearchGiven the variability of symptoms which characterize thedisease, diagnosing the MS patient, particularly early in thehistory of the disease, has been difficult (Matthews, Acheson,Batchelor, & Weller, 1985). The pathology underlying the diseasebecame apparent with post mortem analysis, but definitivediagnosis was only possible at autopsy (DeJong, 1970). JeanCruveilhier has been credited for first describing MS clinicallyin 1835. He referred to the pathology as "sclerose en taches" or16"en iles" but described it as a disease of the spinal cord(DeJong, 1970). At about the same time, Robert Carswell made anumber of drawings of the pathological states of MS (DeJong,1970). However, it was not until later in the century that JeanMartin Charcot (1877) recognized MS as its own entity, separatefrom other neurological diseases such as neurosyphilis (Hashimoto& Paty, 1986).Diagnosis and SymptomsProblems of diagnosis. Due to the nature of the disease,diagnosis is difficult and many patients have been misdiagnosed(Burnsfield & Burnsfield, 1982). In the past, patients withother neurological diseases may have been included in clinicalstudies of MS (for a review, Rao, 1986). Conversely, individualswho may have been afflicted with MS may have been misdiagnosed assuffering from psychiatric conditions such as hystericalconversion reaction (Langworthy, 1948). For example, Buzzardclaimed in his 1897 paper that due to the transient nature of thesymptoms and the seemingly spontaneous recovery withouttreatment, many patients (especially women) were considered to besuffering from hysteria. This lack of diagnostic precision mayhave resulted in inaccurate prevalence estimates of psychologicalproblems in MS patients. Although these diagnostic issues arenot fully resolved, more formal clinical diagnostic criteria havebeen employed and are used in conjunction with more definitive17laboratory tests (Poser, Paty, Scheinberg, McDonald, Davis,Ebers, Johnson, Sibley, Siberberg, & Tourtellotte, 1983).Cognitive ImpairmentEarly investigators found that in addition to motor/sensoryproblems, intellectual and cognitive deterioration could be afeature of the disease (Ombredane, 1929). Charcot (1877)indicated that MS patients had a particular mental state which hedescribed as "..Marked enfeeblement of memory; conceptions areformed slowly; the intellectual and emotional faculties areblunted in their totality"(page 194). Ombredane (1929) observed72% of his patients to have deterioration of memory ranging fromminimal to severe. Emphasizing the occurrence of intellectualdeficits, Surridge (1969) found almost two thirds of his patientsto have intellectual impairment. Jambor (1969) found hispatients to have general and specific intellectual impairments.The most marked deficits were general intellectual efficiency,non-verbal reasoning and memory functions. In contrast to thesehigh rates of cognitive impairment, Cottrell and Wilson (1926)noted the relative rarity of intellectual deficits in theirpatients and suggested that cognitive impairment occurred only inlong standing cases, and that even then it was confined to asmall subgroup of patients.The variations in definition or scope of mental symptomswhich are reported in the earlier literature make it difficult to18determine the relative prevalence of cognitive and affectivesymptoms. For example, no distinction was drawn betweencognitive and emotional disturbances; rather, they were typicallygrouped under the general rubric of `mental symptoms' (Dercum,1912). Although early reports recognized often both phenomenathe two were not always separated in the presentation of data(Berger, 1905). Charcot's (1877) original descriptions alludedto both types of symptoms with his reference to "foolish laughterfor no cause" and "marked enfeeblement of memory". Although suchqualitative description may capture the clinical presentation ofsome patients, the lack of separation between cognitive andemotional problems in empirical studies does not allow foraccurate estimates of emotional or cognitive impairment in the MSpopulation (for a review, Rao, 1986).The variation in these reports of so-called "mental"symptoms indicated the need for a clearer definition ofpsychological and affective disorders in MS. Recent studies haveattempted to clarify this issue by using more formal and diverseassessment techniques (Rao, 1984; Minden & Schiffer, 1990).Emotional Symptoms: Mood and Personality ChangesEarly researchers were aware of the changes in mood thataccompanied the disease (Trimble & Grant, 1982). Since the timeof Charcot, the mood state known as euphoria has been associatedwith MS. Brown and Davis (1922) stated that a large percentage19of their patients (71%) seemed too cheerful and unconcernedabout their disease. In addition, Cottrell and Wilson (1926)found 63% of their sample to be euphoric and 84% appeared to beeutonic (a sense of physical well being as opposed to mental wellbeing). One problem regarding the definition of euphoria was thesubjective rating by the clinician as to what might constitutebeing "too cheerful". In addition, emotional lability(inappropriate changes in mood for no apparent reason) has beendiscussed (Charcot, 1877; Cottrell & Wilson, 1926).Early studies on the subject of depression revealed thatdepression was more common in MS (reviewed in Minden et al, 1987)in comparison to the general population (3-9%, Gregory &Smeltzer, 1983). Cottrell and Wilson (1926) found 10% of theirsample to be depressed while Sugar and Nadell (1943) found sevenof their 28 patients (25%) to be depressed. Ombredane (1929)believed that depression did occur but occurred only early in thedisease. However, depression gave way to euphoria later in thedisease and tended to be accompanied by intellectual slowing. Inantithesis to the above findings, Brown and Davis (1922) wereunable to find any evidence of depression in their sample.The idea of a premorbid personality which predisposescertain persons to develop MS was discussed by Langworthy(1948). He suggested that MS patients had poor premorbidadjustment, characterized by immaturity in interpersonalrelationships and emotional displays. A later trend in20personality research stemmed from the appearance of the MinnesotaMultiphasic Personality Inventory (MMPI). MS patients tended tohave elevated scores on the so-called "neurotic triad" (Baldwin,1952). Specifically, MS patients tend to have elevated scores onthe hypochondriasis, depression and hysteria scales.The older research was plagued by confounding variables,imprecise definitions and inconsistent assessment measures. Someproblems addressed in earlier research are not yet clear.However, definite progress has been made with more recentinvestigations using more explicit criteria and more sensitivemeasurement techniques.Current Understanding of MS Diagnostic Criteria MS is a difficult disease to diagnose but in recent yearsdiagnosis has been facilitated by the introduction of a set ofguidelines (Matthews, Compston, Allen, & Martyn, 1991). Thefirst systematic attempt to establish a criteria for diagnosiswas published in 1965 (Schumacher, Beebe, Kibler, Kurland,Kurtzke, McDowell, Nagler, Sibley, Tourtellote, & Willmon, 1965).This diagnostic system was used to select only patients who haddefinite MS for clinical trials and thus permitted bettergeneralization of findings. Six requirements must be fulfilledin order for the diagnosis of clinically definite MS to be made.21These are as follows: 1) there must be objective abnormalitieson physical examination; 2) these abnormalities must reflectprimarily white matter dysfunction; 3) from neurological exam orhistory, there must be evidence of involvement of two or moreseparate parts of the central nervous system that occurred atseparate times (disseminated in time and space); 4) the onset ofsymptoms is within the expected age range (10-55 years); 5) thepattern must fit into one of the following courses: at least twoclear-cut episodes of functionally significant worsening, eachlasting over 24 hours and separated by at least one month, or aslow progressive development over at least 6 months; 6) acompetent physician must be satisfied that no other disease canexplain the symptoms (Schumacher et al., 1965).More recently, a set of criteria was proposed by Poser etal. (1983) which expanded on Schumacher's and included greaterspecificity. This new set of guidelines incorporates the resultsof ancillary tests such as magnetic resonance imaging (MRI) forenhancing the confidence in the diagnosis and include bothprobable and possible diagnostic categories. Although medicalresearchers have begun to limit clinical trials to including onlythose with a "definite" or "probable" diagnosis, these additionalgroups can be used to add greater flexibility to the researchdesign (Rao, 1986).The confidence in diagnosis of MS has been an ongoingconcern and misdiagnosis is not limited to older research. A22high false positive rate still occurs in the diagnosis of MS.Herndon and Brooks (1985) report that up to 10% of peoplediagnosed as having the disease in fact do not have MS but inactuality have other specific diagnoses. More recent researchhas suggested that the symptoms of MS are still occasionallymistaken for psychiatric disorders. Skegg, Corwin & Skegg (1988)found that 16% of their sample of 91 MS patients were initiallyreferred to psychiatrists before a subsequent diagnosis of MS wasmade. To date, no specific laboratory test has been found tounequivocally identify MS. Although new laboratory tests such asoligoclonal banding or evoked potentials can be helpful, thediagnosis remains a clinical one (Hashimoto & Paty, 1986). Sountil a laboratory test is found to differentiate MS from otherclinical entities with certainty, this problem remains.Motor/Sensory LossesImpairment of motor and sensory systems are the hallmarksymptoms of MS (Matthews, Compston, Allen, & Martyn, 1991). Thesensory losses may be double vision, optic neuritis (loss ofvision in all or parts of the visual field), loss of tactilediscrimination ability, bladder and bowel dysfunction and poorlimb position sense whereas motor problems may be weakness,pariesis, or loss of coordination (Gulick, 1991). According toMatthews et al. (1991), the incidence of initial symptoms hasbeen broken down as follows: motor weakness 40%; optic neuritis2322%; parasthesiae 21%; diplopia 12%; vertigo 5%; bladder andbowel disturbance 5%.Assessment of physical disability. The physical signs andsymptoms are the basis of clinical diagnosis (Sibley, 1990). Ascale was developed to identify the extent of neurologicaldisability in MS patients (Kurtzke, 1955) and is the acceptedsystem for comparing subjects. Eight functional systems areexamined with this scale: pyramidal, cerebellar, brainstem,sensory, bowel and bladder, visual, mental, and other. Each ofthe functional systems with the exclusion of the "other" scale,is graded from normal (grade 0) to maximally impaired (grade 5 or6), while the "other" scale is graded as a 0 (none) or 1(present). The functional systems are mutually exclusive interms of neuroanatomy. A later expansion of the scale (Kurtzke,1983) included a scale for evaluating overall physical disabilityin MS. This 10 point rating scale, termed the expandeddisability status scale (EDSS), graded by increments of 0.5classifies MS patients from 0 (no disability) to 10 (death due toMS). A turning point occurs at the 6 point mark indicating thatthe patient needs a cane/crutches for ambulation.Cognitive ImpairmentCognitive changes are now a recognized feature of thedisease process in Multiple Sclerosis (for a review see Rao,1986). The literature suggests that: 1) there is little doubt24that cognitive dysfunction is often associated with MS(VanderPlate, 1984) and 2) cognitive impairment is more prevalentthan early researchers had estimated (Rao et al., 1991b); and3) there is a general consensus as to which functions areaffected and which functions are spared (Matthews et al., 1991).Frequency of cognitive impairment.  The method by whichcognitive disability is assessed has profound effects on theobserved prevalence (Peyser et al., 1980). Standard neurologicalmental-status examination generally produce lower estimates ofcognitive impairment than do more extensive neuropsychologicaltests. In earlier estimates of cognitive impairment, cognitiveproblems may have been missed due to the emphasis placed onsensory/motor impairments or were assumed to be the direct resultof the sensory/motor impairment (Reitan et al., 1971).Several studies have employed the neurological mental statusexam or neurological exam in order to assess the nature or degreeof cognitive problems in MS (Rabins, Brooks, O'Donnell, Pearlson,Moberg, Jubelt, Coyle, Dalos, & Folstein, 1986; Beatty & Goodkin,1990). These screening devices tended to yield rather lowresults. A study by Kahana et al. (1971), using a neurologicalexamination, found 25% of their sample of MS patients to beintellectually impaired. Peyser et al. (1980) found only 13% oftheir sample to be cognitively impaired on the standardneurological examination.25Neurological screening devices, although quick andrelatively inexpensive, have been found to be insufficientlysensitive to detect cognitive impairment in the MS patient(Peyser et al., 1980). For example, Peyser et al. (1980) foundthat half of those patients who were described as having intactmentation on a standard neurological assessment in fact wereimpaired on neuropsychological examination. More recent studieshave found that the prevalence of cognitive problems in MS isgreater using more sensitive neuropsychological tests than witha standard mental status exam (Franklin et al., 1989). Staplesand Lincoln (1979) studied 29 MS patients with severe, longstanding disability with 29 muscular dystrophy patients matchedfor age, sex, and socioeconomic status. Sixty percent of the MSpatients were found to have some evidence of memory impairment.Furthermore, Rao et al. (1984) found that 43% of their sample ofchronic progressive MS patients had mild disruption of memorywhile 21% exhibited moderate to severe memory problems.Research has shown that not only is intellectualdeterioration a feature of the disease process, but it may alsobe evident in the early stages of the disease (van den Burg,Zomeren, Minderhoud, Prange, & Meijer, 1987; Klonoff et al.,1991; Beatty et al., 1989). A study by Canter (1951) wasinstrumental in determining that cognitive deficits are evidentin the early stages of the disease. Canter examined armyveterans who developed MS after entering the service.Significant intellectual losses were reported in these26individuals on the Army General Classification Test