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Patterns of cognitive impairment in multiple sclerosis and their relationship to neuropathology on magnetic… Ryan, Lee 1993

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We accept this thesis as conformingto the required standardPATTERNS OF COGNITIVE IMPAIRMENT IN MULTIPLE SCLEROSISAND THEIR RELATIONSHIP TO NEUROPATHOLOGYON MAGNETIC RESONANCE IMAGINGbyLEE RYANB.Mus., The University of Toronto, 1979B.Sc., The University of Toronto, 1988M.A., The University of British Columbia, 1989A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF PHILOSOPHYinTHE FACULTY OF GRADUATE STUDIESDepartment of PsychologyTHE UNIVERSITY OF BRITISH COLUMBIAAugust 1993copyright Lee Ryan, 1993In 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 P ci10/0 y The University of British ColumbiaVancouver, CanadaDate^dit.si- 0.26,1 093DE-6 (2/88)AbstractRecent reviews (Peyser & Poser, 1986; Rao, 1986) suggest that Multiple Sclerosis resultsin cognitive impairments in the areas of learning and memory, abstract reasoning,information processing efficiency, and, often, visual-spatial ability. Whether this patternapplies to the individual with MS is unclear. Due to the disseminated distribution of MSneuropathology, patients may undergo idiosyncratic cognitive changes dependent upon thesite of white matter lesions. The present study explored this question using clusteranalysis on the neuropsychological data from a group of mildly disabled MS patients(n = 177) and a well-matched control group (n=89). In a group of MS patients who wereidentified with unequivocal cognitive impairment, the resultant clusters indicated that MSdoes not result in a characteristic pattern of impairment. Two clusters were obtained thatresembled the pattern described in the literature, while the majority of patients clusteredinto groups with specific deficits in one or two areas, with normal performance in others.In order to identify associations between cluster groups and lesion sites, frequency tableswere constructed for the presence of a lesion on Magnetic Resonance Imaging in 24 brainsites. An association was obtained between two lesion sites and two cognitive tests.Visual-spatial impairment, as assessed by the Benton Visual Retention test, was associatedwith lesions in the genu of the corpus callosum and with more lesions throughout thecorpus callosum. Impaired performance on Paired Associates, a test of learning andmemory for novel verbal associations, was associated with a lesion in the deep whitematter of the left parietal lobe. The results support the hypothesis that MS results inmultiple patterns of cognitive impairment depending on the individual placement of whitematter lesions. Identifying and characterizing the heterogeneity of the impairment maygreatly increase our understanding of the role of myelin in cognition and the functions ofwhite matter tracts in the brain.Table of ContentsAbstractTable of ContentsList of TablesList of Figures^ viChapter One Introduction^ 1Cognitive Changes in MS^ 2The Pattern of Impairment in MS^4Neuropathological Correlates 6Present Study^ 8Chapter Two Neurological and Clinical Aspects of MS^10Clinical Aspects^ 10Epidemiology and Genetics 13Neuropathology and Pathophysiology^15Pathogenesis of MS^ 17Diagnostic Tests 18Diagnostic Criteria 23Disability Assessment^ 24Chapter Three Neuropsychological Functioning in MS^26Early Studies of Intellectual Functioning^26Characterization of the Impairment: 1980 to Present 29Prevalence of Cognitive Impairment^37Correlates of Cognitive Impairment 38Patterns of Cognitive Impairment 40Conclusion^ 42Chapter Four Neuropathological Correlates of Cognitive Impairment^44Emotional Functioning^ 44Disease Variables 44Cognitive Impairment 45Lesion Placement: Role of the Corpus Callosum^48Other Imaging Techniques^ 49Summary and Future Directions 51Chapter Five Methods^ 55Subjects and Test Procedures^55Cognitive Test Battery and Analyses^56Magnetic Resonance Imaging and Cognitive Deficits 62ivChapter Six Results^ 67Demographics^ 67Neuropsychological Battery Descriptive Statistics 68Incidence of Impairment^ 68Cluster Analysis Results 69Description of the Clusters 71Validation of Cluster Patterns^73Alternative Validation Approach 77MRI Results^ 77Chapter Seven Discussion^ 81Future Directions in MS Research^86Appendix A The Extended Disability Status Scaleand Functional Systems Scales^ 89Appendix B Description of Neuropsychological Test Battery^92Appendix CReferencesTablesFiguresLesion Sites Associated with Verbal Fluency,Memory, and Visual-Spatial Functions^97102117134List of TablesTable 1^Expected frequency values of lesions for ahypothetical lesion site with a baserate of 10%.^118Table 2^Chi square values and resultant p values for hypotheticalgroup data varying lesion baserate and percentage oflesion occurrence.^ 119Table 3^Demographic variables. 120Table 4^Disease variables and neurological data for the MS patients. 121Table 5^Means, standard deviations, and statistical tests for MS andcontrol subjects on the neuropsychological test battery.^122Table 6^Percentage of MS patients with scores below the 5thpercentile of the normative sample on the tests.^123Table 7^Frequency of impaired test scores for subjects in the MSand control groups.^ 124Table 8^Demographic and disease characteristics for the MSsubjects in the impaired cluster groups.^125Table 9^Ratio of control to MS subjects in the 10 impaired clusters. 126Table 10^Intertest correlations between the clustering and validationtests computed separately for the impaired and unimpairedclusters.^ 127Table 11^Mean standardized scores for the impaired groups on theclustering and validation tests.^ 128Table 12^Percentage of MS and controls with a lesion in each of50 brain sites.^ 129Table 13^Mean number of total lesions for the impaired clusters.^131Table 14^Percentage of subjects in the impaired cluster groupswith a lesion present in the genu and the deep white leftparietal region.^ 132Table 15^Frequency table for lesions in the genu and deep whiteleft parietal region for the reconstructed MS groups.^133List of FiguresFigure 1^Cognitive profiles for the impaired clusters.^134Figure 2^Cognitive profiles for the unimpaired clusters.^135Figure 3^Profiles for MS patients from three unimpaired clusterswith an over-representation of MS patients.^136Figure 4^Profiles for the five impaired clusters on the clustering testscompared with profiles on the validation tests.^137Figure 5^Profiles for the ten unimpaired clusters on the clusteringtests compared with profiles on the validation tests.^138vi1Chapter 1IntroductionCurrent understanding of brain and behaviour relationships derives predominantlyfrom knowledge of the effects of cortical or grey matter lesions. Recent research hasextended this knowledge to include the cognitive sequelae of diseases that affectsubcortical or deep grey regions of the brain, such as Parkinson's Disease and Huntington'sDisease (Saint-Cyr, Taylor, & Lang, 1988). Relatively little is known, however, about therole of myelin in cognitive functioning. Indeed, many of the diseases associated withdementia such as Alzheimer's and Huntington's can result in extensive lesions to whitematter. Multiple Sclerosis (MS) is of particular interest to cognitive psychologists becauseof the nature of its neuropathology. MS is characterized by the destruction of myelin, thewhite substance that protects and insulates axons. Myelination is an important parameterin the regional maturation of the nervous system. The myelination of functionally alliedsystems of fibres is synchronized in an orderly sequence and tempo (Yakovlev & Lecours,1967). Since this process continues well into the years of maturity, myelination may playan essential role in plasticity of brain organization as new experiences are integrated.Research into the cognitive sequelae of MS may provide insight into the role of neuronalmyelin in cognition.MS is a progressive disease of unknown etiology affecting the central nervoussystem. It results in multiple focal areas of demyelination, with virtual sparing of corticalneurons until late in the disease process (Waxman, 1982). For the majority of patients,MS manifests itself as recurrent attacks of physical symptoms lasting anywhere from a fewminutes to several weeks with intervening periods of remission. Prominent symptomsinclude generalized muscle weakness, proprioceptive sensory loss, and impairment in fine2motor coordination. For a given individual, the symptom pattern, course, and outcome ofMS is extremely variable, making diagnosis and prognosis difficult.Cognitive Changes in MSCognitive and emotional changes accompanying MS were acknowledged as farback as Charcot's lectures on the disease in 1877 (cited in Peyser & Poser, 1986). Earlyresearchers noted emotional changes including depression, lability, euphoria, and denial,together with a general loss of intellectual ability (e.g. Cottrell & Wilson, 1926; Moxon,1875). These changes, however, were considered a rare and relatively unimportantfeature of MS, and if present, were assumed to occur only in later stages of the diseaseprocess when neuronal degeneration was extensive. MS continues to be described in theneurology literature almost exclusively as a motor/sensory disease (e.g., Hashimoto &Paty, 1986; Kandel & Schwartz, 1985; McKahn, 1982).Recent investigations have established that MS may result in impairment on avariety of neuropsychological and intellectual tests. Impairment is not confined to latestages of the disease, but is evident in a substantial number of patients in relatively early ormild stages. In samples of patients with little functional disability, no current exacerbationof symptoms, and in whom no cognitive decline is evident on neurological examination,the incidence of impairment ranges from 30% to 50% (Ivnik, 1978; Klonoff, Clark, Oger,Paty, & Li, 1991). Indeed, for some patients, difficulty in memory and concentration maybe the earliest and most prominent complaint (Young, Saunders, & Ponsford, 1976).Counterintuitively, the severity of impairment correlates poorly, if at all, with measuresassumed to reflect severity of pathology, including degree of disability, age at diagnosis,years since onset of symptoms, or number of relapses (Baumhefner et al., 1990; Huber etal., 1987; Rao et al., 1985). The impairment is not adequately accounted for bypsychological distress associated with chronic disease or other psychiatric conditions suchas depression (Good, Clark, Oger, Paty, & Klonoff, 1992; Jambor, 1969; Peyser,Edwards, Poser, & Filskov, 1980).3Recent reviews (Peyser & Poser, 1986; Rao, 1986) emphasize cognitive changes inthe areas of learning and memory, abstract reasoning, and information processingefficiency. Construction and visual-spatial ability are also frequently affected. Whileverbal skills and overlearned information tend to remain relatively intact, classic focalaphasias have been described in the literature, although rarely (Achiron, Ziv, Djaldetti,Goldberg, Kuritzky, & Melamed, 1992).The most consistent finding is impairment in learning and memory for both verbaland visual novel information. The deficit is more likely to be seen on tests of recall ratherthan recognition (Rao, Hammeke, McQuillen, Khatri, & Lloyd, 1984), and is particularlyevident when the information requires novel associations between previously unrelatedmaterials (Carroll, Gates, & Rhodan, 1984; Klonoff et al., 1991). However, on tasksrequiring immediate recall of short spans of information (such as Forward Digit Span), MSsubjects perform similarly to controls (Grant, McDonald, Trimble, Smith, & Reed, 1984;Rao, Leo, & St. Aubin-Faubert, 1989).In the area of abstract reasoning and problem solving, early studies indicated thattests of concept formation and rule learning may be impaired (e.g., Reitan, Reed, &Dyken, 1971), but this finding is inconsistent. Since 1980, most studies have obtainednormal conceptual reasoning ability in groups of patients with relapsing-remitting diseasecourse (Heaton, Nelson, Thompson, Burks, & Franklin, 1985; Jennekens-Schinkel, vander Velde, Sanders, & Lanser, 1989), but impaired performance in chronic-progressivepatients (Heaton et al., 1985; Rao et al., 1984). Overall, the preponderance of negativeresults indicates that conceptual reasoning is less likely than memory processes to beaffected in MS.More recently, investigators have focused on information processing efficiency inMS. Sufficient evidence exists to suggest that patients with MS may have particulardifficulties in this area. Studies that included tests such as Word Fluency, Stroop Color-Naming, and Backward Digit Span have all indicated impaired performance in MS4compared to normal control groups, regardless of the disease course (Heaton et al., 1985;Klonoff et al., 1991; van den Burg, van Zomeren, Minderhoud, Prange, & Meijer, 1987).For example, a recent study by Rao and his colleagues (Rao, St.Aubin-Faubert, & Leo,1989) examined MS patients' mental processing speed using the Sternberg paradigm. Thistask requires subjects to identify whether a probe is contained within a set of digits held inmemory. Mean reaction time is plotted for digit sets of increasing length. The resultantslope of the line indicates speed of memory scanning that is uncontaminated by motorspeed. Rao and his colleagues found that, while total number of errors did not differbetween groups, MS patients obtained a mean memory scanning speed that was 47%slower than a matched control group.Finally, performance on constructional and visual-spatial tasks (such as the WAIS-R Block Design) is often impaired in MS, but is confounded with motor speed andcoordination that are inevitably disrupted in MS (Peyser & Poser, 1986). However,several studies that included tests without a speed/motor coordination component havefound evidence for impairment in this area (Rao, Leo, Bernardin, & Unverzagt, 1991).The Pattern of Impairment in MSTaken together, the results of recent neuropsychological research identifycognitive impairment as an important aspect of MS. However, the particular pattern ofimpairment expected in an individual with MS is unclear. Ample evidence exists tosuggest that cognitive impairment is not ubiquitous among MS patients. Performance onneuropsychological tests invariably ranges from superior to severely impaired. Severalresearchers have highlighted the increased variability of scores among MS patients whencompared to controls (Klonoff et al., 1991; Rao, 1986), even in the absence of significantmean group differences (Jermekens-Schinkel et al., 1989). Statistically, the resultingincrease in variance for the MS group decreases the likelihood of finding group differencesusing tests of mean differences, and makes the use of many multivariate proceduresdifficult (Clark & Ryan, 1993; Ryan, Clark, Klonoff, & Paty, 1993). The presence of5greater variability among test scores raises interesting hypotheses regarding the nature ofcognitive impairment in MS.One hypothesis is that the general pattern of impairment described above applies tomost (or all) MS patients, and that group variability reflects individual differences in theseverity of neuropathology. By this view, when cognitive impairment is present, a similarpattern will be manifest in all MS patients, but the degree of impairment will depend onfactors such as the extent of demyelination. The assumption has been that, as with otherneuropathological conditions such as Alzheimer's or Huntington's Chorea, a characteristicpattern of impairment exists in MS. For example, Rao (1990) has described MS as aprototypical "subcortical" dementia, highlighting a pattern of decreased speed ofinformation processing, inefficient retrieval of previously learned material, and difficultywith abstract conceptualization, with intact verbal skills and an absence of "cortical"features such as aphasia, agnosia, or apraxia.Alternatively, there may not be a characteristic pattern of cognitive deficit in MS.Prevailing theories of brain-behaviour relationships are based on a relatively invariantassociation between brain site and cognitive function. In MS, while demyelination occurswith high frequency in certain brain areas, patients have very different lesion distributionsas assessed by brain imaging techniques such as Magnetic Resonance Imaging (MRI)(Hashimoto & Paty, 1986). Individuals may undergo idiosyncratic cognitive changesdependent upon the site, size, type, and distribution of the white matter lesions. Forexample, MS patients with a preponderance of lesions in the frontal lobes might exhibit avery different pattern of cognitive impairment than MS patients with a large percentage oflesions in the corpus callosum. Further, although a single lesion in MS may be discrete interms of the area it occupies, it is likely to affect many cortical areas, since the myelinatedtracts are comprised of axons from multiple and disparate areas of the cortex, making theinvariance assumption untenable. Thus, group studies may mask a wealth of informationdue to averaging artifacts, since the inclusion of several differentially impaired subgroups6within a single sample could lead to the conclusion that MS results in mild impairment onvirtually every cognitive test available, a view that accords well with the generalimpression expressed in recent reviews of the literature (Peyser & Poser, 1986).In support of this position, Beatty (1992) has investigated whether Rao'scharacterization of MS as a subcortical dementia actually applies to the individual withMS. He argues that, while the group data indeed show deficits in typical "subcortical'areas, the pattern is evident in only a small percentage of individual patients. The majorityof the MS patients would not be considered impaired in any area, while others haveisolated deficits, such as in memory or abstract reasoning.Neuropathological Correlates of Cognitive Impairment in MSConsideration of the nature of the neuropathology in MS is an important aspect ofunderstanding cognitive changes in MS. In recent years the advent of in vivo structuralbrain imaging techniques, such as computerized tomography (CT) and magnetic resonanceimaging (MRI), have allowed the relationship between neuropathology and cognitiveimpairment in MS to be investigated. MRI is of particular interest because of itssensitivity to demyelinating lesions. MRI has been shown to be 10 times more sensitivethan unenhanced CT in identifying lesions in MS. Although one cannot distinguish onnormal MRI between areas of edema and areas of demyelination (Paty, 1990), thetechnique allows more precise localization and estimates of the extent of pathologyevident at a particular time (Ormerod, du Boulay, & McDonald, 1986).Neuroimaging studies have found a modest but consistent relationship between theextent of neuropathological changes and the severity of cognitive impairment. Most oftenthese studies have used a global measure of pathology such as the total number of lesionsweighted by size (Franklin, Heaton, Nelson, Filley, & Seibert, 1988), total area of lesionoutlined on MRI scans (Bautnhefner et al., 1990), or measurements of ventricular dilationthat are presumed to reflect lesion load in the periventricular regions (Rao et al., 1985).For example, Franldin et al. (1988) correlated the total number of lesions weighted by size7on MRI with performance on various neuropsychological tests. Tests of learning andmemory correlated modestly, with Pearson's correlation values ranging from .31 to .36,while tests with a motor speed component correlated somewhat higher, from .45 to .47.It is difficult to interpret the results of studies using these global measures. Forexample, Rao et al. (1985) found that the maximum width of the third ventricle was thebest predictor of global cognitive impairment, compared to other measurements such asthe width of the lateral ventricles. They argued that dilation of the third ventricle is a goodindicator of periventricular demyelination, and that lesions here disrupt the prefrontal-limbic white matter tracts thereby producing memory and conceptual deficits. However, itis difficult to understand why the same should not be true of dilation of the lateralventricles, except if employing a circular argument. Such nonspecific indicators ofneuropathology give little insight into the relationship between affected area and cognitivedysfunction, and one is sobered by the finding that the strongest relationships found areaccounting for at best 20% to 22% of the variance on tests.Expecting anything more than a modest relationship between such global measuresis probably unwarranted given what is known about brain functioning in general, andphysical symptoms in MS in particular (for discussion, see Clark et al., 1992). Thesituation would be analogous to a correlation between the amount of lesion load andambulatory difficulty in MS patients. While larger numbers of lesions may increase thelikelihood that one occurs in an area important to motor functioning, a single well-placedspinal or cerebellar lesion can totally incapacitate an individual (Peyser & Poser, 1986).Only by looking at factors including localization, size, and distribution of lesions can onebegin to understand the effect of white matter lesions on cognition.This view has been embraced by several recent papers that focus on demyelinationwithin the corpus callosum (CC) (Huber et al., 1987; Pozzilli, Bastianello et al., 1991;Rao, Bernardin, Leo, Ellington, Ryan, & Burg, 1989). In one study, Rao, Leo,Haughton, St. Aubin-Faubert, and Bernardin (1989) found that the size of the CC8(presumably measuring amount of atrophy due to demyelination) predicted performanceon measures of memory scanning speed, sustained attention, rapid problem solving, andmental arithmetic, tasks that are often affected in other "subcortical" dementias such asHuntington's Chorea. In contrast, total number of cortical lesions was the best predictorof recent memory, abstract reasoning, language ability, and visual-spatial problem solving,areas of cognition most closely associated with a classic "cortical" dementia, such asdementia of the Alzheimer's type. Unfortunately, CC atrophy was equally correlated withtests of verbal skill and judgement that should be "cortical" in nature, such as theVocabulary and Comprehension subtests of the WAIS-R. As well, the CC is not themajor site of pathology in Huntington's, so it is not clear why these two diseases shouldresult in similar cognitive outcomes. The CC has been more often associated with inter-cortical transfer, as in the work of Sperry (for example, Sperry, Gazzaniga, & Bogen,1969). Nevertheless, the finding of a correlation between CC atrophy and processingefficiency measures is interesting and warrants further investigation. More generally, theapproach taken by Rao and his colleagues suggests that a more detailed assessment of theplacement of lesions may be fruitful in predicting not only the overall severity of the MSpatient's cognitive impairment, but the specific nature of the impairment as well.Present StudyThe purpose of the present study was to investigate the pattern of cognitiveimpairment in MS and its relationship to neuropathology. The Multiple Sclerosis Study atthe University of British Columbia provided a unique opportunity to address this question.A large group of MS patients (n = 177), who met stringent diagnostic and researchinclusion criteria, were tested on a battery of neuropsychological and intellectual tests. Animportant aspect of the study was the inclusion of a well-matched control group (n = 89)who underwent the same set of tests so that comparisons to a normative sample could bemade. Lesion data from MRI scans, administered on the day of neuropsychological9testing, were available for 154 MS subjects and 66 control subjects. The images werecoded for lesion presence in 50 predetermined sites.Utilizing this extensive data base, the present study attempted to determinethrough statistical techniques the pattern (or patterns) of impairment in a group of clearlycognitively impaired MS patients. Given the individual nature of the neuropathology, wehypothesized that rather than one typical or characteristic pattern of MS, subgroups ofpatients with different profiles of impairments would be evident. While global measures ofneuropathology may be associated with the presence of cognitive impairment, lesionplacement and distribution should be important determinants in the pattern of cognitiveimpairment. That is, we hypothesized that individual patterns of impairment will berelated to the area of lesion occurrence on MRI.Before describing the methods, the following three chapters review currentknowledge regarding the clinical and neurological aspects of MS (Chapter 2), theliterature on cognitive impairment (Chapter 3), and research into associations betweencognition and measures of neuropathology (Chapter 4).Chapter 2Neurological and Clinical Aspects of Multiple SclerosisThis chapter reviews the clinical and neurological aspects of Multiple Sclerosis(MS), including disease characteristics, epidemiology, etiological hypotheses, and clinicalscales used to describe MS disability. Laboratory tests and neuroimaging techniques usedfor diagnosis are reviewed. The role of myelin in normal signal conduction and theneuropathology associated with MS are also discussed.Clinical AspectsCourse and prognosis. Seventy percent of MS patients experience a pattern ofexacerbation and remission of symptoms, while the remaining thirty percent undergochronic and unremitting deterioration from the outset. Age of onset is usually between 10and 59 years. While MS is often referred to as a "debilitating" neurologic disease, in factonly a small proportion of patients, estimated at 20 to 25%, eventually become severelyhandicapped (Peyser & Poser, 1986). Many persons are able to carry out normal or near-normal lives. As well, in a significant number of patients, the disease becomes static and isconsidered arrested (Hashimoto & Paty, 1986). In a small number of well-documentedinstances from random autopsy series, the disease is never manifest symptomatically(Gilbert & Sadler, 1983; Herndon & Rudick, 1983). The demonstration of asymptomaticlesions through techniques such as MRI suggests that the disease may be more benign thanis usually thought, and that the prognosis of the disease appears to be considerably betterthan has been believed in the past (Ebers, Paty, & Sears, 1984).Even in those patients who continue to experience exacerbations, new attacks arenot necessarily due to the production of new