Neuropsychology Review, Vol. 8, No.

2, 1998

Neuropsychological Aspects of Multiple Sclerosis

Jan C. Brassington1,2 and Nigel V. Marsh1

Since S. Rao's ["Neuropsychology of Multiple Sclerosis: A Critical Review," A Journal of Clinical and Experimental Neuropsychology, Vol. 85, pp. 503-542] (1986) seminal review, considerable research has been undertaken on the neuropsychological consequences of multiple sclerosis. This review incorporates the research literature of the last decade in presenting an overview of the current state of our knowledge concerning the etiology, course, symptoms, assessment, consequences, and treatment of multiple sclerosis (MS). The concept of subcortical dementia is revisited in light of the most recent literature documenting the neuropsychological deficits in patients with MS. The view that cognitively heterogeneous patient groups may disguise more specific patterns of focal neuropsychological impairment is considered. A critical review of the recent literature is also presented, detailing the degree to which recent research has addressed the areas of research need identified by Rao in 1986. Given recent advances in our knowledge, the need for more attention to be directed toward the evaluation of rehabilitation and psychological intervention is highlighted.
KEY WORDS: Multiple sclerosis; neuropsychological consequences of multiple sclerosis; clinical neuropsychology of multiple sclerosis.

INTRODUCTION

ETIOLOGY

Multiple sclerosis (MS) is a degenerative disease of the central nervous system (CNS). It is one of several known diseases that causes the destruction of the myelin sheath of nerve fibres. Scar-like lesions called sclerotic plaques form in the areas where demyelination has occurred, and block or distort the normal transmission of nerve impulses (Bennett et al, 1991). MS is a complex disease whose clinical manifestations and course vary considerably from one patient to another. It is now recognized that despite its physical basis, psychiatric and cognitive abnormalities are common in this disease and add considerably to the distress and disability of the patient. This paper reviews the current literature on MS, with particular emphasis on the neuropsychological aspects of the disease.
Department of Psychology, University of Waikato, Hamilton, New Zealand. 2 To whom correspondence should be addressed at Department of Psychology, University of Waikato, Private Bag 3105, Hamilton, New Zealand.
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While the etiology of MS remains a mystery, the considerable amount of research that has been undertaken in this area to date implicates genetic, environmental, and immunologic variables. Proposed explanations for MS include a slow-acting virus, a delayed reaction to a common virus, or an autoimmune reaction in which the body attacks its own tissues. Theories propounding the existence of a viral agent working in combination with genetic susceptibility have gained a great deal of support. However, evidence of a viral etiology in MS is largely circumstantial and the transplanting of brain matter from people with MS into nonhuman primates has so far not resulted in transmission of the disease (Knight, 1992). Current studies of genetic susceptibility to MS are based on the hypothesis that MS is an autoimmune disease. Researchers have focused on human leukocyte antigen (HLA) genes, T-cell receptor genes, and immunoglobulin genesthe genetic loci recognised to play a major role in the immune response (Haegert and Marrosu, 1994). To date the
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1040-7308/98/0600-0043$15.00/0 1998 Plenum Publishing Corporation

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Brassington and Marsh creased risk of multiple sclerosis seen in native people moving out of Africa to the United States correlates with the extent to which Caucasian genes are introduced into the Afro-American community. Some races, for example, Eskimos, Japanese, Chinese, American Indians, Asian Indians, Australian Aborigines, New Zealand Maoris, Pacific Islanders, and Africans, have an extremely low incidence of MS (Knight, 1992; Poser, 1994). Skegg et al (1987) confirmed the clinical impression that MS is rare in the Maori population of New Zealand, as they found no Maori cases of MS in their sample when the expected number of cases (adjusted for age) was 11.7. Comprehensive reviews of the epidemiological research conducted in the area of multiple sclerosis have been published recently (Poser, 1994; Rosati, 1994). Both Poser and Rosati belie the proposed relationship between the frequency of MS and geographical latitude, noting instead the importance of ethnicity in epidemiological surveys. Exceptions to the high prevalence-high latitude theory undermine its credibility and provide support for the importance of genetic factors. A few studies have reported socalled epidemics of MS, linking members of the same school, street, sporting team, or community (e.g. Kurtz et al, 1982). Such findings may be the result of statistical chance. Poser discards the evidence for these epidemics because the data are based on the date of diagnosis or onset, rather than the time that MS was actually acquired. It is now generally accepted that disease acquisition occurs before puberty (Poser, 1994). Poser (1994) suggests that to maintain consistency across studies of epidemiology prevalence MS needs to be concisely measured by determining "the number of symptomatic MS patients, diagnosed or not, in an ethnically homogeneous population, who have lived until the age of puberty in the same naturally defined geographical area" (p. 187). Likewise, risk studies employing control subjects need to ensure that controls subjects and patients with MS are of the same ethnic origin and raised in the same locality, as well as being matched for age and sex. Poser (1994) suggests that same-sex primary or high school classmates are ideal. He concludes that while genetic factors seem to be the overriding determinant in the acquisition of MS, environmental factors appear to have more influence in the clinical onset. The lower prevalence of MS in the white population of Australia and New Zealand compared to the British Isles may be the result of a protective influence

