Cognitive IDlpairDlents in Multiple Sclerosis Implications for Rehabilitation Neuropsychological functioning in multiple sclerosis (MS) has recently become an area of increased interest to health care professionals. This article reviews how various cognitive domains are affected by MS. Studies have shown impairments in individuals with MS in the areas of memory, information processing, complex attention, visuospatial functions, and executive functioning while ability is generally preserved in the intellectual and language domains. The implications of these findings for cognitive rehabilitation in MS is discussed.
John Deluca, PhD Susan K. Johnson, PhD
Kessler Institute for Rehabilitation, West Orange, N], and University of Medicine and Dentistry of New JerseyNew Jersey Medical School Newark, NJ
Multiple sclerosis (MS) is the most common nontraumatic neurological illness that affects younger and middle-aged adults.! Until recently, most clinicians have assumed that cognitive or affective disturbances were only observed in severe cases (e.g., cases of dementia). For instance, in a review of the literature, only twenty years ago it was reported that cognitive impairments were observed in only about 3% of the MS population. 2 However, over the past two decades, armed with more sophisticated neuropsychological tests than the assessments used previously, recent studies estimate that 43% to 65% of patients with MS suffer some degree of cognitive impairment. 3,4 The purpose of this article is to provide an overview of the types of cognitive impairments frequently observed among individuals with MS. It is not designed to be an exhaustive review of the literature. For such a discussion the reader is referred to more thorough reviews.!,5 The first section describes the cognitive impairments observed in MS. The next section describes variables that affect cognitive performance. Last is a brief discussion of cognitive rehabilitation in the MS population.
Dr. Johnson was funded by Department of EducationNIDRR grant H133PI0002-92 to UMDNJ-New Jersey Medical School. NeuroRehabill993; 3(4):9-16 Copyright © 1993 by Andover Medical.
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NEUROREHABILITATION / FALL 1993
HOW VARIOUS COGNITIVE DOMAINS ARE AFFECTED BY MS Although a decline in motor skills is the most obvious deficit in individuals with MS, 6 this discussion focuses on areas of cognitive functioning that are not generally compromised by sensorimotor impairments.
Language Function Language function is generally not seriously impaired in individuals with MS. Aphasia is uncommon in MS, which is consistent with the notion that language disorders are primarily a result of cortical lesions whereas MS is primarily a whitematter disease. Though isolated cases of "aphasia" in individuals have been reported, 7 they are considered rare. The most common language deficit observed in individuals with MS is decreased performance on tests of verbal fluency where subjects are required to name as many words as possible in a specified category within a time limit. A number of studies have reported decreased verbal fluency in MS subjects relative to controls. 4,8-IO Although compromised verbal fluency has been traditionally associated with frontal system involvement, II a recent study 12 found that anterior corpus callosum atrophy was positively related to verbal fluency impairments in MS subjects. On tests of naming or oral comprehension, MS subjects generally do not perform differently from controls. 5,8 However, some exceptions have been reported. 13 Overall, decreased verbal fluency has been consistently shown in individuals with MS, though other aspects of language dysfunction are rare.
Intellectual Functions Many of the studies examining intellectual functioning in MS subjects have suffered from significant methodological difficulties ranging from a lack of a control group, inappropriately matched controls, and small sample sizes, to not controlling for the effects of various disease variables on cognitive performance. 5 Generally speaking, Verbal IQ on the WAIS-R is not significantly different between MS subjects and controls. 5,6,14 When the
individual subtests of the WAIS-R are examined, some group differences have been reported. For instance, Heaton et al. 13 reported that a chronicprogressive MS group did significantly worse than controls on the Arithmetic and Similarities subtest of the WAIS, but not on the Vocabulary, Digit Span, Information and Comprehension subtests. In contrast to Verbal IQ, Performance IQ is usually reduced in MS groups relative to controls. 5,6,14 While this VIQ-PIQ split suggests selectively greater impairment in visuoperceptual processing in individuals with MS, interpretation of Performance IQ may be confounded by sensorimotor difficulties and/or decreased speed of processing (which would impair performance on timed tests). Thus, it appears that verbal intellectual functions which are not compromised by the sensorimotor deficits ofMS are fairly well preserved and are a relative strength that can be used to compensate for impaired functioning in other areas.
Attention/Concentration Functions and Short-Term Memory Deficits in attention and concentration in individuals with MS have been demonstrated by a number of investigators. 13,15 Attentional deficits may play an underlying role in other cognitive problems, such as memory and information processing. Digit span, a widely used test of attention, concentration, and immediate memory span, has usually been found to be intact (i.e., not different from controls) in MS subjects. 4 ,13,16 However, others have reported 8 ,IO,17 impaired Digit Span performance in MS. Fischer IO found that MS subjects' were not impaired on Visual Memory Span and suggested that individuals with MS are particularly susceptible to interference. Some studies 9 ,18 have found that individuals with MS were impaired on the Trail Making Test-a visuomotor tracking test. However, the psychomotor demands of the task make this test difficult to interpret in MS. Attention and short-term memory (although generally intact) may be particularly susceptible to interference in individuals with MS. Grant et al. 18 found that their MS group was impaired on the
Cognitive Impairments in Multiple Sclerosis
Brown-Peterson Consonant Trigram Test, particularly when mathematical calculation was used as a distractor. Thus, adding complexity to a speedof-processing task differentially affected the MS group. However, the finding of vulnerability to interference on the Brown-Peterson Test was not replicated in another study4 which found the task insensitive to detecting cognitive problems in MS. The presence of attention/short-term memory deficits in individuals with MS remains controversial. Overall, simple attentional skills appear to be intact in these individuals. However, with increased task complexity MS subjects tend to demonstrate impaired performance.