even thoughthey were in the early stages of the disease. In addition,intellectual impairment was evident in a test retest situationafter a six month period on the Wechsler-Bellevue Memory Test,further suggesting that cognitive deficits are seen early in thedisease. Ivnik (1978) reinforced these findings with hislongitudinal study indicating that deterioration of a number ofcognitive functions was evident on average three years later.Pattern of cognitive impairment. Reviews of the literaturesuggest that there is general agreement to the cognitiveabilities that are spared and those that are impaired in MS(Matthews et al. 1991). For example, several authors havedemonstrated differential impairments in memory both verbal andnon-verbal and immediate and delayed recall ( Jambor, 1969; Rao &Hammeke 1984; Staples & Lincoln, 1979). A review by Rao (1986)summarizes that the capacity of short term memory tends to bespared, while retrieval strategies from short and long termmemory tend to be impaired. Minden et al. (1990) have found 30%of their patient sample to have severe memory impairment, 30% tohave moderate impairment of memory and 40% to have mildly orunimpaired memory. Similarly, Rao et al, (1984) found 21% oftheir sample to have moderate to severe memory impairment, 43% tohave mild problems and the remaining 36% to be comparable tonormals with no apparent memory deficits. These findings suggestthat MS patients can be differentially affected with respect tomemory functions.27Several researchers have indicated that the performanceIntelligence Quotient (IQ) is affected, possibly due to thereliance on motor skills whereas Verbal IQ is less affected in MS(Reitan et al., 1971; for a review see Rao, 1986). Accordingly,the Full scale estimate will be lower. In a review of theliterature, Rao (1986) demonstrated that in a large number ofstudies (eight), both the Verbal IQ and the Performance IQ weredeficient, however, the average Verbal IQ was higher than thePerformance IQ by seven to 14 points. The results of theliterature review suggest that although Verbal IQ and PerformanceIQ decline in MS, verbal/linguistic performance may not be asseverely affected as visuomotor processes.Furthermore, deficits in abstraction or conceptualizationhave been reported (Beatty & Gange, 1977). Specifically, MSpatients tend to perseverate, have difficulty shifting sets andresponding to feedback (Peyser et al., 1980; Rao, 1986).Although a chronic-progressive (C/P) disease course isassociated with greater impairment of cognitive functioning, thepattern of impairment in the relapsing-remitting (R/R) diseasecourse is similar to that seen in the C/P form (Heaton, NelsonThompson, Burks & Franklin., 1985). As a general rule, memoryfunctions, both verbal (Klonoff et al., 1991) and nonverbal(Grant, McDonald, Trimble, Smith & Reed, 1984), verbal fluency(Beatty et al. 1989), and perceptuomotor speed (van den Burg etal., 1987) seem to be impaired in early stage R/R MS. This28typical pattern tends to leave verbal intellectual and primarylanguage abilities unaffected (Rao, 1986).Several studies in the MS literature have shown MS patientsperform more poorly on the Word Fluency Test than normal controlsor other neurological disease control groups (Beatty et al.,1989; Caine, Bamford, Schiffer, Shoulson & Levy, 1986; van denBerg et al., 1987). This test is of particular interest becauseperformance should not be impaired by the motor/sensory lossesassociated with MS. In the Word Fluency Test, the patient namesas many words as he/she can think of that begin with a specificletter in one minute. This procedure is done for three letters,F, A, and S. This particular test is known to be sensitive tobrain damage (Benton 1968).Relation Between Motor\Sensory Loss and CognitionUsually the greatest difference in mean scores onneuropsychological tests between MS patients and normal controlsoccur on tasks that load on motor/sensory functioning (for areview, Peyser & Poser, 1986; Ivnik., 1978). Beatty andGange (1977) found that their MS patients performed much worsethan controls on tests such as Finger Tapping, Foot Tapping, GripStrength, Grooved Pegboard, Static Steadiness, all of which havea substantial motor component. Klonoff et al. (1991) foundsimilar results on variables measuring motor functions in theirearly stage R/R patients.29A study by Reitan et al. (1971) addressed the relationshipof motor impairment and cognitive skills. They state that theinconsistencies in the literature on the prevalence of cognitiveimpairment is dependent on the types of tests used. They arguethat if assessment of cognitive function is based on testsmeasuring verbal information skills, MS patients would showlittle impairment. However, if tests of motor/problem solvingwere used for assessing these same patients, their performancewould appear to be greatly deficient. With this rationale, theirstudy divided all tests of the Halstead neuropsychologicalbattery into categories depending on which functions each testwas assumed to assess. The categories ranged from groups oftests which involve primarily motor skill (finger tapping), tothose tests that have a large percentage of motor component butinvolve a problem solving component as well (Tactual PerformanceTest, Digit Symbol), finally, to tests which have virtually nomotor component which load on such functions as memory orabstract conceptualizations (Halstead Category Test). Results ofthis study indicated that on all 29 tests, the MS group had lowermean scores. However, the greatest difference was found on thecategories containing tests involving motor components. The MSgroup also performed significantly worse than the controls on allother tests, even tests without substantial motor component. Theresults of this study suggest that motor impairment may worsenperformance on tasks requiring these skills, but the poorerperformance on cognitive tests by MS patients cannot beattributable to deficits in motor/sensory functions.30Cognitive impairment can be detected in MS patients whoexhibit no appreciable physical symptoms (Klonoff et al., 1991).However, if examination is not comprehensive, this impairment maynot be detected. In early stage MS patients, Jouvent, Montreil,Benoit, Lubetzki, Tournier-Lasserve, des Lauriers, Widlocher,Lhermitte and Lyon-Caen (1989) found 46% to have cognitiveimpairment and Klonoff et al. (1991) found their mild (KurtzkeEDSS <6.0) R/R patients to be deficient relative to the controlgroup on 50% of the neuropsychological tests. Therefore, it isfairly clear that patients with mild physical disease can haveintellectual deterioration.The literature suggests that there is a non-significant orweak relationship between the degree of the patient's physicaldisability and his/her intellectual/cognitive ability. Severalstudies have now investigated this relationship and found nocorrelation between Kurtzke scores and cognitive ability. Astudy by Marsh (1980) assessed 48 definite MS patientsrepresenting varying disease courses and found no significantcorrelation between severity of illness and cognitiveimpairment. van den Burg et al. (1987) examined 40 mild stage MSpatients and also found no relationship between intellectualability and MS advancement - namely length of illness anddisability status scores. A study by Lyon-Caen, Jouvent, Hauser,Chaunu, Benoit, Widlocher, & Lhermitte, (1986) also supports thisfinding. They found no correlation between degree of handicap(EDSS scores) and cognitive impairment in their sample of 2131probable and definite MS patients and nine patients with recentonset optic neuritis.Other investigations have found a significant but weakcorrelation between performance on neuropsychological tests anddisability status. Beatty et al.(1990) found that EDSScorrelated weakly with the Symbol Digit Modalities test, a testwith a heavy motor component (r=.62). However, when the motorcomponent is removed, as in the immediate recall from short termmemory, the correlation drops to r=.31. Some of the abovestudies examined selected ranges of disability scores and maysuffer from attenuation. Hence, the resulting correlations whichinclude the entire spectrum of physical disability may be thebetter estimate of the relationship between physical disabilityand cognitive ability.Furthermore, it has been suggested that the longerindividuals have had the disease, the more likely they are tohave psychological problems (Marsh, 1980). With increasedsophistication of specific neuropsychological tests thisstatement has not been consistently verified (Beatty et al.,1990). Due to the great variability of the disease, people whoare in the early stages of the disease may have many physical andcognitive problems whereas others who have had the disease for anumber of years may follow a relatively benign course (Matthewset al, 1985). A study by Beatty et al. (1989) found evidence tosuggest that the length of time a person has had the disease is32related to but not a good predictor of the degree of cognitiveimpairment. Other studies using cross sectional designs alsohave not revealed a relationship between cognitive decline andduration of illness (Ivnik, 1978, Marsh, 1980; Rao et al.,1991a). The lack of a significant relationship between cognitivefunctioning and duration of illness underscores two major themesof this project. First, cognitive impairment need not be a latestage effect but may in fact be present at disease onset (Young,Saunders & Ponsford, 1976). Second, the cognitive impairment mayoccur in the absence of profound motor/sensory deficits (Franklinet al., 1989).DepressionDepression is a frequent concomitant of MS (Schiffer et al.,1983; Minden & Schiffer, 1990). MS patients are thought to bemore depressed than would be expected given their level ofdisability (Rabins et al., 1986) and more depressed than patientswith other disabling diseases such as Muscular Dystrophy(Surridge, 1969), mixed neurological disease (Whitlock & Siskind,1980), or spinal cord injured (Dalos, Rabins Brooks, & O'Donnell,1983). In a recent study and review of the literature, it wasnoted that the true prevalence of depression in MS lies in therange of 27-54% (Minden & Schiffer, 1990).Depression as an early and late stage effect. Depressionhas been recognized as an early (Young et al., 1976) as well as a33late stage effect of MS (Minden et al., 1987). In fact someresearchers have speculated that depression may be one of thepresenting symptoms of the disease (Goodstein & Ferrell, 1977).Furthermore, Whitlock and Siskind (1980) examined MS patients andother neurological controls and found that the MS patients theyexamined were more likely to have had psychiatric episodespredating the onset of their disease. Their results led Whitlockand Siskind to speculate that the early depressive episodes mayin fact have been initial MS symptoms.Definition and Description of depression. It is clear thatdepressed mood is a common occurrence in MS (Whitlock & Siskind,1980; Schiffer et al., 1983; Minden et al., 1987;). In terms ofdefinition of depression, the mood change reported by thesepatients in some cases may not be classified as clinicaldepression. Most studies which identify "depression" in an MSgroup employ a self report measure such as the Beck DepressionInventory (BDI) or Zung Self-Rating Depression Scale (Whitlock &Siskind, 1980; Rao et al.,1991a). The reported differences inthese depression measures between the MS group and normalcontrols may be statistically significant but the resulting meanscores may still be in the normal range. For instance, one study(Beatty et al., 1989) reported a significantly increased level ofdepression (as assessed by the BDI) in R/R patients but yet theresulting mean on the BDI was only 7.5. According to Beck, Ward,Mendelson, Mock and Erbaugh (1961), a score of 7.5 is indicativeof "mild" depression, and not until a score of approximately 2034would a person be classified as having "severe" depression. Incontrast, Schiffer et al. (1983) found that 37% of their MS grouphad had at least one major depressive episode according to thethird edition of the Diagnostic and Statistical Manual (DSM-III). The different results between these two studies may stemfrom the fact that Beatty et al. (1989) looked only at mild stageR/R patients whereas the latter study was interested in older,more diverse sample.In addition to the varied definitions of depressionfound in the MS literature, the choice of rating scales has beenproblematic. Items included in certain self report measures ofdepression may well be confounded with the symptoms of thedisease (Minden & Moes, 1990). This problem may present itselfwith the MS patient reporting more so called depressive symptomsthereby artificially inflating their depression scores. In theBeck Depression Inventory, three of the 21 items may beconfounded with the disease, the Zung self-rating scale has twoitems corresponding to psychomotor problems, and a further eightitems which tap into physiological disturbance (Lezak, 1983).The Zung has a total of 20 items and the proportion of itemswhich might be assessing the physical symptoms of MS is high(40%), thereby making this measure a questionable choice fordetermining the extent of depression in MS patients. Thedepression scale of the MMPI as well contains a large number ofitems which could possibly measure somatic body complaintscharacteristic of those found in MS. Schiffer (1990) has stated35that the MMPI is a poor choice for use in medical populations.Therefore, when interpreting the results of such studies, cautionmust be used as the estimate of depression often contains itemsthat are actual symptoms of the disease (Marsh, Hirsh, & Leung,1982).Interaction Between Depression and Cognitive ImpairmentEvidence for a relationship between cognitive impairment anddepression in MS can be found in the literature (Goldstein &Shelly, 1974; Weingartner & Silberman, 1982). It has beendocumented that depressed patients can have lowered scores oncognitive tests. A review by Weingartner and Silberman (1982)discuss the effects of depression on cognition. They summarizeevidence suggesting that depression can lead to decreased memory,attention and information processing ability. Depression canproduce both qualitative and quantitative changes in thoughtprocesses. A correlational study by Stenager, Knudsen and Jensen(1989) found that as physical disability (EDSS) increases, so dodepression scores and furthermore, patients who are most severelyphysically disabled are those with the greatest impairment incognitive function. Unfortunately, this study does not supplythe correlation coefficients that lead to the conclusions.Therefore, it is not possible to determine the strength of theserelations.36Some authors have argued that cognitive deficits are atleast partly attributable to the affective disorders seen in MS.Goldstein and Shelly (1974) found that cognitive tests wereunable to discriminate between MS and neuropsychiatric patientsand from reviewing the literature, they found that MS patientsshow affective disturbance on the MMPI. These two facts leadthem to speculate that affective disturbance may be partly atthe root of the intellectual deficits (Goldstein & Shelly,1974). However, as previously mentioned, the MMPI may not be thebest scale to assess affective disturbance in the MS patientsthat these researchers observed (Marsh et al., 1982).Several studies concluded that depression and cognitivedeficits are not related (Schiffer et al.,1983; Peyser et al.,1980). Schiffer et al. (1983) compared two groups of MSpatients: those who had primarily cerebral involvement and thosewho had spinal cord and cerebellar involvement. The cerebralgroup was found to be more depressed and to have had moredepressive episodes than the spinal cord/cerebellar group.There were no differences in intellectual functioning betweenthe two groups suggesting that depression is not predictive ofcognitive dysfunction. Furthermore, a study by Peyser et al.