HLA gene region (and in particular the HLA-DR2 haplotype that is common in Caucasians) has been identified as playing a role in MS susceptibility in most populations (Haegert and Marrosu, 1994). Much research has indicated a genetic basis for MS. First-degree relatives of affected individuals are 6-8 times more at risk than the general population, with siblings being most at risk (White et al, 1992). Twin studies have established that MS affects both twins more frequently in monozygotic than dizygotic dyads (White et al, 1992). However, the relatively low concordance rate (approximately 25%) in monozygotic twins has led to the suggestion that MS is a polygenetic condition (Poser, 1994). Women are approximately twice as likely to develop the disease as men. Skegg et al. (1987) found a female-male ratio of 2.7:1 in the northern region of New Zealand and 3.0:1 in the southratios considerably higher than in most studies elsewhere. For people living in the Western World the lifetime risk of developing MS is approximately 1:800. This increases to 1:50 for the offspring of affected individuals and 1:20 for siblings (Compston, 1994). In support of an environmental explanation for the etiology of MS are research findings indicating that siblings who develop MS do so in the same calendar year rather than at the same age, and that prevalence rates of MS have been found to decrease systematically as latitude of habitation nears the equator (Knight, 1992). Kurtz et al. (1979) found that in equatorial countries prevalence figures were as low as 1/100,000, compared to rates of 6-14/100,000 in the southern United States and in southern Europe, and 30-80/100,000 in Canada, northern Europe and in the northern United States. Skegg et al (1987) found the prevalence rate for the non-Maori population of New Zealand to be 24/100,000 in the northern regions and 69/100,000 in the southern regions. Similarly, Miller et al (1990) found a sevenfold difference in the frequency of MS existing between Otago, New Zealand, and Queensland, Australia. Uncertainty surrounding the etiology of MS has been further confounded by migration studies showing that people who move from a high-risk latitude to a low-risk latitude (e.g., Europeans immigrating to South Africa) or vice versa (e.g., Afro-Asians immigrating to Israel) carry with them some of the risk from their place of origin, but only if this movement occurs after the age of 15 (Knight, 1992). However, Compston (1990) suggests that this migratory evidence is not entirely straightforward, and that the in-

Multiple Sclerosis in the environment. Rosati (1994) notes that better control of ethnicity in research on epidemiology and risk factors will better clarify the role of genetic susceptibility and help identify the environmental factors affecting primary acquisition of MS.

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quently used terms, no consensus was reached on the definition (Lublin and Reingold, 1996). Benign MS was defined as disease in which a patient remains fully functional in all neurologic systems 15 years postonset. Malignant MS was described as a rapidly progressive course, leading to significant disability in multiple neurological systems or death a relatively short time after disease onset (Lublin and Reingold, 1996). There is currently no explanation as to what causes the cycles of relapses or remissions, or what determines the progression of the disease. Nor is there any known treatment to reverse the effects of MS or halt the process of demyelination. Much research has been undertaken in recent years for treatments to slow the rate of demyelination and treat immune system dysfunction. Corticosteroids, adrenocorticotropic hormone (ACTH, a pituitary hormone that stimulates the adrenal glands), and other antiinflammatory agents may be administered during exacerbation to hasten remission. These drugs are known to produce mood changes, and should be considered when assessing affective changes in patients with MS (Gerland and Zis, 1991). Some research has been conducted on the apparent relationship between stressful life events and exacerbations in the disease course. Grant et al. (1989) employed the Life Events and Difficulties Schedule with 39 people with MS and 40 matched control subjects. Significantly more people with MS experienced marked life adversity in the year prior to symptom onset (77% compared to 35% of the controls), with the excess most evident in the six months prior to disease onset. Such stressors were hypothesized to disturb an already unstable neuroimmunological system. Warren et al. (1991) compared 95 pairs of patients with MS in exacerbation and remission, and found that those experiencing an e x a c e r b a t i o n scored higher on emotional disturbance and intensity of stressful events. White (1990) describes several subtypes of patients with MS. Approximately 50% have a mixed or generalized type, which involves the optic nerve, the brain, the cerebellum, and the spinal cord. Another 30-40% have a cerebellar form and 5% have an optic nerve form. Kira et al. (1996) found statistically significant differences in brain and spinal magnetic resonance images (MRI) to support the validity of two clinical classifications of MS in Japanese patients. What was termed "Western-type MS" was characterized by widespread demyelination in the

DISEASE COURSE Multiple sclerosis is a disease that can affect any part of the CNS, including the optic nerves, brain stem, cerebellum, spinal cord, subcortical white matter, and the cortex. Cortical lesions show destruction of myelin, but the nerve cells are left essentially intact. A particularly distressing feature of MS is the unpredictable nature of the disease trajectory. A great deal of uncertainty follows the diagnosis. Aronson (1997) found that an unstable disease course was associated with poorer quality of life among people with MS. While there is wide variation in the course of the disease, individual cases have in research, to date, frequently been characterized as chronic-progressive or relapsing/remitting. Chronic-progressive MS assumes a gradual and steady deterioration, while relapsing/remitting MS follows a stepwise degenerative path of exacerbations interspersed with periods of stability or even slight improvements (Bennett et al, 1991). However, these categories are imprecise at best. Lublin and Reingold (1996) note that due to the lack of clear biological markers there has been no common meaning among clinicians for the terms used to distinguish between the various forms of MS. Consequently, an international survey of relevant professionals was undertaken to develop a consensus on definitions and terminology used to describe the forms and clinical stages of MS. Agreement was reached about the following definitions: (a) relapsing-remitting MSrelapses with full recovery or with sequelae and residual deficit upon recovery, periods between relapses characterized by lack of disease progression; (b) primary-progressive MSdisease progression from onset with occasional plateaux and temporary minor improvements allowed; (c) secondary-progressive MSinitial RR disease course followed by progression with or without occasional relapses, minor remissions, and plateaux; (d) progressive-relapsing MSprogressive disease from onset, with clear acute relapses, periods between relapses characterized by continuing progression; (e) relapsing-progressive MS though one of the most fre-