lesions, but may be the symptomaticexpression of existing lesions through physiological alterations. These alterations include101 1heat or fever, changes in calcium concentration, dehydration, infection, emotional trauma,and stress (Peyser & Poser, 1986).Characteristic symptoms and signs. The symptoms and neurological signs ofMS tend to vary in nature and severity over time. At some point in the course of thedisease, 75% of MS patients will experience ocular disturbance, muscle weakness,spasticity and hyperreflexia, a positive Babinski reflex, absent abdominal reflexes,dysmetria or intention tremor, and bladder disturbance; 50-75% of patients will experiencevisual nystagmus, gait ataxia, dysarthric speech, paresthesias, or alterations in vibratory orposition sense (Poser, Presthus, & Horsdal, 1966). At any given time, however, theclinical picture for a patient is highly individual. Some of the neurological signs andsymptoms that are characteristic of MS are briefly reviewed. A more comprehensivedescription of clinical onset patterns is described in Hashimoto and Paty (1986).Optic neuritis (ON). ON is first manifest as pain behind the eye which is madeworse by moving the globe, followed later by decreased visual acuity and acentral field scotoma. Symptoms resolve spontaneously in 70 to 80% ofpatients, but cortical visual evoked potentials remain abnormal. Approximatelysix weeks after onset, optic nerve atrophy is apparent on examination. ON isthe presenting symptom in 16% of patients with definite MS, and will occur inat least 60% of patients at some time. For patients who present with ON, theoverall risk of developing MS is 35%, but increases with higher geographicallatitudes (75% in the United Kingdom).Internuclear opthalmoplegia (INO). The patient experiences horizontal diplopia(double vision) due to a lesion in the medial longitudinal fasciculus (MLF).The MLF is a midline dorsal fiber tract connecting the lateral gaze center (thesixth nerve nucleus) and the contralateral third nerve nucleus in the midbrain.MS lesions are usually bilateral, hence diplopia occurs with lateral gaze in both12directions. Bilateral INO in young adults is almost pathognomic for MS.Acute onset INO has a high recovery potential.Trigeminal neuralgia (tic douloureux). A lesion at the fifth nerve root entry zonein the pons causes pain in areas of the trigetninal nerve distribution, particularlythe face. The pain is severe, sharp and repeated, and is triggered by sensorystimulation of the area. Trigetninal neuralgia is rare in patients under age 50unless they have MS.Lhermitte's symptom. This symptom is brought on by forward neck flexion, andis manifest as an electric buzzing sensation that travels down the back andsometimes into the legs. The sensation sometimes travels downward into thearms, or reverses, rising upward from the lower back. Lhermitte's symptomarises from damage to the posterior columns of the cervical spinal cord. It isnot specific to MS but occurs with many forms of cord compression damage.Acute transverse myelitis (ATM). In its complete form, ATM results in loss ofall sensory and voluntary motor function below the level of the functional cordtransection. It is more likely in MS to see partial cord transection. The moreacute the onset of the symptoms, the fuller and more rapid a recovery.Complete ATM carries with it a poor prognosis, often resulting in eithercomplete paraplegia or significant residual impairments.Useless hand of Oppenheim. The hand (or hands) become virtually uselessbecause of a lack of tactile discrimination and movement feedback. Alldiscriminatory sensory modalities are affected, including vibration, two-pointdiscrimination, graphesthesia, stereognosis, and proprioception. This symptomis rarely seen in diseases other than MS. The lesion is most likely in theposterior columns of the lemniscal system, and is usually unilateral.Paroxysmal symptoms. Seizures occur in 5% of patients with MS, which is twicethe expected rate of seizures in the population. Other paroxysmal symptoms13include tonic spasms, positive sensations or paresthesias, and monocularblindness. It has been suggested that such paroxysmal symptoms are due totransverse ephaptic impulse spread (axonal cross-talk occurring within andacross poorly insulated demyelinated tracts).Facial myokymia. Facial myokymia is a sensation of twitching around the eyesand movement under the skin that is caused by single fiber and motor unitcontractions in the musculature.Radicular syndromes. Radicular numbness and pain is due to root entry lesionsand is therefore similar to trigeminal neuralgia.Heat sensitivity. MS patients show a characteristic temperature sensitivity. Feveror heat results in symptom exacerbation, even to the extent of quadriplegia.Because the symptoms are dissipated when body temperature returns to normal,an episode of heat-induced symptoms has been called a pseudo-relapse. Heattypically results in visual blurring, diplopia, paresthesias, ataxia, and legweakness. This sensitivity can be useful for diagnosis, since a patient willexhibit worsened symptoms after being immersed in hot water.Neurophysiological research has shown that the reliability of impulseconduction in demyelinated fibers decreases with increased temperature(Waxman, 1982). Although the reason for this is not clear, it may explain heat-induced symptom exacerbation.Other symptoms. Other symptoms that are less unique to MS, but neverthelessfrequently experienced, include gait ataxia, dysarthria, incontinence,constipation, and muscle weakness.Epidemiology and GeneticsEpidemiological studies have demonstrated that multiple factors, both genetic andenvironmental, must be implicated in the etiology of MS (for review, see Gonzalez-Scarano, Spielman, & Nathanson, 1986). The female to male ratio of MS prevalence is 314to 2, but as age of onset increases, the frequency of male cases increases. The overallincidence of the disease is approximately 10 cases per 100,000, but this is complicated bya worldwide distribution that is influenced by both geographical latitude and racial origin.Generally, the colder the climate, the higher the incidence of MS. Areas of highprevalence (50 to 80 cases per 100,000) include north and central Europe, Canada, NewZealand, and parts of southern Australia. Unusually high prevalence is found in theShetland and Orkney islands off the coast of Scotland, with 184 and 309 cases per100,000, respectively (Pokanzer, Prenney, Sheridan, & Kundy, 1980). There are alsoareas of exceptionally low prevalence compared to other areas of similar climate. Forexample, Japan's incidence is low (<10 per 100,000), and MS is almost nonexistent amongnative Indian and Inuit in Canada (Hashimoto & Paty, 1986).Migration studies show an unusual risk pattern. Immigrants moving from low riskto high risk areas assume the new risk of acquiring the disease if the move occurs beforeage 15. Over age 15, lifetime risk remains similar to their place of origin (Norman,Kurtzke, & Beebe, 1983). The second generation of immigrant families show similar ratesof incidence to the country they are born into, regardless of the place of origin of theirparents (Leibowitz, Kahana, & Alter, 1973). These findings suggests a third importantetiological factor, namely, a developmental critical window in which environmental factorsmay exert an effect.The heritability pattern of MS suggests some familial hereditary susceptibility.Ebers et al. (1986) reported a concordance rate for monozygotic twins of 30%, whileconcordance for dizygotic twins was 3%. Risk for all other first-order relatives was also3%, which is still about 25 times greater than the general population in high-risk areas.Risk decreases as the degree of relatedness decreases.Taken together, these findings have led researchers to consider a multi-factoretiological model that includes exposure to some environmental factor(s) during a critical15period of development. Susceptibility to environmental factors is mediated by both racialand familial genetic factors.Neuropathology and PathophysiologyCNS Myelin. CNS myelin is formed by a laminar spiral of oligodendroglial (OG)cell membrane that creates an insulating sheath around axons (Kandel & Schwartz, 1985).Each OG cell myelinates 20 to 40 sections of axons within its immediate vicinity.Segments of myelin from individual OG cells along a single axon are separated from eachother, creating periodic interruptions referred to as the Nodes of Ranvier. Myelin, beingderived from plasma membrane, is 70% lipid and 30% protein. Compared to gray matter,white matter is low in water content. Myelinated axons are typically thicker and longerthan unmyelinated axons.The myelin sheath is characterized by high electrical resistance and lowcapacitance, thereby acting as an effective insulation for the electrical currents that arepropagated along the axon. The electrical signal in a myelinated axon is conducted bysaltatory conduction, that is, the impulse jumps discontinuously from node to node ratherthan continuously along the axon. The action potential spreads passively along themyelinated sections, or internodes. At each node, repolarization occurs due to the highdensity of sodium channels situated there (10,000 per square micrometer at the nodesversus <25 per square micrometer along the internode). Potassium channels are foundalong the internodal membrane underneath the myelin or just beside the nodes. The roleof these "leak" channels is unclear, but they are thought to contribute minimally toconductance. Saltatory conduction allows the myelinated axons to propagate signals withgreater velocity, to conduct impulses at higher frequencies, and to expend less energy perimpulse than in unmyelinated fibres.Neuropathology in MS. MS is characterized by multiple focal lesions occurringthroughout the white matter of the CNS (Prineas, Kwon, Cho, & Scharer, 1984). Lesionsdo not respect fiber tracts or other anatomical boundaries, but tend to be disseminated16throughout the CNS. The organization of CNS myelin lends itself to patchy loss.Microlesions are first produced by the loss of a single or several adjacent OG cells, whichthen combine into confluent, larger lesions. The earliest lesions are probably areas ofinflammation with collections of lymphocytes, plasma cells, macrophages, and increasedwater content replacing hydrophobic myelin. Over time, the degree of inflammationdecreases and the presence of astrocytes signal the beginning of gliosis. As gliosiscontinues, astrocyte processes proliferate causing fibrillary tangle plaques (Hashimoto &Paty, 1986). Water content also increases, although extracellular edema recedes. In laterstages preservation of the axon is less consistent and, eventually, complete cell deathoccurs due to Wallerian degeneration (Hille, 1984).Lesions occur most frequently at the optic nerve, the spinal cord, theperiventricular region, and within the corpus callosum. In later stages of the disease,virtually no area of white matter is spared. To give an indication of the extent ofneuropathology, Brownell and Hughes (1962) found 1,594 distinct lesions in 22 cases thatcame to autopsy. The majority of the plaques occurred in the white matter, but 26% werelocated at the junction of cortex and white matter, and a small number within the corticaland deep grey matter. Plaques within the grey matter have been described elsewhere assmaller and less well defined (Hashimoto & Paty, 1986).Effects of demyelination. Demyelination of a single axon results in slower signalconduction and desynchrony of the signal due to differing amounts of demyelination alongthe length of the axon. As well, conduction block of high frequency signals may occur,since demyelinated axons cannot conduct signals fast enough so that high frequencysignals tend to bunch up on one another (Waxman, 1982). Desynchrony of signals alsooccurs within a tract of axons, since signal speed will differ for each axon depending onthe amount of demyelination.Recovery of function. A fundamental research question is the extent to whichdemyelinated axons are capable of sustaining an action potential. It appears that, at first,17there may be complete signal conduction block. Since the demyelinated areas are nowlow resistance and high capacitance, too much of the electrical current is lost duringpassive spread to initiate another depolarization at the next high density sodium channelarea. Over time, however, there is at least partial return of functioning (Waxman, 1982).Remyelination can occur, but is slow and incomplete in the CNS and is not likely sufficientto restore functioning (Prineas & Connell, 1979). The presence of new sodium andpotassium channels in previously myelinated areas of the axon suggests that the channelsare redistributed to allow signal propagation by continuous conduction. It is not knownwhether new channels are formed along the internodal membrane, or whether there is amigration of the existing channels from the nodes of Ranvier.Pathogenesis of MSTwo theories have gained most interest. The viral theory suggests a slow virus,either with a long latency period or incubation period calculated from epidemiologicalmigration studies to be between 10 and 20 years. Since most MS patients have high levelsof antibodies to measles, a measles variant has been a favorite candidate. However, non-MS siblings have high measles antibodies as well, and MS patients have high levels ofantibodies to many other viruses. To date, there have been only negative results fromattempts to isolate a virus from MS brain tissue.A variant of the viral theory is the critical window theory. The theory suggeststhat a viral infection occurring during a critical period in normal immune systemdevelopment causes a secondary abnormal immune response. The response slowlydevelops into a full blown autoimmune process. Physiological findings from CNS studiesdocumenting systemic immune system abnormalities are consistent with this hypothesis(Haffler & Weiner, 1989). The genetic disposition suggested by familial risk studies(Ebers et al., 1986) may be a tendency to produce high levels of antibodies. The theoryaccords well with findings from epidemiological and migration studies. For example,measures of measles antibody titers are arranged in a pattern similar to the at-risk18distribution, ranging from highest to lowest in MS females, MS males, non-MS siblings,age and sex matched childhood friends, and random controls (Paty, Dossetor, Stiller, etal., 1977).One important aspect of the pathogenesis of MS is the demonstration by means ofenhanced CT and MRI (Poser, 1980) of an alteration in the permeability of the blood-brainbarrier. In the periphery, CNS myelin is identified as a foreign substance and is destroyedby the immune system. Changes in the integrity of the blood-brain barrier might result inimmune-mediated demyelination wherever these breakdowns occur. This theory accordswell with the abundance of demyelinating lesions in the periventricular regions and aroundsmall blood vessels in the deep white matter.Diagnostic TestsDiagnosis of MS is difficult because a) the symptoms are transient, lastingsometimes not more than hours or minutes, b) although many signs, symptoms, andlaboratory findings are characteristic of MS, none are specific to the disease, and c) manyof the symptoms are often of the type associated with psychogenic conversion reactions.The diagnostic dilemma increases when symptom onset closely follows a stressful event.While the diagnosis of MS is primarily made on the basis of clinical information, severallaboratory tests have been useful as diagnostic aids.Computerized tomography (CT). Brain imaging techniques have become animportant tool, particularly in demonstrating the pattern of multiple and spatiallydisseminated lesions characteristic of MS. The CT scan is an image produced bycomputerized reconstruction of the degree to which different tissues absorb transmitted X-rays (Oldendorf, 1980). In order to compute such an image, a narrow X-ray beam istransmitted through the head, and the X-ray photons on the other side are detected andcounted. The reduction in the number of photons emerging relative to the number ofphotons emitted is the attentuation value. Multiple projections (a row or strip ofattenuation values) are obtained at different angles through the head. The mathematical19calculation of the attenuation values for tissue deep within the brain is complex, butessentially consists of the addition of projections to create a 2 dimensional matrix. Thereconstructed image reflects the fact that different tissues absorb X-rays to differingdegrees. Bone and calcifications within the brain have very high attenuation values andappear white on the image, whereas soft tissues yield intermediate values appearing grey;CSF and fluid is much less attenuating, thereby appearing very dark on the image.A routine CT scan of an MS patient substantially underestimates the number oflesions, as is evident from post mortem studies. Administering intravenous radiopaquecontrast material will increase the number of lesions visible on the scan. Enhancement isusually done by scanning one hour after the injection of a high dose of iodine contrastmaterial. The delayed scan permits the contrast material to penetrate the blood-brainbarrier in areas where the permeability has been altered to only a minor degree. Enhancedlesions are associated with disease activity and may be clinically active lesions. Forexample, Ebers, Paty, and Sears (1984) reported one or more enhanced lesions in 56% ofpatients experiencing acute exacerbation, in 45% of patients with some worsening in thelast 3 months, but in only 9% of patients with no recent physical changes. Thus one in tenpatients with inactive MS had enhanced lesions on CT scan that were asymptomatic.Enhanced lesions have been shown to disappear with the administration ofadrenocorticotrophic hormone (ACTH) or other corticosteroid treatments (Goodkin,Ransohoff, & Rudick, 1992). Paty (1990) suggests that routine scans identify areas ofdemyelination, while enhanced lesions are likely areas of active inflammation anddemyelination. Enhanced scans may obscure lesions visible on routine CT, highlightingthe need for both types of scans.Magnetic resonance imaging (MRI). MRI is of particular diagnostic valuebecause of its greater resolution than CT scanning. A structural tomographic image of thebrain is generated when the distribution of hydrogen nuclei in brain tissue is measured(Jernigan, 1990). When atomic nuclei with uneven numbers of protons are placed in a20strong magnetic field, the protons will orient parallel to the force of the field and precess,or spin in an elliptical orbit around the longitudinal axis of the magnetic field. The protonhas a characteristic frequency of precession that depends on the field strength of themagnet. A radio signal tuned to this characteristic frequency will displace the protons bycausing them to absorb energy and thus precess through a wider circle. Once the signal isdiscontinued, the protons give off a predictable amount of energy as they return to theirlow energy state. The strength of the energy signal they emit can be measured, andreflects the concentration of protons in the tissue. The rate at which they return to theirlow energy state can also be measured (relaxation time), either as the exponential time toreturn to the longitudinal plane (Ti) or to the transverse plane (T2). These parameters areinfluenced differently by tissue characteristics such as temperature, viscosity, and proteincontent. Relaxation measures provide much of the anatomical detail and sensitivity totissue abnormalities.Since tissue types differ in water content and other characteristics, a structuralimage of the brain is produced by spatially encoding the signals. On Ti weighted images(inversion recovery) white matter is light contrasting with dark areas indicating grey orabnormal white matter. T2 weighted images (spin echo) yield a homogeneous grey imagewhere luminescences indicate abnormal white matter. The optimal sequence forvisualizing demyelination in MS is a multislice, multiecho, spin echo (T2) scan, including asequence where CSF is "not white", so that lesions can be differentiated from the CSFaround the ventricles (Paty, 1990; Ebers, Paty, & Sears, 1984).MRI is positive in over 90% of MS patients (Hashimoto & Paty, 1986). With aresolution of approximately 3 mm, however, small lesions are not seen. MRI is ten timesmore sensitive than unenhanced CT, particularly in identifying brain stem and cerebellarlesions. Because of its resolution, MRI has been valuable in evaluating the distribution oflesions in MS. In a recent study of 62 patients (Baumhefner et al., 1990), the MRI wasabnormal and consistent with the diagnosis of MS in 60 patients. Of these 60 patients,2175% had abnormality in the upper cervical cord, 35% had cerebellar lesions, 42% hadbrain stem lesions, and 100% had lesions located in the cerebrum. There were, onaverage, approximately 100 cortical lesions for every one lesion in the brain stem or thecerebellum.Apart from increasing overall sensitivity to the presence of lesions, MRI has beenuseful in assessing disease activity. In studies obtaining a series of MRI for each patient,asymptomatic new lesions were frequent in both relapsing-remitting and chronic-progressive patients, indicating that MS is a more active process than is indicated byclinical evaluation. Individual lesions can be seen to evolve and resolve independent ofone another (Thompson et al., 1992). MRI can be used as an indicator of disease activityover time, and statistical guidelines have been developed by several investigators that takeinto account measurement error so that erroneous inferences regarding disease activityversus measurement artifact are not made (Goodkin, Ross, Medendorp, Konecsni, &Rudick, 1992).An MRI obtained with gadolinium infusion is similar to contrast-enhanced CT inhighlighting areas where there is breakdown of the blood-brain barrier (Grossman,Braffinan, Brorson, Goldberg, Silberberg, & Gonzalez-Scarano, 1988). Although routineMRI cannot distinguish inflammatory lesions from demyelinated or gliotic regions,gadolinium-diethylene penta-acetic acid (Ga-dTPA) injected will show not only areas ofblood-brain barrier breakdown, but also improves detection of new lesions, particularly inthe subcortical areas. When used with series of MRIs, it is useful in demonstratingreactivated chronic lesions. Enhancement of old lesions or new lesions have been shownto correlate with clinical relapse in relapsing-remitting MS patients, with newabnormalities occurring seven times more frequently than clinical events (Thompson et al.,1992). On the basis of the evidence from series studies of enhanced and unenhancedMRI, Paty (1990) has suggested that new lesions are probably areas of inflammation thatbecome demyelinated only after several episodes of inflammation have repeatedly22damaged a particular area of white matter. The evidence suggests that the disease processis between five and seven times more active than assessed by clinical evaluation.Evoked potentials. The hallmark of demyelination in studies of the physiology ofsingle fibers is slowed signal conduction (Waxman, 1982). It is this slowed conductionthat allows the use of cortical evoked potentials (EP) in the diagnosis of MS. EP is ameasure of the time between a stimulus presentation and an agreed upon part of theresultant neuronal signal. In MS, EPs typically show a longer latency but near normalwave form, implying the slowed conduction characteristic of demyelinated fibers. EPs areuseful for detecting lesions along the auditory, optic, and somatosensory pathways.CSF abnormalities. A pattern of multiple monoclonal globulins (IgG), referredto as oligoclonal banding, is evident in the CSF of over 90% of patients with MS (Ebers,1984; Ebers & Paty, 1979). In contrast, only 8% of other neurological patients show suchbanding. Half of these non-MS patients have a history of infectious or inflammatoryconditions (encephalitis, polyneuritis, meningitis) which would be expected to arouse animmune response restricted to the CNS. The banding found in MS indicates an immuneresponse in the CNS sometime in the past. Interestingly, the banding pattern seen in MS isvariable from one patient to another, but remains the same once developed. Theobservation has given weight to an autoimmune theory of MS where the CNS immuneresponse, once developed, is perpetuated. Banding is found in 40% of suspected MScases, 14% of which will develop into clinically definite MS within 2 years, in contrast to7% of suspected MS cases without banding who will develop clinically definite MS withintwo years (Hashimoto & Paty, 1986). While banding is a useful diagnostic test in earlysuspected MS, the absence of banding does not exclude MS. However, positive bandingand a positive MRI together are the best predictors of future development of clinicallydefinite MS.23Diagnostic CriteriaDiagnosis is made only when evidence indicates recurrent or chronic diseaseaffecting multiple areas of the CNS; hence the diagnostic criteria of evidence supportingthe dissemination of lesions in both time and space (Poser, Paty, McDonald, Scheinberg,& Ebers, 1984). The criteria allow MS to be distinguished from single white matterlesions, and from lesions that are not chronic or progressive. The average time from firstsymptoms to diagnosis is usually reported in studies as between 5 and 10 years (Klonoff etal., 1992).The Schumacher et al. (1965) criteria. The most widely used diagnosticscheme until recent years was that of Schumacher et al. (1965). The criteria include 1)objective abnormality on neurologic examination attributable to CNS dysfunction; 2)evidence of involvement of two or more separate parts of the CNS; 3) objectiveneurologic evidence that reflects predominantly white matter involvement; 4) involvementthat occurs temporally as either two or more episodes of worsening separated by a periodof 1 month or more, or a slow or stepwise progression of signs and symptoms over aperiod of at least 6 months; 5) the age of the patient at onset falls within the range of 10 to50 years; and 6) the condition cannot be explained better by some other disease process.The Poser et al. (1983) criteria. Because of the development of ancillary clinicaland laboratory procedures that assist in diagnosis of MS, a new set of diagnostic criteriawas developed by Poser et al. (1983). Not only are the types of acceptable evidenceexpanded and detailed, but the definition of terminology and