(1980) came to similar conclusions that cognitive dysfunction anddepression are independent of one another. They found that54.7% of their MS group were considered cognitively impaired butfound no evidence to suggest that this impairment was due todepression (Peyser et al., 1980). Finally, Staples and Lincoln37(1979) summarized results of several studies concluding that"Intellectual deterioration occurs in MS as a result of centralnervous system (CNS) involvement and is not found as a result ofmood changes..."(Staples & Lincoln, 1979 p. 153).The interaction of cognitive impairment, depression, andmotor/sensory problems in MS has not yet been elucidated. Thereare few studies in the literature dealing with the relativeeffects of both motor/sensory losses and depression on cognitiveability especially in the mild stages of the disease. Jambor(1969) has addressed this issue, but only superficially. Thepatients he studied had intellectual impairment and he statedthat " MS patients tend to get symptoms of anxiety and depressionin the early stage of their lower intellectual efficiency"(Jambor, 1969, p. 773).Social DisabilityWhat can MS patients no longer do? MS can impose limits ona person's ability to live a normal life (Sandford & Petajan,1990). For example, getting around can be a major drawback forthose MS patients who have motor/sensory problems (Gulick, 1991).Similarly, bowel and bladder problems can discourage patients'participation in activities because of possible incontinence(Gulick, 1991). Depression generically is characterized by areduced motivational state resulting in an inability to interactwith others (DSMIII-R). Moreover, cognitive losses such as38memory problems, or impaired ability to think abstractly mayinterfere with the quality of life experienced by these persons.These three spheres (sensory/motor losses, depression, orcognitive problems) have been recognized as having disablingeffects on the quality of life of the MS patient (Sandford &Petajan, 1990; Stenager et al., 1989). The relative effects ofthe impairments faced by MS patients on social disability havenot yet been established. Table 2.1 summarizes the literature onthe subject of the symptoms of MS and their effects on the dailyliving activities of the patient.The daily living problems of the MS patient have beendiscussed in Chapter 1. Sandford and Petajan (1990) have triedto quantify the effects of MS on daily living activities with theSickness Impact Profile (SIP). The SIP is a scale whichcharacterizes the effects of an illness on physical andpsychosocial activities. They state that MS patients aresignificantly more dysfunctional on 13 of the 15 areas of dailyliving than are rheumatoid arthritis patients, cancer patientsand normal controls.Quality of life can be influenced by employment status.When assessing a person's quality of life, their occupationis of great importance. Neff (1985) indicated that work fulfillshuman needs for a feeling of personal worth and self esteem and39it contributes to one's identity. Work is needed: 1) in orderto obtain material goods, 2) to be active, and 3) to be respectedby others. A disease like MS, with its unpredictable course, caninterfere with the ability for one to carry out what used to benormal aspects of employment. The changes that occur can forcechanges in typical work patterns and possibly lead to reducedwork load or cessation of employment.A survey conducted in the US indicated that fourout of ten MS patients were dismissed from their positions orleft their employment as a result of their disease. A furtherone out of ten persons with MS changed jobs due to their disease.The survey went on to point out that those MS patients whoremained employed continued to work but worked fewer hours thanother, non MS, co-workers (US Department of Health and HumanServices, 1985). In fact this figure may underestimate theprevalence of unemployment as another study quoted that 77% oftheir sample of MS patients were unemployed (LaRocca, Kalb,Kendall & Scheinberg, 1982).These results suggest that MS can interfere with a person'sability to carry on with productive employment at any stage ofthe disease. According to Neff's (1985) definition, a person whohas ceased employment should be negatively affected by thischange of status resulting in a lowered opinion of personal worthand self esteem. The ill effects of forced cessation ofemployment on MS patients has not been adequately studied.40The effects of cognitive impairment on social functioning.There are few reports in the literature dealing with theeffects of cognitive problems on the ability of MS patients toremain active in the work force. A study by Franklin et al.(1989) looked at individuals who were minimally impaired (KurtzkeEDSS=3.2) (Kurtzke, 1983). Two thirds were sufficientlycognitively impaired to preclude productive employment. Aninvestigation which examines the impact of cognitive dysfunctionon psychosocial functioning in MS is a study by Rao et al.(1991b). Rao et al. (1991b) identified a cognitively impairedsubgroup of MS patients who were in the mild stage of the diseaseas measured by the EDSS (4.1)(Kurtzke, 1983). Their criteria forcognitive impairment was four or more failed tests on their 31test battery so their MS group was divided into "impaired" and"intact" groups. There were no differences between the impairedgroup and the intact group in demographics or length of illness.The impaired group, however, was less likely to be employed andmoreover, engaged in fewer social activities.A further investigation performed by Stenager, Knudsen andJensen (1991) has looked at the effects of cognitive dysfunctionon how socially active a group of MS patients were. Theseresearchers divided their MS group according to EDSS scores andcompared the resulting five groups on the Katz Adjustment Scale(a scale designed to estimate the amount of social/spare timeactivities). They found that physical disability alone was able41to account for the diminished level of social activities. Theyfound that those patients who were minimally impaired (KurtzkeEDSS 1-2) had no decrease in social activities whereas withincreasing levels of physical disability, the level of socialactivities declined. They go on to state that earlier research(Stenager et al., 1989) indicated that there is a highcorrelation between physical disability and cognitivefunctioning. Therefore they reasoned that the level of socialactivities declines with decreasing cognitive ability (Stenager,et al., 1991).The effects of depression and physical disability. Theresults of the above studies lend credence to the hypothesis thatcognitive dysfunction has its effects on the ability of the MSpatient to remain socially active. However, depression andphysical disability may also play a role. Table 2.1 summarizes anumber of relevant investigations which deal with this issue.Physical disability has been found to have an effect onemployment status. LaRocca et al., (1982) found that higherKurtzke (EDSS) scores (Kurtzke, 1983) were predictive ofunemployment in their sample. However Franklin et al. (1989)found that in their sample where the EDSS scores were very low,cognitive impairment alone was able to account for the high rateof unemployment. With respect to social/recreational activities,Stenager et al. (1991) found that increasing EDSS led to adecreased level of sparetime and recreational activities.However, these researchers found no effect in the Kurtzke42+Rao et al. 1991b+Franklin et al. 1989-Stenager et al. 1989*-Franklin et al. 1989+La Rocca et al. 1982 +Beck &Beamesderfer,1974+Stenager et al. 1991+Rao et al. 1991b +Stenager et al. 1991+Matson & Brooks 1977** + DSM III-R(Symptom)TABLE 2.1 LITERATURE REVIEW ON THE EFFECTS OF COGNITIVE IMPAIRMENT, DEPRESSION AND PHYSICAL DISABILITY ON VOCATIONALAND RECREATIONAL ACTIVITY IN MS INDEPENDENT MEASURESCOGNITIVE^PHYSICAL^ DEPRESSIONIMPAIRMENT DISABILITY (EDSS)EMPLOYMENTSTATUSD ME EP AE S LEISUREN U ACTIVITIESD RE EN ST^OUTLOOKFOR FUTURE+ had an effect- had no effect? no published studies found* Employment Status used as the Independent Measure and Cognitive Impairment as theDependent Measure** Looked at Self Concept vs. changes in Physical Abilityrange 1-2. Physical disability has also been found to influencehow an MS patient feels about him or herself. Matson and Brooks(1977) looked at self concept in MS patients and found thatincreasing EDSS led to a lowered self concept in their sample.Outcome measures such as social disability in MS as a resultof depression have been given no consideration in theliterature. Both the well recognized psychiatric manual(DSMIII-R, A.P.A., 1983) and The Beck Depression Inventory (Beck& Beamesderfer, 1974) refer to the symptoms of depression asleading to a pessimistic outlook for the future and workinhibition. But, these areas have not yet been specificallyaddressed in the MS literature.Rationale and Motivation for the Current StudyThe rationale for the current study is to determine whethercognitive impairment is evident in early stage R/R MS and whetherbeing cognitively impaired is predictive of the level of socialfunctioning. There is a paucity of literature on the subject ofsocial functioning in R/R MS. The selection of mild MS patientswith no concurrent medical or psychiatric problems in therelapsing-remitting form was a good choice for the current studyfor four reasons. The subjects that were studied were mildly (orvery slightly) physically disabled. The low level of disabilityprovided a group whose physical functioning would not confound toany great degree any changes in cognitive functioning that were44found. Second, one of the dependent measures of the currentstudy is employment status which could easily be influenced bydecreased motor/sensory ability. Third, selecting patients whohave no history of drug use or psychiatric problems provided aclean sample, free from confounding factors that have beenproblematic in other investigations. Finally, selecting onlyrelapsing-remitting patients and testing them solely in remissionallowed for an estimate of cognition in the stable form of thedisease.The study by Rao et al. (1991b) was the motivating factor tothe current study. The Rao et al. (1991b) study is differentfrom the current study in many respects. The sample which wascharacterized by the Rao group was not only older (mean age 45.7years), and hence, having a longer disease duration (9.5 years)but also comprised of patients with relapsing- remitting,chronic-progressive, and chronic-stable (38,19, and 43%respectively) disease courses. Their results can be generalizedto an older, sicker, more heterogeneous population. The questionthat was asked in the current study was whether cognitiveimpairment has any effect on psychosocial adjustment in earlystage, R/R MS patients.Another difference in the Rao study and the current study isin the proportion of patients who are medicated (42% were takingprescription medication at time of testing in the Rao study).One of the stipulations for inclusion in the current study was45that no drug regimens are currently in progress therebyeliminating one potentially confounding variable. One of thedependent measures used by the Rao study was the Zung DepressionScale. A further difference was the use of the EnvironmentalStatus Scale (ESS) which provides an assessment of socialhandicap as a result of the disease. The current study used theBeck Depression Inventory (BDI) for the measure of depressionand data from a structured interview in order to establish theextent of social disability.SummaryIt can be concluded from this review that cognitive,affective, and motor/sensory problems are manifestations of thedisease process of multiple sclerosis even in the early stages.One of the important findings of this review is that MS patientscan undergo a social disability that can be seemingly out ofproportion with their physical symptoms. The correlationsbetween physical disability, cognitive and affective problemshave not been found to be consistently high and it is not clearwhether these dimensions are independent. The question that isleft unanswered is: if the dimensions are independent, how muchdoes each contribute to the social disability faced by MSpatients. Recognizing the basis of the social problems thataffect the MS patient is of primary importance for treatmentplanning particularly in the early phases of the disease.46CHAPTER IIIMETHODSThis chapter will outline the methods to identify whethercognitive impairment exists in early R/R MS and if it has arelation with motor/sensory losses or depression. Furthermore,this investigation will try to determine whether cognitiveimpairment, or alternatively depression or motor/sensory losseshave any effect on the ability of MS patients to cope witheveryday life activities. This chapter provides a detailedmethodological section outlining subject selection, assessmenttechniques, and analyses.Hypotheses and PredictionsQuestionsAnalysis I. Does there exist a subgroup of MS patients whoare cognitively impaired? Is the cognitive impairment specificor is it a widespread decline of function? The impairment ishypothesized to be unrelated to demographic such as age, level ofeducation, socioeconomic factor or disease-related variables suchas EDSS scores or length of disease.Analysis II. Is the observed subgroup with cognitiveimpairments less likely to be employed? Is the impaired subgroupless