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CNS including the cerebral and cerebellar white matter. "Asian-type MS," on the other hand, was characterised by severe inflammation in the spinal cord and optic nerve. Two-thirds of people with MS are diagnosed between the ages of 20 and 40 with no definitive reason for onset (White, 1990). The transient and variable nature of MS symptoms make it difficult to diagnose, and a considerable delay between onset of the disease and diagnosis is common. Skegg et al (1987) found a mean delay of 3.5-4 years from time of onset to diagnosis. In a large-scale study of siblings with MS, Robertson et al. (1996) found no significant correlation for age of onset. There was also no pair-wise concordance for presenting symptoms or degree of disability at the time of assessment. However, a strong correlation was found in the disease course of the siblings. Onset of MS before age 15 is extremely rare and late onset (i.e., after 40) is usually characterized by a faster progression of the degenerating process and shorter length of survival (Rao, 1986). Life expectancy following the onset of MS symptoms is generally estimated to be more than 30 years, and yet like everything else to do with the disease, this is variable and a duration of only a few months has been reported in some cases (White et al, 1992). In a 16year follow-up study by Sadovnick et al. (1991), 145 deaths were identified among 3126 patients with MS. Cause of death was able to be ascertained for 119 of the deceased patients. Fifty-six deaths were due to complications of MS (e.g., pneumonia, pulmonary edema with choking, pulmonary embolism, renal failure). Sixty-three deaths were not directly due to complications of MSfor example, suicide (a rate significantly greater than that of the age-matched general population), malignancy (rates significantly less than that of the age-matched general population), acute myocardial infarctions, and stroke (rates not significantly different to that of the age-matched general population).

Brassington and Marsh or optic neuritis (Knight, 1992). Optic neuritis is a broad term denoting inflammation, degeneration, or demyelinization of the optic nerve. It results in temporary partial or total loss of vision, usually occurring over several hours or days. Retrobulbar neuritis is optic neuritis that occurs far enough behind the optic disk so that no early changes of the optic disk are visible by opthalmoscope. MS is the most common cause for this (Lechtenberg, 1988). Bladder dysfunction is a common presenting problem in patients with MS, with many more experiencing urinary problems during the course of the disease. Common symptoms include urinary urgency, frequency, dysuria, nocturia, and incontinence. Treatment for bladder dysfunction may include fluid restriction, anticholinergic agents, and catheterization (Lechtenberg, 1988). A variety of other symptoms, occurring either singly or in groups, may also signal the onset of MS. These include vertigo, seizures, nystagmus, ataxia, diplopia, hemiplegia, deafness, facial paralysis or facial pain, experiencing "pins and needles" or numbness in the limbs, gait disturbances, auditory hallucinations, aphasia, and emotional changes (Knight, 1992; White et al, 1992). Initial episodes are often disregarded or not investigated due to their mildness and spontaneous remission. A latency period, sometimes as long as 10 years, may follow the initial symptom(s) of MS, with more symptoms occurring as the disease progresses. Periods of remission become shorter and exacerbations tend to leave people more impaired than they were previously. It appears that pathologic events in MS (evidenced using MRI) are more frequent and extensive than is readily observed by way of clinical symptoms and signs (Rudick, 1992). Spasticity is a dominating feature of multiple sclerosis. It presents clinically as increased resistance to passive elongation of the muscles, particularly in the lower limbs, but is often also experienced in the upper limbs. It is caused by overactive nerve cells located along the spinal cord. Cervera-Deval et al. (1994) found that spasticity and weakness were the neurological symptoms that exerted the most detrimental influence on patients' social and vocational lives. Baclofen (Lioresal) is the most commonly used antispasticity agent (Lechtenberg, 1988). Fatigue is one of the most common and debilitating complaints associated with MS affecting as many as 90% of patients, with 40% considering fatigue to be their most serious symptom (Krupp et al,

SYMPTOMS Due to the numerous sites in which it is possible for MS lesions to develop, there is wide variation in the symptomatology of different patients with MS and changes within individual patients over time. Early symptoms of MS commonly include weakness in one or more limbs, incontinence, and retrobulbar

Multiple Sclerosis 1988). Fisk et al. (1994) found that almost half of their sample of 85 people with MS reported fatigue every day, and over half reported fatigue to be either their worst or one of their worst symptoms. Furthermore, the severity of fatigue was unable to be predicted from routine clinical assessment. Schwartz, Coulthard-Morris, and Zeng (1996) examined the interrelationships between fatigue and neurological, psychosocial, and cognitive functioning in 139 patients with MS. Only the patients' perceived control over their own environment and depression were found to be associated with fatigue. Patients in this study interpreted fatigue as impairing their cognitive performance and fatigue was found to limit social, work, and overall role performance, but not physical performance. Vercoulen et al. (1996) did not find any association between subjective ratings of fatigue severity and depression or Expanded Disability Status Scale score. However, psychological factors such as a low sense of control over symptoms and focusing on bodily symptoms were found to influence the experience of fatigue, as was impairment in daily life. Moller et al. (1994) also found fatigue to be unrelated to depression. Fatigue in this sample was unrelated to cognitive decline, but was related to brainstem and midbrain abnormalities detected using MRI. It remains unclear whether the fatigue experienced by people with MS differs to that experienced by healthy adults. Kersten and McLellan (1996) found that the same causes of fatigue were identified by people with MS and healthy control subjects, namely heat or humidity, household activities, and manual work. By employing a quadriceps test with fully ambulatory patients with MS and healthy control subjects, Kersten and McLellan found that while muscle fatiguability was similar for both groups, perceived fatigue levels were disproportionately higher in patients with MS. The authors suggest that central mechanisms such as a change in motor neuron excitability, a presynaptic block, or a decrease in voluntary effort, may be responsible for both muscle weakness and the frequent sense of fatigue experienced by people with MS. Amantadine has been used to treat fatigue, with a response rate between 36% and 66%. However irritability, insomnia, and hyperactivity are possible side effects, making the use of medication problematic for some patients (Schwartz, Coulthard-Morris, and Zeng, 1996). As the disease in MS progresses, and the involvement of subcortical white matter becomes more