other aspects of diagnosisthat require subjective input from the clinician are made clear. Episode refers to theoccurrence of symptoms with or without objective confirmation on neurologicalexamination lasting more than 24 hours. Remission is an improvement of signs orsymptoms lasting more than 24 hours, while remission lasting more than 1 month isconsidered "significant". The types of evidence used in these criteria include clinicalevidence (objective abnormal signs on neurological examination), paraclinical (Evoked24Potentials or MRI/CT lesions that are subclinical or asymptomatic), and laboratorysupported evidence (positive findings of oligoclonal banding, increased IgG levels, evokedpotentials, MRI, or CT). As with the Schumacher criteria, the new guidelines requireevidence of multiple lesions disseminated in both time and space. The categories fordiagnosis are outlined below.Clinically Definite: Two episodes, separated by 1 month, with clinical evidence oftwo separate lesion sites; or, two episodes separated by 1 month with clinicalevidence of one lesion and paraclinical evidence of another.Laboratory Supported Definite: Two episodes, with clinical or paraclinicalevidence of one lesion plus oligoclonal banding; or, one episode with clinicalevidence of two lesions plus oligoclonal banding; or, one episode with clinicalevidence of one lesion, paraclinical evidence of another, together with banding.Clinically Probable: Two episodes with clinical evidence of one lesion; or, oneepisode with either clinical evidence of two lesions or clinical evidence of onelesion with paraclinical evidence of another.Laboratory Supported Probable: Two episodes and oligoclonal banding.Disability AssessmentKurtzke (1955) devised the Disability Status Scale (DSS) to be used to assesstreatment outcome in drug studies of MS. The scale, with 10 grades ranging from "0 =normal" to "10 = death from MS", was intended to measure the maximal functioning ofeach patient as limited by neurologic deficits. The scale considers ambulation, work anddaily activities, and assistance requirements. In higher (more impaired) grades, the scalefocuses on restrictions of movement, the inability to care for oneself, and difficulty incommunication. Only objectively verifiable defects due to MS (i.e., as evident onneurological exam) are included in the scale. Thus the scale does not include symptoms.Kurtzke also provides a rating of individual Functional Systems (FS), including pyramidal(P), cerebellar (C11), brain stem (BS), sensory (S), bowel and bladder (BB), visual (V),25cerebral or mental (Cb), and other (0). While the DSS gives an overall picture offunctioning of the patient, the FS scales are independent anatomically and not additive (forexample, as P worsens, C11 will improve because as plegia increases ataxia will decrease).Kurtzke later revised the scale (Kurtzke, 1983) because clinicians and researcherswished to note smaller differences in clinical status. The Extended Disability Status Scale(EDSS) was developed by dividing each of the 10 categories into two. These categoriesare used extensively now and are described in more detail in Appendix A. The FS scaleswere also modified, and are used as an index of neurological impairment or abnormality ineach domain. The EDSS is used as a scale of general disability due to neurologicalimpairment, but is not a handicap scale. Thus, a concert pianist with an EDSS of 3 or 4will be severely handicapped at work, while for other patients, this level of disability willinterfere minimally with work or daily activities.Chapter 3Neuropsychological Functioning in MSTwo recent reviews (Peyser & Poser, 1986: Rao, 1986) summarizing theneuropsychological functioning of MS patients highlight a triad of impairment in learningand memory, problem solving and conceptualization, and information processingefficiency. Visual-spatial skills are often affected, while prior knowledge, skills, andlanguage functions remain intact. Emotional changes include depression, euphoria, andlability. While these conclusions are the product of more than 40 years ofneuropsychological research, it is sobering to consider that Charcot, in his 1877 lectures,gave a remarkably similar description of MS on the basis of clinical observation of a fewpatients at the Salpetriere. In a widely quoted passage he remarked that, for mostpatients, "There is marked enfeeblement of memory; conceptualizations are formed slowly;the intellectual and emotional faculties are blunted in this totality. The dominant feelingappears to be a sort of almost stupid indifference in reference to all things. It is not rare tosee the patient give way to foolish laughter or, on the contrary, melt into tears withoutreasons" (quoted in Peyser & Poser, 1986). The harshness of Charcot's description islikely due to the severity of the cases he observed. Nevertheless, while research methodshave changed, clearly our basic conception of the psychological functioning of MSpatients has remained relatively intact over the last 100 years. In every era, MS continuesto be characterized by enigmas, and research seems to generate more questions thananswers (Namerow & Thompson, 1969). The present chapter reviews the extantliterature on cognitive functioning in MS.Early Studies of Intellectual and Neuropsychological FunctioningProbably the first systematic attempt to assess the intellectual functioning of MSpatients was carried out in France by Ombredane in 1929 (described in Peyser & Poser,26271986). Using techniques that were forerunners of current neuropsychological testingmethods, Ombredane administered tests of attention, memory, manipulation of spatial andtemporal relationships, comprehension, and calculation to a random sample of 50 MSpatients. Of this group, 72% displayed varying degrees of intellectual difficulty, and 12%of these patients he considered to be globally demented. In general conversation,Ombredane found that most of the patients appeared perfectly intact, but once the patientbegan to carry out intellectual exercises, the deficits became apparent. He concluded thatintellectual impairment was an integral component of MS.A different conclusion was drawn in North America. Until well into the 1940s,researchers judged intellectual functioning solely on the basis of observations made duringclinical interviews (Bramwell, 1905; Moxon, 1875). One very influential study by Cottrelland Wilson (1926) reported that, of 100 patients who were extensively interviewed, only 2showed intellectual impairments. More recent epidemiological surveys employing a briefmental-status examination administered by neurologists have supported these findings(Kurtzke, Beebe, Nagler, Auth, Kurland, & Nefzger, 1972). Outcomes such as these haveencouraged the opinion among clinicians that intellectual functioning is not an importantaspect of MS (for example, see McKahn, 1982).The development of individually administered intelligence tests in the 1950s and1960s created a resurgence of interest in the intellectual functioning of MS patients(Canter, 1951; Fink & Houser, 1966). Results on tests such as the Wechsler AdultIntelligence Scale (WAIS; Wechsler, 1955) were inconsistent. For example, Reitan, Reed,and Dyken (1971) found that MS patients, compared to controls matched on age andeducation, were significantly lower on every WAIS subtest except Information,Comprehension, and Arithmetic. On these three, MS performance was also lower, butnot significantly. In contrast, Jambor (1969) found no differences between MS patientsand normal controls (again matched on age and education level) on Verbal IQ,Performance IQ, Similarities, Block Design, or Digit Span. MS patients did no worse on28cognitive measures than other brain-damaged groups (Goldstein & Shelley, 1974; Ivnik,1978; Jambor, 1969; Matthews, Cleeland, & Hopper, 1970), physically disabled patients(Jambor, 1969), or psychiatric patients (Goldstein & Shelly, 1974; Jambor, 1969). In eachstudy, group differences occurred, but none consistently. Vowels (1979) explained thelack of group differences by noting that an intelligence test such as the WAIS is heavilyinfluenced by educational experience, and suggested that MS may disrupt more dynamicproblem-solving abilities, leaving overlearned knowledge and skills relatively intact.Vowels' explanation accords well with the observation made by Rao (1986) that amongthe WAIS and WAIS-Revised (Wechsler, 1981) subtest scores, Digit Span is consistentlythe lowest on average for MS patients, followed closely by Arithmetic, two tasks requiringefficient mental manipulation of information.A more consistent picture is revealed by the neuropsychological tests included inthese early studies. Clearly, MS patients exhibited substantial cognitive impairment on avariety of tests that could not be explained by impairment in motor functioning. Forexample, Reitan et al. (1971) found the MS group to be impaired on tests from theHalstead-Reitan Neuropsychological Battery (Reitan & Davison, 1974) that do not rely onmotor speed and coordination, including the memory and location scores from the TactualPerformance Test, and Categories, a test of inferential rule-learning. MS groups were alsoimpaired compared to other groups with neurological conditions causing motordysfunction such as muscular dystrophy (Ivnik, 1978; Jambor, 1969; Surridge, 1969). Themost consistent finding from these early studies was difficulty in learning and memory,including tests of multiple-trial list learning (Beatty & Gange, 1977), sentence learning(Jambor, 1969) and paragraph recall, both immediate and delayed (Beatty & Gange, 1977;Staples & Lincoln, 1979).The inconsistencies in many of these early studies are difficult to explain, since thestudies do not adequately describe their subject samples and inclusion criteria. Factorssuch as diagnostic criteria, the percentage of patients with relapsing-remitting versus29chronic-progressive course, current medications, and the percentage of patients currentlyexperiencing relapse, may have a major impact on the outcome. For example, symptomexacerbations causing motor incoordination, sensory deficits, and general fatigue have alarge impact on test performance. Inclusion of patients currently in relapse might changethe group mean sufficiently to indicate deficits that would not otherwise be apparent.Diagnostic procedures alone may account for substantial differences in thesestudies. Compare, for example, Jambor (1969), who found no impairment on the WAIS,with Reitan and his colleagues (1971), who found impairment on virtually every test given,including 8 of 11 subtests of the WAIS. Both studies recruited subjects on the basis of aprior diagnosis of MS reported in hospital records. However, Reitan discarded half of hissample on the basis of clinical information contained in hospital records, so that theremaining 133 patients (of whom 30 were randomly chosen and contacted) were"unequivocal" MS. In contrast, Jambor contacted by letter an unreported number ofpatients diagnosed with MS, and tested the first 105 patients who agreed to co-operate.Reitan's sample was older (mean 36.43 years, sd 9.83) than Jambor's sample (mean 32.3years, sd not reported, but with a criterion cutoff of age 40). Finally, Reitan included allsubject scores on every test, while Jambor excluded subjects from each test if sensory andmotor impairment were judged to hamper their performance. Taken together, it isreasonable to assume that these differences in procedure resulted in a more homogeneoussample being tested by Reitan, a sample that may have included more late-stage andfunctionally disabled MS patients.Thus, while early studies warranted the conclusion that cognitive impairment ofsome type occurs in at least some patients with MS, it is difficult to draw conclusionsabout the nature of the impairment.Characterization of the Impairment: Studies from 1980 to the PresentMore recent studies have applied clearer guidelines for diagnosis (Poser et al.,1983) and have been more thorough in reporting sample characteristics such as disease30course, age of onset of symptoms, years since diagnosis, current level of disability, andnumber of subjects experiencing relapse (Peyser, Rao, LaRocca, & Kaplan, 1990). Theemphasis has moved from the question of whether or not cognitive impairment occurs tounderstanding the nature of the impairment and its relationship to other aspects of thedisease process. A large number of recent studies have focused on identifying thecomponents of a cognitive function that are affected by MS. By far the most extensivelyresearched area has been aspects of learning and memory, but has also included abstractreasoning and conceptualization, visual-spatial functioning, and information processingefficiency.Memory and learning. As with the early studies, the most robust finding in theliterature is a consistent impairment in learning and memory for both verbal and visualnovel information. The deficit is more likely to be evident on delayed tests of free or cuedrecall rather than recognition (Carroll et al., 1984; Rao et al., 1984). When presented withverbal materials such as word lists, paired associate lists, or short stories, MS patientsacquire information incrementally over trials, but at a slower rate (Carroll et al., 1984;Grant et al., 1984; Rao et al., 1984; Rao, Leo, & St.Aubin-Faubert, 1989). MS patientshave particular difficulty in acquiring novel associations between unrelated pairs of words(Klonoff et al., 1991; Minden, Moes, Orav, Kaplan, & Reich, 1990), and in organizingwords into semantically logical groups that facilitate recall (Carroll et al., 1984). Incontrast, on tasks requiring immediate recall of short spans of information such asForward Digit Span, MS group performance is similar to controls (Grant et al., 1984;Heaton et al., 1985; Rao, Leo, & St. Aubin-Faubert, 1989).Several researchers have investigated whether the memory impairment in MScould be accounted for by a more rapid rate of forgetting. There have been conflictingreports as to whether MS patients are more susceptible to interference on the Brown-Peterson trigram paradigm, a test designed to measure rate of forgetting (Peterson &Peterson, 1959). Rao, Leo, and St. Aubin-Faubert (1989) found that although there was a31trend to recall fewer trigrams, the MS group showed the same rate of forgetting ascontrols after retention intervals of 3, 6, 9, and 18 seconds filled with an interference task.In contrast, Grant, McDonald, and Trimble (1989) found a clear effect of rapid forgettingwith an interference task during the intervals. One should not assume, however, thatpoorer performance on the Brown-Peterson task indicates a change to the memory systemper se. The Grant et al. (1989) study was conducted with MS patients, about half ofwhom were experiencing exacerbations at the time of testing, whereas all but 2 of thepatients in Rao, Leo, and St. Aubin-Faubert (1989) were in remission at testing. As Muter(1980) has pointed out, the Brown-Peterson task is as much a measure of distractibility asit is of forgetting rate, and patients in an active phase of the disease may differ on such ameasure. The best indication that rapid forgetting is not associated with MS comes fromseveral studies that have shown that, once learned, information is retained over delayssimilarly in MS and control groups, providing one takes into account the original amountof information learned (Minden et al., 1990; Rao, Leo, & St. Aubin-Faubert, 1989).The finding that recognition tests are less likely to be impaired than tests of freerecall has led some researchers such as Rao (1986) to suggest that the memory deficitstems from difficulty with retrieval rather than encoding or rapid forgetting. However,Rao et al. (1984) found recognition to be impaired in chronic-progressive patients. Aswell, Minden et al. (1990) did not find any differences between MS patients and controlsin the pattern of recall and recognition memory performance. They found thatperformance for both groups was improved on recognition testing, but the MS groupremained significantly impaired in comparison to controls. The average increment in theMS group's memory performance on recognition was no larger than it was for thecontrols. Indeed, Minden et al. (1990) found that memory impaired MS patients'performance benefitted less by the presentation of retrieval cues for novel pairedassociates, a finding that cannot be explained easily by a retrieval deficit.32The finding that MS patients have more difficulty with novel associative learningand do not benefit from semantic cueing might suggest that MS patients have a semanticencoding deficit. Beatty, Goodkin, Beatty, and Monson (1989) examined this hypothesisusing Wicken's (1970) release from proactive interference (PI) paradigm. Frontal lobelesion patients who also exhibit memory deficits fail to show the normal release from PIafter a categorical shift, suggesting that memory impairment associated with frontaldysfunction arises from an inability to adequately encode the semantic aspects of thematerials (Freedman & Cermak, 1986). Beatty et al. (1989) found that even those MSpatients with clear impairment in memory and other "frontal lobe" functions showednormal release from PI. In another study, Grafman, Rao, Bernardin, and Leo (1991)showed that MS patients encode incidental properties of the stimuli, such as the modalityof presentation or the frequency of presentation. Although MS subjects were impaired inrecall and cued recall for the materials, they were able to estimate the frequency of theprior presentations of the word with the same accuracy as controls. Taken together, theseresults suggest that MS patients are not impaired in the encoding and representation ofeither semantic or incidental aspects of the materials, but rather in the use of strategicaspects of memory. Decreased use of strategy as an explanation for MS memoryimpairment is consistent with Carroll et al. (1984) who found that MS patients were lesslikely to spontaneously employ a semantic strategy as an aid to accurate performance on averbal recognition task.Conceptual and abstract reasoning. Conceptualization or problem solvingability has been most often tested with the Category Test (CAT) from the Halstead-ReitanBattery or the Wisconsin Card Sorting Test (WCST). Most studies since 1980 have notfound impairment on the CAT when MS patients with a relapsing-remitting course weretested (Heaton et al., 1985; Jennekens-Schinkel et al., 1989; Klonoff et al., 1991).Chronic-progressive MS groups, however, have been found to be impaired on the CAT,the WCST (Heaton et al., 1985), and Levine's (1966) Concept Formation Test (Rao et al.,331984). For example, Heaton et al. (1985) found that chronic-progressive patientsperformed worse on both CAT and WCST compared to a relapsing-remitting group, andboth MS groups made more perseverations on the WCST than the control group. Incontrast, Jennekins-Schinkel et al. (1989) found that chronic-progressive and relapsing-remitting groups performed virtually identically to one another and compared to normalcontrols on all measures of the CAT and the WCST. The only significant finding was thatscores for the MS group as a whole were more variable than controls. Finally, whilePeyser et al. (1980) found that 54.7% of an MS group were above the normative cutofffor classifying brain damage on the CAT (50 errors; Reitan, 1986), Jennekins-Schinkel etal. (1989) point out that using such a cutoff in their study would have misclassified 54% ofthe MS patients and 58% of control subjects as having organic brain dysfunction.Increased perseverative responding has been frequently reported in MS patients,either regardless of disease course (Heaton et al., 1985) or only in patients with chronic-progressive MS (Rao & Hammeke, 1984). Beatty et al. (1990) found that a group ofchronic-progressive MS patients differed from controls on the WCST only in the numberof perseverative responses; number of categories achieved, and failures to maintain setwere similar, suggesting that MS patients have difficulty abandoning a formerly correcthypothesis. Jennekins-Schinkel et al. (1989) also found that their MS group tended tohave difficulty in using the "if correct, then shift" strategy, but this difference did not reachstatistical significance.While the evidence suggests that difficulties in conceptual reasoning are morelikely to occur for chronic-progressive than relapsing-remitting MS patients, patients inthe former group tend to be older, have more severe disability, and are in effectexperiencing an exacerbation at the time of testing. Beatty et al. (1990) found that whendisease variables (such as duration of symptoms and age at onset) and demographicvariables (such as age and education) were controlled for, course type contributed nothingto the prediction of performance on a number of cognitive tasks, including the WCST.34Negative results, both with relapsing-remitting (Klonoff et al., 1991) and chronic-progressive (Jennekins-Schinkel et al., 1989) groups indicate that it is not necessarily thecase that MS results in impaired conceptual ability. The most consistent finding appearsto be increased variability in performance, suggesting that only a subgroup of MS patientsare impaired on these measures.Visual-spatial ability. When assessing the performance of MS patients on testsof visual-spatial and constructional abilities, a major difficulty arises. Most of the tests areeither pencil and paper copying tests, or are heavily reliant in other ways on motorcoordination, speed of responding, and visual acuity. Thus, although MS groups are likelyto be impaired on tests such as Object Assembly and Block Design (Heaton et al., 1985;Klonoff et al., 1991; Reitan et al., 1971), it is unclear whether their poor performance isattributable to impairment in visual-spatial functioning. For example, Franklin et al.(1988) reported that 52% of MS patients were impaired on a figure copying test.Jennekens-Schinkel, Lanser, van der Velde, and Sanders (1990), employing a similarfigure copying test, also showed that MS patients made more errors. The errors,however, were due to difficulty controlling pencil stroke, rather than structural details,suggesting a motor and coordination problem rather than a visual-perceptual deficit.Similar negative results have been found on the Hooper Visual Organization Test, anidentification task for cut-up pictures that requires no motor response (Minden et al.,1990; Rao et al., 1991). However, Rao et al. (1991) found significant impairment onother subtle visual-perceptual tasks such as judging line orientation, matching faces shownat different angles, and choosing identical complex designs from an array that differed onlyin small details. Poor performance on these tasks was not attributable to decreased visualacuity. Rao concluded that visual-spatial impairment was common among MS patients.Language functioning and classic focal symptoms. Classic aphasic syndromesassociated with focal brain lesions are rarely reported in the MS literature. However,several cases have been described (Olmos-Lau, Ginsberg, & Geller, 1977). For example, a35recent case report (Achiron et al., 1992) described two patients with relapsing-remittingMS having acute onset of aphasic symptoms. Interestingly, both patients were severelynonfluent aphasic, that is, they could express only a few abnormal syllables with preservedlanguage comprehension and markedly impaired writing ability. In both cases, languagefunctioning improved over several weeks. MRI indicated large plaques in the left frontalregion in one patient, and in the left centrum semiovale in the other, neither of which wereevident on MRI several months previously.Both Rao (1986) and Peyser and Poser (1986), in their reviews of the literature,are cautious in their conclusions that language dysfunction is rare in MS, since few studieshave administered language testing to groups of MS patients. Jennekins-Schinkel et al.