likely to be engaged in social or recreational activities?47Do the types of activities that are undertaken differ as afunction of group membership? Is there any relation betweengroup membership and a pessimistic outlook for the future?Analysis III. Does there exist a subgroup of MS patientswho are depressed? How does being depressed interfere withvocational, social/recreational activities and outlook for thefuture? Do the patients who are the most physically disabled inthe MS sample have limited vocational or social/recreationalactivities or a more pessimistic outlook for the future? Howdoes cognitive impairment rank as a predictor of socialdisability in comparison to depression and motor/sensory losses?Are these phenomena (cognitive impairment, depression, physicaldisability) independent or is there much overlap in terms ofgroup membership?PredictionsThe third analysis was performed with respect to certainpredictions. The literature search in chapter two (See Table2.1) was the source from which these predictions were made.Table 3.1 summarizes the predicted outcomes of being in theimpaired range for each symptom.Referring to Table 3.1, It was predicted that beingcognitively impaired would have an adverse effect on all three ofthe social outcome measures. Those who are cognitively impaired48TABLE 3.1 PREDICTED RESULTS OF THE EFFECTS OF COGNITIVE IMPAIRMENT, DEPRESSION ANDPHYSICAL DISABILITY ON VOCATIONAL AND RECREATIONAL ACTIVITIES INDEPENDENT MEASURESDEPENDENTMEASURESEMPLOYMENTSTATUSLEISUREACTIVITIESOUTLOOKFOR FUTURECOGNITIVE^PHYSICAL^ DEPRESSIONIMPAIRMENT DISABILITY (EDSS)+ + +++ +1/3^ 2/3( + = Effect)( - = No Effect)3/3should be less likely to be employed, the level ofsocial/recreational activities should be reduced and the outlookfor the future should be pessimistic. Physical disability, itwas predicted, should only affect one of the three measures.Those patients who are physically impaired should be less likelyto be employed but the social and recreational status should beunaffected and their outlook for the future should be fairlyoptimistic. The number and type of social and recreationalactivities are more able to be changed in order to compensate forincreased physical disability. However, the requirements of thework place are less under the control of the individual and thusnot able to be changed. These predictions were forecast asmotor/sensory problems faced by this particular sample are veryminimal. The symptoms of depression can include work inhibitionand pessimism (towards the self and future) as some self reportmeasures (Beck & Beamesderfer, 1974) and diagnostic criteria(DSMIII-R, A.P.A., 1983) have suggested. Therefore, it waspredicted that being depressed should lead to two of the threemeasures being affected. Those MS patients who are depressedshould be more pessimistic towards the future and be less likelyto be employed.Sampling Procedures A large database has been established which includesneuropsychological test scores, MRI scans, neurological50assessments and interview data for MS patients and normal controlsubjects. The MS patients were considered for inclusion to thestudy during their visit to the UBC MS clinic. One of fiveneurologists administered a standard neurological exam and ratedthe severity of disability with the Kurtzke EDSS. If the subjectmet the criteria, neuropsychological assessment was completedwithin a month of their clinic visit. If any changes in physicalstatus were reported, the patient underwent another neurologicalexam on the day of the neuropsychological assessment. The entireneuropsychological procedure, interview and MRI scan required oneday to complete. Each subject gave informed consent for theprocedure.SubjectsMS patients were selected providing that they met thefollowing criteria: 1) diagnosis of clinically definite MS (Poseret al., 1983) with relapsing remitting course and in remission attime of testing; 2) in the early or mild stage of the diseaseand functionally independent (Kurtzke <6); 3) aged less than 50years and having been diagnosed before the age of 40 years; 5)having had no complicating drug regimens, medical problemsconcurrent with MS or psychiatric disorders predating thediagnosis of the disease; 6) no excessive recreational drug use.Each subject was asked to recruit a same-sex, non-relative whowas similar in terms of socioeconomic and educational status toact as a control who meets the above criteria where applicable.51Clinically definite MS was defined according to Poser et al.(1983) criteria. According to this criteria, clinically definiteMS (CDMS) can be diagnosed if the patient has had two attackswith clinical evidence of two separate lesions or two attacks,clinical evidence of one lesion and paraclinical evidence ofanother, separate lesion. Paraclinical evidence may be elicitedby procedures such as evoked potentials, Computerized Tomography(CT) scans, MRI, oligoclonal banding (abnormal cerebrospinalfluid in the form of a pattern of multiple monoclonal globulinsseen in 90% of patients with CDMS) or the hot bath test (the heatof the hot bath can exacerbate the symptoms of MS and this testhas been used as a crude diagnostic test). Relapsing remittingMS was defined as a disease course characterized by "relapses"or a worsening of a preexisting symptom or appearance of a newsymptom which lasts for at least 24 hours which is followed by a"remission" or recovery or partial recovery of function(Hashimoto & Paty, 1986). Relapses must be separated in time byat least one month for a R/R course to be diagnosed.Assessment techniquesNeuropsychological Tests of Interest: AdministrationThe neuropsychological battery that was used to assesscognitive impairment was administered by a trainedpsychometrician, and the order in which the tests were presentedwas random. The battery was comprised of 23 different tests52which measured a variety of cognitive/intellectual andsensory/motor functions of which 13 were chosen for the currentinvestigation. The tests which were chosen have been documentedto be performed poorly by MS patients (Klonoff et al., 1991, Rao,1986) and were representative of a large number of functionstested by the larger battery.Word Fluency Test(FAS). The examiner presents the subjectwith a letter of the alphabet and instructs him or her to say asmany words as he or she can that begin with that letter. Thepatient then proceeds to recite words in the given category overa one minute trial. The subject is instructed not to use wordsthat are normally capitalized (proper nouns) or to add manysuffixes to one root word. The letters F,A, and S were used.The score was the total number of admissible words for the threeletters. This test was of interest as it does not seem to haveany appreciable sensory or motor component to it. For example,Beatty et al. (1989) reported a correlation of -.37 for the WordFluency Test and EDSS. Similarly, a correlation of .25 has beenfound between performance on the Word Fluency Test and theGrooved Pegboard test (both hands) (Good et al., unreporteddata). In addition, deficits in neuromuscular components ofspeech production have not been reported to occur early in thedisease (Matthews et al., 1991). Therefore, should a low scorebe obtained, sensory/motor losses cannot adequately explain thisdeficit. This test was used as a criterion test which divided53the group of MS patients into a cognitively impaired subgroup anda cognitively normal subgroup.Beck Depression Inventory (BDI). For this self reportmeasure of depression, the subject selects the one statement outof four statements which most generally applies to them. Thereare a series of twenty one categories in which the statements ineach category were rated from 0 to 3. The score is the sum totalrating of all the categories. The higher the score, the moredepressed the patient. According to Beck, Ward, Mendelson, Mockand Erbaugh (1961) a score of approximately 17 translates to amoderate level of depression and a score over approximately 20 isindicative of severe or clinical depression. The BDI is a goodmeasure of depression for the MS sample as it has only a fewitems which are sensitive to somatic body complaints (Lezak,1983).WAIS-R FIQ, VIO and PIO. The Wechsler Adult IntelligenceScale (WAIS-R) (revised in 1981) is a composite battery testcomposed of eleven subtests. The subtests are categorized intoVerbal Intelligence quotient (VIQ) comprised of six subtests andPerformance Intelligence quotient (PIQ) which comprises fivesubtests depending on the underlying ability being measured. TheFull scale Intelligence Quotient (FIQ) is a standardized scorewhich is incorporated from all eleven subtest raw scores. Thesethree estimates are standardized according to the age of thesubject. This test is used extensively in MS research and is a54good benchmark upon which to compare results of the current studyto other MS studies.Grooved Pegboard. A motor sensory task which involvesplacing small pegs into slotted holes within a board. The pegsare keyhole shape in cross section. The board is a small boxwith a 5 X 5 grid with each hole able to accommodate each peg.The slotted holes are angled in different directions thereforethe pegs must be first arranged in the proper orientation beforethey can be inserted. The obtained score is the time taken toinsert all pegs with 1)right hand; 2)left hand; 3) both hands.This test was chosen as it requires the integrity of the sensorysystem, speed, and coordination, all three of which tend to beimpaired. It is a sensitive test for motor/sensory function inMS patients.Category Test (Halstead, Abbreviated form). A stimuluspattern is presented on a screen in front of the subject whichconsists of figures usually four in number at one time. Thesubject also has access to four buttons, numbered one to four.The stimulus figure(s) will, in some fashion, form a patternwhich corresponds to one of the numbers on the buttons. Forexample, the first (practice) pattern involves presenting thesubject with the Roman numerals I through IV and the subject mustpress the corresponding button (1 through 4). A later patterninvolves presenting the patient with four objects, three of whichare the same. The correct answer is to press the button55corresponding to the position of the odd figure (1st, 2nd, 3rd,4th). The rules for determining which button to press changeperiodically in a predetermined fashion. The subject is not toldwhat is the selection rule but he/she can monitor his/herprogress as a bell is sounded when a correct button is pressedand a "buzz" is sounded when an incorrect button is pressed. Thescore is the number of errors and is thought to measureabstracting ability.Trail Making Test (Trails B-A). Trails A involves joiningconsecutively numbered spheres in a timed trial. Trails Binvolves again joining spheres but this time the subject mustalternate between numbers and letters in sequential order(1-A-2-B-3-C etc). There are the same number of spheres on eachsheet. Trails B is thought to involve a conceptualtracking/information processing component which adds to the timefor that trial. By subtracting the time taken for A from thetime taken for B, a crude measure of information processing timeresults.Sentence Repetition. The sentences are presented to thesubject who must repeat them word for word (immediate recall).Each sentence is one syllable longer than the previous one. Thebeginning sentence has 10 syllables and the longest one has 26syllables. The score is the number of sentences rememberedcorrectly and is a measure of immediate verbal recall.56Memory for Objects. Fifteen items are placed on a tray andthe subject is allowed to view them for one minute. The trayis taken from view and the subject must recall all the items.The score is the number of items that were recalled and measuresimmediate visual recall.Benton Visual Retention Test(BVRT). The subject is shown acard which contains (usually) three figures, two large and onesmall. There is a ten second exposure time and a ten seconddelay time before the subject is given a piece of paper on whichto draw the design. There are ten designs in each form (Form Cwas administered) and the score is the number of errors made.This test is another measure of visual recall.Minnesota Multiphasic Personality Inventory (MMPI). TheMMPI is a personality test which is comprised of 439 true/falseitems. The items were coded onto several computer cards and thecards were read by an optic scanner. The 439 items can bedivided into a number of scales. A number of items were used todetermine the patient's future outlook.Demographic and Neurological DataDemographic information on each patient and normal controlswas obtained by a semi-structured interview. Personal anddemographic information were recorded (age, marital status,education, sex, handedness, employment status, and occupational57status) and the patients' feelings about the disease, as wasfactual information (e.g.. family history of MS and otherdiseases). Information regarding neurological status and diseasehistory was obtained from the UBC MS clinic (age at diagnosis,age of onset, number of relapses, Kurtzke Expanded DisabilityStatus Sale (EDSS) and Kurtzke functional scales, duration).Data Collection and EntryFatigue has been often associated with MS and this factcould have potentially confounded results on neuropsychologicaltests. However, subjects were given predetermined rest periodsthroughout the lengthy battery. Furthermore, the presentation ofneuropsychological tests was randomized so that the tests laterin the battery would not always be the same and more prone toeffects of fatigue.The neuropsychological data were entered into an interactivecomputer program designed specifically for the investigation.The MMPI scores were recorded on computer cards and read by anoptic scanner. The demographic and neurological data wereentered in computer file. The data were analyzed by the computerprogram Statistical Package for the Social Sciences (SPSS-Xversion 3.0) on the UBC main frame system (MTS).58AnalysesAnalysis I The purpose of the first analysis was to identify whetherthere existed a subgroup of MS patients in this sample who werecognitively impaired. The following questions where then asked:1) Is the observed cognitive impairment a specific loss of aparticular function (in this case spontaneous word generation) oris it a widespread decline of many functions?; and 2) Are theobserved cognitive problems a result of demographic ordisease-related variables?In order to divide the MS group into two subgroups, theresults of the Word Fluency Test were used. This particular testwas chosen because the motor/sensory demands of this task areminimal and thus allow for a