Information Processing There is considerable evidence suggesting that MS subjects acquire information at a slower rate than do controls. 5 Rao et al. 4 suggested that slowed information processing speed is as common as are problems with recent memory, conceptual reasoning, and verbal fluency in individuals with MS. DeLuca et al. 19 found that both MS and chronic fatigue syndrome subjects were impaired on the Paced Auditory Serial Addition Test (PASAT) when compared to healthy controls. Litvan et al. 14 reported that MS subjects were impaired at the two fastest rates of presentation on the PASA1~ but were not impaired on the speed-of-memory scanning as measured by the Sternberg Memory Scanning Paradigm. They speculate that MS subjects could be impaired on the PASAT and not the Sternberg task because of a working memory (number of items that can be held in short-term memory) deficit, problems with procedural activation of computation skills, or reduction in the number of processes they can simultaneously activate. They favored the working memory interpretation and proposed that the MS subjects can keep only a limited amount of information in their rehearsal loop and that the faster rates of the PASAT have overtaxed that system. Others have been supportive of this concept. 10 Interestingly, Rao et al. 20 did find deficits on the Sternberg memory scanning test. They found that scanning rate, which they considered a measure of pure cognitive speed (i.e., independent of motor in-
11
volvement), was significantly slower in the MS subjects when compared to controls. The discrepant findings on information processing tasks (as well as those seen in Digit Span and Brown-Peterson) may be due to the fact that cognitive changes in MS are extremely variable. The problem of heterogeneity within the MS population is best addressed by acknowledging and rigorously defining the various disease-related variables within MS, such as disease type, duration of illness, and degree of neurologic disability, and then attempting to define cognitive changes in relation to these variables. Ra0 5 noted that problems of fatigue in MS may contribute to slowing of cognitive processing speed and sugges.ted that these problems may be related to frontal-subcortical system dysfunction. The question of how fatiguing illnesses or fatigue in general can affect cognitive functioning is an important area for future research. 19 Slowing of mental processing as well as forgetfulness, impaired abstract reasoning, altered personality with apathy, and depression, have been cited as hallmarks of subcortical dementias. 21 A number of investigators have characterized the MS cognitive pattern as a possible subcortical dementia. 5 ,9,22,23 Although this is an intriguing and controversial topic, a discussion here is beyond the scope of this article. Interested readers are referred to Mahler and Benson. 22
Memory The most commonly observed deficit, and the function that has received the most research attention in individuals with MS, is memory. Despite the rather extensive literature documenting memory impairments in people with MS, the specific nature of the memory disorder remains unclear. Questions remain as to whether compromised memory is a function of impairment in the retrieval of information or a problem in the acquisition of information, or both. The majority of studies have concluded that short-term memory is unimpaired in MS (as previously discussed), and that impairments in longterm memory are a result of deficient retrieval mechanisms. Thus, for instance, when required to recall paragraph-length stories, MS subjects recall
12
NEUROREHABILI1ATION / FALL 1993
fewer story items than do controls for both immediate and 30-minute-delayed free recall. 9,10,24 Verbal list-learning tasks have also supported the retrieval failure hypothesis. 25 Others have reported that recognition memory in MS does not differ from controls despite deficient recall,25,26 which further supports the retrieval fi:\ilure hypothesis. However, close examination of the aforementioned paradigms reveals several weaknesses in the design, which make a retrieval failure hypothesis difficult to conclude with certainty. For instance, a number of studies l ,27 have shown that although MS subjects recall fewer "items" relative to controls, when the "amount" of information on immediate recall (i.e., initial acquisition) is taken into account, performance does not differ between groups during delayed free recall. This suggests that although MS subjects may be deficient in the initial learning of material, retrieval of this acquired information does not differ from controls. Yet, other studies have not upheld this finding.10,IS The retrieval vs acquisition hypothesis was tested directly by DeLuca et al. 17 MS and control subjects were administered a verbal list-learning task, and the groups were equated on the amount of information acquired during the learning phase by training subjects to a criteria rather than by administering a fixed number oflearning trials. Training subjects to a criteria ensured that all subjects initially learned the "same" amount of information. If the MS group recalled fewer words than did controls following a thirty-minute delay, this would support a retrieval hypothesis. In contrast, ifthe MS group required more trials to learn the word list but performance did not differ from that of controls following a thirty-minute free recall trial (i.e., retrieval), this would support the notion of impaired acquisition. The results of the study did not show impaired retrieval, and supported a deficient acquisition hypothesis. Other recent studies have provided evidence for impaired acquisition of information in MS. For instance, memory dysfunction in MS has been found to result from slowed informationprocessing speed,14,28 poor initial learning, 27 and impaired working-memory capacity. 16
However, given the vast individual variability observed among MS subjects, a simple retrieval vs acquisition hypothesis is unlikely to be robust enough to explain the nature of memory impairments in all MS subjects. For instance, there is good evidence that the types of memory impairments in MS differ among MS subpopulations. Differences in memory performance have been observed between relapsing remitting, chronic progressive, and relapsing progressive MS groups. The influence of these subgroups and other factors on performance is discussed below. Despite the objective evidence demonstrating memory impairments in MS, impairments are frequently not acknowledged by the patients themselves. For instance, in a survey of 1180 individuals with MS, regarding their perceived cognitive deficits,29 only one third of the respondents reported having any cognitive difficulties compared to the 45%-65% impairment observed using objective testing. Difficulties in metamemory were also reported by Beatty and Monson 30 who found that individuals with MS who were impaired on recognition memory and the Wisconsin Card Sorting Test (WCST) were also impaired on a metamemory questionnaire. These subjects overestimated their actual performance, indicating a lack of insight regarding their abilities. In summary, recent work demonstrating deficits in initial learning and information-processing efficiency challenges the retrieval failure hypothesis as the mechanism of memory impairment in MS. A greater understanding of memory impairments has significant implications for rehabilitation (see last section).
Executive Functions
Ra0 5 summarized eleven studies and reported that seven out of eight found impairment on at least one measure of concept formation when MS subjects were compared to normal controls or non-brain-damaged controls. Ra0 5 cited four other studies where MS subjects were compared to groups of mixed brain-damaged subjects with no differences found between the two groups on tests of concept formation. Similar results have been observed in more recent studies. 4,S,22,30 For instance, Rao et al. 4 found that a large sample of
Cognitive Impairments in Multiple Sclerosis
individuals with MS were impaired on the Booklet Category Test and the WCST. Beatty and Monson 30 have interpreted impairments on WCST and verbal fluency as evidence of frontal lobe involvement in MS. These findings suggest that individuals with MS may have trouble forming concepts, shifting sets, and incorporating feedback and demonstrate perseverative tendencies. Furthermore, performance of individuals with MS more closely resembles that of a brain-damaged population than that of normal controls.