(1990), Jambor (1969), and Heaton et al. (1985) did not find group differences on taskssuch as naming common objects, repetition of words and sentences, or verbalcomprehension. It would appear that, although isolated cases of frank aphasia occur,language functioning is unlikely to be impaired in MS.Processing efficiency. The concept of processing efficiency is complex andfraught with difficulty. Shallice (1988) describes this ability as the application of aschema, or task-specific organization, that places a particular pattern of demands on a setof specific functional subsystems necessary to attain a goal. The efficient application of aschema is multifaceted, and includes (at least) mental processing speed, sustainedattention, a good repertoire of and ability to choose among strategies, parallel tracking ofmultiple sets of information, execution of plan sequences, flexibility in the face offeedback, and the suppression of automated responses. Generally, one can say that"efficiency" is the ability to execute a complex task successfully with a minimal amount ofeffort. Clearly, then, efficient processing is likely to affect every test in every cognitivedomain.In the neuropsychological literature, efficiency is considered to be most directlyassessed by tests such as Backward Digit Span, Trails B, Word Fluency, Mental36Arithmetic, the Stroop Color Naming Task, and aspects of the WCST such asperseverations and set losses (Lezak, 1983; McCarthy & Warrington, 1990; Shallice,1988). A key element in all of these tasks is the production of rule-guided responses inconjunction with the suppression of highly automated, but inappropriate, responses(Norman & Shallice, 1986).In recent years, the subject of information processing has garnered considerableattention in the MS literature. Results to date suggest that MS patients may haveparticular difficulties in this area. For example, tests of verbal fluency using letters,animals, and occupations as cues for retrieval have all shown MS patients to be uniformlyand severely impaired compared with normal control groups, regardless of the diseasecourse (Heaton et al., 1985; Klonoff et al., 1991; Rao, St. Aubin-Faubert, & Leo, 1989;van den Burg et al., 1987). Interestingly, in contrast to most other tests where MS groupsshow increased variability, the variance of the MS group on fluency tasks is either thesame or lower than the control group, suggesting a consistent impairment across mostindividuals. Van den Burg and colleagues (1987) found that MS patients were alsosubstantially more susceptibility to interference from more salient aspects of stimuli, asmeasured by the Stroop Color Naming test.A recent study (Rao, St. Aubin-Faubert, & Leo, 1989) measured MS patients'mental processing time using the Sternberg (1969) paradigm. On this task, subjects holdin memory a digit set (either 1, 2 or 4 digits), and are asked to respond "yes" or "no" asquickly as possible to whether a target presented on the computer screen belongs to thedigit set. Sternberg showed that, as set size increases, there is a linear increase in reactiontime. The slope of the line can be considered a pure measure of memory scanning speedindependent of basic reaction time. Rao, St. Aubin-Faubert, and Leo (1989) found that,while total number of errors did not differ between the groups, the MS group had a meanslope of 100 msecs per digit, which was 47% slower than the control group, with a meanslope of 68 msecs per digit.37Taken together, the results of these studies suggest that MS may result in difficultyin several aspects of information processing efficiency that may translate on complex tasksinto difficulty with general organization and execution of plans or schemata. The resultsaccord well with the findings discussed earlier of difficulties with mental arithmetic, pooruse of strategy on problem solving and memory tasks, perseverative responding, anddifficulty with consistent retrieval of previously learned information. The contribution ofthese types of impairments to other complex tasks clearly warrants further investigation.In 1977, Beatty and Gange reported the intriguing finding of a significantcorrelation between scores on various memory tests and scores on motor tests such asFinger Tapping and Static Steadiness from the Halstead-Reitan Battery. This finding wasreplicated by Rao et al. (1984) who showed that memory impairment among chronic-progressive MS patients was related to decreased upper motor extremity coordination andgait ataxia, despite the fact that the memory measures did not rely on motor responses.Beatty and Gange (1977) suggested that the neuropathology of MS affects a unitarysubstrate mediating both these cognitive functions. It is tempting to speculate thatdisruption of the temporal organization of neuronal signals responsible for fine motorcoordination may have a similar effect on complex cognitive tasks by disrupting theefficient and coordinated processing of information.Prevalence of Cognitive ImpairmentIn groups of MS patients with heterogeneous length of illness and disease course,likely half of the sample will show evidence of some cognitive impairment. For example,Heaton et al. (1985) found that on cognitive tests with no motor component, 46% ofremitting-relapsing and 72% of chronic-progressive MS patients were within the impairedrange on a global measure of cognitive functioning. These estimates are similar to earlierstudies that did not consider disease course (e.g., Ombredane, 1926, 70%; Surridge, 1969,61%; Peyser et al., 1980, 55%). Rao's group (Rao et al., 1991) has recently reported acareful study of prevalence using a sample of 100 MS subjects (39 relapsing-remitting, 1938chronic-progressive, 42 chronic-stable), and 100 age-, education-, and gender-matchedcontrols. Employing criteria that excluded 95% of the normative sample, Rao reportedthat 48% of the MS subjects were cognitively impaired. Considering that 5% of thesesubjects would likely have occurred by normal variation in ability, he puts the final figurefor incidence of impairment at 43%. In specific areas of functioning, 21% of the MSpatients were impaired on the WAIS-R Verbal IQ, 22 to 31% on tests of learning andmemory, 13 to 19% on abstract reasoning tasks, 11 to 25% on processing efficiencymeasures, and 13 to 19% on visual-spatial tasks. These are likely conservative estimatessince the study did not include subjects with severe motor or visual impairment, subjectsresiding in a nursing home, or subjects who had previously undergone neuropsychologicalevaluation at their centre.While the prevalence estimates of cognitive impairment are surprisingly high, therehas been a tendency to characterize the MS deficit as mild (Beatty & Gange, 1977;Goldstein & Shelley, 1974; Peyser & Poser, 1986). Surridge (1969) categorizedintellectual deterioration in comparison to premorbid functioning. Of the patients studied,40.7% showed evidence of mild deterioration, 13.9% moderate, and 6.5% severedeterioration. Other studies (e.g., Rao et al., 1984; Vowels & Gates, 1984) foundconsiderably higher rates of severe and incapacitating deficits.Correlates of Cognitive ImpairmentAlthough depression has been suggested as the cause of poor cognitiveperformance in patients with MS (Goldstein & Shelley, 1974; Weingartner & Silberman,1982), this hypothesis is not borne out by studies directly addressing the question. Jambor(1969) found that MS patients who were clinically depressed did no worse, and actuallydid better on some measures, than nondepressed MS patients. No correlation has beenfound between depression on the Minnesota Multiphasic Personality Inventory andabstract reasoning tasks (Peyser et al., 1980). Even in a group of relapsing-remitting MS39patients with mild neurologic involvement and minimal functional disability, cognitiveimpairment is not associated with depression (Good et al., 1992).Impairment is not confined to late stages of the disease, but is evident in asubstantial number of patients in relatively early or mild stages. Indeed, for some patients,difficulty in memory and concentration may be the earliest and most prominent complaint(Young et al., 1976). Borberg and Zahle (1946) reported that of 330 patients, 41.6%showed signs of euphoria and dementia within the first 3 years of the disease. In samplesof patients with little functional disability, no current exacerbation of symptoms, and inwhom no cognitive impairment is evident on neurological examination, the incidence ofcognitive impairment on neuropsychological testing ranges from 30% to 50% (Grant etal., 1989; Ivnik, 1978; Klonoff et al., 1991), figures not particularly lower than the generalprevalence rates described earlier. Ivnik (1978) tested 3 groups varying in years since theonset of symptoms (1 to 5 years, 6 to 10 years, and greater than 10 years) and found nodifferences between the groups on various cognitive tests, even tests sensitive to motorimpairment. Others (Heaton et al., 1985; Rao & Hammeke, 1984) have failed to find acorrelation between length of disease and impairment on conceptual reasoning tasks.Counterintuitively, the severity of impairment correlates poorly, if at all, withmeasures assumed to reflect severity of pathology, including degree of disability ornumber of relapses (Baumhefner et al., 1990; Huber et al., 1987; Rao et al., 1985).Franklin, Nelson, Filley, and Heaton (1989) described 12 cases where cognitiveimpairment far outweighed neurologic disability, sufficient to severely incapacitate theseindividuals in their daily functioning at work and at home. Beatty et al. (1990) found thateducation and gender were the best predictors of performance, while disease variablessuch as course type, duration, and age at onset, contributed little to prediction ofperformance on a number of tasks that are sensitive to MS group impairments. A slighteffect of level of disability was found for those tests that put a premium on speededresponses, visual acuity, or required rapid complex informational processing. Beatty40emphasizes, however, that although statistically significant, level of disability was not anaccurate enough predictor of test performance to be of any practical importance.It would appear that chronic-progressive disease course is more likely to beassociated with cognitive impairment (Beatty et al., 1989), and the impairments have beenshown to be consistently more severe than in relapsing-remitting groups in the areas ofinformation processing speed (Litvan, Grafman, Vendrell, & Martinez, 1988), learning andmemory (Jambor, 1969; Rao et al., 1984), and problem solving (Peyser et al., 1980). Forexample, memory performance in chronic-progressive patients is more severely impairedthan in relapsing-remitting patients, to the extent that they learn less (Heaton et al., 1985),show less incremental learning over multiple trials, and are more likely to be impaired onboth recognition and recall (Rao et al., 1984). However, Beatty et al. (1990) employedmultiple regression to show that disease course did not predict performance on cognitivetests independent of other factors. Rather, chronic-progressive course was highlypredictive of increased disability that influenced some, but not all, cognitive measures.Patterns of Cognitive ImpairmentThe preponderance of periventricular and frontal lobe plaques have led researchersto consider whether the cognitive impairments found in MS are similar to those found inother diseases with striatal and frontal damage, such as Huntington's disease orParkinson's disease. The pattern of cognitive functioning characteristic of such"subcortical" groups includes slow and inefficient information processing, impairedmemory retrieval, difficulty in problem solving and abstract conceptualization, with anabsence of aphasia or apraxia (Cummings & Benson, 1984). Rao (1990) has highlightedthe similarity of this pattern to the impairments found in MS groups. He and others(Beatty, 1992; Vowels & Gates, 1984) have postulated that many, if not all, of the mooddisturbances and cognitive deficits that occur in MS may be accounted for by frontal lobedysfunction.41The description of a characteristic pattern of deficits implies that the pattern shouldbe evident in most, if not all, MS patients who are experiencing cognitive difficulties. Thehypothesis that a diffuse disease results in a prototypical pattern of deficits has been borneout in the past, particularly in the case of dementia of the Alzheimer's type. The courseand pattern of cognitive impairment are the major sources of diagnostic information forAlzheimer's dementia, and are 89% correct on post-mortem examination (Wade, Mirsen,Hachinski, Fisman, Lau, & Mersky, 1987).Whether or not MS patients show a typical subcortical pattern of cognitiveimpairment is unclear. Only two papers to date have addressed this question. Rao et al.(1991) calculated the percentage of MS patients who were impaired in a range ofcognitive functions. While these authors conclude that the overall pattern of cognitiveimpairment is compatible with a "subcortical dementia" classification, they also point outthat impairment is not uniform in MS. They found that, for example, half of the 31patients impaired on one memory measure were normal on another. Sustained attentionand visual-spatial perception were as likely to be impaired as memory functioning.Importantly, as many or more MS subjects were impaired on verbal measures such asVocabulary as on measures of abstract reasoning, and as many subjects were impaired onconfrontational naming as on measures of information processing, findings that are notconsistent with Cummings and Benson's (1984) description of subcortical dementia.Unfortunately, Rao et al. (1991) did not report the frequency with which variouscombinations of areas of cognitive impairment occurred. The results do, however, arguefor a substantial amount of heterogeneity in the types of impairment experienced by anindividual with MS.Beatty (1992) has pointed out that the results of current research give strongsupport to the hypothesis of a subcortical or frontal dysfunction. As a group, MS patientsdisplay all the characteristics associated with this subtype of dementia. However, oninspecting the data for individuals, Beatty et al. (1989) found that only 12% of the MS42patients they tested exhibited the expected pattern of impairment in memory and problemsolving and information processing speed. While the majority of patients were withinnormal limits on all tests, the remaining patients exhibited relatively isolated deficits in oneor another area of functioning. In general, measures of various "frontal" tasks, includingperseverative responses on the WCST, verbal fluency, and recognition memory, wereindependent of one another.Beatty (1992) argues that the heterogeneity of cognitive impairment in MS may bea powerful tool for understanding the cognitive processes underlying complexinformational tasks. For example, Beatty and Monson (1991) identified a group of MSpatients who were impaired on the WCST, another group impaired on recognitionmemory, and a third group who were impaired on both the WCST and recognitionmemory. Only the group impaired on both tasks had difficulty with metamemory; that is,they overestimated their recall on memory testing by more than 50%. In contrast, thepatients who were impaired on one or the other test, but not both, were able to predicttheir recall performance as accurately as normal controls (Beatty & Monson, 1991).ConclusionIn reviewing the literature, it is clear that many questions still remain unansweredregarding the cognitive impairment associated with MS. Early clinical observations,followed by more systematic psychometric testing of intellectual functioning, establishedthat cognitive impairment is an important aspect of the disease. While many of the earlystudies suffered from methodological problems, more recent studies have replicated andextended their findings with samples that are well described (see Peyser et al., 1990). Thetrend in MS research (and, indeed, in neuropsychological research in general) is movingtoward more indepth study of a single area of functioning (e.g., Jennekens-Schinkel etal., 1989; Rao, Leo, & St. Aubin-Faubert, 1989), rather than administering a broad rangeof clinical tests. While this approach may add more detailed knowledge of a particulararea of functioning in MS, it may also muddy the waters. There is the risk that, by43focussing on each area individually, we prematurely assume that the characterization ofcognitive impairment associated with MS is complete. We know that, on average, groupsof MS patients will be impaired on a variety of tests, particularly those that requirelearning of new materials, abstraction and conceptualization, mental processing efficiency,and, perhaps, visual-spatial ability. What is lacking, however, is an understanding of howthese findings generalize to the individual MS patient. Beatty's work (1992; Beatty &Monson, 1991) would suggest that substantial heterogeneity exists within this group.Without first identifying the nature of this heterogeneity, group studies will continue to behampered by averaging artifacts that may obscure a wealth of information. At issue ishow best to combine information about group performance with adequate assessment ofthe individual, a dilemma for many domains of psychology.Chapter 4Neuropathologic Correlates of Cognitive ImpairmentThe advent of in vivo structural brain imaging techniques such as CT, and morerecently, MRI, has allowed an investigation of the association between cognitiveimpairment and neuropathology of the individual MS patient. The increased resolution ofMRI has quickly made it the imaging method of choice for these studies (see Chapter 2).More recently, several studies have employed positron emission tomography (PET) andsingle photon emission tomography (SPECT) in order to determine the metabolic orfunctional integrity of brain regions.Emotional FunctioningOne important purpose for studies was to establish that cognitive impairment, evenin early stages of the disease, was due to neuropathology and not to other confoundingfactors such as depression and psychological distress. The body of existing literaturesuggests that measures of cognitive functioning show a moderate relationship to the globalmeasures of neuropathology, even in early or mild MS. In contrast, no relationship hasbeen found between neuropathology and level of depression. For example, Clark et al.(1992) found no correlation between ventricular size and depression, although significantcorrelations were found with cognitive performance. Others (Reischies, Baum, Brau,Hedde, & Schwindt, 1988) have failed to find a correlation between the number of lesionson MRI and emotional disturbance including depression, irritability, or euphoria.However, patients with severe emotional lability had a greater number of total lesionscompared to MS groups with other emotional disturbances.Disease VariablesFew studies have found associations between measures of neuropathology andillness variables. In one study, total area of abnormal signal on MRI in the cerebrum,4445cerebellum, or brain stem did not correlate with age of onset, illness duration, or numberof exacerbations (Baumhefner et al., 1990). Only the brain stem lesion measure wasmoderately correlated with functional disability as measured by the Kurtzke (1983) ED SS(r = -.35). No correlation has been found between ventricular size on CT and length orseverity of illness (Rao et al., 1985), and between number of MRI lesions and the EDS S(Franklin et al., 1988).Cognitive ImpairmentThe majority of the studies in this area have investigated the relationship between aglobal measure of neuropathology (such as total number of lesions or total area of lesions)and a global measure of cognitive impairment (such as a clinical rating of severity). Thisapproach has yielded conflicting results. In one study, Huber and his colleagues (1987)classified MS subjects as minimally, moderately, or severely impaired on aneuropsychological test battery. MRI scans were coded on a 5 point scale for cerebralatrophy relative to age, atrophy of the corpus callosum (CC), and severity ofperiventricular lesions. The only significant difference between the groups on thesemeasures was that atrophy of the CC was greater for the severely impaired group; generalatrophy or periventricular lesions did not differ. In contrast, Franklin et al. (1988)correlated the total number of lesions weighted by size on MRI with performance onindividual neuropsychological tests. Correlations with tests of learning and memoryranged from .31 to .36, while tests with a motor component correlated somewhat higher(e.g., Trails A, r = .47). The total lesion score correlated .35 with a cognitive summaryscore derived from the test battery. These authors accounted for the positive finding withthe larger number of subjects (60 vs 32 in Huber's study), the more extensive test battery,and the choice of chronic-progressive patients in whom impairment was more likely to befound. Other researchers have also found a relationship between number of cerebral lesionand "grades" of overall cognitive ability (Callanan, Logsdail, Ron, & Warrington, 1989).46Rating scales of impairment and number of lesions may restrict the range of valuesdenoting the extent of neuropathology, thereby artificially restricting the strength of theobtained correlations. In light of this, several studies have employed total lesion area astheir measure of pathology. Studies that calculate the actual area of each lesion present onMRI slices have, indeed, shown somewhat larger correlations with cognitive measures.Baumhefner et al. (1990) found that the total area of cerebral abnormal signal intensity onMRI correlated -.5 with performance on the Symbol-Digit Modalities test, a test that issensitive to generalized cognitive impairment. Rao, Leo, et al. (1989), also using totallesion area on MRI, found consistent correlations with tests from various areas ofcognitive functioning, in particular, with tests of memory and abstract reasoning. Forexample, after partialling out the effects of age and education, they obtained a correlationof-.49 with number of categories completed on the WCST, and correlations in the orderof -.31 to -.48 with delayed memory measures.Ventricular enlargement, either on CT (Rao et al., 1985), or on MRI (Clark et al.,1992) is associated with cognitive impairment on a variety of tests. Ventricularenlargement is presumed to reflect the preponderance of demyelinating lesions within thewhite matter surrounding the ventricles. For example, Rao et al. (1985) found that alinear measurement, the maximum width of the third ventricle, predicted performance ontests of learning, memory, and conceptual reasoning. Somewhat surprisingly, a subjectiveglobal rating of ventricular enlargement was better than any linear measurement inclassifying patients with impairment on multiple cognitive tests. As mentioned earlier, noventricle measure correlated with length of illness or with the EDSS.Clark et al. (1992) measured ventricle size on MRI for 123 relapsing-remitting MSpatients. An important feature of this study was the inclusion of a well-matched controlgroup (n = 60). Ventricular enlargement and periventricular white matter lesions occurwith normal ageing. Memory functions and speed of information processing also declinewith age. Hence, without a control group, one cannot be assured that an association47between ventricle size and various cognitive tasks is not a normal phenomenon of aging.Clark et al. (1992) calculated the correlation matrix for 9 linear and area ventricularmeasures and 12 neuropsychological tests. For the MS group, 29 of the possible 108correlations were significant, while none of the correlations for the normal controls weresignificant. Of note was the finding that the tests with the highest demand on tactile andmotor functions, such as the Tactual Performance Test, had fewer significant correlationsthan measures of memory, supporting the hypothesis that motor dysfunction does notaccount for cognitive impairment.While studies of ventricular size have obtained a consistent association withcognitive performance, the magnitude of the relationship is modest, usually withcorrelations in the order of .2 to .4. These are several possible reasons for this. As Clarket al. (1992) point out, ventricular enlargement is a secondary measure of disease burden,since it may reflect pathology only in the periventricular region, and may not includedemyelination distal to the ventricles. Number of lesions or total lesion area throughoutthe brain may be better estimates of the extent of global pathology. The correlationsobtained with these measures, however, are not much larger. Instead, the difficulty maybe in the very notion that the extent of pathology should correlate equally well with testsof memory, abstract reasoning, visual-spatial ability, and so on. In classic neurology,cognitive functions are assumed to some degree to be localized in specific grey matterregions. To date, there is no comparable theory for the effects of white matter lesions oncognition. Since one well-placed spinal or cerebellar lesion can render a patient incapableof walking, it is not inconceivable that the same is true for white matter lesions andcognitive functions. Given the idiosyncratic nature of MS neuropathology, whether ornot a particular cognitive function is affected in an individual may depend on such factorsas the localization, size, and distribution of their lesions. For this reason, one should notexpect a strong fit between cognitive measures (particularly individual test scores) andglobal measures of neuropathology. Global indicators of neuropathology give no clue as48to the relationship between affected area and cognitive dysfunction, and one is sobered bythe finding that the strongest relationships found are accounting for at best 20 to 22% ofthe variance on tests.Lesion Placement and the Role of the Corpus CallosumSeveral recent papers that focus on demyelination within the corpus callosum(CC). Huber et al. (1987) found that a rating of atrophy of the CC was associated withmore severe cognitive impairment. To investigate this further, Rao and his colleagues(Rao, Leo, et al., 1989) found that the total area of the CC (presumably measuringamount of atrophy due to demyelination) predicted performance on processing efficiencymeasures such as memory scanning speed, sustained attention, and rapid problem solving.In contrast, total number of cortical lesions was the best predictor of recent memory,abstract reasoning, language ability, and visual-spatial problem solving, areas of cognitionmost closely associated with classic "cortical" dementia. Unfortunately, CC atrophycorrelated equally well with tests of verbal skill and reasoning that should be "cortical" innature, such as the Vocabulary and Comprehension subtests of the WAIS-R.Pozzilli et al. (1991) based their hypotheses on neuropsychological and animalliterature suggesting that the anterior CC (the genu) is specifically involved in cognitivefunctions, while the posterior CC (the splenium) is involved in sensory integration. Theyused multiple regression analysis using area of the genu, splenium (both corrected forbrain size), periventricular lesion area, and subcortical lesion area (lesions separate fromthe ventricles) to predict performance on various cognitive and visual-spatial tasks. Theyfound a specific and independent association between anterior CC size and VerbalFluency, independent of the periventricular and subcortical lesions. However, noindependent relationship of the anterior CC was found with other cognitive tasks includingproblem solving and memory performance. No independent relationship was found for theposterior CC to any of the cognitive measures, including visual-spatial and constructionaltasks. Thus, while CC atrophy is clearly associated with cognitive impairment, it remains49to be seen whether CC atrophy is related to specific functions or is simply another markerof the extent of total cerebral demyelination, in the same way as ventricular enlargement.Several papers have classified lesions according to brain regions. Swirsky-Sacchetti et al. (1992) calculated total lesion area on MRI in the frontal, temporal, andparieto-occipital regions unilaterally. Multiple regression analyses indicated that leftfrontal lobe involvement best predicted performance on problem solving, verbal recall, andword fluency tasks. Left parieto-occipital involvement best predicted deficits in verballearning and visual integrative skills such as the Hooper Visual Organization test. Incontrast, Huber, Bornstein, Ranunohan, Christy, Chakeres, and McGhee (1992) did notfind any function-specific association with area of MR1 lesion in the left and righthemispheres, or in left and right frontal, temporal, parietal, and occipital lobes. Totallesion area, regardless of distribution, correlated best with the vast majority ofneuropsychological tests, ranging from r = .31 for a problem solving test (Category Test)to r = .82 for an alternate sequencing task (Trails B). Most correlations were in the orderof .5 to .6, substantially larger than those obtained in similar studies, a particularlysurprising outcome given that the study only included 35 patients. The correlations wereconsistent across all areas of lesion placement. As with the CC studies, it remains unclearas to whether white matter lesions show functional specificity similar to those seen withgrey matter lesions.Other Imaging TechniquesPerhaps all of the measures, including ventricular enlargement, number of lesions,lesion area, and CC atrophy, reflect difftise processes that are not adequately captured bythe structural abnormalities evident on MRI. Functional studies have identified someinteresting reasons to believe that this is the case. Feinstein, Kartsounis, Miller, Youl, andRon (1992) have shown that Ti relaxation time values on MRI taken from samples ofnormal-appearing frontal lobe tissue correlated as highly with cognitive ability as did totallesion area, including naming ability (Pearson's r = -.43), problem solving (Spearman's r =50-.43) and visual memory (Speartnan's r = -.50). Only frontal lobe samples were obtained,so it is not clear whether this phenomenon is specific to frontal lobe functioning orwhether it would apply to other areas as well. A similar intriguing association between Tiparameters and severity of cognitive decline has been reported in the Alzheimer's literature(Besson, Crawford, & Parker, 1989). Increased Ti relaxation times reflect the presenceof microscopic abnormalities including perivascular inflammation, myelin breakdown, andastrocyte hyperplasia in normal-looking white matter (Allen, Glover, & Andersen, 1981).Evidence for decreased blood-flow of the frontal lobes and the left temporal lobehas been found using single proton emission computerised tomography (SPECT) in agroup of 17 MS patients with impaired verbal fluency and memory performance comparedto a well-matched control group (Pozzilli, Passafiume, et al., 1991). Blood-flow wasmeasured by uptake of Tc99m HMPAO, a radio-pharmaceutical that passes the blood-brain barrier and is trapped within functioning cells. In spite of the metabolic asymmetryof the left hemisphere in the MS patients, no lateralized differences appeared on MRI. Ina second study measuring cerebral metabolic rates for glucose uptake using positronemission tomography (PET) with the analog tracer deoxyglucose, Pozzilli et al. (1992)found metabolic asymmetry only in those MS patients who had extensive CC atrophy onMRI compared with controls or with other MS patients without CC atrophy. Left frontal,temporal, and parietal association cortices showed significantly lower metabolic levels onthe left than on the right for this group. Again, no asymmetry was found in thedistribution of lesions on MRI for any group. The asymmetry of metabolic functioning isconsistent with evidence from animal studies showing that normal metabolic interactionsbetween the hemispheres are disrupted with callosotomy in the rat (Soncrant, Horwitz,Sato, Holloway, & Rapoport, 1986).Investigations of the relationship between cognition and functional measures of thebrain are in their infancy, and thus it is difficult to understand the implications of thesefindings. The importance of these studies, however, is that they highlight changes to the51functional status of brain regions that may be distal to structural abnormalities evident onMRI. The findings of frontal lobe dysfunction and left temporal lobe dysfunction are ofparticular interest because of their association with cognitive impairments found in MSpatients, including abstract reasoning, verbal fluency, perseverative responding, andlearning and memory.Summary and Future DirectionsThe relationship between cognition and neuropathology in MS is sufficientlyestablished to rule out alternative explanations for the impairment such as depressed moodor motor dysfunction, even in samples of early and mildly affected MS patients. Whilesome studies have obtained surprisingly high correlations, (e.g., Huber et al., 1992), mostresearchers have found that, at best, global measures of neuropathology account forapproximately 20% of the test variance. The result, replicated often, that increasedneuropathology is associated with increased cognitive impairment has not broadened ourunderstanding of the role of myelin in cognitive functioning. Evidence thus far supportingthe hypothesis of more specific relationships between lesion site and cognitive functions(as would be predicted by models of grey matter lesions) is contradictory. The question ishow to best to proceed with future research in this complex area.As with the cognitive literature, a major problem concerns the heterogeneity of theMS subjects. With the exception of Clark et al. (1992), who included 123 MS subjects,no study described earlier included more than 64 MS subjects, and some, as few as 17(Pozzilli, Bastianello, et al., 1991). The average number of subjects was 36. ConsideringRao et al.'s (1991) estimate of the prevalence of cognitive impairment (43%), the typicalstudy included 15 subjects with cognitive impairment. However, since cognitiveimpairment is not consistent across all areas, far fewer subjects would be impaired on anyone test. Correlations, multiple regression, or statistical tests of area-specific associations,particularly using individual test scores, will suffer from a lack of power due to thepreponderance of unimpaired subjects.52A second difficulty with the research to date is its reliance on clinicalneuropsychological tests. One can fail a complex task such as the WCST for manyreasons, and expecting that one specific lesion site will be associated with its impairment isan oversimplification. (Indeed, this is one good reason why global measures ofneuropathology correlate moderately with virtually every neuropsychological test, sincethey are multifaceted and draw on numerous abilities.) The work of Beatty (1992; Beatty& Monson, 1991) exemplifies this. He found that subgroups of MS patients with memoryimpairment differ qualitatively from MS patients with problem solving and memoryimpairment. Both groups are impaired in their ability to recognize previously learnedmaterials, but their underlying deficits may differ. Analysis of the quality of impairment onneuropsychological tests may be essential prior to identifying associations with anatomicalbrain regions.The techniques of neuropsychology employed to identify the behavioural sequelaeof focal cortical or grey matter damage may prove fruitful in this regard. By carefullyselecting groups of MS patients (or even several patients) who are differentially impairedin two cognitive areas, double dissociations between impairment and lesion sites can beidentified (Shallice, 1988; Teuber, 1955). In this way, hypotheses may be generated as tothe function(s) of particular white matter tracts and replicated with similarly impaired MSpatients.Several developments in MRI scanning and analysis may be of particular interest inMS research. For example, lesions in MS occur within axonal tracts that often project todistal and diffuse areas of the brain. Two lesions occurring, for example, even a fewmillimeters apart within the internal capsule will affect very different areas of the brain,and may have different behavioural consequences. In subgroups of MS patients whosecognitive impairment is well documented, careful morphometric analysis of lesions, withregistration to a standardized atlas, may be particularly useful in identifying anatomicalcommonalities. The technique reconstructs three dimensional images of a "typical" or53averaged brain (Jernigan, Archibald, Berhow, Sowell, Foster, & Hesselink, 1992). Aswell, the use of gadolinium-dTPA enhanced scans will be of particular interest in thefuture in providing information about the various stages of a lesion (Paty, 1990). A lesionin its early stages of demyelination may have very different effects on cognition than agliotic scar, and MRI cannot disentangle these two on routine scan.An equally intriguing issue for research in MS is the information about brainfunctioning that the structural images of MRI alone cannot provide. Functional imagesand metabolic measures of brain functioning, such as PET and SPECT have already givenindications that MS pathology may result in important brain changes that are diffuse, distalto, and perhaps independent of, the site of lesions (for example, the work of Pozzilli et al.,1992 and Feinstein et al., 1992). An important caveat to the use of measures such as PETand SPECT is that they assume a constant baserate for uptake in all areas of the brain. Ina disease such as MS, where the blood-brain barrier is compromised, the basicassumptions of the model may be violated, leading to erroneous inferences regarding area-specific changes in metabolic functioning. The techniques for assessing in vivo brainchanges need to become better understood before inferences can be made about theinformation they provide.One final caveat: There has been an explosion of papers in this area in recentyears. Unfortunately, the quality of the research has been extremely variable. Reminiscentof the early neuropsychological literature in MS, researchers are inconsistent in theirdescriptions of sample characteristics, with no mention, for example, of how many patientsare experiencing exacerbations, current medications, or recruitment procedures. In severalstudies, MRIs were administered up to six months prior to the date of neuropsychologicaltesting. In one study (Mariani et al., 1991), scans were completed using a range ofrepetition times and echo times. The method section states that four images were"usually" obtained on the axial plane, and coronal slices were "frequently" obtained. Nomention was made of how many slices were used for each subject to obtain the numerical54estimates of lesion area. Further, although this was designed as a longitudinal study with24 months intervening between the two test sessions, no attempt was made to precisely re-position the head for scanning, or even to use the same scan protocol on the two sessions.Thus, changes in lesion area from one session to the other may have had little to do withactual changes in neuropathology.Another study (Izquierdo, Campoy, Mir, Gonzalez, & Martinez-Parra, 1991)assessed MS patients using the WAIS (a test that was revised in 1981) and an obscurememory battery that is not described in detail, with no control group, and usingunspecified normative data to assess impairment. The authors then correlated the memorymeasures with lesion area in the periventricular region, the brain stem, the corona radiata,the centrum semiovale, and the basal ganglia. Based on the finding that onlyperiventricular lesions correlated (.34 to .44) with 4 of the 11 memory measures, theyconcluded that verbal learning and memory disturbances are specifically due toperiventricular lesions. With only 17 subjects, it is highly likely that the number of patientswith lesions in an area such as the basal ganglia was close to zero, but the authors fail toreport the actual incidence of lesions within each area.Clearly, there is a need for researchers in this area to provide detailed informationregarding both the imaging techniques employed and the methods for neuropsychologicalassessment. Without such information, the outcomes of studies remain uninterpretable.Chapter 5MethodsSubjects and Test ProceduresThe MS patients were volunteers from the University of British Columbia MSClinic who met the following criteria: 1) age less than fifty; 2) a diagnosis of clinicallydefinite MS with relapsing/remitting course; 3) in remission at the time of the assessment;4) diagnosis made before the age of forty; 5) functionally independent as assessed usingthe Kurtzke Clinical Rating Scales and the Expanded Disability Status Scale (Kurtzke,1955; 1983); 6) no medication or excessive non-prescribed drug usage (e.g., alcoholabuse, cocaine use); 7) no other complicating medical condition; and 8) no history ofpsychiatric illness predating the diagnosis of MS. These criteria ensured a relativelyhomogeneous sample that was free from many of the possible confounding factorsdiscussed in the literature (Klonoff et al., 1991; Peyser et al., 1990).Where possible, the MS subjects were asked to find a same sex, unrelated controlsubject of similar background and interests. Once potential control subjects wereidentified, they were interviewed by phone to ensure that they met the same criteria whereappropriate as the MS group, including age, medical complications, psychiatric history,and drug usage.Medical history and most recent neurological examination results were obtainedfor the MS subjects through the MS Clinic records. On the test day, all subjects wereinterviewed in order to obtain demographic information, and several psychological andpersonality tests were administered. A neuropsychological test battery was thenadministered in random order. The battery took approximately 3 hours to complete, andsubjects were given appropriate rests during the examination period. The MRI wasadministered during the afternoon on the same day. The present study included 177 MS5556patients and 89 matched controls with complete neuropsychological and historical data.Of this group, scans were available for data analysis for 150 MS patients and 66 controls.The procedures in the present study were approved by the University of BritishColumbia Clinical Screening Committee, and informed consent was obtained from allsubjects.Cognitive Test Battery and AnalysesThirteen tests were selected for analysis in the present study. These tests wereadministered as part of a larger neuropsychological battery (described in Klonoff et al.,1991). The tests were selected because they cover a range of cognitive functions thathave been assessed previously in MS, including five areas of interest: verbal skills, learningand memory, abstract conceptualization, information processing efficiency, andconstructional abilities. The tests included the Information, Vocabulary, Digit Span,Arithmetic, Similarities, Picture Completion, and Block Design subtests from the WechslerAdult Intelligence Scale-Revised; the Benton Visual Retention Test; Word Fluency (FAS);Trails A & B, and Categories from the Halstead Reitan Neuropsychological Battery;Paired Associates from the Wechsler Memory Scale - Revised; Memory for Objects. Adescription of each test is provided in Appendix B.Analyses performed included: 1) descriptive statistics and significance testscomparing MS and controls for each neuropsychological test; 2) an analysis describing thedistribution of impairment within the MS group; 3) a cluster analysis that identifiedpatterns of impairment across tests from various cognitive domains; and 4) twoindependent validations of the cluster solutions.Descriptive statistics. Mean group performance was analysed with Hotelling'sT-square omnibus test to control for Type I error rate, and followed up with univariatet-tests. All significance levels were reported for one-tailed t-tests, since brain damage tothe MS group was expected to result in decreased levels of performance compared tomatched controls. Group differences in variance were tested using Hartley's F-max ratios.57Incidence of impairment. Since the purpose of the present study was toinvestigate patterns of impairment in MS, a logical first step was to identify those subjectswhose cognitive impairment was unequivocal.On each test, the scores of all subjects were standardized relative to the controlgroup. That is, z-scores were calculated using the mean and standard deviation of thecontrol group. Scores that reflect number of errors or response times were multiplied by-1, so that negative z-scores consistently reflected poor performance. Impairment on asingle test was operationally defined as a z-score of -1.64 or greater, which is consistentwith the significance level chosen for the one-tailed t-tests described earlier, and indicateda level of performance worse than 95% of the normative sample. The percentage of MSsubjects who were impaired on each of the 13 tests was calculated.In order to classify subjects as "impaired" or "unimpaired", the number of tests outof 13 that met this criterion were counted for each subject. The number of impaired testsrequired to classify a subject as cognitively impaired was derived by examining thedistribution of impaired tests for the control group, and choosing the number thatexcluded at least 95% of the control group. Such a stringent criterion likelyunderestimates the prevalence of significant cognitive impairment among the MS patientsas some subjects may decline from a high level of premorbid functioning to performancelevels that would still be considered within the average range.For the purposes of the cluster analyses, two groups were formed. The impairedgroup included MS and control subjects (i.e., 5%) who fell below the cutoff describedabove. The unimpaired group included MS and control subjects (95%) who were notclassified as impaired.Cluster analysis. Cluster analysis was employed in order to identify patterns ofimpairment. Cluster analysis is a non-inferential statistical technique that can be used onmultivariate data in order to create classifications by forming relatively homogeneousgroups of subjects with similar profiles of scores across multiple variables. Cluster58analysis is thus a descriptive technique that is particularly useful when the structuralaspects of multivariate data are of interest and a large number of subjects are included in astudy (Kaufman & Rousseeuw, 1990).The most widely used and best investigated method of clustering is the hierarchicalagglomerative method (Ward, 1963). Ward's minimum variance method, used in thepresent study, considers all possible combinations of profiles. The method computes adistance measure (squared Euclidean distance) between profiles and combines the pairwith the smallest sum of the-squared differences to form the first "cluster". Subsequently,it combines profiles that minimize the increase to the within-group sum of squaredvariance. The technique parcels the total sum of squares into "within-group" and"between-group" variability, thus yielding a measure of the percentage of variabilityaccounted for by the clustering solution. In an ideal cluster solution, group memberswould obtain very similar profiles of scores, thus yielding a minimal within-group errorterm. As well, an ideal solution would yield group profiles that are clearly distinguishablefrom one another. Thus, the majority of the variability should be accounted for by thebetween-group term.Ward's (1963) method is not as sensitive to small outlier groups as are other typesof cluster techniques (Milligan, 1980), but has been shown empirically to yield moreaccurate clusters than three other techniques, namely single linkage, complete linkage, andaverage linkage. The method is biased toward finding severity groups or spherical clusters(Blashfield, 1976). Golden and Meehl (1980) showed that Ward's method yielded equallyhigh or higher values of coefficient kappa compared with other techniques. Coefficientkappa indicates the improvement in classification over random assignment. However, nomatter which technique is employed, the stability of the cluster solution is determined bythe reliability of the measures being clustered. The more unreliable the test variables, theless susceptible the clusters will be to replication (Kaufman & Rousseeuw, 1990).59Morris, Blashfield, and Satz (1981) point out that cluster methods using differenttypes of distance measures and combination criteria will yield different cluster solutions forthe same data set. They further point out that, even with randomly generated profiles,cluster analysis will yield a solution. Thus, the empirical assessment of internalconsistency in the obtained cluster solution using other statistical methods such asdiscriminant function analysis is critical. Validity of the cluster profiles may be assessed bydetermining their ability to predict performance on an independent set of measures.Cluster solution. In the present study, cluster analyses were carried outseparately for the impaired and unimpaired groups. Solutions were obtained separately forthe two groups in order to determine: 1) whether patterns arose that were specific to theimpaired group or occurred naturally in the unimpaired group; and 2) whether profilesoccurred within the unimpaired group with an overrepresentation of MS subjects thatmight signal early or less severely impaired profiles. Clustering was carried out on threeof the 13 tests using Ward's (1963) hierarchical method. Tests from the three areas ofcognition that showed evidence of impairment in the present study were included, namely,learning and memory (Paired Associates), information processing efficiency (WordFluency), and constructional ability (Benton Visual Retention). The tests have no finemotor coordination component, and have the widest range of scores of the tests withineach cognitive area.The cluster solutions were chosen when 85% of the variability was between-group.Since Ward's method tends to keep groups separate with similar profiles that show anoverall severity difference, the resultant group profiles were examined visually and anysimilar profiles were combined, provided that they were also combined as the next steps inthe clustering solution. Discriminant function analyses were performed using the clustergroups as criteria and the 3 clustering variables as predictor variables, both before andafter groups were combined because of visual similarity. This procedure ensured that theresultant groups were consistent and that group discriminability was maintained.60Cluster validation. One of the major assumptions in neuropsychological researchis that impairment of function resulting from brain damage is constant (Shallice, 1988).Thus, the clusters should predict the profile of performance on a new set of tests that tapcognitive operations similar to those necessary for the three clustering tests. In order tovalidate the cluster profiles, different tests were chosen from the test battery thatemphasize the same three cognitive functions, namely, memory, processing efficiency, andconstructional ability. The tests are compared briefly below.Word Fluency versus Similarities. Both of these tests require that the subject retrieveappropriate information in response to a rule, while suppressing other informationthat comes to mind, perhaps more readily, that does not fit the rule. Word Fluencyrequires subjects to access words on the basis of similar first letters whilesuppressing other more fluent responses, such as words that are semanticallyassociated with the previous word. Similarities requires the subject to identify thefeature that two items have most in common. The word or aspect of the two itemsthat is correct will be the higher-order category; for example, "apple and banana"are both fruits; "table and chair" are both furniture. Subjects must suppress otheraspects that come to mind, such as that "table and chair" are made of wood, havelegs, etc. There are obvious differences between the tasks; Word Fluency is atimed test, requiring subjects to make continual responses over a one-minuteperiod, while Similarities requires a single, untimed, response. However, both areconsidered tests that require efficient selection and retrieval of verbal information,and both have been associated with frontal lobe dysfunction.Benton Visual Retention versus Block Design. Both tests require copying of ageometric design, one using pencil and paper and the other by actually placingblocks in a similar configuration. Performance on the Benton may be impairedbecause the subject has difficulty remembering the visual array for short intervals,since the test was administered with a ten second interval from presentation to61copy. Memory is not a necessary component of Block Design since the design tobe copied is visible to the subject at all times. However, both these tests aresensitive to constructional and visual-spatial difficulties, and the Benton has beenshown consistently to be more closely related to performance on other copyingtasks than memory tasks.Paired Associates versus Memory for Objects. The tests require the subject to recall alist of words after a short delay. While Memory for Objects presents study itemsin a visual array (subjects see the actual objects arranged on a table), all the objectsare easily encoded verbally, and hence the test likely reflects verbal memory morethan visual memory. Paired Associates also requires the subject to recall items, butin response to an associative cue that was presented with the item at the time ofstudy. As well, Paired Associates are presented over three trials, whereas Memoryfor Objects entails one-trial learning. These two tests may be most similar on thefirst trial of Paired Associates. Despite these differences, if subjects are impairedin the areas of learning and/or retrieving verbal information, they would likely havedifficulty on both of these tests. Memory for Objects is likely a less sensitivemeasure of memory ability; this conjecture is supported by the finding that mostcontrol subjects perform the test without error.Cluster validation analyses. A discriminant function analysis was performedusing the validation tests as predictors and the original cluster groups as criterion groups.This provided an overall correct classification rate for each cluster group. Chi-squarestatistics were calculated in order to assess the improvement in classification over chanceassignment. Analyses were carried out separately for the unimpaired and impaired groups.A second approach was to consider the pattern of differences between theimpaired clusters on the three tests, and to determine whether the profile pattern was alsofound with the replication tests. For each of the three clustering tests, differences betweenthe cluster groups were assessed with a one-way Analysis of Variance (ANOVA) and62Tukey pairwise followup procedures. A single hypothesis was generated describing thegroup differences expected with the validation test. For example, if only one cluster groupobtained significantly better performance than all other groups on the clustering test, thenthis pattern should obtain on the validation test as well. Groups with similar performancewere combined so that each hypothesis was tested using a t-test.Magnetic Resonance Imaging (MRI) and Cognitive DeficitsThis section describes the methods and analyses used to determine the relationshipbetween cognitive impairment profiles to findings on the