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widespread, diffuse cognitive changes are more likely to emerge. However, impairment in cognitive functioning has also been reported in the early stages of the disease, so should not be overlooked in cases where physical disability is not yet advanced (Hotopf et al, 1994; Klonoff et al, 1991). Hotopf et al. describe two case presentations of cognitive impairment occurring in the absence of other obvious symptoms, with MS diagnosed at a later date on the basis of MRI, cerebrospinal fluid (CSF) and electrophysiological findings. Rao, Leo, Bernardin, and Unverzagt (1991) found that the frequency of cognitive dysfunction in a community-based sample of 100 patients with MS was 43%. Memory, attention, conceptual reasoning, verbal fluency, and abstracting abilities are commonly impaired, with relative sparing of language functions (Ron et al, 1991). Cognitive difficulties can also be compounded by the emotional symptoms and psychiatric manifestations that sometimes accompany this disorder. An overview of psychiatric disorders in MS is provided by Minden (1992). In a sample of 50 patients with MS, Arias Bal et al. (1991) found that 54% showed signs of psychopathology and 46% presented with signs of neuropsychological deterioration. Psychiatric changes readily found in patients with MS include affective disturbances, psychoses, and personality changes (Peterson and Kokmen, 1989). Depression and bipolar affective disorders, manic episodes, euphoria, emotional lability (pathological laughing and weeping), and suicidal ideation have been reported in conjunction with MS since the time of Charcotthe French neurologist credited with first describing the disease (Minden and Schiffer, 1990; Knight, 1992). Euphoria refers to an abnormal emotional state of cheerful complacency out of context to the total situation. This is found primarily in patients with advanced, disseminated disease (Mahler, 1992). It has been hypothesized to involve extensive bilateral and subfrontal demyelination, with scarring that isolates the limbic and diencephalic regions from prefrontal control; however, this has not been verified by MRI studies (Minden and Schiffer, 1990). Episodes of mania may also be precipitated by ACTH and prednisone, which are sometimes used to treat symptoms of MS during exacerbations (Minden et al, 1988). Hutchinson et al (1993) concluded that the increasing evidence of affective disorders occurring in conjunction with MS indicates that the former is organic in nature and due to the MS disease process. They presented seven case studies (out of 550

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Brassington and Marsh subsequent publication by Poser et al. (1983) specified that a diagnosis of MS requires the occurrence of two attacks (i.e., neurological symptoms) each lasting a minimum of 24 hours, and separated by at least a month. Furthermore, the attacks should be caused by lesions in two distinct areas of the CNS (e.g., blurred vision and a numb limb). This provided research criteria whereby patients could be classified as having clinically definite, clinically probable, or clinically possible MS. Worldwide adoption of these diagnostic criteria has improved the comparability of studies undertaken in different countries. Poser (1994) advocates the use of clinically definite and clinically probable patients only in MS research. Given the number of drug trials currently underway in MS research, more emphasis has recently been placed on improving the tools employed to measure clinical outcomes. The complications of the task are obvious when one considers the range, and variation of symptoms and course in the disease. The Multiple Sclerosis Clinical Outcomes Assessment Task Force was convened by the National Multiple Sclerosis Society Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis to address this difficult task. The Task Force has 16 members representing 5 countries and the allied disciplines of neurology, psychology, biostatistics, epidemiology, and drug development. The starting point for the Task Force has been to define the precise purpose, clinical dimensions, and desirable attributes of an optimal clinical outcome measure (Rudick et al., 1996). The final product will include recommendations and guidelines for distribution to medical advisory boards, investigators, and clinical trial sponsors whose goal is optimal design strategies for MS clinical trials. In 1955 Kurtzke designed the Disability Status Scale (DSS), a 10-point rating scale which provided an overall rating of disability in patients with MS. In an attempt to increase its clinical sensitivity this scale was extended to include half-point increments in 1983, becoming the Expanded DSS (EDSS; Kurtzke, 1983). This is currently the most widely used scale for the standardisation of research samples of patients with MS. It rates patients in terms of the restrictions imposed by the disease, focusing primarily on ambulation as the indicator of disablement. The EDSS has been criticized for a number of reasons including lack of sensitivity to clinical changes not affecting mobility, and interrater variability in ratings of patients with lower EDSS scores where ambula-