Visuospatial Skills Visuospatial functions have proved difficult to evaluate in individuals with MS. This is because many traditional neuropsychological tests require the use of functions that are compromised in MS. For instance, motor problems are common in MS, as are visual problems (e.g., blurred, double vision, optic neuritis, etc.). However, studies that have separated motor from visuospatial skills still demonstrate compromised visuospatial ability. For example, Rao et al. 4 reported that MS subjects were impaired relative to controls on the Benton Facial Recognition Test, Judgment of Line Orientation, and Visual Form Discrimination. Although the evidence suggests that visuospatial functions can be impaired in MS, care must be taken so that assessment of visuospatial ability is not contaminated by a more primary visual problem.
VARIABLES THAT CAN AFFECT COGNITIVE FUNCTION Affective Issues Several studies have reported affective changes in individuals with MS, ranging from inappropriate euphoria to severe depression. 31 ,32 The levels of depression are higher in MS than in other disabling neurologic diseases,22,33 and thus may not be solely attributable to the consequences ofliving with a chronic, disabling disease. Additionally, psychiatric morbidity is high in the MS population 6,34 when compared to the general population. The influence of depression on cognition has been the area most often examined. The vast
13
majority of these studies has reported that depression and cognitive impairment are not statistically significantly correlated. 8, 10, 14,35 For a more detailed discussion of affective issues in the MS population, refer to the article by Larocca et al. elsewhere in this issue.
Disease Progression Disease type. Two major subtypes of MS are generally recognized: relapsing remitting and chronic progressive. In addition, a relapsing progressive subtype has also been identified. Although disease type has been shown to influence cognitive performance, the results are not clear or definitive. In general, chronic progressive MS has been associated with greater cognitive impairment than the relapsing remitting subtype. 8 ,18 For instance, Heaton et al. 13 found that 98% of chronic progressive individuals were impaired on neuropsychological tests compared to one third of the relapsing remitting group. Yet, using multiple regression techniques, Beatty et al. 36 found that cognitive performance could not be predicted by disease type and its confounds-age, disease duration, and disability status. Disability status and illness duration. The majority of studies have found that the Expanded Disability Status Scale (EDSS) and other such scales that attempt to measure degree of neurologic involvement are not correlated with cognitive dysfunction, although "mild" correlations have been reported. 4 Franklin et al,37 note that although the EDSS is the "gold standard" for following the clinical course of MS, it is not adequate for following the course of cognitive function. For instance, Heaton et al. 13 found that although neurological examination ratings were strongly correlated with sensory, motor, and global impairment on their battery, the neurological ratings were essentially unrelated to cognitive impairment. In addition to EDSS, studies have generally found little relationship between cognitive impairment and disease duration. 4,36 It is important to note that illness duration is often confounded by disease type, i.e., individuals with chronic progressive type usually show the greatest cognitive impairment and also have a longer
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NEUROREHABILITATION / FALL 1993
mean duration of illness compared to individuals with relapsing remitting MS. Rao et al. 4 reported that cognitive impairment was not significantly associated with illness duration, depression, disease course, or medication usage. Yet individuals in their cognitively impaired group were less likely to be working, engaged in fewer social, avocational activities, had more sexual dysfunction, had greater difficulty with routine household chores, and exhibited more psychopathology than did the cognitively intact individuals with MS.35 This indicates that although individuals with more severe neurological signs of the disease may not be more cognitively impaired in any linear, predictable fashion, individuals with cognitive impairment are more likely to be generally disabled. For a further discussion of vocational issues in MS, see Brittel et al. in this issue. Medications. Although medications that are prescribed for individuals with MS could potentially adversely affect cognitive function, most studies have found that medication effects have not significantly influenced cognitive performance. Studies have examined the influence of various types of medication, including psychoactive drugs, anticonvulsants, steroids, sedativehypnotics, immunosuppressants, anticholinergics, and muscle relaxants. 10.13.18.20.30 All of these studies found no significant differences between the medicated and nonmedicated MS groups in regard to the level of neuropsychological impairment. In contrast to these studies, Rao et al. 4 reported that 43% of subjects randomly selected from the MS population in the community were taking prescribed medications, and that the medicated group failed more cognitive tests. However, the difference was not statistically significant. Minden et al. 8 found that ariti-anxiety medications had a significant effect on cognitive performance, and prednisone had a marginally significant effect, but no other medications had any effect. The majority of studies have not demonstrated any consistent medication effect on cognitive performance, and the few that have indicate such effects are likely to be minor.