MRI. Subjects included in theanalyses were 150 MS subjects and 66 control subjects who underwent an MRI scan onthe day of their neuropsychological testing.MRI protocol. All subjects were scanned on a Picker International CyrogenicMR 2000 machine, with a magnet strength of .28 Tesla operating at .15 Tesla. Imageswere obtained using a simultaneous multiple 12-slice (1 cm) spin echo sequence with arepetition time of 2000 msecs and two echo times, 60 msecs on the transverse plane and120 msecs on the sagittal plane. Scans were read and coded by a radiologist, Dr. DavidLi, for presence of a lesion in fifty predetermined brain sites.MRI analyses. The main purpose for including an MRI component to the studywas to determine the association between lesion site and cognitive impairment. Severalstatistical problems arise, however, because of the large number of lesion sites and becauseof the small number of subjects in several of the impaired cluster groups.First, due to the large number of lesion sites, the analyses only addressed a singlelesion model, that is, the hypothesis being tested was whether a single lesion site isassociated with a particular cognitive profile. Equally plausible, however, is the scenariowhere a lesion in two or more adjacent sites cause a deficit to occur, or alternatively, alesion occurring in either one site or another may lead to a deficit. Entertaining all thepossible combinations of lesion sites would lead to an unreasonable number of statistical63tests. However, a single lesion analysis will likely rule out the majority of lesion sites, thusallowing further analyses that may include multiple sites.Even considering only a single-lesion model, 50 lesion sites makes Type I error aproblem. One way to decrease error was to pare down the number of sites considered foranalysis by including only those sites with reasonable baserates of lesion occurrence.Although lesions were found in all 50 of the sites in the MS group, the extremely low orhigh frequency of lesions in some sites precluded their usefulness in differentiating theimpaired groups. For example, Clark et al. (1992) found that over 80% of MS patientshad lesions in the periventricular occipital horns, while several other sites had lesionbaserates as low as 3%. Since the smallest cognitive cluster group constituted 5% of theMS sample (n = 8), sites with lesion frequencies below 5% were excluded. Sites withlesion frequencies over 45% were also excluded. Brain stem sites were not included sincethis area would not be considered important for complex cognitive functioning. On thebasis of these exclusion criteria, 24 of 50 sites were chosen for analysis. They includedthe left and right hemisphere 1) frontal, frontal/parietal, and parietal supraventricularregions, 2) temporal horn of the periventricular region, 3) frontal horn and parietal body ofthe deep white matter, 4) internal capsule, 5) frontal, parietal, and temporal grey/whitejunctions, 6) insula of the deep grey matter, and 7) the splenium and genu of the corpuscallosum.For each site, a frequency table was constructed indicating the lesion occurrencefor each of the impaired cluster groups and the combined unimpaired MS group. The bestoutcome for the lesion data would be so obvious that no statistics would be needed; thatis, if all the lesions in a given site fell within one of the cluster groups and none of themoccurred within other groups. Less obvious outcomes were assessed statistically using thechi-square statistic. However, the low lesion baserates in some sites and the small numberof subjects in several of the clusters pose a problem. For example, a frequency table (seeTable 1) was constructed using a hypothetical lesion site with a baserate of 10%. On the64basis of the actual n's obtained from the cluster solution, the table indicates the number oflesions in each cluster that would be expected to occur by chance alone. In this example,the expected frequency (EF) of lesion presence is less than 5 in 42% of the cells (5 of 12).Insert Table 1 hereWhen the EFs are low or if any cell has an EF of 1 or less, the obtained statistic nolonger approximates the chi-square distribution. Siegel and Castellan (1988) suggest thatno more than 20% of the EFs be less than 5, with no EF equal to or less than 1. Theypoint out that as the number of rows and columns of the frequency table increase, and asthe total number of subjects increases, the chi-square statistic approximates thedistribution more closely. However, no guidelines are available in the literature as to whenthe approximation is acceptable. This does not prohibit the analysis of the low baseratesites. It should, however, make one cautious about interpretation of the frequency tableon the basis of the chi-square statistic, particularly when the results are not clear cut.Using the present number of cluster groups and subjects, a lesion baserate of 20% yields 4of 12 of cells (33%) with EFs less than 5. The EFs are acceptable when the lesionbaserate is 30%, yielding 2 of 12 cells (17%) less than 5. Whatever the outcome, theresult will be more interpretable if the result is consistent with the extant literature on aparticular cognitive function. A brief review of the literature on neuropathologicalcorrelates of the three cognitive functions being clustered is contained in Appendix C.In view of these difficulties, chi-square values and alpha levels were obtained froma Monte Carlo series of frequency tables where lesion baserates and outcomes weresystematically varied. The value for alpha was then chosen a priori to be conservativeenough to adequately control chance error, but to include outcomes that weretheoretically meaningful. Table 2 lists the resultant chi-squared statistics and alpha values65for artificially constructed frequency tables at three lesion baserates, 15%, 20%, and 30%.The percentage of lesion occurrence was systematically varied within the smallest group(n = 8) with the remainder of the lesions spread equally (in terms of EF's) throughout theother 5 groups. The smallest group was chosen for the analysis because, statistically, ameaningful result within the smallest group will be most difficult to obtain.Insert Table 2 hereAs is evident from Table 2, alpha increases as the percentage of lesions present inthe group increases, but dramatically decreases as the lesion baserate increases. The chi-square statistic, used with the present group n's, is extremely conservative. At a baserateof 35%, even with lesions occurring in 100% of the smallest group, the chi-square statisticis not significant. Thus an alpha of .01 is adequate to be applied to all the analyses. Whilethis value excludes findings for the smallest group for lesion sites with baserates over25%, the value is less conservative than the Bonferroni adjusted rate of .05 with 24 tests(p=.002). When the same percentage criteria are applied to the next largest group (n=11),all alpha values exceed the Bonferroni adjustment. Bonferroni adjustments to largenumbers of tests are found, in Monte Carlo studies, to be overly conservative (Hays,1973).Even with some highly significant findings, the usefulness of the information islikely theoretical and not diagnostic. For example, with a 20% lesion baserate, if lesionsoccur in 85% of the group with the smallest number of subjects, the diagnostic specificityand sensitivity are good, .84 and .82, respectively, yielding percentage correctclassifications of 84%, with a false positive rate of 15%. The false positive rate increasesas the baserate increases, so that at 40% lesion baserate and 85% of the group with a66lesion present, the false positive rate will rise to 36%, even though the sensitivity remainsat .82.Chapter 6ResultsDemographicsThe demographic information contained in Table 3 indicates that the MS andcontrol groups were well matched on age, education, and female to male ratio. Thedistribution of highest occupational status achieved was similar. The only aspect thatdiffered between the two groups was in the area of current employment status. Fewer MSsubjects were working full time than controls (39.5% vs 66.3%, respectively). MSsubjects were more likely to be unemployed (21.4% vs 2.2% for the controls) or workingpart time (21.5% vs 14.6% for the controls).Insert Table 3 hereThe neurological data for the MS patients are presented in Table 4. The MSsample, on average, began to experience first symptoms at age 27, with an average of 5years from symptom onset to diagnosis. The Kurtzke Functional Scales and EDSSindicate minimal physical dysfunction on neurological examination. In particular, theminimal score on the Mentation subscale is noteworthy, indicating that cognitiveimpairment was not evident in virtually all subjects in the sample on standard neurologicaltesting. The EDSS indicated that the sample was ambulatory and able to function withoutassistance for a full day.67Insert Table 4 hereNeuropsychological Battery Descriptive StatisticsThe comparison of the MS group and the controls yielded a significant multivariateHotelling's T-square (T(264) = 4.23, p < .0001), with 9 of the 13 followup contrastssignificant. Variance for the MS group was larger on 5 tests, as indicated by F-maxstatistics, including one test (Digit Span) where the groups means did not differ. Means,standard deviations, t-test and F-max statistics for 13 neuropsychological tests arepresented in Table 5. All significance levels reported for the t-tests are one-tailed.Insert Table 5 hereIncidence of ImpairmentUsing the control group mean and standard deviation to calculate z-scores,impairment on a test was operationally defined as a z-score of -1.64 or less. This cutoffcorresponds to the 5th percentile of the normal sample. Table 6 indicates the percentageof MS subjects with scores below the 5th percentile. On ten of the thirteen tests, 10% ormore of the MS group were impaired. These include the nine tests with significant groupmean differences, and Digit Span, for which the group variances differed. Nearly a quarterof the MS group were impaired on the Benton Visual Retention Test, Paired Associates,and Trails B-A.68Insert Table 6 hereThe distribution of impaired tests for the two groups is presented in Table 7. Themean number of impaired scores for the MS group (mean = 1.76, sd = 1.91) was largerthan for the control group (mean = .73, sd = 1.08), as indicated by a t-test (t (264) = 4.72,p < .001, two-tailed). Of the total subject sample, 80% of the control group had zero orone impaired test score, while only 55% of the MS group had zero or one impaired testscore. Five control subjects (5%) performed in the impaired range on 3 or more tests,compared to 58 MS subjects (33%). No control subject was impaired on more than 4tests, whereas 14 of the MS patients (8%) were impaired on 5 or more tests. Two MSsubjects were impaired on 9 of the 13 tests. On examining individual profiles for the MSsubjects with 5 or more impaired tests, 8 subjects scored near or substantially below thecutoff on virtually every test administered, suggesting global cognitive decline.Considering the results, any subject with 3 or more z-scores of -1.64 or lower (i.e., belowthe 5th percentile of the control group) was classified as "impaired" for the purposes offurther analyses. Thus, the impaired group consisted of 58 MS and 5 controls. Theunimpaired group included the remaining subjects, 119 MS and 84 controls.Insert Table 7 hereCluster Analysis ResultsCluster analyses were performed separately for the impaired and unimpairedsubjects using Ward's (1963) hierarchical method. The clustering variables were the6970standardized scores on the Benton Visual Retention Test, Paired Associates, and VerbalFluency.The clustering solution for the impaired group with 85% between-group variabilityresulted in 10 groups. The profiles of the 10 groups were graphed, and any groups withprofiles that appeared to be similar in shape but with a severity difference were collapsed.Collapsing visually similar profiles yielded 6 final groups. The combinations correspondedto the next combinations in the cluster analysis, resulting in 63% between-groupvariability. Discriminant function analysis using the 3 clustering variables as predictorsand the original 10 impaired clusters as criterion groups correctly classified 96.83% of thesubjects. After collapsing the profiles to 6 on the basis of visual similarity, the correctclassification rate dropped only slightly to 95.24%. Three of the 6 groups were 100%correctly classified, while the other three groups each had one subject misclassified. Theprofiles of the ten original impaired clusters and the resulting six groups are presented inFigure 1.Insert Figure 1 hereFor the unimpaired subjects, the cluster solution with 85% between-groupvariability yielded 14 groups. These resolved into 10 groups when similar profiles withseverity differences were combined. The visually collapsed groups corresponded to thenext statistical combinations in the cluster analysis, and resulted in 72% between-groupvariability. Discriminant function analysis performed on the 14 original unimpairedclusters yielded a correct classification rate of 91.63%. When collapsed to form 10groups, 89.0% were correctly classified, ranging from 100% correct for 3 of the groups to75% for 1 group. As with the unimpaired groups, the discriminant function analyses71indicated that the unimpaired groups were clearly distinguishable by three scores, and thata minimal amount of discriminability was lost by collapsing the groups on the basis ofvisual similarity. The profiles of the fourteen original clusters and the ten resultingunimpaired groups are presented in Figure 2.Insert Figure 2 hereDescription of the ClustersImpaired cluster groups. Of the six obtained clusters, two showed a decline infunctioning across all three cognitive functions, including memory, processing efficiency,and visual-spatial ability. The two clusters differed in severity, and thus are labeled as theModerate group (n = 20), with the three tests near 1 standard deviation below the mean,and the Severe group (n = 12), with the three tests near 2 standard deviations below themean. Three of the clusters indicated more specific impairment on one or two of the tests.For one group, impairment was confined to the Benton Visual Retention (labelled BVR,n = 9), while for the other two groups impairment was found on the Benton and PairedAssociates (labelled BVR/PA, n = 9), or Word Fluency and Paired Associates (labelledWF/PA, n = 11). The BVR group likely includes subjects with a specific deficit in visual-spatial ability. The other two groups (WF/PA and BVR/PA) are both impaired in theirability to learn novel verbal associations, but one combines with a verbal fluencyimpairment, and the other with a visual-spatial deficit. It is possible that the BVR/PAgroup may be impaired in the acquisition of both verbal and visual novel material, since theBenton Visual Retention was administered with a 10 second delay, and errors may arisefrom an inability to recall the figure, rather than from a perceptual deficit.The final group could not be considered a profile associated with MS, since thegroup contained one MS patient and one control subject. Examining the data for these72two subjects indicated that they both had consistently low scores on the WAIS-R subtests(between -1 and -1.5 standard deviations below the mean). In contrast, their scores on thethree clustering tests were near average. The profiles of their scores are not consistentwith an acquired cognitive impairment, but likely reflect normal variation in cognitiveability. The group was therefore excluded from further group analyses.The impaired clusters (excluding the control subjects) are described on othervariables in Table 8. The MS patients in these groups did not differ in terms of age,education, age at onset of symptoms, or EDSS scores as assessed by ANOVA (all p>.05). While it appeared that fewer female subjects were included in the WF/PA group, thechi-square did not approach significance (chi-square (df 4) = 2.9, p> .05). However, thepercentage of subjects who were unemployed at the time of testing differed substantiallyamong the groups (chi-square (df 4) = 13.38, p < .01). Of the groups, 53% of theModerate group were unemployed, while 82% of the Severe group (9 of 11 subjects)were unemployed. In contrast, the groups with specific impairments obtainedunemployment rates ranging from 10% to 25%.Insert Table 8 hereUnimpaired cluster groups. Most of the unimpaired groups likely reflect normalvariation in test score patterns. Several groups, however, were of interest because of theover-representation of MS subjects in the group, and because of the similarity of theirprofiles to impaired group clusters. The ratio of controls to MS in the entire sample was.71, and a ratio close to this figure would be expected to occur in each of the unimpairedcluster groups. The obtained ratios of MS to control subjects in each group are presented73in Table 9. A chi-square indicated that the obtained frequencies differed significantly fromexpected values (chi-square (df 9) = 26.62, p < .01).Insert Table 9 hereMost of the unimpaired clusters obtained ratios similar to the expected values,while two groups (Clusters 3 and 7) included more control subjects than expected. Onegroup (Cluster 1) included 3 MS subjects only, and was identifiable by their isolatedimpairment on Paired Associates. Two other groups (Clusters 6 and 8), with ratios of .38and .31, respectively, indicated an over-representation of MS subjects. These two groupshad profiles that are visually similar to the BVR/PA group and the WF/PA group, and mayinclude MS patients with less severe cognitive impairment. In Figure 3, the three groupsare graphed using the mean scores for the MS subjects only, and are contrasted with thesimilar profiles from the impaired clusters.Insert Figure 3 hereValidation of Cluster PatternsThe clustering tests and the validation tests are graphed for the impaired groups inFigure 4. Figure 5 presents the graphs for the unimpaired groups. For the impairedgroups, the profiles were visually similar. The one exception is the BVR/PA group; themean for Block Design is a full standard deviation higher than Memory for Objects,whereas the Benton and Paired Associates are similarly impaired. This is consistent withthe hypothesis that this group may have a general deficit in learning both verbal and visual74novel information, rather than a combination of verbal memory impairment and visual-spatial difficulties. In this case, impairment on Block Design would not be expected, sincethe test relies minimally on memory. A discriminant function analysis using the validationtests as predictors and the original clusters as criterion groups yielded an overall correctclassification rate of 46%, where chance classification was 20% given 5 groups, asignificant difference as assessed by 6i-square (chi-square (df 4) = 33.8, p <.001).Insert Figure 4 hereIn contrast, there is less visual correspondence between the patterns for theclustering variables and the validation tests in the unimpaired groups. A discriminantfunction analysis yielded an overall correct classification rate of 14%, which did not differfrom chance classification (10%) (chi-square (df 9) = 1.84).Insert Figure 5 hereValidating the clusters using three other tests highlights a difference between theimpaired and unimpaired groups; that is, tests that are normally unrelated become moreclosely related due to an impairment of function necessary for the completion of both tasks(see Shallice, 1988). This increased correspondence between the clustering and validationtests in the impaired group was evident in the inter-test correlations. The differences inthe magnitude of the correlations between the impaired and unimpaired groups wereassessed with a Fisher z test. In all three cases, the correlations increased significantly for75the impaired group (see Table 10). One must ensure that the correlations did not changedue to increased variability or range of scores in the impaired group (Clark & Ryan,1993). However, F ratios comparing the impaired and unimpaired group variances on allthe tests indicated that only the variance on Memory for Objects was significantly higherfor the impaired group (F=1.79, p<.01). No other value approached significance. Thiswould suggest that the increase in inter-test correlations indicated an increasedcorrespondence among test scores for the impaired group.Insert Table 10 hereAlternative Validation ApproachFor each of the three clustering tests, differences between the 5 impaired clustergroups were assessed with a one-way ANOVA and Tukey pairwise followup procedures.On the basis of the results, a single hypothesis was generated describing the groupdifferences. An a priori t-test on the replication test was then performed in order todetermine whether the same pattern held for the replication test. All alpha levels for t-tests were one-tailed, since in each case the direction of the difference was hypothesized inadvance. Cluster group means in standardized form for the cluster tests and validationtests are presented in Table 11.Insert Table 11 here76Word Fluency versus Similarites. On Word Fluency, the Moderate, Severe, andWF/PA groups were similar to one another, performing worse than the BVR/PA and BVRgroups. ANOVA confirmed this pattern, indicating a main effect of group(F(4,56) = 22.18, p < .0001). Tukey's pairwise comparisons were significant at p < .05for BVR/PA versus Moderate, Severe and WF/PA, and for BVR versus Moderate, Severeand WF/PA. A similar result was obtained on Similarities. BVR/PA and BVR combined(mean = -0.32, sd = .73) had higher mean performance than Moderate, Severe, andWF/PA combined (mean = -1.15, sd = .93) as indicated by a t-test (1(59) = 3.69,p < .0005).Paired Associates versus Memory for Objects. The analyses indicated that theBVR group performed better on Paired Associates than all other groups, with theModerate group intermediate between BVR and the Severe, WF/PA, and BVR/PA groupscombined. An ANOVA indicated a main effect of group (F(4,56) = 16.07, p < .0001),with Tukey pairwise comparisons indicating mean differences at p < .05 for Moderateversus Severe, WF/PA and BVR/PA, and for BVR versus all other groups. Thus, thehypothesis tested on Memory for Objects was that the Severe, WF/PA, and BVR/PAgroups combined^(mean = -1.17, sd = 1.49) would obtained poorer performance thanthe Moderate and BVR groups combined (mean = -.79, sd = 1.11). The t-test failed toreach significance^(1(59) = 1.11, p = .13). The difference appeared to be due to theSevere group, where the mean on memory for objects was substantially higher than PairedAssociates performance (see Table 11). When this group was excluded, the Moderate andBVR groups combined (mean = -.79, sd = 1.11) versus the WF/PA and BVR/PA groupscombined (mean = -1.52, sd = 1.59) differed significantly (1(47) = 1.88, p < .02).Benton Visual Retention versus Block Design. An ANOVA indicated a groupdifference on the Benton (F(4,56) = 43.91, p < .0001), with Tukey pairwise comparisonssignificant at p < .05 for WF/PA versus all other groups, and for the Moderate groupversus Severe, BVR/PA, and BVR groups. Thus, on Block Design, the Severe, BVR/PA,77and BVR groups combined were expected to perform poorly in comparison to theModerate and WF/PA groups. However, a second possibility, discussed earlier, was thatthe BVR/PA group may not be impaired on Block Design, since their poor performanceon the Benton may be due to memory problems, rather than constructional difficulties.Testing the first hypothesis, with Moderate and WF/PA groups combined (mean = -1.09,sd = .94) vs Severe, BVR/PA, and BVR groups combined (mean = -1.57, sd = .86), the t-statistic was significant ((59) = 2.02, p < .025). When the groups were recombined sothat BVR/PA was included with the Moderate and WF/PA groups (mean = -1.08, sd =.96), and compared to the Severe and BVR groups (mean = -1.80, sd = .67), the p valueincreased to p < .001, 1(59) = 3.06.MRI ResultsMS subjects who had undergone MRI on the day of their testing and whose scanswere coded were included in these analyses. MRI data were available from a total of 150MS patients and 66 normal controls. Lesion frequency for the MS and Control groups ispresented in Table 12. For the MS patients, lesions occurred in all 50 sites. For thecontrol group, lesions occurred in 14 of the 50 sites. Both groups had the most lesions inthe periventricular regions and in the body of the CC. The incidence of small white matterlesions occurring in normals has been well documented (Jernigan et al., 1991). The lesionsites included in the present analyses excluded those areas with a large number of controlsubjects. Six sites included in the analyses each had one control subject with a lesion,while one site had two control subjects with a lesion. The sites included the right and lefttemporal horns, the right frontal horn of the deep white matter, the genu and splenium ofthe CC, the midline of the brain stem, and the right cerebellum.Insert Table 12 here78Groupings of MS subjects. Six groups of MS subjects were included in the MRIanalysis. The groups were formed on the basis of the results of the cluster analysis, withthe assumption that the MS patients who fell within three of the "unimpaired" clusters(presented in Figure 3) were experiencing impairment in specific areas, although notsufficiently severe to have been classified as globally impaired according to the presentcriterion. Thus, the first two groups were formed from subjects in the Moderate group(n=18) and the Severe group (n=8). The third group (n=28) included 8 subjects from theimpaired WF/PA group and 20 MS subjects from the unimpaired WF/PA cluster. Thefourth group (n=11) included 8 subjects from the BVR/PA impaired cluster together withthe 3 unimpaired PA cluster subjects. The fifth group (n=19) included 8 subjects from theimpaired BVR cluster and 11 MS subjects from the corresponding unimpaired BVRcluster. Finally, the control group included all other unimpaired MS patients (n=68) whodid not show a pattern suggestive of cognitive impairment.The cluster groups differed marginally in the total number of lesions evident onMRI (see Table 13). There was a trend (F(5,144) = 1.83, p = .10) for the Moderate andSevere groups to have more lesions than the other groups.Insert Table 13 hereCluster by lesion site analysis. Two sites yielded chi-square values significant atthe chosen alpha of p < .01. These sites were the deep white of the left parietal region(chi-square (df=5) = 14.01; p < .01) and the genu of the CC (chi-square (d5) = 13.84;p < .01). The expected frequency and the obtained percentages of the groups with alesion these sites are presented in Table 14.Insert Table 14 hereThe highest percentage of patients with lesions in both sites were within the Severegroup. For both sites, the unimpaired MS group had less lesions than the expectedfrequency. Of interest is the pattern of the groups with frequencies above the expectedvalue. For the genu of the CC, lesions occur most frequently for the Severe and BVRgroups. These two groups have the most consistently low scores on the BVR, suggestingthat the genu may be associated with visual-spatial ability. A higher lesion frequencywould not be expected in the BVR/PA group, since the validation analyses suggestedsimilarity to other memory impaired groups rather than visual-spatial impaired groups. Incontrast, the deep white left parietal region showed an increase in frequency of lesions forall of the groups with poor scores on Paired Associates, ranging from 64% in the BVR/PAgroup to 75% in the Severe group.Thus, the analyses suggested that two sites, the genu and the deep white leftparietal region, may be differentially associated with two cognitive functions, visual-spatialand memory, respectively. In order to further investigate the hypothesis, groups werereformed including subjects whose only impairment was on the Benton, on PairedAssociates, or on Word Fluency. A control group was also formed who were most likelyunimpaired on these three tests.A subject was included in a group only if their score fell at or below theimpairment cutoff of -1.64 standard deviations on one of three tests, but above -0.64 onthe other two tests. For example, the MS patients included in the BVR group all obtainedscores of -1.64 or greater on the Benton, and scored at least one standard deviation higheron Paired Associates and Word Fluency; 21 subjects met these criteria. Similar groups7980were formed for Paired Associates (PA; n = 15) and for Word Fluency (WF; n = 9). MSsubjects were included in the control group only if their performance on all three tests wasabove -0.64 standard deviations, thus decreasing the likelihood that they wereexperiencing difficulty in these cognitive domains. Frequency tables for the genu and theleft parietal deep white region were constructed for the groups, and are presented in Table15.Insert Table 15 hereThe results indicated that, for the genu, 67% of the patients in the BVR group hada lesion in the genu of the CC, in contrast with less than 40% of the patients in each of theother groups (chi-square (df=3) = 7.9, p < .05). In the left parietal deep white region,lesions were present in 80% of the PA group, while less than 35% of the other groups hada lesion in this site (chi-square (df=3) = 8.1, p < .05). Thus, the lesion sites are specificallyassociated with two different cognitive functions.No association was found between lesion site and impairment on Word Fluency.However, the WF group had fewer lesions present on MRI, regardless of site. Onaverage, 72% of the BVR group had more than ten lesions, while 90% of the PA grouphad more than ten lesions. In contrast, 22% of the WF group (2 subjects) had more than10 lesions. The remainder (78%) had between 3 and 7 lesions, suggesting that WordFluency impairment may be a very early manifestation of cognitive impairment, even inpatients with relatively little white matter disease evident on MRI.81Chapter 7DiscussionThe results of the present study indicate that MS results in cognitive impairmentacross a wide variety of neuropsychological tests, despite minimal physical disability andno cognitive decline evident on neurologic examination. This finding replicates others inthe literature (Ivnik, 1978; Grant et al., 1989). Cognitive impairment is not, however,ubiquitous among MS patients. For the majority of the MS patients, cognitive difficultieswere not apparent on any neuropsychological test; 35% of the MS group were above the5th percentile of the normative sample on every test. However, using the 5th percentile asa standard for impairment, 33% of the MS group (58 of 177 individuals) were impaired onthree or more tests, compared with 5% of the control group. Eight of the MS patients(5%) scored near or substantially below the impaired cutoff on the majority of the 13 testsin the battery. Thus, in a small percentage of early stage MS patients, there is evidence forglobal cognitive decline that would be considered severe by clinical standards.Importantly, the results suggest that there is no single pattern of cognitiveimpairment characteristic of MS. Rather, the MS patients classified as impaired resemblea heterogeneous group of brain damaged patients. Two of the clusters suggestedmoderate and severe decline across all three areas of verbal fluency, memory, and visual-spatial ability. Three other clusters were obtained with specific deficits in one or two ofthese areas, highlighting the relative independence of these functions. While the groupsdid not differ in severity of physical disability, the MS patients with global decline infunctioning, particularly those with severe impairment in all three areas, had a high rate ofunemployment. This would suggest that, for MS patients with mild physical disability,cognitive impairment may be sufficiently severe to adversely affect daily functioning.82In a clinical setting, neuropsychological assessment judges an individual'sperformance in each functional area compared to not only normative data, but also toestimates of the individual's premorbid functioning. As well, dissociations between areasof functioning in a given individual may signal impairment, whether or not scores are"impaired" by normative standards. However, this sort of clinical judgement is extremelydifficult to apply in a systematic way in research. By using a stringent criterion forclassification, the present study ensured that only those subjects with unequivocalcognitive impairment were identified. However, the use of such a criterion also likelyunderestimated the occurrence of cognitive impairment. This hypothesis is supported bythe results of the cluster analysis performed with the unimpaired group, which showed anover-representation of MS patients within several of the unimpaired clusters with similarprofiles to the impaired clusters. Using pattern analysis to identify MS patient with lesssevere decline may be most useful in longitudinal studies investigating the natural historyand evolution of cognitive impairment in MS. Taking this into account, the actualincidence of cognitive impairment in MS may be underestimated.The results of the cluster analyses are important on both a clinical and theoreticallevel. Clinically, the information gives a better picture of what deficits are likely to occurin MS patients, and with what frequency. The results suggest that the only way to identifythe pattern of cognitive impairment in an individual with MS is to administerneuropsychological tests that range across cognitive functions. The present studyconcentrated on patterns arising from three areas of cognitive functioning, and it is unclearwhether other patterns, perhaps unique ones, may arise in individuals when other cognitivefunctions are considered.Theoretically, the results suggests that demyelination does not result, as someresearchers have suggested (e.g., Rao, 1986), in a general deficit in information processingefficiency, or in a "subcortical dementia" that is applicable to all MS patients. Rather, thepresent study gives credence to the suggestion that the disseminated lesions result in more83idiosyncratic patterns of deficits, possibly dependent on the site or distribution of lesions.As Beatty (1992) has pointed out, very different conclusions are reached when oneconsiders the results of group studies (the vast majority of the extant literature) andstudies that focus on the individual with MS (for example, Beatty & Monson, 1991).Group studies in MS likely hide a wealth of information because of averaging artifacts,and much of the inconsistency from one study to the next can be explained by the randomcombinations of subgroups of differentially impaired patients. The present study is a goodindication of this phenomenon; group data indicated that the MS group was significantlyimpaired on a large number of measures. However, the mean differences between MS andcontrol groups were minimal, and one might conclude that MS results in mild deficitsacross multiple areas of cognitive functioning. In contrast, the cluster analysis identifiessubgroups of MS patients who are severely impaired in particular areas, with othercognitive functions intact.Only two lesion sites from the MRI analyses were associated with cognitiveimpairment. First, a lesion in the genu was associated with impairment on the BentonVisual Retention test. While the genu itself has not been implicated in visual-spatialimpairment, Le Doux, Wilson, and Gazzaniga (1978) have noted that spatial impairmentsoccur in patients with complete commissurotomy. These researchers emphasize theparticular importance of the posterior section of the CC (the splenium) in visual-spatialfunctioning, connecting the left and right posterior areas of the parietal and occipital lobes.Lesions in the genu in the present study may be indicative of generally more demyelinationwithin the CC which then compromises the connections between the two hemispheres.This hypothesis is supported by the finding that, of the 21 patients who were impaired onlyon the Benton, 11 (or 52%) of the patients had lesions in all three areas of the CC, whileonly 16% of the unimpaired MS, and 20% of those impaired only on Paired Associates,had lesions in all three areas.84If the genu is associated with visual-spatial functioning, then it is a sufficient butnot necessary lesion site for expression of the impairment. A third of the MS patients withspecific impairment on the Benton (i.e., those in the BVR group) did not have a lesion inthe genu, and the mean performance for patients who did or did not have this lesion werevirtually identical. Two possibilities exist; first, patients with and without the criticallesion may be failing the tests for different reasons. The Benton is adversely affected byconstructional deficits, visual perceptual impairment, unilateral attentional neglect, andvisual memory impairment. The integrity of the CC may differentially affect only oneaspect of performance. Secondly, lesions in multiple sites may result in a similarimpairment. For example, lesions in tracts disconnecting the occipital and parietalhemispheres may have a similar impact on visual-spatial skills as a lesion at the grey-whitejunction of the right parietal-occipital association areas. These types of questions are bestanswered in studies of a single subgroup of patients emphasizing a detailed analysis of thequality of impairment and the relationship to neuropathology.The second outcome of interest from the MRI analyses was the associationbetween lesions in the left parietal deep white matter region and impairment on PairedAssociates. In patients with grey matter lesions, memory impairment on verbal tasks suchas list learning and Paired Associates has been associated with left temporal lobe andhippocampal pathology (Milner, 1966; Squire & Slater, 1978). Research into the memorydeficits in Korsakoffs psychosis has also implicated the area around the third ventricle,including the mamillary bodies, the dorsomedial nuclei of the thalamus, and the internalcapsule (Graff-Radford, Eslinger, Demasio, & Yamada, 1984). The qualitative differencesin memory performance arising from damage to these two areas has led to the proposal oftwo types of amnesia, one hippocampal which may affect storage of information and theother diencephalic which may affect encoding or acquisition (for review, see Meudel &Mayes, 1982).85White matter tract lesions may also impair memory performance. Zaidel andSperry (1974), examining commissurotomy patients on standard tests of memory includingpaired associate learning, concluded that co-operation between the hemispheres isnecessary for optimal encoding and retrieval of material.The deep white left parietal lesion in the present study may be disrupting theconnections between areas necessary for optimal encoding of novel verbal associations.The arcuate longitudinal fasciculus sweeps in a large bundle through this region,connecting the superior and middle frontal gyri to extensive sections of the temporal lobe.Patients with frontal lesions perform particularly poorly on a test such as PairedAssociates that requires mental operations to be carried out on the materials, that is,creating new associations between novel pairings of objects (Schacter, 1987). Inargument against this hypothesis, Beatty et al. (1989) did not find similar characteristicsbetween the performance of MS patients who were impaired on memory testing andfrontal lobe memory impaired patients in their ability to semantically encode information.Beatty hypothesizes that MS patients, although capable under optimal circumstances, donot employ semantic encoding spontaneously or with normal efficiency. The differencemay be more one of severity rather than of quality. The answer to this question requires adirect comparison of MS patients and frontal lobe patients.Rao and his colleagues (Rao, 1990; Rao, Leo, & St. Aubin-Faubert, 1989) haveargued that the memory impairment in MS is similar to diencephalic amnesia due toperiventricular lesions disconnecting the thalamo-frontal radiations, and resulting in aretrieval deficit (see Chapter 3). The present finding would suggest that the impairmentarises due to damage to frontal and temporal structures, and would therefore resultprimarily in problems of encoding and the representation of novel material. Both thesehypotheses may ultimately be correct. To date, the studies of memory functioning in MSpatients have considered only group data; no attempt has been made to discern groups ofpatients with different patterns of memory impairment. Thus it is unclear whether a testother than Paired Associates would have identified a different group of patients as beingmemory impaired, and once identified, whether association to other lesions sites mightarise.It is of note that no area on MRI was associated with Word Fluency. Indeed, thegroup with a deficit only in Word Fluency had fewer total lesions than patients with asingle impairment on Paired Associates or on the Benton Visual Retention test. WordFluency impairment may be a very early occurrence in MS, and may represent the generaldecline in efficient processing that is associated with disruption of the normal temporalordering of signals that occurs with demyelination in white matter tracts. The fact thatWord Fluency is one test in the literature that does not result in increased variability in MSpatients compared to controls supports the notion that inefficient processing is aubiquitous feature of MS, even for those patients with minimal neuropathology evident onMRI. MS patients may experience a combination of a general deficit in informationprocessing efficiency together with impairment in particular cognitive functions that areassociated with localized white matter tract lesions.The finding that the genu and the left parietal regions are differentially associatedwith visual-spatial and memory performance in MS does not constitute a true double-dissociation (Teuber, 1955), since the hypotheses were not generated a priori. While it istempting to suggest functional specificity for these areas, with 24 sites and three tests thepossible combinations for finding what appears to be a double dissociation by chancealone is extremely high. Thus, the present study provides only the basis for generatinghypotheses to be investigated in future studies. Since minimal research exists at presentthat identifies the cognitive function of various white matter tracts, the importance ofgenerating such predictions should not be underestimated.Future directions in MS research.Future research attempting to characterize the cognitive impairment in MS patientsis warranted. The present results apply only to MS patients in relatively early or mild8687stages of the disease process; a rather different set of results may obtain when patientshave progressed into more physically disabling stages of the disease. Studies that follow alarge sample of MS patients longitudinally will be of particular value in understanding thenatural history and progression of the cognitive impairments, an area of research that issorely lacking at present. For example, retesting the patients in the current study after aperiod of 2 to 3 years would give a rich data base from which to address questionsregarding the rate of decline and the stability of both the severity and of the patterns ofimpairment over time. The relationship of longitudinal changes in cognition to changes onMRI is of interest as well. Most crucial, from a clinical standpoint, such a data base wouldbe helpful in understanding the implications of cognitive decline for a patient's ability tofunction adequately in daily life.A more fruitful approach in answering questions regarding cognitive impairmentand its relationship to neuropathology will be to identify small subgroups of patients whoare impaired in specific functions, and to then study these patients in depth. Onceidentified, careful characterization of the quality of their impairments should precedeattempts to identify dissociations between the groups in terms of the quantity anddistribution of neuropathology. The heterogeneity of cognitive impairment resulting fromMS cannot be disregarded. Indeed, this heterogeneity makes MS an extremely interestinggroup to study in order to elucidate the mosaic of functional aspects of cognition throughwhat Geshwind (1965A, 1965B) would refer to as "disconnection syndromes". That said,one must be careful in making a direct comparison between white matter lesions that resultin the total destruction of axonal tracts (such as those studied by Geshwind) anddemyelinating lesions. Demyelination within a tract may result primarily in the disruptionof the temporal organization of signals between cortical areas, rather than the completedisconnection between areas. Thus, the behavioural and cognitive effects of these twotypes of lesions may differ.88In addressing the question of the association of cognitive impairment toneuropathology, the research to date has relied almost solely upon the structural aspects oflesions as indicated by MRI. Other MRI measures, such as Ti and T2 relax times (forexample, Feinstein et al., 1992) reflect significant neuropathological changes in normal-appearing white matter in MS. Taking into account other aspects of MS neuropathology,such as active versus stable lesion status (using gadolinium enhanced MRI) and metabolicmeasures (using PET, SPECT, and functional MRI) may provide an undoubtedly morecomplex, but more complete, model of brain functioning in MS.Finally, MS may offer important insights into the role of efficiency in complexcognitive tasks. One of the most striking aspects when testing a person with MS in aclinical setting is the effort that these patients often put forth in completing a task. In spiteof the obvious difficulty they experience, they may look average on actual test results.Clinical neuropsychological tests (or experimental cognitive ones, for that matter) areinsensitive to subtle changes in effortful processing. One of the challenges for this area ofresearch will be to create experimental paradigms that measure efficiency without relyingon reaction time, so that one can parse apart the contributions to a complex task of 'ability'from 'efficient execution of an ability' from 'coordination between abilities' from 'speed'.Such an analysis may be the key to understanding the effects of demyelinating diseases oncognition.Appendix AThe Extended Disability Status Scale and Functional Systems ScalesKurtzke (1983)Functional SystemsPyramidal Functions (P)0 (normal) to 6 (quadriplegia).Cerebellar Functions (C11)0 (normal) to 5 (unable to perform coordinated movements due to ataxia).Brain Stem Functions (BS)0 (normal) to 5 (inability to swallow or speak).Sensory Functions (S)0 (normal) to 6 (sensation essentially lost below the head).Bowel and Bladder Functions (BB)0 (normal) to 6 (loss of bowel and bladder function).Visual (or Optic) Functions (V)0 (normal) to 6 (worse eye with maximal visual acuity less than 20/200;maximal visual acuity of better eye of 20/60 or less).Cerebral (or Mental) Functions (Cb)0 (normal).1 (mood alteration only).2 (mild decrease in mentation) to 5 (dementia; severe or incompetent).Other Functions (0)0 (none) to 1 (any other neurologic findings attributed to MS).8990Expanded Disability Status Scale (EDSS)0.0 = Normal neurologic exam, all grade 0 in FS; Cerebral grade 1 acceptable.1.0 = No disability, minimal signs in one FS.1.5 = No disability with minimal signs in more than one FS.2.0 = Minimal disability in one FS (one grade 2, others 0 or 1).2.5 = Minimal disability in two FS (two grade 2, others 0 or 1).3.0 = Moderate disability in one FS (one grade 3, others 0 or 1), or mild disability in threeor four FS, though fully ambulatory.3.5 = Fully ambulatory but with moderate disability in one FS together with mild in one ortwo others.4.0 = Fully ambulatory without aid, self-sufficient, active 12 hours a day despite relativelysevere disability of one FS (grade 4), or combinations of lesser grades exceedingprevious steps. Able to walk without aid or rest some 500 meters.4.5 = Fully ambulatory without aid, active much of the day, able to work a full day, mayrequire minimal assistance, relatively severe disability (usually one FS grade 4). Ableto walk without aid or rest some 300 meters.5.0 = Ambulatory without aid or rest for about 200 meters. Disability severe enough toimpair full daily activities or requiring special provisions to work a full day (usuallyone FS grade 5 or combinations of grade 4's).5.5 = Ambulatory without aid or rest for about 100 meters. Disability severe enough topreclude full daily activities (same FS grades as 5.0).6.0 = Intermittent or unilateral constant assistance (cane, crutch, brace) required to walkabout 100 meters with or without resting.6.5 = Constant bilateral assistance required to walk about 20 meters without resting.7.0 = Unable to walk beyond about 5 meters even with aid, essentially restricted towheelchair. Wheels self in standard wheelchair and transfers alone, up and about 12hours per day.7.5 = Unable to take more than a few steps, restricted to wheelchair, wheels self but mayrequire assistance in transfers. Cannot carry on in standard wheelchair a full day, mayrequire motorized wheelchair.8.0 = Essentially restricted to bed or wheelchair, but may be out of bed much of the day.Retains many self-care functions and has generally effective use of arms.8.5 = Essentially restricted to bed much of the day, has some effective use of arms.Retains some self-care functions.9.0 = Helpless bed patient, can communicate and eat.9.5 = Totally helpless bed patient, unable to communicate effectively or eat/swallow.10 = Death due to MS.91Appendix BDescription of Neuropsychological TestsThirteen neuropsychological tests were employed in the present study. Thefollowing table summarizes the ability areas that each test measures, as it is described inthe research literature.TestMotorComponentPriorKnowledgeAbstractConceptualLearning &MemoryProcessingEfficiencyConstructionalAbilityInformation )0(Vocabulary XXDigit Span XX XXArithmetic XX XXPicture Completion )0( XXBlock Design XX XX XXBVRT XX )0(Similarities XX ),CXLetter Fluency XX XXTrails A & B XX )0(Categories )0( XXPaired Associates XX XXMemory for Objects XX9293WAIS-R SubtestsThe following tests are taken from the Wechsler Adult Intelligence Test-Revised(WAIS-R; Wechsler, 1981). All WAIS-R subtests are scored according to the WAIS-Rscoring manual and are expressed as age scaled scores using the WAIS-R norms.Information: The subject is asked 29 questions that reflect the amount ofgeneral information that individual has absorbed from the environment. Information testsboth breadth of knowledge and verbal skill, since the test requires formulation of complexverbal responses. It correlates with formal education and motivation for academicachievement, and is among the least affected WAIS-R subtest in brain injured populations(Lezak, 1983).Vocabulary: The subject is asked to define 35 words arranged in order ofdifficulty. Performance on Vocabulary reflects amount of general knowledge, verbal skill,and the ability to organize and formulate thoughts coherently. It deteriorates very littlewith age, and is thus a good indicator of general intellectual and premorbid functioning(Lezak, 1983).Digit Span: Both Forward Span and Backward Span consist of seven pairs ofrandom number sequences that are read aloud at the rate of one digit per second. ForForward Digit Span, the subject is required to repeat back the sequence in the same orderthey heard them. For Backward Span, the subject must repeat the sequence in the reverseorder. Forward Digit Span is considered a measure of working memory capacity, but isalso sensitive to attentional efficiency, since span decreases with anxiety (Baddeley, 1986).Backward Digit Span is a complex attentional task that requires the inhibition of moreautomatic responses and double-tracking in that both the memory for the digits and thereversing operations must proceed simultaneously.Arithmetic: This subtest contains 14 mathematical problems to which the subjectmust answer verbally without the aid of paper and pencil. It is considered a sensitive testof efficient mental processing rather than of mathematical skills, since the most difficult94arithmetic computations are only at the 8th grade level (Lezak, 1983). Difficulties inconcentration and attention, immediate memory, conceptual manipulation, or mentaltracking, will impair performance.Picture Completion: The subject is shown 20 incomplete pictures and asked toidentify the "most important part of the picture that is missing". The test taps the abilityto process detail in a visual array, but also requires judgement regarding both practical andconceptual relevancies. Although it does not require the same complex verbal skills asVocabulary or Information, it assumes a cultural background that allows exposure to suchitems as a horse and saddle, or snow on a woodpile.Block Design: Nine designs are presented to