relatively pure measure of cognitivefunction. In the Word Fluency Test, a higher score is indicativeof better performance. Therefore, to separate the MS group intoa cognitively impaired subgroup and a subgroup whose members haveno cognitive problems, the fifth percentile of the distributionof the normal group was the criterion. The fifth percentile waschosen in order to capture the most impaired persons in the MSgroup and to ensure statistical power. Those MS patients whoscore below this score were considered cognitively impaired;those who score as well or better were considered cognitivelynormal. A Chi-squared analysis was done to determine if a59greater than expected number of MS patients fell below the fifthpercentile.Further analysis was performed in order rule out otherpotentially confounding factors such as demographics or severityand duration of illness. Age and education were examined using aone-way analysis of variance and Tukey's post hoc test todetermine whether any differences could be attributed to thosevariables. Similarly, using a Chi-square test, the contributionof sex was examined among the two MS subgroups and the normalcontrol group. The effects of severity (looking at EDSS and allfunctional scales), duration of illness, age of onset and numberof relapses were investigated using a t-test for independentgroups on the two MS subgroups.One way analysis of variance was employed to detect anybetween group differences on tests of motor sensory capacitiessuch as the Grooved Pegboard. The Grooved pegboard was chosen asa test of motor/sensory ability as it seems to combine a numberof functions on which MS patients have been shown to bedeficient (speed, motor coordination and tactilediscrimination). The hypothesis in question would predict thatboth MS groups should be significantly worse than the normalcontrols. Should the impaired group perform significantly worsethan the other two groups, it could be argued that motor/sensoryproblems could be a confounding factor of the observed cognitiveimpairment.60In order to define the extent of the cognitive impairment,the three groups were compared on all other cognitive tests.This was done in order to determine whether the members of theimpaired group have a problem only in spontaneous word generationor whether their cognitive impairment is generalized or global.Again using the one-way analysis of variance and Tukey's post hoctest, the three groups were compared on the following variables:Full Scale IQ, Verbal IQ, Performance IQ, Category test, PairedAssociate Learning, Trails B-A, Sentence Repetition, Memory forObjects, and Benton Visual Retention.It was conceivable that the preselection of patients interms of so-called cognitive impairment may have beenaccomplished by selecting those persons who had lower premorbidability. This was examined by comparing all three groups(normal, cognitively impaired MS, and cognitively normal MSgroups) on the highest level of academic achievement and thehighest level of occupational status which are thought to befairly good indicators of level of functioning prior to the onsetof the disease (Lezak, 1983). A Chi-square statistic was used.Analysis II The purpose of the second analysis was to determine whetherthe level of social functioning was related to cognitivefunctioning. Social functioning was measured by the employmentstatus and the nature and number of social/recreational61activities. Furthermore, the level of optimism for the futurewas assessed to determine whether cognitive dysfunction wasrelated to greater pessimism towards the future.From the interview data, information regarding employmentstatus was available. Employment status was characterized byfour levels: 1) those who were engaged in full time employmentwhich includes those employed in the household (homemakers) andstudents; 2) those who were employed but were only working partof the time regardless of the reasons given (children, choice,economy, or disease related); 3) those people who were notemployed regardless of the specified reasons; and 4) those whohave retired (all subjects in the study were less than 50 yearsat the time of testing). This analysis tried to determinewhether the cognitively impaired group were more likely to beunemployed or working part time than the cognitively intact orthe normal groups. A Kendall's Tau was used to compare thethree groups in terms of their employment status and a furtherKendall's Tau was used to compare the two MS subgroups onemployment status.Also from the interview data, information was availableregarding how leisure time is spent. Both number and type (forexample, hobbies vs active sports) of recreational activitiesthat were engaged in by the patients were available from thedatabase. The three groups were compared to see whether therewere any differences in terms of the nature of recreational62activities undertaken by each group and to calculate the numberof activities performed by the members of each group. A one-wayanalysis of variance compared the three groups on the number ofactivities whereas a Chi-squared statistic was used to comparethe type of recreational/social activities undertaken by themembers of all three groups.From the MMPI, a scale was derived from items which examinethe optimistic/pessimistic outlook for the future. Five itemswere selected along with an item from the interview (What do yousee for yourself in the future) in order to get a rough estimateof the level of optimism for the future. The items from the MMPIwere as follows:16. I think I got a raw deal from life.83. These days, I find it hard not to give up hope amounting tosomething.101. I don't seem to care what happens to me.252. I usually expect to succeed in the things I do.421. The future seems hopeless to me.A composite score was established by recoding each of the itemsand summing the resulting scores. Items 16, 83, 101, 421, andthe interview item were coded in that if "true" was answered, ascore of 1 was obtained whereas if "false" was answered, a scoreof 0 was obtained. For the remaining item (252), the codingscheme was reversed in that a response of "false" led to a score63of 1 and "true" led to a score of O. The resulting scale had aminimum of 0 (Optimistic for the future) and a maximum of 5(Pessimistic for the future).From the theoretically derived scale, a reliabilitycoefficient was computed in order to determine the validity ofthe scale. The coefficient determined whether the items in thescale indeed measured what was intended (optimism/pessimism). Acorrelation matrix indicated which items should be deleted (a lowcovariance) and after the unwanted items were deleted, a newscale was observed. The three groups were compared on this scaleusing a one-way analysis of variance and Tukey's post hoc test.Analysis III The third analysis attempted to delineate whether cognitiveimpairment, depression, or physical disability was mostpredictive of any decrease in social functioning.In the first analysis, the fifth percentile of thedistribution of the normal controls' scores on the Word FluencyTest established a cognitively impaired and a cognitively normalMS group. A similar procedure to that employed in the firstanalysis was used to identify a group of depressed individualswith the results of the BDI. A cutting score was obtained fromthe distribution of scores of the normal group. A high score onthe Beck Depression Inventory is indicative of higher level of64depression, hence, the ninety-fifth percentile served ascriterion. The ninety-fifth percentile was chosen in order toachieve a balance between statistical power and clinicalmeaningfulness (those patients who report a high level ofdepressive symptoms). Those MS patients scoring above this levelwere considered depressed and those scoring the same or lowerwere considered non-depressed.The MS group was dichotomized in a third manner according totheir scores on the EDSS. No data for the normal controls wereavailable for physical disability, and therefore a slightlydifferent procedure determined the cutting score for "physicaldisability". A higher score on this scale translates intogreater disability. Therefore, those patients with scores in thetop 20 percent of the scale were classified as "physicallydisabled". This procedure ensured that only the most disabledpersons be included in this group and statistical power wasoptimized. All other MS patients were considered to haverelatively mild levels of physical disability.The most disabled persons in each symptom category(cognition, depression and physical status) were able to becompared to their non-impaired counterparts on a number of socialoutcome measures such as: employment status, level ofrecreational/social activities and outlook for the future. Referto Table 3.1 for the predictions on how each of the symptoms of65the disease might affect the social/recreational or vocationalactivities and the optimism/pessimism for the future.Employment status. A two by two Chi-square was thestatistical procedure employed to determine the effect of beingin the impaired group in each of the spheres (cognition,depression or physical status) on employment status. Employmentstatus was dichotomized into a working category versusnon-working category. The working category included people whowere working full time (student and homemaker included) and thoseworking part time. The non-working category included thosepeople who were no longer working (unemployed or retired). Groupmembership was the independent variable. A significantChi-square result indicated that group membership had an effecton employment status (for example, being depressed led to asignificantly greater proportion of being unemployed). Thisanalysis was performed three times, once for each domain(cognitively impaired MS versus normal cognition MS, depressed MSversus normal depression MS, and physically impaired MS versusnormal physically disabled MS).Recreational/leisure activities. The amount of leisureactivities was compared in a manner similar to the way employmentstatus was analyzed. The number of leisure activities wastotalled. The number of leisure activities was the dependentvariable whereas group membership was the independent variable.A t-test for independent groups was performed on the data to66determine whether being in the impaired group led to a decreasednumber of leisure activities undertaken. A t-test forindependent groups was computed for all three domains (cognition,depression and physical status).Outlook for the future. Finally, the contribution of groupmembership to the outlook for the future was examined for eachdomain. The level of pessimism for the future was assessed inthe same manner as in analysis II. A t-test for independentgroups compared the impaired versus the non-impaired groups ineach sphere on their pessimism for the future.Can these phenomena be independent? The final analysis willshow how the MS group breaks down into categories according towhich symptom(s) is/are experienced. The "Extent of disability"will be computed by determining what percentage of the MSpatients are 1) globally impaired (fall in the impaired range forcognition, depression and physical disability), 2) those who arein any combination of two of the three symptoms and 3) those whoare unimpaired (do not fall into the impaired range for anysymptom).In order to test independence, a Chi square analysis and Phicoefficient were computed for each combination of symptoms(Cognition and Depression; Cognition and Physical disability; andDepression and Physical disability). A high Phi coefficient was67indicative of dependence whereas a low Phi coefficient wasindicative of independence.68CHAPTER 4RESULTSSample DemographicsThe MS group was selected according to a very specific setof criteria and were comparable to the control group in terms ofdemographic variables (see Table 4.1). Controls were selected byasking the MS patient to recruit a same-sex non-relative who hada similar personal background. Of the 181 MS patients, 131(72.9%) were female, whereas 64 of the 90 normal controls (71.1%)were female. The mean age of the MS group was 36.2 (standarddeviation of 7.8 years, range 19 to 53) compared to the controlswho averaged 35.5 years (standard deviation 7.3, range 21 to 55years). The groups were almost equivalent in terms of education,with the MS group having had 13.6 years (standard deviation 2.19,range 7 to 19) in contrast to the Normal group having had 13.9years (standard deviation 2.20, range 10 to 19).The two groups were also similar on other variables. Nodifferences were found between the two groups in terms of maritalstatus (X2 (2) =3.57, p>.05). Similarly, no group differences werefound on highest level of occupational achievement (X 2 (2) =1.49,p>.05). The single variable where a difference was found wasemployment status (X 2 ( 3 )=21.7,p<.0001).69TABLE 4.1 DEMOGRAPHICS OF THE ORIGINAL SAMPLE: MS VERSUS CONTROLMS CONTROL T or X2 pAGE(SD) 36.2(7.8) 35.5(7.3) 0.69 1 NSEDUCATION(SD) 13.6(2.2) 13.9(2.2) -1.11 1 NSSEX(%FEMALE) 72.9 71.1 0.031 NSMARITAL STATUSMARRIED 109(60%) 47(52)SINGLE 34(19) 26(29)DIVORCED 38(21) 17(19) 3.57 2 NSOCCUPATIONAL STATUSPROFESSIONAL 35(19%) 23(26)SKILLED 117(65) 55(61)UNSKILLED 29(16) 12(13) 1.49 2 NSEMPLOYMENT STATUS (CURRENT)FULL TIME 96(53%) 17(79)PART TIME 38(21) 14(16)UNEMPLOYED 36(20) 2(2)RETIRED 11(6) 3(3) 21.70 2 .0001LEGEND: 1) t-test used2) Chi square used70AnalysesAnalysis I The purpose of the first analysis was to determine whether asample of MS patients who were impaired on several measures ofcognition existed and whether disease-related or demographicvariables were able to explain this impairment.The fifth percentile in the normal sample on the WordFluency test was a total score of 28 or 9.3 words per minute.Twenty percent of the MS group (37 members) scored below thisscore, and hence were classified as impaired. This percentagewas greater than could have occurred by chance (X 2 (1) =9.06,p<.003). The three resulting groups (MS Impaired, MS Normal,and the Normal Controls) were compared on the followingdemographic variables: age, education, sex, marital status,highest occupational status (while employed) and handedness. Thethree groups were not significantly different on these mentionedvariables. The resulting means with the statistical tests thatwere used are found in Table 4.2.To determine whether a number of disease-related variablessuch as age of onset, disease duration, disability status score,scores on the functional scales, number of relapses and length ofillness could account for the differences in cognitivefunctioning, the variables were compared between the two MS71TABLE4.2DEMOGRAPHICS FOR THE THREE GROUPS: COGNITIVELY IMPAIRED