COGNITIVE REHABILITATION IN THE MS PATIENT Although cognitive impairment in MS is now clearly recognized, cognitive rehabilitation programs to treat these individuals have generally not been incorporated into MS rehabilitation programs. The finding 35 that cognitive dysfunction in MS negatively impacts social and employment functioning (see also Britell et al. in this issue) exemplifies the need for effective cognitive rehabilitation in this population. Because general intellectual functioning is usually preserved and the cognitive problems experienced by many individuals with MS are frequently in the mild-tomoderate range of impairment, the individual with MS is an excellent candidate for cognitive rehabilitation. Though outlining specific interventions for each area of cognitive impairment is beyond the scope of this article, several important points can be made regarding effective cognitive rehabilitation in people with MS. Because of the heterogeneous nature of the eNS lesions, each person with MS brings a unique pattern of cognitive difficulties to rehabilitation. A comprehensive care model such as that illustrated by Larocca,38 which is interdisciplinary in nature and multifaceted in scope, provides the ideal environment for cognitive rehabilitation services. Effective cognitive rehabilitation in MS goes beyond simple assessment and treatment of specific deficits. Intervention must incorporate the entire complexity of an individual's particular life circumstances, ranging from an understanding of the affective component of MS to making realistic goals and objectives (e.g., vocational), to the understanding of the interaction among cognitive, affective, and psychosocial issues on family dynamics. The neuropsychological evaluation should assess intelligence; attention, concentration, and information processing efficiency; verbal and visual memory, both immediate and delayed; executive functions (e.g., problem solving, planning, organization, concept formation, set-shifting, use of environmental feedback, etc.); language functions,
Cognitive Impairments in Multiple Sclerosis
particularly word-finding and expressive skills; and visuospatial and perceptual skills. The report should provide not only areas of deficits but also relative cognitive strengths. The following short example illustrates the importance of understanding the complex cognitive profile of individuals with MS. A 41-year-old woman, diagnosed with MS ten years earlier, was referred for a neuropsychological evaluation to assess her difficulty in learning and remembering what was taught in occupational therapy. The evaluation revealed significant difficulties in informationprocessing speed and efficiency, significantly impaired visuospatial ability and visual memory, and compromised concept formation and problem solving. Contrary to what the therapist thought, verbal memory was not impaired. Attention, verbal intellectual skills, and language (other than word finding) were also within normal limits. Thus, this patient's difficulty in learning how to use a wheelchair was not a result of poor learning and memory nor motivation. Rather, she had difficulty processing the verbal instructions due to decreased processing speed, and difficulty in visually integrating and organizing the spatial arrangement of her chair (e.g., the location of the locking mechanism on the chair), due to a visual perceptual impairment.
15
tive for patients with difficulties in retrieval of information from long-term storage. Thus, identification of the nature of the memory impairment will help determine the most effective intervention strategies.
CONCLUSIONS Clearly, individuals with MS can suffer a wide range of cognitive impairments. The most prevalent appear to be in the areas of memory, efficiency of information processing, complex attention, visuospatial, and executive functioning. Yet, because cognitive changes in MS are extremely variable, cognitive rehabilitation needs to be individualized. A comprehensive rehabilitation program that takes into account the cognitive demands of an individual's environment, as well as their evolving capacities, limitations, motivations, goals, and sources of support, holds the best promise for a successful outcome.
REFERENCES However, utilization of the results of a comprehensive neuropsychological evaluation must go beyond simply outlining cognitive strengths and weaknesses. The impact of these strengths and weaknesses on the everyday functioning of the patient in his or her environment is the key to effective treatment planning. Furthermore, an "impairment" (e.g., compromised memory) may not necessarily result in a "disability" or "handicap" for the individual. For instance, individuals with mild-to-moderate memory impairments can usually live independently and work effectively. Simple identification of, for example, a "verbal memory impairment" contributes little to the design of an appropriate intervention. More detailed analysis of the components of memory can be used directly in rehabilitation. For example, utilization of a memory log book will be a less effective aid to individuals who demonstrate impairments in the acquisition of information than will techniques designed to improve the efficiency of information processing. Memory logs are most effec-
1. Rao SM, ed. Neurobehnvioral aspects of multiple sclerosis, New York: Oxford University Press, 1990.
2. Kurtzke JF, Beebe Gw, Nagler B, et al. Studies on the natural history of multiple sclerosis. 6. Clinical and laboratory findings at first diagnosis. Acta Neurol Scand 1972; 48: 19-46. 3. Peyser JM, Rao SM, Larocca NG, et al. Guidelines for neuropsychological research in MS. Arch Neuroll990; 47:94-97.
4. Rao SM, Leo GJ, Bernadin LB, et al. Cognitive dysfunction in MS. 1. Frequency, patterns and predictors. Neuroll991a; 41:685-691. 5. Rao SM. Neuropsychology of multiple sclerosis: A critical review.] Clin Exp Neuropsychol 1986; 8(5):503-542. 6. Ron MA Multiple sclerosis: psychiatric and psychometric abnormalities. ] Psychosomatic Res 1986; 30(1):3-11. 7. Achiron A, Ziv I, Djaldetti R, et al. Aphasia in multiple sclerosis: Clinical and radiologic correlations. Neuroll992; 42:2195-2197. 8. Minden SL, Moes EJ, Orav J, et al. Memory impairment in multiple sclerosis.] Clin Exp Neuropsycholl990; 12(4):566-586.
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9. Caine ED, Bamford KA, Schiffer RB, et al. A controlled neuropsychological comparison of Huntington's disease and multiple sclerosis. Arch Neurol 1986; 43:249-254. 10. Fischer jS. Using the Wechsler Memory ScaleRevised to detect and characterize memory deficits in multiple sclerosis. Clin Neuropsychol 1988; 2(2): 149-172. 11. Benton AL. Differential behavioral effects in frontal lobe disease. Neuropsychologia 1968; 6:5360. 12. Pozzilli C., Bastianello S, Padovani A, et al. Anterior corpus callosum atrophy and verbal fluency in MS. Cortex 1991; 27:441-445. 13. Heaton RK, Nelson LM, Thompson DS, et al. Neuropsychological findings in relapsingremitting and chronic-progressive multiple sclerosis.] Consult Clin Psychol1985; 53(1):103-110. 14. Litvan I, Grafman j, Vendrell P, et al. Slowed information processing in multiple sclerosis. Arch Neurol1988a; 45:281-285. 15. Grafmanj, Rao SM, Litvan I. Disorders ofmemory. In: Rao SM, ed. Neurobehavioral Aspects of Multiple Sclerosis. New York: Oxford University Press, 1990; 102-117. 16. Litvan I, Grafman j, Vendrell P, et al. Multiple memory deficits in patients with multiple sclerosis. Arch Neurol1988b; 45:607-610. 17. DeLucaj, Berger SB,johnson SK. The nature of memory impairments in multiple sclerosis: Acquisition vs retrieval.] Clin EXfJ Neuropsychol (submitted). 18. Grant I, McDonald WI, Trimble MR, et al. Deficient learning and memory in early and middle phases of multiple sclerosis.] Neurol Neurosurg Psychiatry 1984; 47:250-255. 19. DeLucaj, johnson SK, Natelson BH. Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. Arch Neurol in press. 20. Rao SM, St. Aubin-Faubert P, Leo GJ. Information processing speed in patients with multiple sclerosis.] Clin Exp Neuropsycholl989; 11 (4):471477. 21. Cummings jL, Benson F. Subcortical dementia: Review of an emerging concept. Arch Neurol 1984; 41:874-879. 22. Mahler ME, Benson DF. Cognitive dysfunction in multiple sclerosis: A subcortical dementia? In: Rao SM, ed. Neurobehavioral Aspects of Multiple Sclerosis. New York: Oxford University Press, 1990; 88-10 1. 23. Filley CM, Heaton RK, Nelson LM, et al. A comparison of dementia in Alzheimer's disease and multiple sclerosis. Arch Neuroll989; 46:157-161.