the subject printed on cards. Thesubject must mentally partition the visual design so that it can be replicated using blocksthat are on a different scale than the picture. Block Design measures nonverbal reasoningand problem solving, and requires intact visual-spatial organizational ability. The test istimed, so that additional points are given for speed of responding. Thus, test performanceis difficult to interpret by speed alone when the subject is motorically impaired.Similarities: A test of verbal concept formation and retrieval of verbalinformation, the subject must identify what each of a pair of words has in common. Thecorrect response is a higher-order category, such as "forms of art" for "poem and statue".Other Neuropsychological Tests:Benton Visual Retention Test (BVRT): The subject is presented a card withgeometric designs for 10 seconds. The card is removed and the subject is asked toreporduce the designs as accurately as possible. Scoring consists of errors inreproduction. The test is sensitive to visual-spatial ability, visual detail and spatialorganization, as well as immediate memory for nonverbal information. However, theBVRT has higher correlations with tests of design copying than with memory tests,suggesting that the constructional component far outweighs the memory component95measured by the test (Benton, 1979). The test is not timed, and thus is a good test ofconstructional ability in patients with difficulty in fine motor coordination.Word Fluency: The subject is told a letter of the alphabet and asked to producewords beginning with that letter as quickly as possible, without using proper names orplaces, or repeating a word with different suffixes. Subjects are given one minute torespond to each of three letters (F, A, and S). Scoring is the total number of correctwords produced. Fluency tests with letters require the subject to chose optimal strategiesfor retrieval (such as a grouping of words starting with "st..."). The test also requiressubjects to limit responses to those that conform to the rules by suppressing moreautomatic responses that come to mind, i.e., words that are semantically related.Although fluency may be impaired in some aphasic groups, it is more often impaired dueto difficulty monitoring verbal responses, effective strategy use, mental organization, andprocessing efficiency (McCarthy & Warrington, 1990). The test can be extremelyimpaired in subjects for whom no other language disturbance is evident.Trails A and B: In Trails A, the subject joins a series of numbered dots. In TrailsB, the subject joins dots according to an alphanumeric sequence (e.g., 1 - A - 2 - B). Onboth parts of the test, the score is the time in seconds to complete the test. Trails Ameasures visual scanning speed and motor speed, since the numeric sequence isoverlearned or automatic. Trails B, however, requires mental tracking of two sets ofinformation and switching between them. The task is therefore considered a complexattentional task requiring efficient mental tracking and flexibility. Impairment in motorspeed will also adversely effect performance. However, one way to control for individualmotor speed it to subtract time on Trails A from Trails B. Since the number of dots onboth forms are the same, this scoring controls for both motor speed and speed of visualscanning.Categories Test: Part of the Halstead-Reitan Neuropsychological AssessmentBattery (Reitan & Davison, 1974), on this test subjects are presented with a series of slide96sets. Each set is made up of geometric designs with a number concept underlying it. Thesubject's task is to determine the rule based on feedback as to whether their responses (1to 4) are correct or incorrect. Scoring is the total number of errors. Pendleton andHeaton (1982) note that the test is an experiment in learning that requires effectivelearning skills, problem solving, and abstract concept formation. However, the test alsorequires intact visual-spatial ability.Paired Associate Learning: Word pairs were taken from the two alternate formsof the Wechsler Memory Scale-Revised (Russell, 1975). Twenty word pairs are readaloud to the subject, half that are semantically associated (e.g., king - queen), the otherhalf without prior semantic association (e.g., cabbage - pen). Memory for the pairs istested by presenting the first word of the pair and asking subjects to recall the word thatmade up the pair. There are three learning trials. Scoring is the total number of correctpairs over the three trials, but can also be broken into the number of low and highassociate pairs that were learned over three trials. The pairs without semantic associationrequire abstract conceptualization, since the subject must devise some association betweennovel paired words.Memory for Objects: Subjects are presented with 15 common objects (e.g.,spoon, pen, watch, etc) simultaneously for one minute. They are then asked to recall asmany objects as possible. Scoring is the total number of objects correctly recalled. Sinceall the objects can easily be encoded verbally, Memory for Objects is as much a test ofverbal memory as it is a test of visual memory.97Appendix CThe following section is a brief literature review of what is known about braindamage, either to cortical grey matter regions or to white matter tracts, resulting incognitive impairment in the areas of verbal fluency, memory, and visual-spatial ability.Lesion Sites and Cognitive FunctioningAs discussed in the introduction, the effect of white matter lesions on cognitiveprocesses has only recently begun to be explored. The vast majority of theneuropsychological literature deals with grey matter or cortical lesions, with the exceptionof some discussion of the effect of damage to the corpus callosum (for example, Sperry'sresearch into "split-brain" patients; see Sperry et al., 1969). Hence, the following sectiondescribes the effect of lesions to the cortex, and not to white matter unless explicitlystated. I have tried to emphasize, where possible, studies in the literature that haveemployed the same, or very similar, tests to the ones used in the present study, or thathave implications for white matter disease.Constructional Impairment. The Benton Visual Retention test and block designare two of many tests that are sensitive to constructional difficulties (Benson & Barton,1970). While some patients may do poorly on all such tests, others may exhibit veryparticular deficits, say, in copying designs vs drawing freehand, etc. Lesions to bothhemispheres may cause impairment to constructional ability, but tend to differ qualitatively(Walsh, 1987). In general, however, lesions to the right hemisphere are more likely toproduce constructional deficits than to the left, and more likely when the lesion isposterior rather than anterior. The most widely discussed area is the junction between theparietal, temporal, and occipital lobes. Lesions confined to the temporal lobes do notresult in constructional difficulties, while damage extending into the parietal and/oroccipital areas often results in constructional apraxia (Luria, 1973).Nielsen (1975) put forward a disconnection model of constructional apraxia. Heposits that the right posterior cortex contains the basic module for spatial integration,98while the left hemisphere contains the motor control center for the right hand. Unilaterallesions to the right parietal area will result in impairment, as will lesions to the tractsconnecting the two hemispheres. In this latter case, an uneven spatial ability between thetwo hands will be exhibited. This notion was put forward independently by Le Doux et al.(1978) based on their observations of a patient with a complete commissurotomy. Bytheir view, lesions to the corpus callosum may result in spatial difficulties, particularly toright handed individuals. As well, lesions within the tracts of the deep white in the righthemisphere may produce spatial difficulties to the left hand when the lesion disrupts theconnections between the posterior cortex and the motor control for the left hand. LeDoux et al. (1978) argue that such as lesion would only produce a constructional deficit ifthe subject is predominantly left handed.The third area that has been implicated in constructional impairment is the frontallobes. From extensive case observations, Luria and Tsvetkova (1964) described two typesof constructional apraxias; lesions to the parietal-occipital area produce disturbances in thespatial organization of elements, while lesions to the frontal lobes produce a loss ofregulation of sequential behaviour, and an inability to compare the ongoing results ofefforts with original intentions. The difference can be seen between the two types ofconstructional difficulties in that frontal lesion patients improve when given a detailedprogramme to follow, whereas parietal-occipital lesion patients do not (Walsh, 1987).Verbal Fluency. The classic lesion study of word fluency is Milner (1964).Milner compared the performance of patients with left frontal, right frontal, or lefttemporal lobectomy on Thurstone's Word Fluency test. This test requires the patient towrite as many words as possible in 5 minutes beginning with the letter S, and then as manyfour-letter words which begin with C. Milner found that the left frontal cases performedpoorly compared to either the right frontal or left temporal groups, indicating thespecificity of verbal fluency to the left frontal region, rather than to the language dominanthemisphere in general. Further, she found a double dissociation between the left frontal99and left temporal groups on verbal fluency and verbal recall. Left frontal patientsperformed poorly on verbal fluency but adequately on paired associates, while the reversewas true of the left temporal patients. Benton (1968) confirmed these findings using theverbal equivalent of Thurstone's task, where subjects say as many words aloud in oneminute periods beginning with the letters F, A, and S. (This is the form of the verbalfluency test used in the present study.) Benton found that left frontal and bilateral frontallesion groups were impaired when compared to a right frontal lesion group. Importantly,Benton found that the impairment was evident in patients whose other verbal abilities,including comprehension, reading, fluent speech, and object naming abilities, were intact.His patients showed similar verbal fluency difficulties in both verbal and writtenresponding. This led him to concluded that verbal fluency is a higher-level languagefunction that is not modality specific.Memory Impairment. No other area of cognition has been more closely studiedin neuropsychology than the impairment of memory due to brain damage. The vastliterature can be broadly organized according to various memory phenomena such as shortterm memory, autobiographical memory, and the acquisition, retention, and retrieval ofnovel information. For present purposes, the latter area, namely learning and rememberingnovel information, will be discussed since the tests used for clustering and replication(paired associates and memory for objects) fit into this category.Most consistently associated with deficits in the acquisition of new material are thetemporal lobes. The findings are based predominantly on studies of anterior temporallobectomy, a surgical treatment for intractable complex partial epilepsy. The resectiontypically includes the anterior 6 cm (approximately) of the temporal lobe, and includes theunderlying structures of the uncus, amygdaloid nucleus, and part of the hippocampus andparahippocampal gyms. These patients and others with temporal lesions of differentorigin exhibit difficulty in learning and retention of new material. When damage isbilateral, the resultant memory deficit can be dramatic, as in the case of HM (see100Baddeley, 1990). This line of research has focussed attention on the role of thehippocampus, in particular, in anterograde amnesia.The left and right temporal lobes have been described as material-specific. Theright temporal lobe differentially affects visuospatial and non-verbal pictorial material,while the left temporal lobe results in more severe deficits in learning verbal material.Verbal material deficits occur whether the retention of material is measured byrecognition, free recall, or rate of associative learning, as in the case of paired associates(Smith & Milner, 1981). The generality of this material specificity is not conclusive,however. Warrington and Shallice (1969) have shown that patients with temporal ortemporal-parietal lesions on the left side have difficulty with verbal memory for all formsof auditory material, but little or no difficulty with the same material presented via thevisual modality, suggesting a modality-specific, rather than a material-specific, deficit.The general finding, however, of memory impairment on tests such as list learning andpaired associates after left temporal lesion is incontrovertible, and is further supported byunilateral ECT studies (e.g. Squire & Slater, 1978) and by sodium amytal ablation studies(see Milner, 1966).The specificity of the memory deficit on the basis of lateralization of lesion is notclearcut, and lesions to both temporal lobes can result in verbal memory impairment. Thatis, the material specificity described above is seen in the comparison of performancebetween verbal and nonverbal forms of memory tests. For example, a right temporallesion may result in impairment to verbal memory tests, but will likely have a greaterdetrimental effect on pictorial information. The most severe memory impairment for bothtypes of materials occur when lesions are bilateral. Zaidel and Sperry (1974), examiningcommissurotomy patients on standard tests of memory including paired associate learning,concluded that the intact functioning and co-operation between the hemispheres isnecessary for optimal encoding and retrieval of material, and hence can be seriouslydisrupted by dissection of the commisural tracts.101The deficits associated with Korsakoffs psychosis has implicated the area aroundthe third ventrical as important for memory function. This area includes the mamillarybodies, the dorsomedial nuclei of the thalamus, and the internal capsule. While bilateraldamage to the thalamic nuclei and surrounding areas can cause profound amnesia,unilateral thalamic damage (usually due to intracerebral haemorrhage) can cause rathersevere memory impairment, and this impairment seems to follow the same right/lefthemisphere bias for material specificity as is seen in temporal lobe lesions (Graff-Radfordet al., 1984). However, these cases usually have abnormalities in other intellectualfunctions and in personality, and are best described as part of a more global "subcortical"dementia. These distinctions have become important in describing MS patients, as severalauthors (Rao et al., 1984) have described MS memory deficits as more closely resemblingthose seen in diencephalic damaged patients rather than those with temporal orhippocampal damage.The last area that has been implicated in impairment of memory functioning is thefrontal lobes. There is debate currently in the literature as to whether or not there isindeed a "frontal" memory disorder, or whether poor performance on memory tasks byfrontal patients is a function of other processes that are impaired, such as the integratedexecution of behaviour and rule following (see Schacter, 1987). Patients with frontallesions may perform poorly on a test such as paired associates, which require the personto carry out mental operations on the materials (ie, creating new associations betweennovel pairings of objects). In contrast, when frontal patients are required to merely repeatthe material frequently, they are quite able to retain new information.ReferencesAchiron, A., Ziv, I., Djaldetti, R., Goldberg, H., Kuritzky, A., & Melamed, E. (1992).Aphasia in multiple sclerosis: Clinical and radiologic correlations. Neurology, 42,2195-2197.Allen, I.V., Glover, G., & Andersen, R. (1981). 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The frequency table uses the actualnumbers of subjects obtained from the cluster solutions.MS groupA^B^C^D^E^Fn=68 n=18 n=8 n=28 n=11 n=17 N=150118Table 2Chi square values and resultant p values for hypothetical group data varying lesionbaserate and the percentage of lesions occurring within the smallest cluster group (n= 8).I^Lesion baserateII % lesionsin cluster n=8I chi square (df=5) I^p valueIi coz , "'I I III IUV 075%85%60%75%85%100%85%100%12 .7420.2439.375.269.1214.0519.736.7910.33< .05< .01< .001> .05> .05< .02< .002> .05> .0525%“IIII3 5%Demographic variables.Table 3MS ControlsNumber of subjects 177 89Age (years) 36.2 (7.8) 35.2 (7.0)Education (years) 13.5 (2.2) 13.9 (2.2)Sex (h):Female 72.9 70.8Male 27.1 29.2Highest Occupational Status (%):Professional/Managerial 27.1 38.2Clerical 28.8 20.2Technical 25.5 21.3Unskilled 12.4 12.4Housewife 1.7Student 3.4 7.9No occupation 1.1Current Employment Status (%):Full time 39.5 66.3Part time 22.1 14.6Unemployed 19.2 4.5Housewife 9.6 4.5Student 4.5 9.0Retired^5.1^1.1119Table 4Disease variables and neurological data for the MS patients.Age of first symptoms 26.6 (7.3)Age of diagnosis 31.4 (8.0)Age at assessment 36.6 (7.8)Number of relapses since Dx 4.7 (2.6)Duration of disease since Dx 5.2 (3.5)Relapses per year 0.9 (1.1)Kurtzke Scales:Pyramidal 1.2(0.9)Cerebellar 0.5 (0.9)Brain Stem 0.5 (0.8)Sensory 0.8 (0.9)Bowel/Bladder 0.5 (0.8)Visual 0.5 (0.8)Mentation 0.03 (0.2)Extended Disability Scale 2.0 (1.2)120121Table 5Means, standard deviations, and statistical tests for MS (n = 177) and Controlsubjects (n = 89) on the thirteen neuropsychological tests included in the battery.Test MS Controls t-value^F-maxInformation 10.53 (2.52) 10.38 (2.61) <1 1.07ocabulary 11.50 (2.34) 12.08 (2.54) 1.84* 1.17ID igit Span 10.84 (2.86) 11.10 (2.34) <1 1.49*'thmetic 10.77 (2.66) 11.19 (2.71) 1.20 1.04Similarities 10.46 (2.25) 11.01 (2.23) 1.90* 1.02I' ictureCompletion 9.32 (2.37) 10.08 (2.19) 2.52** 1.17I: lock Design 9.96 (2.58) 11.20 (2.32) 3.82*** 1.24I: enton VisualI' etention Errors 4.34(2.86) 3.04(2.29) 4.01*** 1.56*ord Fluency 36.99 (11.68) 41.65 (10.27) 3.20*** 1.29ategory Errors 21.99 (13.23) 19.91 (11.84) 1.25 1.25l'thred Associates 43.36 (7.13) 47.62 (5.84) 5.21*** 1.49*Trails B-Aemory for36.64 (20.61) 26.99 (14.43) 4.43*** 2.04***Objects 12.25 (1.75) 12.93 (1.44) 3.40*** 1.48** p< .05 ** p<.01 *** p<.001All p values are one-tailed.122Table 6Percentage of MS patients with scores below the 5th percentile (standard score of-1.64 or less) of the normative sample on the neuropsychological tests.Test % MS < 5th percentileWAIS-R Su btests:Vocabulary 3.38Information 2.26Digit Span 10.73Arithmetic 7.34Similarities 12.43Picture Completion 13.56Block Design 18.08Neuropsychological Tests:Benton Visual Retention 24.29Word Fluency 12.43Categories 10.73Paired Associates 22.03Memory for Objects 15.82Trails B-A 23.16123Table 7Frequency of impaired test scores for subjects in the MS and Control groups.Impairment was defined as a score falling below the 5th percentile of the controlgroup.ImpairedTestsMultiple Sclerosis (n = 177) Controls (n = 89)Frequency I Percentage 'Cumulative Frequency I Percentage 'Cumulative0 62 35 35 53 60 601 36 20 55 18 20 802 21 12 67 13 15 953 29 16 83 2 2 974 15 9 92 3 3 1005 7 4 966-7 4 2 988-9 3 2 100124Table 8Demographic and disease characteristics for the MS subjects in the impaired clustergroups. One control subject was clustered in each of the groups with the exceptionof the BVR/PA group.Moderate Severe WF/PA BVR/PA BVRNumber of MS subjects 19 11 10 9 8Mean age (years) 36.1(9.2) 40.3 (5.6) 38.0 (8.5) 37.9 (9.5) 38.0 (6.2)Education (years) 12.9 (1.7) 12.9 (1.8) 12.1 (2.9) 13.1 (2.1) 13.0 (2.0)Age at onset (years) 27.4 (6.9) 30.1 (7.6) 24.3 (9.0) 22.6 (5.5) 29.9 (5.7)Sex (% female) 74% 82% 30% 78% 88%Kurtzke EDSS 2.7 (1.4) 2.5 (1.1) 2.4 (1.2) 2.0 (0.8) 2.8 (1.6)% unemployed 53 % 82 % 10 % 22 % 25 %I125Table 9Ratio of Control to MS subjects in the 10 unimpaired clusters. The ratio of Controlsto MS subjects participating in the study was .71 (j-square (df = 9) = 26.62, p <.01).Cluster n (MS) I n (Controls) C/MS Ratio1 32 8 6 .753 5 10 2.04 4 3 .755 23 16 .706 13 5 .387 17 19 1.128 26 8 .319 9 8 .8910 11 9 .82126Table 10Intertest correlations between the clustering and validation tests computedseparately for the impaired and unimpaired subjects. Fisher z statistics indicatedsignificantly larger correlations within the impaired group.I CorrelationWord Fluency/SimilaritiesBenton/Block DesignPairs/Memory for Objects.33 .19 2.50*.46 .37 1.69*.32 .21 1.84*Impaired I Unimpaired I Fisher z* p <.05, one-tailed127Table 11Mean standardized scores for the impaired groups on the clustering and validationtests.Word Fluency and Similarities:Test WF/PA^I^Severe Moderate I^BVR I BVR/PAWord Fluency^-1.61^-1.58Similarities -1.08^-1.14Paired Associates and Memory for Objects:-1.53-1.19-.32-.20.52-.44Benton Visual Retention and Block Design:Test WF/PA I BVR/PA I^Severe I Moderate BVRPaired AssociatesMemory for Objects-2.52-1.35-2.43-1.73-1.93-.59-1.18-.86-.08-.65TestBenton Visual RBlock DesignSevere I BVR I BVR/PA I Moderate I WF/PA-2.54 -2.51 -2.13 -.90 .04-1.80 -1.80 -1.03 -1.43 -.50128Table 12Percentage of MS (n=150) and Controls (n=66) with a lesion in each of 50 sites:I Slice^ % MS^J % Controls ISupraventricular:Frontal right 20.8Frontal left 21.4Frontal/parietal right 17.5Frontal/parietal left 14.5Parietal right 32.5Parietal left 33.1Periventricular:Frontal horn right 84.4 25.8Frontal horn left 85.7 30.3Occipital horn right 77.9 21.2Occipital horn left 79.2 18.2Temporal horn right 42.2 1.5Temporal horn left 40.3 0Parietal body right 83.1 7.5Parietal body left 83.1 6.1Deep White:Frontal horn right 17.5 1.5Frontal horn left 14.3 0Occipital horn right 4.5 0Occipital horn left 3.9 0Temporal horn right 3.9 0Temporal horn left 4.5 0Parietal body right 43.5 0Parietal body left 44.2 1.5Internal Capsule:Right 17.5 0Left 14.9 0Grey/White Junctions:Frontal right 20.8 0Frontal left 16.9 0Parietal right 20.1 0Parietal left 22.1 0Occipital right 5.8 0Occipital left 1.9 0Temporal right 13.6 0Temporal left 11.7 0Table 11, continuedDeep Grey:Insula right 6.5 0Insula left 4.5 0Basal Ganglia right 1.9 0Basal Ganglia left 0.6 0Thalamus right 1.3 0Thalamus left 1.3 0Corpus Callosum:Body 74.0 22.7Genu 37.0 1.5Splenium 42.2 1.5Brain Stem:Midline 20.8 1.5Cerebellum right 24.0 3.0Cerebellum left 11.0 0Pons right 24.7 0Pons left 20.1 0Mid Brain right 14.9 0Mid Brain left 14.9 0Medulla right 11.7 0Medulla left 10.4 0129Table 13Mean number of total lesions for the impaired cluster groups.Group N Mean number of total lesionsModerate 18 16.0 (7.1)Severe 8 16.4 (6.1)WF/PA 8 13.5 (6.0)BVR/PA 11 15.2 (5.1)BVR 17 12.5 (6.4)130131Table 14Percentage of subjects in the impaired cluster groups with a lesion present in thegenu and the deep white left parietal region.Genu of the CC Deep White Left ParietalExpected frequency: 37% 45%Unimpaired (n=68) 28 % 29 %Moderate (n=18) 44 % 50%Severe (n=8) 88% 75%WF/PA (n=28) 36% 71 %BVR/PA (n=11) 27% 64 %BVR (n=17) 53 % 35 %132Table 15Frequency table for lesions in the genu and deep white left parietal region for thereconstructed MS groups with isolated impairment on one of the three clusteringtests, compared to a group of MS patients with normal performance on all threetests.Genu of the CC Deep White Left ParietalExpected frequency: 37% 41%Unimpaired (n = 37) 22 % 35%BVR (n = 21) 67% 33%PA (n = 15) 40% 80 %WF (n = 9) 22 % 35%cn^-0 4-. 4)cn a) cnv—I^N 41:), 7:3."1::) 0 'Oa)0 rn+4 cda)^3-o .... o.w II> - acjg °4 CU^2a) 7:1 6"E g 3. .— 1-.F.. > _6474=ti) c)^-1a" cil^00 all 0CI3 7.5., a)6 ,-; tt-^c.)^-2....Ci)V)^v)^-315 liiry A,)oo _.—-t, =2 4.. 0'a 72 4-'16cL. 0 c-.).g^ 3(L)^, ..--:,.4 (I) •<4.• (1) 2o 4.-4-i CIO kf))^c/)CA /-.^ aoo F3^..7..^1o t-,', 0 .—co‘.^v)a. w>a.) '-' "TL' .^0^04▪ ., 5 T3 .6 1.'-ooc -10.2)• (f)• a ce^-2—■ oa)go '6^' 5^-31...^4.).4 'ill S .9..MS = 10 Controls = 1MS = 1 Controls = 1ModerateMS = 19 Controls = 1•ft """""""""" •.. a . ... ..... . -to*........BVR/PAesMS =9N.At. .,.;.._..... ..^.... %. ..•• ....^•WF^BVRSevereMS = 11 Controls = 1...^....._ ______At,..... .- ..• 4.a, ........ ........... 4)BVRMS = 8 Controls = 1......._._....._^•. .._......._.., ..,...,.......,........_^....^.. _.•••... ../.•WF/PAWF BVR PA WF BVR PA WF BVR PAWF BVR PA WF BVR PACluster 8MS = 26 Controls = 8.^4...,.41,Cluster 1^Cluster 2^Cluster 3^Cluster 4PAWF BVR PABVR BVRWFPA PAWF BVR WFMS = 8 Controls = 6•^MS = 5 Controls = 10 MS = 4 Controls = 3MS = 3 Controls =0MS = 11 Controls = 9Cluster 9^Cluster 10MS = 8 Controls = 6• WF BVR PA^WF BVR PA"a•-. co^3> .44 c.)o 04 4..^2 2co 4o.) 0.) o^.0^a.^tii4.) 0^3 1.. = 4)^ID^t% 3 catu ---; u^:73^P. 00o v) c.4 ›, 0a. 0 =^4 -1co c :=4 u,6. s 130^46^-2t•-• "04.... 0Cn0^ -3T.)73 4C 0114....,V crl.1—, V cna — 0a. ti) c4z4e •^c.,. _.a 0 2 ;,—3..4 -5^24)o^T'-toi)L. a) Cl)•o W2.71^C0^r14 -a :0g. 10 ._0 g i ._>1-. c^a0. 0 ---z 2^0a) ,,,^P.0 co 13 13CCO - i> v CO.... U V0 13U 0 112 2..N 0 cg^-2e4 -0 oV ^8a g 4-4 I—.o 0o o -3Vi .4' 17,' P4 3Cluster 6MS = 13 Controls = 5II 1i414 /"..*1rNI.Cluster 7MS = 17 Controls = 19P ''''''' •.•. saa../**aCluster 5MS = 23 Controls = 16"4-•...WF BVR PAWF BVR PA^WF BVR PA^WF BVR PABVR/PAIt\•.8it.I'........WF^BVR^PAWF/PAWF^BVR^PABVR................--.............-.......---......--.........---....—.........---•••S.•• ••••••••t^.ie•WF^BVR^PA0---• Unimpaired MS = 3^ • Impaired MS — 90------0 Unimpaired MS = 26^0--• Unimpaired MS = 13^ • Impaired MS — 10 Impaired MS = 8cn"•C.) •c7400 0C4WI -0 0•caa) r:LiModerate Severe WF/PA32101-2-3WF^BVR^PA BVR/PA BVR 411).•■•••••••••••40.•-••••••■Sm^BD^MOt) gi75 rg77) 40-; • -I0 0 (/)i... .6-, 3•O c ticw- - =^20 .a.,) c> 0, o^cnti't^cotr=1 g . -.a) =1.4-, Z elTo^.-> >,-, cf)0L 0a 0re) 0° 712 6A P.tg t^ ..., v.co4.1 co cY3 1co. as c..g e^co,:s- -0 o a)-.. ,-, • --,a^:v., c),...04_, ........ , ,._, -3• 44.44*.^•••••■•••S m•^ BD MO^•WF BVR PACluster 1 Cluster 2 Cluster 3 Cluster 4 Cluster 5li•"".."......'N% .vN•s..• „..... •111•... . ..•^...... 4,Cluster 8 Cluster 944^.3 (4-9 Cluster 10•^. ..... -4•Cluster 7u 7:3 0O E E0 citt 0O 04 ,,^34., E-0 0 "01--, U 0^20oi^r)cn 0 CE)^14.) CU. CI a4-,CO 5. c")T1O• 0 0VI(t)4.)=•^C.)^1o)00a) .-. 0:10-1 ■-:^2=O li E= v)En MI •-....‘..^ 34-.a) ,—; r,.... a ApCI) 4-.•ig C4 • ..0 V)^3E o 4-'0*E *-ri !,)^20 = coa) cO +-. 0 io4.) (1)C:4 if^.11^14)= '' 70^50 ..1...^m 84-10 ''.2 tl.)›^0P.cn ^cuO 0^IDT 'a' 8 3 g -1= t^-2.,-; 2 0 00^'ca,. 1.-..,...,,-:go ... 0, ,...^-3 Cluster 6

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