MS,NORMAL MS, AND NORMAL CONTROLSF or X2^pMSIMPAIREDMSNORMALNORMALCONTROLSAGE(SD)^36.5(8.3) 36.1(7.7) 35.5(7.3) .28 1 NSEDUCATION(SD)^13.0(2.1) 13.7(2.2) 13.9(2.2) 2.09 1 NSSEX (%FEMALE)^75.7 72.2 71.1 0.27 2 NSHANDEDNESS(%RIGHT) 94.6 91.6 92.2 2.14 2 NSMARITAL STATUSMARRIED^21(57%) 88(61%) 47(52)SINGLE 6(16%) 28(19%) 26(29)DIVORCED^10(27%) 28(19%) 17(19) 1.06 2 NSOCCUPATIONAL STATUSPROFESSIONAL^7(19%) 28(19%) 23(19%)SKILLED^23(62%) 94(65%) 55(61%)UNSKILLED^7(19%) 22(15%) 12(13%) 1.80 2 NSLEGEND: 1) Oneway ANOVA used2) Chi-square statistic used72subgroups. Disease-related variables are listed in Table 4.3.T-tests for independent groups revealed that the two groups werenot significantly different with respect to the above mentionedvariables. EDSS between the two groups were almost the same(t(46.9) = 1.03, p>.05), and the two groups were similar onvariables such as duration of illness (t (179) =0.38, p>.05);number of relapses (t (179) =0.46, p>.05); age of onset(t (179) =-.13, p>.05); and age at diagnosis (t (179) =0.02, p>.05).As 18 comparisons were made, the Bonferroni correction of .006(.10/18) was used.In order to validate the presence of cognitive impairment,the performance on other neuropsychological tests was examined.Using a one-way ANOVA followed with Tukey's post hoc test, thefollowing results were found (see Table 4.4 for a summary). Evenwith the Bonferroni correction of .008 (.10/13), all ANOVAs weresignificant. Of all the neuropsychological tests examined, thecognitively impaired MS group had the poorest performance on allvariables. The cognitively impaired group performedsignificantly worse than the normal MS group and the normalcontrol group on Full Scale IQ, Verbal IQ, the Word Fluency Test,Halstead Category Test and Sentence repetition while theunimpaired MS group and the normal controls did not differ onthese variables. All three groups were significantly differenton Performance IQ, and the Wechsler Paired Associates learning.However, the MS impaired group was the most deficient in bothcases. Tukey's post hoc test showed that the normal control73DISEASE-RELATED VARIABLESTABLE 4.3COGNITIVELY IMPAIRED MSFOR THEAND THE NORMAL MSt^pMSIMPAIREDMSNORMALSEVERITY(EDSS) 2.2 2.0 1.03 NSDURATION 5.4 5.1 0.38 NSNUMBER OF RELAPSES 5.0 4.7 0.46 NSAGE ONSET 26.3 26.5 -0.13 NSAGE OF DIAGNOSIS 31.1 31.0 0.02 NSKURTZKE FUNCTIONAL SCALESPYRAMIDAL 1.35 1.15 1.13 NSCEREBELLAR 0.57 0.50 0.44 NSBRAINSTEM 0.43 0.45 -0.16 NSSENSORY 0.78 0.75 0.22 NSBOWEL/BLADDER 0.54 0.50 0.32 NSVISUAL 0.54 0.55 -0.06 NSMENTAL 0.11 0.03 1.47 NS74TABLE 4.4 NEUROPSYCHOLOGICAL VARIABLES FOR COGNITIVELY IMPAIRED MS, NORMAL MS, AND NORMAL CONTROLS MS^MSIMPAIRED^NORMAL NORMAL F pFIQ 94.2 105.2 108.2 21.3 .0001VIQ 96.8 106.9 107.4 13.4 .0001PIQ 92.2 102.2 107.8 23.2 .0001WORD FLUENCY 21.8 41.0 41.8 67.6 .0001CATEGORY TEST 27.9 20.9 19.8 5.8 .0036TRAILS B-A 42.7 36.2 27.0 10.8 .0001SENTENCE REPETITION 17.4 19.2 19.5 10.6 .0001MEMORY FOR OBJECTS 11.9 12.3 12.9 6.4 .0019BENTON (ERRORS) 4.9 4.3 3.1 7.0 .0006PAIRS (TOTAL) 40.2 44.0 47.7 17.8 .0000GROOVED PEGBOARD(R) 87.1 77.9 62.4 17.8 .0001GROOVED PEGBOARD(L) 95.8 87.1 65.6 20.0 .0001GROOVED PEGBOARD(B) 73.9 64.4 50.9 20.5 .0001^ Indicates homogeneous subsets75group performed at a higher level than the other two groups onMemory for objects, Trails B-A and the Benton Visual Retentiontest. No differences for these tasks were found between the twoMS subgroups. See Figure 1 for a graphical representation of theperformance on neuropsychological tests for the three groups.In order to determine whether the cognitively impaired groupwas selected solely on the basis of poorer premorbid ability, theresults of the highest level of occupational achievement andyears of education were compared. Again, no differences werefound on these variables. These data are presented in Table4.2.The results of tests of motor/sensory ability showed thatthe normal control group performed significantly better than bothMS subgroups. Tukey's post hoc test found no differences betweenthe two MS subgroups on Grooved Pegboard Left and Right.However, using both hands, not only did the normal controlsperform significantly better than the two MS subgroups but therewas a significant difference between the two MS subgroups.Results of the above analyses are presented in Table 4.4.Analysis II The purpose of the second analysis was to determine whetherbeing cognitively impaired had any effect on the adaptability ofthe MS patient in terms of 1) vocational, 2) recreational and76-0.4coa)0Uco,i-0.8-1.2Ki-1.6Figure 1 - Neuropsychological Performance0.0 ---() ^0^0^o^-2.0o Normal controls• Normal MS• Cognitively impaired MS1^1^I^1^I^I^I^I^IWFTOT* FIQ* VIQ* PIQ** CAT TRAIL SENS MEM BVRT PAIRS**TOT* B-A*** REP* OBJ*** (E)***Neuropsychological Test* cognitively impaired significantly different than the normal MS and normal controls** all three groups significantly different from each other*** normal controls significantly different than the normal MS and cognitively impaired MS0■01■1■01.••••■■social activities. In addition, the purpose of this analysis wasto determine whether cognitive impairment was predictive of amore pessimistic future outlook.Using a Kendall's Tau, a measure of the association betweentwo variables similar to a Pearson's correlation coefficient(Howell, 1987), there was a difference in current employmentstatus among the three groups (T=0.268, p<.0001). Comparing thetwo MS groups, it was found that they did differ on their currentemployment status (T=-.142, p<.021). The MS impaired group wereless likely to be working full time (41% versus 56% of the normalMS group were employed full time) and more likely to beunemployed (32 vs 17% MS normal). See Table 4.5.The question of whether cognitive impairment interferes withsocial and recreational activities (soc/rec) was examined in twoways. The first analysis examined whether the total number ofsoc/rec activities was reduced in the cognitively impaired grouprelative to the other two groups. The results of a one-way ANOVAshowed that there was a significant difference among the threegroups (E,k2,270) =10.1, p‹.0001). Tukey's post hoc test showedthat all three groups differed from one another with thecognitively impaired participating in the lowest average numberof soc/rec activities (1.97) followed by the MS normal group(2.33) and finally an average 2.62 activities for the normalcontrol group. Again, see Table 4.5.78TABLE 4.5 VOCATIONAL/RECREATIONAL VARIABLES FOR THE COGNITIVELYIMPAIRED MS, NORMAL MS AND NORMAL CONTROLS ANALYSIS II MS^MSIMPAIRED NORMAL NORMAL^F or X2 pEMPLOYMENT STATUSFULL TIME^15(41%)^81(56)^71(79)PART TIME 7(19)^31(22)^14(16)UNEMPLOYED^12(32)^24(17) 2(2)RETIRED^3(8) 8(6)^3(3)^0.268* .000-0.142** .021TOTAL SOCIAL/RECREATIONAL ACTIVITIES NUMBER^1.97^2.33^2.62^10.11 .0001TYPEACTIVE^1(3%)^1(1)^1(1)RECREATIONAL 2(6) 5(4) 4(5)AROUND HOME^0(0)^4(3)^5(6)HOBBIES^9(25)^41(29)^20(22)SOCIAL 17(47)^57(40)^42(47)FAMILY^3(8) 16(11) 8(9)VOLUNTEER^3(8)^15(11)^6(7)TRAVEL^1(3) 2(1) 3(3)^8.25 2^NSOUTLOOK FOR THE FUTURE0.162 0.035^0.034 15.43^.005 LEGEND: 1) Oneway Anova2) Chi-square*used Kendell's tau** used Kendell's tau on the two MS subgroups^ indicate homogeneous subsets79The second way in which soc/rec activities were examined wasin the type or pattern of activities that was undertaken. A chisquare statistic found no systematic relations among each groupin terms of what types of soc/rec activities each group preferred(See Table 4.5).A reliability analysis was performed on the items of theMMPI to determine the overall accuracy of the scale usingCronbach's alpha (Kaplan & Saccuzzo, 1982). The reliabilitymeasure was computed by obtaining a correlation matrix among allitems on the scale with the estimated variance of the true scorein the numerator and the estimated variance of the true scoreplus the error variance in the denominator. Among MMPI items,correlations ranged from .07 to a maximum of .45 with an overallreliability of .28.^The low intercorrelations suggested thateach item was measuring a different domain.There are several potential reasons for this low internalconsistency. First, scales with high reliability usually havemore than 40 items (Kaplan & Saccuzzo, 1982) and second, whencorrelating two dichotomous variables with unequal marginalprobabilities, the maximum resulting correlation obtained willfall short of a 1.00 values, with more unequal splits leading toa lower maximum correlation (Comrey, 1978). Reviewing themarginal probabilities of each of the items, it was observed thatthere was great variability and furthermore, only five items wereincluded on the scale. These two facts may well be the reason80why the overall reliability of the scale was low and why thedecision was made to drop the MMPI items. Due to this lack ofinternal consistency, a decision was then made to drop all MMPIitems but retain only the interview item "what do you see foryourself for the future?". Using this interview item alone,pessimistic future outlook could be determined and was thus amore accurate measure to address the question.A one-way ANOVA showed that the MS impaired group felt morepessimistic about the future than either the MS normal or normalcontrol group (E (2,266) =5.43, p<.005). Tukey's post hoc testindicated that the MS impaired group was significantly morepessimistic than the other two groups, whereas the other twogroups were not significantly different from one another. SeeTable 4.5.Analysis III The purpose of the final analysis was to determine whetherother symptoms of the disease (for example, depression orphysical disability) may also be predictive of the social outcomemeasures discussed in the Analysis II (employment status,social/recreational activity and pessimism toward the future.Table 4.6 presents the relevant statistical information. Table4.7 summarizes the predicted and observed outcomes. Table 4.8shows the percentage of patients who are impaired on acombination of symptoms or having only one symptom or alternately81TABLE 4.6 VOCATIONAL/RECREATIONAL VARIABLES FOR THE COGNITIVELY IMPAIREDMS, COGNITIVELY NORMAL MS, DEPRESSED MS, NON-DEPRESSED MS, PHYSICALLY DISABLED MS, AND NON-PHYSICALLY DISABLED MS. ANALYSIS III GROUP MEMBERSHIPIMPAIRED NORMAL TOTALCOGNITIONDEPRESSIONPHYSICAL DISABILITY373834144143147181181181EMPLOYMENT STATUSIMPAIRED NORMAL X2COGNITION 60/40* 78/22 4.23 .034DEPRESSION 58/42 78/22 5.50 .019PHYSICAL DISABILITY 62/38 77/23 2.54 NS*(WORKING/NON-WORKING)LEISURE ACTIVITIESIMPAIRED NORMALCOGNITION 1.97 2.33 -2.69 .004DEPRESSION 2.05 2.31 -1.94 .027PHYSICAL DISABILITY 2.06 2.30 -1.65 NSOUTLOOK FOR THE FUTUREIMPAIRED NORMALCOGNITION 0.16 0.03 2.01 .026DEPRESSION 0.13 0.04 1.54 NSPHYSICAL DISABILITY 0.11 0.04 1.19 NS82TABLE 4.7 PREDICTED AND OBSERVED RESULTS OF THE EFFECTS OF COGNITIVE IMPAIRMENT, DEPRESSIONAND PHYSICAL DISABILITY ON VOCATIONAL AND RECREATIONAL ACTIVITIES ANALYSIS III INDEPENDENT MEASURESDEPENDENTMEASURESEMPLOYMENTSTATUSLEISUREACTIVITIESOUTLOOKFOR FUTURETOTALCOGNITIVE^PHYSICAL^ DEPRESSIONIMPAIRMENT DISABILITY (EDSS)+/+ +/ - +/++/+ -/ - -/++/+ - / - + / -3/3 \^3/3^1/3 \ 0/3^ 2/3 \ 2/3( + = Effect)( - = No Effect)(Expected / Observed)TABLE 4.8 GROUP MEMBERSHIPEXTENT TOTAL PERCENTAGEGLOBAL 2 1.1%COGNITION &DEPRESSION 6 3.3%COGNITION &PHYSICAL DISABILITY 6 3.3%DEPRESSION &PHYSICAL DISABILITY 6 3.3%PHYSICAL DISABILITY 20 11.0%DEPRESSION 24 13.3%COGNITION 23 12.7%NO IMPAIRMENT 94 51.9%84not being in the impaired range on any of the symptoms.The percentage of the MS group who fell in the depressedrange according to the 95th percentile criterion was establishedas was the percentage falling beyond the 90th percentile on theEDSS. Thirty eight of the 181 MS patients were shown to be inthe depressed range using the 95th percentile procedure on thescores of the Beck Depression Inventory. The cutting score wasfound to be 11. A score of this magnitude would be indicative ofmoderate depression (Beck et al., 1961). Any MS patient whoobtained a score of 12 or greater on the BDI was placed in the"depressed" group. The BDI scores for the depressed group rangedfrom 12 to a maximum of 36. A chi square statistic determinedthat the number of MS patients in the depressed range wasunlikely to have occurred by chance alone (X 2 (1) =10.94, p<.001).Thirty four (19%) of the 181 MS patients were found to be in thephysically disabled range, which was determined by having an EDSSof greater than 3.5. The EDSS scores for the physically disabledgroup ranged from 3.5 to 6.0. As no data were available for thenormals on the EDSS, a similar check to see whether more MSpatients fell in this group than would be expected by chance,could not be done. Table 4.9 gives the mean scores on criterionmeasures for the three impaired groups and the normal controls.For each symptom of MS (cognition, depression and physicaldisability), the impaired and the normal MS groups were compared85TABLE 4.9 MEAN SCORES ON CRITERION MEASURES FOR COGNITIVELY IMPAIREDMS, DEPRESSED MS AND NORMAL CONTROLS NWORDFLUENCYTESTBECKDEPRESSIONINVENTORYKURTZKEEDSSCOGNITIVEIMPAIRMENT 37 21.8(^4.5) 7.9(7.9) 2.3(1.5)DEPRESSION 38 36.8(11.7) 16.2(4.9) 2.3(1.1)PHYSICALDISABILITY 34 34.4(11.9) 8.9(7.6) 3.9(0.7)TOTAL MSGROUP 181 37.1(11.9) 7.5(5.8) 2.0(1.2)NORMALCONTROLS 90 41.8(10.4) 3.5(3.7) N/A86on employment status and the data are presented in Table 4.6. Itwas predicted that each symptom should have an effect on theemployment status. Chi square statistics showed that cognitiveimpairment and depression both had an effect (X 2 (1) =4.23, p<.040for cognition; X2 (1) =5.50, R<.019 for depression) while physicaldisability had no effect (X2 (1) =2.54, p>.05).The same procedure for social/recreational activities(soc/rec) was done for each of the three symptoms of MS. Thepredicted outcome was that only impaired cognition should have aneffect on soc/rec. However, these predictions were not entirelysupported with a t-test for independent groups. Since apredictive model was used, a one-tailed t-test was employed. Forcognition, a significant result was found using a t-test forindependent groups (t (179) =-2.69, p=.004). Therefore, cognitiveimpairment does affect the total number of leisure activities aperson undertakes. Depression also had an effect: t (179) =-1.94,R=.027. A trend towards significance was found for physicaldisability in terms of the number of soc/rec an MS patientundertakes (t (179) =-1.65, p>.05).As previously stated, another purpose of this analysis wasto determine which of the MS symptoms were more likely to lead toa pessimistic outlook for the future. It was predicted that bothdepression and cognition would have an effect on the patient'soutlook for the future. However, this analysis showed