24. Rao SM, Hammeke TA, McQuillen MP, et al. Memory disturbance in chronic progressive multiple sclerosis. Arch Neurol1984; 41 :625-631. 25. Rao SM, Leo Gj, St. Aubin-Faubert P. On the nature of memory disturbance in multiple sclerosis.] Clin Exp Neuropsychol1989; 11:699-712. 26. Carroll M, Gates R, Roldan F. Memory impairment in multiple sclerosis. Neuropsychologia 1984; 22:297-302. 27. van den Burg W, van ZomerenAH, Minderhoud jM, et al. Cognitive impairments in patients with multiple sclerosis and mild physical disability. Arch Neurol1987; 44:494-501. 28. Beatty WW, Goodkin DE, Monson N, et al. Anterograde and retrograde amnesia in patients with chronic progressive multiple sclerosis. Arch Neurol1988; 45:611-619. 29. Sullivan MjL, Edgley K, Dehoux E. A survey of MS. Part 1: Perceived cognitive problems and compensatory strategy use. Can] Rehabil 1990; 4(2):99-105. 30. Beatty WW, Monson N. Metamemory in multiple sclerosis. ] Clin EXfJ Neuropsychol 1991; 13:309-327. 31. Rabins pv. Euphoria in multiple sclerosis. In: Rao SM, ed. Neurobehavioral Aspects of Multiple Sclerosis. New York: Oxford University Press, 1990; 180-185. 32. Rao SM, Huber Sj, Bornstein RA. Emotional changes with multiple sclerosis and P'arkinson's disease.] Consult Clin Psychol 1992; 60(3):369377. 33. Whitlock FA, Siskind MM. Depression as a major symptom of multiple sclerosis.] Neurol Neurosurg Psychiat 1980; 43:861-865. 34. Schiffer RB. Disturbances of affect. In: Rao SM, ed. Neurobehavioral Aspects of Multiple Sclerosis. New York: Oxford University Press, 1990; 186195. 35. Rao SM, Leo Gj, Ellington L, et al. Cognitive dysfunction in multiple sclerosis: 2. Impact on social functioning. Neurology 1991 b; 41 :692-696. 36. Beatty WW, Goodkin DE, Hertsgaard D, et al. Clinical and demographic predictors of cognitive performance in multiple sclerosis. Arch Neurol1990; 47:305-308. 37. Franklin GM, Nelson LM, Heaton RK, et al. Clinical perspectives in the identification of cognitive impairment. In: Rao SM, ed. Neurobehavioral Aspects of Multiple Sclerosis. New York: Oxford University Press, 1990; 161-175. 38. Larocca NG. A rehabilitation perspective. In: Rao SM, ed. Neurobehavioral Aspects of Multiple Sclerosis. New York: Oxford University Press, 1990; 215-229.
John Deluca, PhD Susan K. Johnson, PhD
Kessler Institute for Rehabilitation, West Orange, N], and University of Medicine and Dentistry of New JerseyNew Jersey Medical School Newark, NJ
Multiple sclerosis (MS) is the most common nontraumatic neurological illness that affects younger and middle-aged adults.! Until recently, most clinicians have assumed that cognitive or affective disturbances were only observed in severe cases (e.g., cases of dementia). For instance, in a review of the literature, only twenty years ago it was reported that cognitive impairments were observed in only about 3% of the MS population. 2 However, over the past two decades, armed with more sophisticated neuropsychological tests than the assessments used previously, recent studies estimate that 43% to 65% of patients with MS suffer some degree of cognitive impairment. 3,4 The purpose of this article is to provide an overview of the types of cognitive impairments frequently observed among individuals with MS. It is not designed to be an exhaustive review of the literature. For such a discussion the reader is referred to more thorough reviews.!,5 The first section describes the cognitive impairments observed in MS. The next section describes variables that affect cognitive performance. Last is a brief discussion of cognitive rehabilitation in the MS population.
Dr. Johnson was funded by Department of EducationNIDRR grant H133PI0002-92 to UMDNJ-New Jersey Medical School. NeuroRehabill993; 3(4):9-16 Copyright © 1993 by Andover Medical.
10
NEUROREHABILITATION / FALL 1993
HOW VARIOUS COGNITIVE DOMAINS ARE AFFECTED BY MS Although a decline in motor skills is the most obvious deficit in individuals with MS, 6 this discussion focuses on areas of cognitive functioning that are not generally compromised by sensorimotor impairments.
Language Function Language function is generally not seriously impaired in individuals with MS. Aphasia is uncommon in MS, which is consistent with the notion that language disorders are primarily a result of cortical lesions whereas MS is primarily a whitematter disease. Though isolated cases of "aphasia" in individuals have been reported, 7 they are considered rare. The most common language deficit observed in individuals with MS is decreased performance on tests of verbal fluency where subjects are required to name as many words as possible in a specified category within a time limit. A number of studies have reported decreased verbal fluency in MS subjects relative to controls. 4,8-IO Although compromised verbal fluency has been traditionally associated with frontal system involvement, II a recent study 12 found that anterior corpus callosum atrophy was positively related to verbal fluency impairments in MS subjects. On tests of naming or oral comprehension, MS subjects generally do not perform differently from controls. 5,8 However, some exceptions have been reported. 13 Overall, decreased verbal fluency has been consistently shown in individuals with MS, though other aspects of language dysfunction are rare.