patients with MS presenting over 10 years) in which the neurological symptoms of MS developed after a history of bipolar affective disorder. Skegg (1993) also investigated the prevalence of MS presenting initially as a purely psychiatric disorder. Two of the 91 patients were considered likely candidates, lending support to the existence of such a phenomenon, while also alluding to its rarity. Pure dementia and psychiatric symptoms associated with dementia have been reported in conjunction with a small number of cases (e.g. Fontaine et al, 1994; Hotopf et al, 1994). Debate concerning the nature of psychiatric changes evident in some patients with MS has been ongoing. Gerland and Zis (1991) discuss the complexity of separating the effects of biological and psychosocial factors in patients with MS who present with major affective disorders. They outline three possible hypotheses. First, that MS acts as a psychological stressor in persons biologically and/or psychologically predisposed to major depressive and manic episodes. Second, that the structural lesions produced by MS cause affective disorders. Third, that there may be a genetic link in susceptibility to MS and to affective disorders. Research to date points to a correlation between depressive symptoms in patients with MS, disability, and lack of social support, while depressive episodes would seem to be a result of structural lesions (Gerland and Zis, 1991). Bipolar mood disorder has been recorded in conjunction with MS at a greater rate than that predicted by chance, and without a predisposing family history (Gerland and Zis, 1991). This suggests an organic etiology for the affective disorders witnessed in some patients with MSthat is, that they result from the pathological demyelination of the disease. A few accounts of short-lived psychoses with symptoms indistinguishable from schizophrenia have been reported in MS (Feinstein, du Boulay and Ron, 1992). As a rule they occur in the absence of a positive family history, when MS is well established, and at a later age than is common for schizophrenia, suggesting a causal role for brain pathology. It seems likely that psychotic and emotional symptoms are due to an interaction of biological, psychological, and social factors.

ASSESSMENT In 1982, a multidisciplinary group met in Washington to develop diagnostic guidelines for MS. The

Multiple Sclerosis tion is less impaired (e.g., Noseworthy et al., Canadian Cooperative MS Study Group, 1990). Other scales, such as the Ambulation Index (Hauser et al, 1983), the Neurologic Rating Scale (Sipe et al, 1984), and the Rivermead Mobility Index (Collen et al., 1991) have been developed in recent years. While these correlate significantly with the EDSS, for research purposes the latter has remained the gold standard for measuring impairment in MS to date. The EDSS together with the Kurtzke Functional Systems (FS), the Incapacity Status Scale (ISS), and the Environmental Status Scale (ESS) make up the Minimal Record of Disability for multiple sclerosis (MRD), published by the International Federation of Multiple Sclerosis Societies (1984). This is the most widely employed scoring system with MS populations, and was established to provide uniformity of data collection and enable comparison of clinical and research results. The MRD was designed to accommodate the classification of dysfunction developed by the World Health Organisation (1980). Hence measurement accounts for impairment (the FS and EDSS), disability (ISS), and handicap (ESS). The FS scale is comprised of eight scales: cerebellar, brainstem, pyramidal, sensory, bowel and bladder, visual functioning, mental functioning, and spasticity. This framework enables quantification of the neurological examination. The ISS is a 16-item inventory of functional disability in daily living activities. Finally, the ESS measures seven areas of social performance or need: work status, financial and economic status, place of residence, personal assistance, transportation, community assistance, and social activity. Solari et al (1993) examined the validity of a self-administered version of the MRD by measuring the level of agreement between patients' self-assessment and neurologists' independent ratings. They concluded that a self-administered version limited to assessment of ambulatory ability, daily living, and social activities could be an accurate and cost-effective method for obtaining comprehensive profiles of patients' abilities. Neurological Assessment MS is difficult to diagnose in its early stages because a definite diagnosis requires that signs and symptoms be evident in multiple sites within the CNS, and fluctuate over time. Until the development of MRI to detect demyelinating plaques in the brain, and the increased sensitivity of CSF analyses to en-

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able the detection of oligoclonal abnormalities, other conditions such as neurosyphilis were occasionally misdiagnosed as MS (Mahler, 1992). Similarly, the behavioral changes that result from cerebral MS have been known to lead to an incorrect diagnosis of some other CNS or psychiatric disorder. MRI is the most sensitive technique available to detect the brain lesions produced by MS. Goodkin et al (1994) review the use of MRI with patients who have MS. Rudick (1992) comments that while the EDSS has been found to correlate with the extent of brain-stem and cerebellar involvement visible using MRI, forebrain lesion load is more closely related to measures of cognitive and memory impairment than to motor dysfunction. Baumhefner et al. (1990) drew similar conclusions from their study of 62 patients with progressive MS in whom plaque burden in the cerebrum was strongly correlated with neuropsychological functioning. Despite its value as a confirmatory test, Paty et al (1991), Rudick (1992), and Poser (1994) caution against being overly confident about diagnosing MS without sufficient clinical and CSF data to supplement the results of MRI. Poser (1994) states that the proliferation of MRI scanners in the U.S. has led to an escalation of misdiagnoses of MS. He notes that AIDS, Lyme disease, sarcoidosis of the CNS, myalgic encephalomyelitis, and in particular disseminated encephalomyelitis, to name but a few, all produce imaging patterns resembling those seen in patients with MS. Rudick (1992) echoes these concerns, stating that the "injudicious use of MRI scanning or overinterpretation of MRI scans constitutes the leading cause of an inaccurate diagnosis of MS at the present time" (p. 685). At autopsy, MS lesions are easily detectable as pinkish-grey scars, about 5-15 mm in length, randomly distributed throughout the CNS (Knight, 1992). Although computed tomography scans are less sensitive than MRI they may also reveal MS lesion sites and are useful for measuring ventricular enlargement. CSF analyses can be highly diagnostic of MS, revealing increased levels of gamma globulin and oligoclonal bands. However, in the early stages of MS it is rare for these findings to show up. Abnormal electroencephalogram readings showing focal or diffuse slowing; abnormal visual, auditory and tactile evoked potentials; and an abnormal blink reflex are all paraclinical tests used as corroborative evidence when diagnosing MS (White et al, 1992).