thatwhile cognitive impairment impacts on a person's outlook,87depression and physical disability do not: (Cognition:t(40.57) =2.01,p=.026; Depression: t (44) =1.54, p>.05; Physicaldisability: t (39.75) =1.19, p>.05). A one-tailed t-test was againemployed.By adding up the number of positive effects for eachsymptom, a rough estimate can be made as to which symptom is mostsocially disabling for the MS patient. As can be seen from Table4.7, impaired cognition results in all three measures of socialdisability (3/3) being affected, while physical disability leadsto no effect (0/0) and depression leads to two of the three (2/3)measures being affected.The final analysis attempted to determine whether thesesymptoms can occur separately, or in any combination. Theresults, found in Table 4.8, show that more than half the MSpatients (51.9%) did not fall in the impaired range for any ofthe symptoms. Roughly one percent of the MS sample can beclassified as globally impaired (in the impaired range in allthree symptoms) and a relatively equal percentage are onlyimpaired on one symptom (12.7, 13.3 and 11.0% respectively forcognition, depression and physical disability). Eighteen of the181 (9.9%) MS patients fell in the impaired range in acombination of two symptoms. Three and one third percent (3.3%)were in the impaired range for cognition and depression, the samepercentage were in the impaired range for depression and physical88disability and a further 3.3% were in the impaired range forcognition and physical disability.Phi coefficients were computed for each combination ofsymptoms. A Phi coefficient is a measure of associationperformed on two dichotomous variables and thus is similar to aPearson correlation (Howell, 1987). The observed coefficientswere:cognition and depression: .01; cognition and physicaldisability: .04: and depression and physical disability: .03.89CHAPTER FIVEDISCUSSIONS AND CONCLUSIONSPrecautions Interpreting the Results of This StudyBefore discussing the results of this study, a number ofmethodological issues should be addressed. The first issue issampling and subsequent generalization. When designing thecurrent study, specific criteria were used so that any founddifferences could be attributed to the effects of MS, not otherpotentially confounding variables. Only patients diagnosed withclinically definite MS with a R/R disease course and mildphysical disability were accepted into the study. To ensure ahigh degree of diagnostic certainty, the Poser et al. (1983)criteria were used for diagnosis. In addition, only patients whowere diagnosed before the age of 40 were included, to furtherreduce the possibility of including patients with atypical MS.To avoid confusing the effects of active disease progression andrelapse-related variables such as anxiety or depression, patientswere tested in remission. Furthermore, only patients with mildMS (EDSS <6.0) were chosen to limit the motor/sensory problemswhich might interfere with cognitive test performance. Finally,all patients were less than 50 years old upon entry into thestudy to minimize the effects of aging.Exclusion criteria were also strictly enforced so tominimize confounds. No patient was accepted into the study with90any medical problems concurrent with MS. This criteria ensuredthat other problems could not be used as explanations for anyobserved results. Another exclusion criteria stated that apatient with a psychiatric problem predating their diagnosis wasnot included. This restriction ensured that if a subject had apsychiatric diagnosis, it may have been a result of MS. Inaddition, no subject took part in the study if they werecurrently on any prescribed medication that had any potentialcentral nervous system effects. Some MS therapies can have apotentiating effects on mood or cognition. If it were deemedappropriate, patients medicated with certain drugs were permittedin the study after a one week wash out period. In addition, nosubject took part in the study who had a history of excessiverecreational drug use (more than once a week). Finally, if apotential subject had had any previous neuropsychologicalassessment, the patient was not included. When applicable, thenormal controls had to meet these criteria. Hence, any observeddifferences between this sample of MS patients and the controlgroup are most likely due to MS.The resulting sample had relatively benign physicaldisability while potential confounding variables were minimized.However, by employing strict sampling criteria, the deleteriouseffects of MS may be underestimated. For example, those patientswho are in the midst of a relapse might likely be more depressed(Cleeland et al., 1970) and may be less likely to be doing socialand recreational activities. In addition, by excluding patients91who had psychiatric disorders predating the onset of the disease,patients where the first manifestations of the disease wereconsidered as psychiatric problems would be excluded. Thisgroup, in all probability, would have been impaired on measuresof social activity. Hence, any differences that are found in themild, stable form of the disease can only be assumed tounderestimate the effect size for the MS patients.Related to the sampling and generalization issue is thepotential problem of whether the population from which the samplewas drawn is representative of the population of MS patients ingeneral. In their paper on external validity of experiment,Bracht and Glass (1968) discuss the difference between theexperimentally accessible population versus the targetpopulation. They define the experimentally accessible populationas the population of subjects available to the experimenterand the target population as the population of subjects aboutwhom the experimenter is interested to generalize the findings.The current study uses a clinic based sample. The use of thistype of sample may be biased in terms of a different type ofpatient selection.^For example patients who are aware of theirproblems and see the need for treatment may be more likely to usethe MS clinic. Rao et al. (1991a) have suggested that a sampledrawn from a local MS society may be more representative of theentire MS population. Nelson, Franklin, Botelier, Baum and Burks(1988) have also suggested that University based samples mayunder represent those patients who experience a milder course.92However, they found that there were no differences in employmentstatus between a clinic based sample and the "general population"of MS patients. Hence, although the experimentally accessiblepopulation used in this investigation may not be representativeof the entire MS population, the bias, if present, in allprobability underestimates the degree of social disability.The second issue of concern is whether the control group wassuitable for the research question. Clearly in a static groupdesign there is no perfect control group. The "normal" controlis often used in MS research but lacks the elements of medicationeffects, hospitalization and the effects of having a chronic,disabling disease (Rao, 1986). Other control groups have beenused such as patients with Huntington's disease (Caine et al,1986), chronic pain (Rao & Hammeke, 1984), Muscular dystrophy(Jambor,1969) and brain damaged (Ross & Reitan, 1955). Each typeof control group has its own strengths and drawbacks forpotential research strategies depending on the hypothesis inquestion. The control group used in this study was selected forminimal confounds. Since the MS patients provided their owncontrols (each patient was asked to recruit a person who wascomparable in background), the two groups were similar indemographic variables. As the research question was to whatextent MS was interfering with the lives of the patients, notwhether the effects of MS are different from other neurologicaldisorders, a normal control group was appropriate.93The third issue to be addressed are the potentiallyconfounding variables of instrumentation and fatigue. First, theMS patient and his or her control were tested on the same day,throughout the four years of the study. Therefore if any of thetesting instruments changed over time (i.e. deterioration of thetape recording instruments, sensitivity of the interviewer), bothgroups should have been affected equally. Secondly, fatigue hasbeen suggested as a possible reason for lower scores onneuropsychological tests. This potential confound was controlledby varying the order of presentation of tests and havingpredetermined rest breaks for all subjects. Furthermore, MSpatients perform as well as normals on certain ability tests suchas verbally mediated material but do considerably worse on othertests (i.e. memory and constructional functions). If fatiguewere the underlying reason for cognitive problems in MS, thendeficits should be observed on all tests. Hence, it is unlikelythat either fatigue or instrumentation problems could explain thedeficits on neuropsychological or social activitymeasures.A fourth precaution in the interpretation of the results ofthis study is the issue the overall type I or experiment wiseerror rate. Any time a large number of significance tests areperformed, the probability of finding one or more significanteffects just by chance is increased. The major question in thisexperiment was to what extent each of the symptoms of MS wereaffecting the social life of the patient and a total of nine94significance tests were done to address this question. All othertests of significance were performed to validate theappropriateness of the grouping procedures. Hence, whencalculating the experiment wise error rate, only the crucial ninetests of significance were included with p=.05 as the contrast-wise error rate.^The overall alpha was calculated as .37 usingthe Tukey's method (Howell, 1987).A related question is whether in this study it is moredetrimental to make a type I error (finding a significant effectwhen none exists) or a type II error (failing to find an effectwhen one does exist). In a study such as this, it would be worseto make a type II error and, for example, conclude thatcognitive impairment has no effect on social enjoyment andemployment status. One way of counteracting a high falsepositive rate is to decrease the per comparison alphas. However,by doing this procedure, the type II error rate increases.Furthermore, by examining the group by group effects found in thecurrent study, it is fairly unlikely that both depression effectsoccurred just by chance and even more unlikely that all threecognition effects were artifacts. Therefore, the experiment wiseerror rate may be indicative of one or more false positiveresults, however, a type I error is preferable in this type ofresearch.95The final issue to be discussed is the definition ofdepression. In the current study, depression was defined as anelevation of self reported depressive symptoms on the BeckDepression Inventory (BDI) relative to the normal controls.Those MS patients who scored in the high end of the BDI scalewere labelled "depressed". The mean score for the depressedgroup is 16.2 which is in strong contrast to the non-depressedgroup who had an average of 5.1 and the normal controls with amean score of 3.5. According to the guidelines set by theinstrument (Beck et al., 1961), a score of 16 would be indicativeof moderately severe depression. Although the definition ofdepression used in the current study is not equivalent to thepsychiatric diagnosis of depression, it is consistent withdepressed mood.SignificanceFindingsThe purpose of the first analysis was to determine whether agroup of MS patients who were cognitively impaired could beidentified. The results of this analysis suggest that thereexists a subsample of mild, R/R MS patients who are cognitivelyimpaired. The impairment experienced by these people is a wideranging deficit, affecting many different functions includingmemory, abstraction ability, reasoning, general intelligence,visuomotor tracking and information processing efficiency. The96results of the first analysis also suggest that neitherdemographic factors nor neurological factors could account forthe cognitive impairment in this group. These results areconsistent with the more recent literature on the subject ofcognitive loss in early MS. Cognitive deficits have beenreported in early MS (van den Burg et al., 1987; Beatty et al.,1989) and in patients with R/R disease course (Heaton et al.,1985; Klonoff et al., 1991).The results also suggests that cognitive impairment may bean independent phenomenon from physical disability andmotor/sensory losses. Specifically, even in the absence ofsevere physical disability (the MS impaired group had an averageEDSS score of 2.2 while the normal MS group's mean was 2.0),impairments in cognitive functioning were found. Nor doesperformance on motor/sensory tasks seem to be predictive ofcognitive functioning. Inconsistent results have been reportedin the literature regarding the relationship between cognitiveimpairment and extent of physical disability. Some researchershave found a weak correlation between the two (Beatty & Gange,1977; Surridge, 1969; Stenager et al., 1989), while others havefound no relation (Franklin et al. 1989; van den Burg et al.,1987; Rao et al., 1984; Lyon-Caen et al., 1986). The results ofthis study support the latter finding of no strong relationbetween cognitive impairment and physical disability.97The mathematical reasons for the inconsistencies in theliterature regarding the relation between severity of illness andstatus of cognitive functioning have been discussed in chapter 2.A more common sense explanation for these discrepancies may befound by examining lesion distribution. Given the nature of thedisease, lesions may occur at any given site. Depending on thelocation and size of the lesion, different patterns of deficitsmay occur. For example, a MS patient with lesions only in thespinal cord may have severe physical disability, but since thecortex is spared, the disease may have no impact on his/hercognitive functioning. Similarly, a patient without lesions inthe motor/sensory areas, but with lesions in other areas of thecortex may have the opposite pattern of deficits. Although theabove assertion has not been formally tested in the literature,there is some evidence to suggest that a subsample of patientsmay have predominantly spinal cord lesions early in the diseasecourse.The two MS groups did not differ from one another on the"mentation" functional scale (a measure of cognitivedysfunction), an outcome which was not consistent with theresults of the neuropsychological investigation. The mentationscore is graded on a continuum from 0 (normal) to 5 (dementia orchronic brain syndrome). The cognitively