Intellectual Functions Many of the studies examining intellectual functioning in MS subjects have suffered from significant methodological difficulties ranging from a lack of a control group, inappropriately matched controls, and small sample sizes, to not controlling for the effects of various disease variables on cognitive performance. 5 Generally speaking, Verbal IQ on the WAIS-R is not significantly different between MS subjects and controls. 5,6,14 When the
individual subtests of the WAIS-R are examined, some group differences have been reported. For instance, Heaton et al. 13 reported that a chronicprogressive MS group did significantly worse than controls on the Arithmetic and Similarities subtest of the WAIS, but not on the Vocabulary, Digit Span, Information and Comprehension subtests. In contrast to Verbal IQ, Performance IQ is usually reduced in MS groups relative to controls. 5,6,14 While this VIQ-PIQ split suggests selectively greater impairment in visuoperceptual processing in individuals with MS, interpretation of Performance IQ may be confounded by sensorimotor difficulties and/or decreased speed of processing (which would impair performance on timed tests). Thus, it appears that verbal intellectual functions which are not compromised by the sensorimotor deficits ofMS are fairly well preserved and are a relative strength that can be used to compensate for impaired functioning in other areas.
Attention/Concentration Functions and Short-Term Memory Deficits in attention and concentration in individuals with MS have been demonstrated by a number of investigators. 13,15 Attentional deficits may play an underlying role in other cognitive problems, such as memory and information processing. Digit span, a widely used test of attention, concentration, and immediate memory span, has usually been found to be intact (i.e., not different from controls) in MS subjects. 4 ,13,16 However, others have reported 8 ,IO,17 impaired Digit Span performance in MS. Fischer IO found that MS subjects' were not impaired on Visual Memory Span and suggested that individuals with MS are particularly susceptible to interference. Some studies 9 ,18 have found that individuals with MS were impaired on the Trail Making Test-a visuomotor tracking test. However, the psychomotor demands of the task make this test difficult to interpret in MS. Attention and short-term memory (although generally intact) may be particularly susceptible to interference in individuals with MS. Grant et al. 18 found that their MS group was impaired on the
Cognitive Impairments in Multiple Sclerosis
Brown-Peterson Consonant Trigram Test, particularly when mathematical calculation was used as a distractor. Thus, adding complexity to a speedof-processing task differentially affected the MS group. However, the finding of vulnerability to interference on the Brown-Peterson Test was not replicated in another study4 which found the task insensitive to detecting cognitive problems in MS. The presence of attention/short-term memory deficits in individuals with MS remains controversial. Overall, simple attentional skills appear to be intact in these individuals. However, with increased task complexity MS subjects tend to demonstrate impaired performance.
Information Processing There is considerable evidence suggesting that MS subjects acquire information at a slower rate than do controls. 5 Rao et al. 4 suggested that slowed information processing speed is as common as are problems with recent memory, conceptual reasoning, and verbal fluency in individuals with MS. DeLuca et al. 19 found that both MS and chronic fatigue syndrome subjects were impaired on the Paced Auditory Serial Addition Test (PASAT) when compared to healthy controls. Litvan et al. 14 reported that MS subjects were impaired at the two fastest rates of presentation on the PASA1~ but were not impaired on the speed-of-memory scanning as measured by the Sternberg Memory Scanning Paradigm. They speculate that MS subjects could be impaired on the PASAT and not the Sternberg task because of a working memory (number of items that can be held in short-term memory) deficit, problems with procedural activation of computation skills, or reduction in the number of processes they can simultaneously activate. They favored the working memory interpretation and proposed that the MS subjects can keep only a limited amount of information in their rehearsal loop and that the faster rates of the PASAT have overtaxed that system. Others have been supportive of this concept. 10 Interestingly, Rao et al. 20 did find deficits on the Sternberg memory scanning test. They found that scanning rate, which they considered a measure of pure cognitive speed (i.e., independent of motor in-
11
volvement), was significantly slower in the MS subjects when compared to controls. The discrepant findings on information processing tasks (as well as those seen in Digit Span and Brown-Peterson) may be due to the fact that cognitive changes in MS are extremely variable. The problem of heterogeneity within the MS population is best addressed by acknowledging and rigorously defining the various disease-related variables within MS, such as disease type, duration of illness, and degree of neurologic disability, and then attempting to define cognitive changes in relation to these variables. Ra0 5 noted that problems of fatigue in MS may contribute to slowing of cognitive processing speed and sugges.ted that these problems may be related to frontal-subcortical system dysfunction. The question of how fatiguing illnesses or fatigue in general can affect cognitive functioning is an important area for future research. 19 Slowing of mental processing as well as forgetfulness, impaired abstract reasoning, altered personality with apathy, and depression, have been cited as hallmarks of subcortical dementias. 21 A number of investigators have characterized the MS cognitive pattern as a possible subcortical dementia. 5 ,9,22,23 Although this is an intriguing and controversial topic, a discussion here is beyond the scope of this article. Interested readers are referred to Mahler and Benson. 22
Memory The most commonly observed deficit, and the function that has received the most research attention in individuals with MS, is memory. Despite the rather extensive literature documenting memory impairments in people with MS, the specific nature of the memory disorder remains unclear. Questions remain as to whether compromised memory is a function of impairment in the retrieval of information or a problem in the acquisition of information, or both. The majority of studies have concluded that short-term memory is unimpaired in MS (as previously discussed), and that impairments in longterm memory are a result of deficient retrieval mechanisms. Thus, for instance, when required to recall paragraph-length stories, MS subjects recall