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Brassington and Marsh while disease duration and disability were unrelated to cognitive impairment in their sample, disease course seemed to be a sensitive marker of cognitive decline. Patients with a chronic-progressive disease course demonstrated greater impairment in cognitive performance. Heaton et al. (1985) also reported that a chronic-progressive disease course was associated with greater impairment in cognitive, as well as sensory and motor domains. However, they also found a relationship between the degree of neuropsychological impairment and disease duration, as did Beatty et al. (1990). Beatty et al. observed a strong association between disease duration, disease type, and disability status, noting that a longer disease duration, greater physical disability, and a chronic-progressive course of MS were indicative of poorer performance on all of their cognitive measures except remote memory. However, the more commonly reported finding of an absence of any correlation between the physical and cognitive functioning in patients with MS infers that the latter cannot be ascertained from a neurological examination. Hence the value of neuropsychological assessment. Sandroni et al. (1992) found that fatigue in patients with MS was associated with slow reaction time on memory tasks. Geisler et al. (1996) recently undertook to evaluate the effects of amantadine hydrochloride and pemoline (used to treat fatigue) on cognitive functioning in patients with MS. They found that neither of these drugs enhanced cognitive performance in patients with MS compared with the placebo c o n d i t i o n , c o n c l u d i n g as Schwartz, Coulthard-Morris, and Zeng (1996) did, that cognitive functioning in people with MS is independent of fatigue. Given these discrepancies further examination of the relationship between fatigue and cognitive functioning in people with MS would appear to be warranted. A number of theorists have discussed the paradigms of "cortical" and "subcortical" dementias (Penman, 1991; Rao, 1986; Ryan et al, 1996). Cortical dementia is the more profound, characterized by amnesia, aphasia, apraxia, agnosia, and visual spatial disorderreminiscent of Alzheimer's disease. People with subcortical forms of dementia have relatively intact verbal intelligence and language functioning in comparison to their visuospatial and memory skills. This pattern is associated with diffuse white-matter involvement and relative sparing of the cortical mantle (e.g., Huntington's disease, Parkinsonism, Korsakoff syndrome, Friedreich's ataxia, and

Rao (1995) notes that neuropsychological testing of patients with MS is now being incorporated as a secondary outcome measure in several ongoing clinical trials. For example, Interferon Beta 1-b (Avonex) has been demonstrated to reduce the number of MS plaques evident in MRI scans and has recently been approved by the American Federal Drug Authority as a treatment for relapsing-remitting MS. In a longitudinal trial following 30 patients with MS receiving different doses of Avonex, Pliskin et al (1996) reported a significant improvement in visual reproduction test performance in patients receiving the high dosage, while no significant change was recorded in their EDSS scores. The mean lesion area of the high-dose group of patients did not change over time, whereas the low-dose and placebo patient groups displayed an increase in total lesion area of between 28 and 36%. Neuropsychological Assessment Since the 1980s there has been a surge of interest in the cognitive function and dysfunction evident in people with MS. Research has clearly demonstrated that along with the sensory and motor dysfunctions, cognitive deficits are commonly exhibited. Impairments in memory, learning, conceptual reasoning, speed of information processing and reaction time, attention, concentration, and executive functioning (planning, sequencing, problem solving, selfm o n i t o r i n g and s e l f - c o r r e c t i n g ) are typical. Repetition speech, fluency, and comprehension are generally intact, although mild deficits in naming and word generation occur with some regularity. Neuropsychological assessment is valuable for ascertaining the extent of cognitive dysfunction in a patient, and identifying particular areas of cognitive strength and weakness. Recent research has demonstrated that neuropsychological testing is sensitive to short-term changes in cognitive functioning (Feinstein etc al., 1993). The degree of cognitive impairment evident in people with MS seems to be unrelated to their neurological disability status or disease duration (Maurelli et al., 1992; Penman, 1991; Rao et al., 1991). This is considered to be due to variability in lesion sitesa patient with predominantly spinal cord or optic nerve involvement may be severely physically disabled, but have little or no cerebral demyelination and therefore show little cognitive change. Feinstein, Kartsounis et al. (1992) found that

Multiple Sclerosis MS). Subcortical dementia is considered to be distinguished by forgetfulness, diminished insight, cognitive slowing (e.g., impaired manipulation of learned knowledge), dysarthria, depression, and personality changes characterized by apathy and lack of initiative (Peterson and Kokmen, 1989). The pattern of cognitive impairment evident in many people with MS is characteristic of lesions in frontal and subcortical systems. The concept of subcortical dementia remains controversial and is later revisited in the context of the most recent neuropsychological research in MS. Brief mental status screening questionnaires, such as the Mini Mental Status Exam, need to be supplemented with other measures to reliably detect the cognitive deficits present in many patients with MS (Beatty and Goodkin, 1990; Swirsky-Sacchetti, Field et al, 1992). Of the individuals with MS who have cognitive difficulties, approximately 80% display relatively mild impairment (Rao, 1986). However even mild impairment can significantly disrupt the ability of people to carry out their usual activities of daily living and meet the expectations of a busy, modern society. Much research has been undertaken in the previous decade to examine the specific nature of memory impairment in patients with MS. Information processing ability and abstract reasoning have also received substantial attention. These areas of cognitive functioning are now considered in detail, followed by an examination of the neuroanatomical correlates of cognitive impairment and the assessment of affective and behavioral functioning in patients with MS. Intellectual Functioning Cross-sectional studies of intellectual functioning have recorded small but consistent differences between people with MS and normal control subjects (Rao, 1986). Significantly greater differences are recorded on performance scales than verbal scales, which is likely to be a result of the sensorimotor impairment experienced by most people with MS. Longitudinal studies have demonstrated a small but significant decline in intellectual functions over time, with verbal IQ scores remaining less affected than performance IQ scores (Penman, 1991; Rao, 1986). Patients with MS in the study by Rao, Leo, Bernardin and Unverzagt (1991) averaged 6.3 points lower than control subjects on the Wechsle-Adult Intelligence ScaleRevised (WAIS-R) Verbal IQ. At