impaired group had anaverage score of 0.11 while the cognitively normal MS group hadan mean score of 0.03, both scores translating into essentiallynormal mental status (a score of 1 is given when there is98evidence of mild alteration of mood). Scores on the mentationscale were not significantly different between the two MSsubgroups. However, using a more comprehensive examination, onegroup would be categorized as having problems in cognition.Hence, using more sensitive techniques to assess the presence orabsence of impaired cognition, a higher, and possibly moreaccurate, estimate of the status of cognitive functioning isfound than with the mentation score. These results are inagreement with those of Peyser et al. (1980) who reported morepatients with cognitive impairment were found with acomprehensive neuropsychological battery than with a standardneurological exam.The purpose of the second analysis was to determine whetherbeing cognitively impaired lead to a decrease in psychosocialfunctioning. The results of this analysis suggest that cognitiveimpairment is related to a decrease in social, vocational andrecreational activities relative to a group of MS patients whoare not cognitively impaired and a group of normal controls.The findings indicate those patients who are experiencingcognitive problems are more likely to be unemployed or workingpart time, less likely to be engaging in social or recreationalactivities and more likely to be pessimistic about the future.However, there does not seem to be an effect on the kinds ofsocial and recreational activities undertaken by members thisgroup relative to the other groups. These findings suggest that99cognitive impairment may be interfering with MS patients' abilityto carry on normal life activities.In their small sample of minimally physically impaired MSpatients, Franklin et al. (1989) found that two thirds werecognitively impaired to such a degree that these people weresignificantly functionally disabled at work or at home. Rao etal. (1991b) found that being cognitively impaired was mostdisabling in terms of remaining employed and socially andrecreationally active. The above findings are reinforced by theresults of the current study.The third analysis was performed to determine whethercognitive impairment, depression, or physical disability wasmore predictive of social disability. Cognitive impairment wasfound to be the most handicapping for these MS patient, leadingto a significant decline in the ability to remain in the workforce, more problems maintaining the same level of social andrecreational activities and a reduction of the level of optimismtowards the future. These results are consistent with thefindings of Rao et al. (1991b) and Franklin et al. (1989).The results of the current study found that being depressedwas detrimental to the ability to remain active in the work forceand to the number of leisure activities undertaken. The findingsof the current study also indicate that physical disability didnot lead to a decrease in any of the social outcome measures.100The average EDSS for the physically disabled group was 3.9, whichtranslates into being fully ambulatory without aid with onefunctional system a grade 4 (Kurtzke, 1983). Therefore, in themild stages of MS, physical disability per se does not appear tobe as disabling as cognitive impairment and depression. However,as physical disability increases, the associated negative effectswould likely become more apparent.The results of the Analysis III also suggest that, due tothe nominal Phi coefficients that were observed, impairmentin each of the symptoms can be independent. Although there wassome overlap in terms of group membership, the majority ofsubjects were either unimpaired (51.9%) or impaired on only onesymptom (37%). This finding is consonant the more recentliterature on the relationship among cognitive impairment,depression, and physical disability (Rao et al., 1991a; Minden,Orav & Reicht, 1989).Cardinal FindingsThe cardinal findings of this study are three-fold. First,a group of MS patients who were cognitively impaired relative tothe normal sample were found. Similarly, a group of patients whowere depressed were also identified. These two groups were foundeven though the sample was comprised of young, early, mild, R/RMS patients. A third group was defined based on the degree ofphysical disability. Second, the three symptoms seem to be101relatively independent. Third, cognitive impairment seemed to bemost debilitating in terms of maintaining employment andremaining socially and recreationally active. Depression seemsto be the next most disabling followed by physical disabilitywhich, at this mild stage, did not seem to have any palpableeffects on vocational and recreational activity.ImplicationsThere are three main themes of this project which haveimplications for clinical use. First, because estimates ofcognitive and affective functioning are needed to plan realisticlife goals for the patient and family, all patients shouldundergo a comprehensive neuropsychological examination (asopposed to a brief mental status exam or neurological assessmentof cognitive function) as well as an assessment for the level ofdepression early in the course of the disease. Second, sincecognitive impairment, depression and physical disability can beindependent phenomena in mild R/R MS, successful treatment of onesymptom (i.e. depression) does not necessarily lead to a decreasein other areas (i.e. cognition). Finally, each of the threesymptoms of MS can contribute to social disability, however, someappear to be more handicapping than others.102Neuropsychological Assessment and Level of DepressionThe first clinical implication to be discussed is the needfor the MS patient to undergo an in-depth neuropsychologicalassessment, including a determination of their level ofdepression. Hashimoto and Paty (1986) discuss the ethicaldilemma involved in discussing the potential problems of MS whenspeaking to patients about their diagnosis. They state thatthere has been a tendency in medicine to "protect" the patientfrom the harsh realities of the disease. In some cases, thepatient's neuropsychological status is a sensitive issue, andsome patients may not wish to know their status. Furthermore,the clinician who focuses on cognitive and affective problems maycreate an unwarranted anxiety for the patient and family.However, if the potential problems associated with MS are notaddressed, the patient's family, employer, or others mayinappropriately attribute the patient's forgetfulness orinability to make decisions as an attempt for attention orsympathy rather than to the disease. Hence, an accurateassessment of cognitive functioning is crucial to supplypotentially valuable information for patients and others to planrealistic life goals.Complete neuropsychological assessment can be timeconsuming, expensive and tiring. Neurological examinations ofmental processes, on the other hand, are quick, easy toadminister and relatively inexpensive. However, the current103study indicated that mental status examinations may not besensitive enough to detect the cognitive problems experienced bythe MS patient, a conclusion that others have drawn as well(Peyser et al., 1980). Hence, for adequate knowledge of how MSis affecting the patient, neuropsychological assessment with anextensive battery of cognitive tests is crucial.In addition to neuropsychological assessment, determiningthe level of depression in the mild MS patient can provideinformation for patients, family members and others with respectto the emotional changes that may be occurring. A quick selfreport measure may be all that is needed. However, some of thepopular depression inventories contain items which are indicativeof somatic body complaints common in MS and could be mistaken forsymptoms of depression. Therefore, care should be taken in thechoice of such measures and in the analysis of the final result.Nevertheless, assessment of the level of depression is criticalfor understanding how the disease is affecting the individual MSpatient.Depending upon the results of the assessment of cognitiveimpairment or depression, the choice of treatments will beinfluenced. Some MS treatments are known to cause mood andcognition related side effects. For example, methyl prednisone,an anti inflammatory drug used to control acute exacerbations, ismore likely to cause euphoric side effects (Williams, 1981).However, in severe cases or upon withdrawal of the drug,104depression has been noted (Williams, 1981) and a clinician maydecide not to treat a depressed patient with this drug. Inaddition, both Baclophen (anti-spastic) and ditropan(anticholinergic for bladder control), two drugs commonly used inMS, have been reported to induce cognitive side effects (CanadianPharmaceutical Association, 1989). The potential for reducedalertness may be even more problematic for the MS patientcurrently experiencing cognitive problems. Therefore, it isimportant to assess cognitive and affective functioning and toincorporate these results into the determination of a treatmentplan.Independence of PhenomenaThe second implication of this study is related to thefinding of the relative independence of the three symptoms:cognitive impairment, depression and physical disability.Although these symptoms can exist together in the same patient,the current study suggests that they are not causally related.The implication that follows is that impairment in one symptom,does not necessarily predict impairments in other symptoms.The independence of the three symptoms is an importantfactor to consider when establishing rehabilitative programs forthe MS patient. For example, if a patient with both depressedmood and cognitive problems is seen by a therapist, the clinicianmay assume that the cognitive problems are a result of the105depression, and thus, can be alleviated by treating thedepression. However, by merely treating the depressed mood, theproblems in cognition may not be helped. Similarly, depressionin MS has been suggested as a reaction to the loss of physicalfunction and is frequently left untreated. Antidepressanttherapy (the treatment of choice for endogenous depression)however, has been found to be beneficial for the depressed MSpatient. Therefore, by recognizing that all three problems arenot likely causally related, each of the symptoms can be treatedindividually and the MS patient may benefit optimally fromhis/her rehabilitative program.Differential Effects on Social AbilityThe final implication of this study relates to thedifferential effects of each of the three symptoms onpsychosocial functioning. The results of this study should makethose associated with MS patients aware of the potentialpsychosocial adaptation problems which can be related tosymptomatological impairments outlined above. The MS literaturedealing with the effects of impaired cognition, depression andphysical disability on social and vocational handicap is limitedto studies concerning the effects of one symptom withoutadequately investigating the relative effects of each. Hence,the current study makes an important contribution to the field.106Clearly, the symptoms focussed on in the present studycontribute in varying degrees to the social disabilityexperienced by the patient. It is therefore critical for theclinician to acknowledge the existence of and potential problemsassociated with each symptom. Instead of prescribing treatmentplans based on physical problems, rehabilitative energy should bespent on problems associated with cognitive and affectivechanges. For example, the effect size of cognitive impairment onvocational status could be decreased by teaching cognitiveretraining techniques (i.e. memory enhancement). Whether thepatient can remain employed, but by taking on a less mentallychallenging position, is an alternative that could beinvestigated. In terms of leisure activities, life-style changescould be made to lessen the impact of cognitive impairment onultimate life satisfaction. If the patient is depressed,antidepressant therapy has been shown to have modest beneficialeffects in MS (Schiffer & Wineman, 1990) and may therefore besuccessful in maintaining premorbid levels of social andrecreational activity as well as employment status.Ideas for future researchThe results of this study suggest that cognitive impairmentmay be the most disabling aspect of the disease in the earlystages. Longitudinal assessment of these MS patients can givevery important information about the disease progression. Onequestion that could be asked is whether cognitive functions in107the identified group of cognitively impaired MS patients continueto decline with disease progression. For those patients who aredepressed early in the disease, does their depression tend to getworse later in the disease or can their depression lessen? Withrespect to social outcome measures, later in the disease, iscognitive dysfunction the most handicapping of the symptoms ofMS? Can the phenomena (cognitive impairment, depression andphysical disability) still be independent later in the diseasecourse? All these questions could be addressed using alongitudinal approach.The results of this study suggest that perhaps measures ofsocial disability could provide an informative benchmark in orderto measure treatment effectiveness. For example a hypotheticalcase study could be as follows. A moderately depressed patientis tried on an antidepressant medication. After a period oftime, this person's progress is monitored. A decrease of 4points is seen on the BDI (which brings her score from 19 to 15,still in the moderately depressed range). However, beforebeginning the treatment, this person was only working part time.After treatment, this person has increased her work load to threequarter time and is beginning to regain previous levels ofsocial functioning. The social outcome measure is much moreinteresting and informative in terms of therapeutic success thanthe 4 point drop on the BDI. A future study might use socialoutcome measures as an estimate of the successfulness of aparticular therapy. For example by teaching cognitive coping108skills (i.e. memory enhancement techniques) to a group of MSpatients who are cognitively impaired, an assessment of thetherapeutic intervention could be made in terms of the certainspecific social outcome measures.Another interesting question to ask is whether there is acommon underlying lesion or lesion pattern for each of thesymptom groups. For instance, does the cognitively impairedgroup have a different layout of lesions than does the depressedgroup or the physically disabled group? 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