12
NEUROREHABILI1ATION / FALL 1993
fewer story items than do controls for both immediate and 30-minute-delayed free recall. 9,10,24 Verbal list-learning tasks have also supported the retrieval failure hypothesis. 25 Others have reported that recognition memory in MS does not differ from controls despite deficient recall,25,26 which further supports the retrieval fi:\ilure hypothesis. However, close examination of the aforementioned paradigms reveals several weaknesses in the design, which make a retrieval failure hypothesis difficult to conclude with certainty. For instance, a number of studies l ,27 have shown that although MS subjects recall fewer "items" relative to controls, when the "amount" of information on immediate recall (i.e., initial acquisition) is taken into account, performance does not differ between groups during delayed free recall. This suggests that although MS subjects may be deficient in the initial learning of material, retrieval of this acquired information does not differ from controls. Yet, other studies have not upheld this finding.10,IS The retrieval vs acquisition hypothesis was tested directly by DeLuca et al. 17 MS and control subjects were administered a verbal list-learning task, and the groups were equated on the amount of information acquired during the learning phase by training subjects to a criteria rather than by administering a fixed number oflearning trials. Training subjects to a criteria ensured that all subjects initially learned the "same" amount of information. If the MS group recalled fewer words than did controls following a thirty-minute delay, this would support a retrieval hypothesis. In contrast, ifthe MS group required more trials to learn the word list but performance did not differ from that of controls following a thirty-minute free recall trial (i.e., retrieval), this would support the notion of impaired acquisition. The results of the study did not show impaired retrieval, and supported a deficient acquisition hypothesis. Other recent studies have provided evidence for impaired acquisition of information in MS. For instance, memory dysfunction in MS has been found to result from slowed informationprocessing speed,14,28 poor initial learning, 27 and impaired working-memory capacity. 16
However, given the vast individual variability observed among MS subjects, a simple retrieval vs acquisition hypothesis is unlikely to be robust enough to explain the nature of memory impairments in all MS subjects. For instance, there is good evidence that the types of memory impairments in MS differ among MS subpopulations. Differences in memory performance have been observed between relapsing remitting, chronic progressive, and relapsing progressive MS groups. The influence of these subgroups and other factors on performance is discussed below. Despite the objective evidence demonstrating memory impairments in MS, impairments are frequently not acknowledged by the patients themselves. For instance, in a survey of 1180 individuals with MS, regarding their perceived cognitive deficits,29 only one third of the respondents reported having any cognitive difficulties compared to the 45%-65% impairment observed using objective testing. Difficulties in metamemory were also reported by Beatty and Monson 30 who found that individuals with MS who were impaired on recognition memory and the Wisconsin Card Sorting Test (WCST) were also impaired on a metamemory questionnaire. These subjects overestimated their actual performance, indicating a lack of insight regarding their abilities. In summary, recent work demonstrating deficits in initial learning and information-processing efficiency challenges the retrieval failure hypothesis as the mechanism of memory impairment in MS. A greater understanding of memory impairments has significant implications for rehabilitation (see last section).
Executive Functions
Ra0 5 summarized eleven studies and reported that seven out of eight found impairment on at least one measure of concept formation when MS subjects were compared to normal controls or non-brain-damaged controls. Ra0 5 cited four other studies where MS subjects were compared to groups of mixed brain-damaged subjects with no differences found between the two groups on tests of concept formation. Similar results have been observed in more recent studies. 4,S,22,30 For instance, Rao et al. 4 found that a large sample of
Cognitive Impairments in Multiple Sclerosis
individuals with MS were impaired on the Booklet Category Test and the WCST. Beatty and Monson 30 have interpreted impairments on WCST and verbal fluency as evidence of frontal lobe involvement in MS. These findings suggest that individuals with MS may have trouble forming concepts, shifting sets, and incorporating feedback and demonstrate perseverative tendencies. Furthermore, performance of individuals with MS more closely resembles that of a brain-damaged population than that of normal controls.
Visuospatial Skills Visuospatial functions have proved difficult to evaluate in individuals with MS. This is because many traditional neuropsychological tests require the use of functions that are compromised in MS. For instance, motor problems are common in MS, as are visual problems (e.g., blurred, double vision, optic neuritis, etc.). However, studies that have separated motor from visuospatial skills still demonstrate compromised visuospatial ability. For example, Rao et al. 4 reported that MS subjects were impaired relative to controls on the Benton Facial Recognition Test, Judgment of Line Orientation, and Visual Form Discrimination. Although the evidence suggests that visuospatial functions can be impaired in MS, care must be taken so that assessment of visuospatial ability is not contaminated by a more primary visual problem.
VARIABLES THAT CAN AFFECT COGNITIVE FUNCTION Affective Issues Several studies have reported affective changes in individuals with MS, ranging from inappropriate euphoria to severe depression. 31 ,32 The levels of depression are higher in MS than in other disabling neurologic diseases,22,33 and thus may not be solely attributable to the consequences ofliving with a chronic, disabling disease. Additionally, psychiatric morbidity is high in the MS population 6,34 when compared to the general population. The influence of depression on cognition has been the area most often examined. The vast
13
majority of these studies has reported that depression and cognitive impairment are not statistically significantly correlated. 8, 10, 14,35 For a more detailed discussion of affective issues in the MS population, refer to the article by Larocca et al. elsewhere in this issue.