51
a three-year follow-up the scores of the patients with MS were essentially unchanged while those of the control subjects increased, widening the gap between the two groups (Bernardin et al, 1993). Ron et al. (1991) used the National Adult Reading lest to obtain estimates of premorbid intellectual functioning hi patients with clinically definite MS, patients with clinically isolated lesions, and normal control subjects. These scores were compared to current functioning on the WAIS. While the control group showed an improvement of 0.7 points, the group with isolated lesions dropped 2.2 points and the group with MS dropped 6.8 points. While examining the pathological association and dissociation of functional systems in 196 people with MS, Clark et al. (1997) found a significant correlation between education and not only the verbal subtests of the WAIS-R, as expected, but also the performance subtests. This suggested to the authors that education may provide a basis for adapting to mild levels of impairment. Memory Functioning Memory disturbance is one of the most consistently impaired cognitive functions in people with MS, being evident in 40-60% of patients (Rao et al., 1993). In general, patients with a chronic-progressive disease course perform more poorly on memory tests than those with a relapsing-remitting course (Mahler, 1992); however, studies of a cross-sectional nature have repeatedly demonstrated that memory disturbance in MS does not follow a distinctive progression (e.g. Rao, Leo, and St. Aubin-Faubert, 1989). Minden et al. (1990) studied 50 patients with MS, and found 30% had severe memory impairment, 30% were moderately impaired, and 40% were either not impaired or only mildly so. Memory dysfunction in this sample was found to be related to impairment of other cognitive functions, lower socioeconomic status, a chronic-progressive disease course, and the use of anti-anxiety medication. Memory impairment was found to be unrelated to the extent of patients' physical disability, the duration of the MS symptoms or levels of depression, upholding the findings of Rao, Leo, and St. Aubin-Faubert (1989). As memory is not a unitary neuropsychological function, MS does not affect all aspects of it equally. Numerous studies during the past decade have examined the nature of memory impairment in patients with MS and demonstrated impaired ability on sev-

52
eral types of tasks, including the Wechsler Memory Scale (particularly the Visual Reproduction and Logical Memory subtests), the Rey Auditory Verbal Learning Test, the California Verbal Learning Test, the Modified Stroop Test, and the Buschke Selective Reminding Test (e.g. Beatty, 1993; Beatty and Monson, 1991a, 1991b, 1994; Beatty et al., 1996; DeLuca et al., 1994; Grafman et al., 1991; Grisby et al., 1994; Rao et al., 1993). Rao et al. (1993) considered that the memory impairment evident in patients with MS involves effortful free recall from secondary (longterm) memory and possibly working (short-term or primary) memory, and that other aspects of memory, including semantic knowledge, storage, and encoding of information into secondary memory, incidental and implicit learning, and recognition memory, appear to be intact. Much effort has been directed recently at determining whether deficits in long-term memory functioning are a function of faulty retrieval mechanisms or impaired acquisition of information. Penman (1991) considered that while short-term memory capacity is relatively unimpaired and recognition memory is rarely impaired, retrieval strategies from short- and long-term memory appear to be deficient. Research by Armstrong et al. (1996), Coolidge et al. (1996) and Rao, Leo, and St. AubinFaubert (1989) supports the finding that memory deficits in people with MS arise primarily from difficulties in retrieving information from long-term storage. This has been demonstrated by inconsistency in recall of information previously entered into secondary memory but normal performance on assessment of recognition, rates of forgetting, and immediate recall of short spans of information. Deficits in retrieval from long-term memory are particularly evident when research participants with MS are required to make new associations between previously unrelated material (Klonoff et al., 1991; Minden et al., 1990). This characteristic pattern of memory impairment differs from that commonly observed in patients with Alzheimer's disease, where primary memory deficits are most evident. Rao, Leo, and St. Aubin-Faubert note that the secondary memory impairment in MS is most like that observed in patients with Huntington's disease (though less severe), closed head injuries, and in the healthy elderly. In contrast with the research implicating an impaired retrieval mechanism, DeLuca et al. (1994) concluded that the verbal memory impairment evident in patients with MS is a consequence of inadequate initial learning or acquisition. Twenty-three