Disease Progression Disease type. Two major subtypes of MS are generally recognized: relapsing remitting and chronic progressive. In addition, a relapsing progressive subtype has also been identified. Although disease type has been shown to influence cognitive performance, the results are not clear or definitive. In general, chronic progressive MS has been associated with greater cognitive impairment than the relapsing remitting subtype. 8 ,18 For instance, Heaton et al. 13 found that 98% of chronic progressive individuals were impaired on neuropsychological tests compared to one third of the relapsing remitting group. Yet, using multiple regression techniques, Beatty et al. 36 found that cognitive performance could not be predicted by disease type and its confounds-age, disease duration, and disability status. Disability status and illness duration. The majority of studies have found that the Expanded Disability Status Scale (EDSS) and other such scales that attempt to measure degree of neurologic involvement are not correlated with cognitive dysfunction, although "mild" correlations have been reported. 4 Franklin et al,37 note that although the EDSS is the "gold standard" for following the clinical course of MS, it is not adequate for following the course of cognitive function. For instance, Heaton et al. 13 found that although neurological examination ratings were strongly correlated with sensory, motor, and global impairment on their battery, the neurological ratings were essentially unrelated to cognitive impairment. In addition to EDSS, studies have generally found little relationship between cognitive impairment and disease duration. 4,36 It is important to note that illness duration is often confounded by disease type, i.e., individuals with chronic progressive type usually show the greatest cognitive impairment and also have a longer
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NEUROREHABILITATION / FALL 1993
mean duration of illness compared to individuals with relapsing remitting MS. Rao et al. 4 reported that cognitive impairment was not significantly associated with illness duration, depression, disease course, or medication usage. Yet individuals in their cognitively impaired group were less likely to be working, engaged in fewer social, avocational activities, had more sexual dysfunction, had greater difficulty with routine household chores, and exhibited more psychopathology than did the cognitively intact individuals with MS.35 This indicates that although individuals with more severe neurological signs of the disease may not be more cognitively impaired in any linear, predictable fashion, individuals with cognitive impairment are more likely to be generally disabled. For a further discussion of vocational issues in MS, see Brittel et al. in this issue. Medications. Although medications that are prescribed for individuals with MS could potentially adversely affect cognitive function, most studies have found that medication effects have not significantly influenced cognitive performance. Studies have examined the influence of various types of medication, including psychoactive drugs, anticonvulsants, steroids, sedativehypnotics, immunosuppressants, anticholinergics, and muscle relaxants. 10.13.18.20.30 All of these studies found no significant differences between the medicated and nonmedicated MS groups in regard to the level of neuropsychological impairment. In contrast to these studies, Rao et al. 4 reported that 43% of subjects randomly selected from the MS population in the community were taking prescribed medications, and that the medicated group failed more cognitive tests. However, the difference was not statistically significant. Minden et al. 8 found that ariti-anxiety medications had a significant effect on cognitive performance, and prednisone had a marginally significant effect, but no other medications had any effect. The majority of studies have not demonstrated any consistent medication effect on cognitive performance, and the few that have indicate such effects are likely to be minor.
COGNITIVE REHABILITATION IN THE MS PATIENT Although cognitive impairment in MS is now clearly recognized, cognitive rehabilitation programs to treat these individuals have generally not been incorporated into MS rehabilitation programs. The finding 35 that cognitive dysfunction in MS negatively impacts social and employment functioning (see also Britell et al. in this issue) exemplifies the need for effective cognitive rehabilitation in this population. Because general intellectual functioning is usually preserved and the cognitive problems experienced by many individuals with MS are frequently in the mild-tomoderate range of impairment, the individual with MS is an excellent candidate for cognitive rehabilitation. Though outlining specific interventions for each area of cognitive impairment is beyond the scope of this article, several important points can be made regarding effective cognitive rehabilitation in people with MS. Because of the heterogeneous nature of the eNS lesions, each person with MS brings a unique pattern of cognitive difficulties to rehabilitation. A comprehensive care model such as that illustrated by Larocca,38 which is interdisciplinary in nature and multifaceted in scope, provides the ideal environment for cognitive rehabilitation services. Effective cognitive rehabilitation in MS goes beyond simple assessment and treatment of specific deficits. Intervention must incorporate the entire complexity of an individual's particular life circumstances, ranging from an understanding of the affective component of MS to making realistic goals and objectives (e.g., vocational), to the understanding of the interaction among cognitive, affective, and psychosocial issues on family dynamics. The neuropsychological evaluation should assess intelligence; attention, concentration, and information processing efficiency; verbal and visual memory, both immediate and delayed; executive functions (e.g., problem solving, planning, organization, concept formation, set-shifting, use of environmental feedback, etc.); language functions,
Cognitive Impairments in Multiple Sclerosis
particularly word-finding and expressive skills; and visuospatial and perceptual skills. The report should provide not only areas of deficits but also relative cognitive strengths. The following short example illustrates the importance of understanding the complex cognitive profile of individuals with MS. A 41-year-old woman, diagnosed with MS ten years earlier, was referred for a neuropsychological evaluation to assess her difficulty in learning and remembering what was taught in occupational therapy. The evaluation revealed significant difficulties in informationprocessing speed and efficiency, significantly impaired visuospatial ability and visual memory, and compromised concept formation and problem solving. Contrary to what the therapist thought, verbal memory was not impaired. Attention, verbal intellectual skills, and language (other than word finding) were also within normal limits. Thus, this patient's difficulty in learning how to use a wheelchair was not a result of poor learning and memory nor motivation. Rather, she had difficulty processing the verbal instructions due to decreased processing speed, and difficulty in visually integrating and organizing the spatial arrangement of her chair (e.g., the location of the locking mechanism on the chair), due to a visual perceptual impairment.
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tive for patients with difficulties in retrieval of information from long-term storage. Thus, identification of the nature of the memory impairment will help determine the most effective intervention strategies.
CONCLUSIONS Clearly, individuals with MS can suffer a wide range of cognitive impairments. The most prevalent appear to be in the areas of memory, efficiency of information processing, complex attention, visuospatial, and executive functioning. Yet, because cognitive changes in MS are extremely variable, cognitive rehabilitation needs to be individualized. A comprehensive rehabilitation program that takes into account the cognitive demands of an individual's environment, as well as their evolving capacities, limitations, motivations, goals, and sources of support, holds the best promise for a successful outcome.
REFERENCES However, utilization of the results of a comprehensive neuropsychological evaluation must go beyond simply outlining cognitive strengths and weaknesses. The impact of these strengths and weaknesses on the everyday functioning of the patient in his or her environment is the key to effective treatment planning. Furthermore, an "impairment" (e.g., compromised memory) may not necessarily result in a "disability" or "handicap" for the individual. For instance, individuals with mild-to-moderate memory impairments can usually live independently and work effectively. Simple identification of, for example, a "verbal memory impairment" contributes little to the design of an appropriate intervention. More detailed analysis of the components of memory can be used directly in rehabilitation. For example, utilization of a memory log book will be a less effective aid to individuals who demonstrate impairments in the acquisition of information than will techniques designed to improve the efficiency of information processing. Memory logs are most effec-
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