Brassington and Marsh patients with MS and 23 control subjects were trained to a specific criterion on a verbal list-learning task, with retrieval and recognition evaluated following a 30 minute delay. While the patients with MS required significantly more trials to reach criterion, their performance did not differ from the control subjects on tests of recall and recognition. DeLuca et al. support their position by drawing attention to prior research in which patients with MS entered significantly fewer words into secondary memory than control subjects on the selective reminding task (e.g., Rao, Leo, and St. Aubin-Faubert, 1989). The authors concluded that studies implicating deficiencies in retrieval processes have failed to control for the amount of information initially acquired during learning. Ryan et al. (1996) suggest that the memory impairment in their sample of patients with MS arose from damage to frontal and temporal structures that would result primarily in difficulty with encoding and the representation of novel material. Beatty et al. (1996) examined 99 patients with MS using the Buschke Selective Reminding Test (SRT) that enables differentiation between acquisition and retrieval from secondary memory. Compared to control subjects, the patients with MS were impaired on all measures of the SRT except recognition memory. However, upon further analysis, three distinct profiles of memory deficits were evident in the sample, leading the authors to conclude that different profiles of memory impairment can be identified in people with MS. The performance of one cluster of patients with MS did not differ from that of the control subjects. The second cluster showed impairment in acquisition, retrieval (recognition and recall), and short-term memory. The third and largest cluster showed mild impairment in shortterm memory and marked impairment in retrieval from secondary memory. Neither a faulty retrieval mechanism nor slowed acquisition were considered to be sufficient to characterize the types of memory impairment evident in patients with MS. Armstrong et al. (1996) hypothesised that the long-term memory impairment evident in people with MS was in part due to limited representation and use of serial order information. Postencoding negative recency with normal recognition and impaired word order recall were evident in their sample of 67 patients. This was considered to be due in part to difficulty in employing temporal order cues in long-term memory. Two separate memory deficits were identified, supporting what appears to be a

Multiple Sclerosis growing opinion among researchers that multiple cognitive processes influence the memory impairment evident in MS. Coolidge et al. (1996) found that learning under interference conditions resulted in significant memory deficits in patients with MS, while no difference was evident under conditions of noninterference. This contrasts with the results of Rao et al. (1984), who found normal rates of forgetting by patients with MS under interference conditions. Strategies to counteract or avoid interference when working with patients who have MS were considered by Coolidge et al. to be an important requirement for their acquisition of new information. Both Rao et al. (1993) and Ruchkin et al. (1994) found that patients with MS showed impaired performance on verbal working memory tasks. Verbal working memory has appeared to be more susceptible to impairment in MS than visuospatial working memory. According to Baddeley's (1986) model of working memory, the verbal working memory system contains a limited duration passive store referred to as a phonological loop. Rao et al found that patients with MS displayed an exaggerated word length effect, considered to be a result of impairment in the control process of articulatory rehearsal. Ruchkin et al. concluded that the evidence provided by behavioral, neuropsychological, and event-related brain potential data indicate that the dysfunction evident in the verbal working memory of patients with MS is at least partly due to impairment of the phonological loop. D'Esposito et al. (1996) explored another component of Baddeley's model of working memory, namely the central executive system (CES) which coordinates the performance of two concurrent tasks. To examine CES functioning dual-task paradigms were designed (a judgement-of-line orientation measure performed at the same time as finger tapping, humming a tune, or reciting the alphabet). The patients with MS exhibited a significantly greater decrement in performance t h a n control subjects d u r i n g the more demanding dual-task conditions (humming or alphabet recitation) compared with the single-task condition. D'Esposito et al. (1996) concluded that this reflects a specific cognitive deficit within working memory indicative of an impaired CES, and that impairment in speed of information processing, common in people with MS, is associated with this CES deficit. In the examination of other features of memory, Beatty and Monson (1991a) found that a sample of

53

45 patients with MS were impaired in memory for temporal order, but not in content recognition. It is noteworthy that patients with MS have been reported to overestimate their ability to remember, indicating that their assessment of their own memory capabilities (i.e., metamemory) may prove to be unreliable (Beatty and Monson, 1991b). These authors found that in a sample of 45 patients with MS, some were impaired on the Wisconsin Card Sorting Test, others were impaired on recognition memory, and still others showed impairment on both these measures. The latter group of patients were found to overestimate their recall on a memory test by more than 50%. Clearly there has been a wide array of research conducted in recent years on the nature of memory impairment in people with MS. The encoding and storage of information in immediate memory appears to be reasonably intact, while recent and remote memory are frequently found to be impaired even in patients with mild physical disability. While the majority of studies and earlier reviews have implicated faulty retrieval mechanisms as the primary memory impairment in MS, further studies controlling for the rate of acquisition of information by research participants will help account for the influence of this on recall. Several studies have reported the presence of separate clusters of MS research participants whose cognitive profiles are uniform, but who become disguised when the sample is considered as a whole (Armstrong et al., 1996; Beatty et al, 1996). Speed of Information Processing Rao, St. Aubin-Faubert, and Leo (1989) compared the nature of information processing in 36 patients with MS and 26 matched control subjects using the Sternberg Memory Scanning test. The patients with MS exhibited a significantly slower overall reaction time. This included a purely cognitive component that was independent of the effects of physical impairment. The results suggest that speed of memory scanning was influenced by the length of illness and possibly more advanced cerebral plaque involvement. Moulthrop and Nudelman also found evidence of slowed mental speed in 33 patients with MS that could not be attributable to motor impairment or lower global cognitive functioning. In contrast, Litvan et al. (1988) found that the performance of patients with MS did not differ from that of control subjects in their speed of memory scanning as assessed by the Sternberg test.

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Brassington and Marsh measures of information processing speed, as difficulty with the former is not generally associated with MS while impairment in the latter is. Sentence comprehension deficits in the patients with MS was found to be associated with slowed information processing speed, leading the authors to hypothesis that information processing speed plays a crucial role in sentence processing. In conclusion, slowed information processing is a major feature of the cognitive profile evident in patients with MS. While being exaggerated by physical impairment, it appears to have a cognitive basis as evidenced when tests of purely cognitive ability are employed. Compromised information processing speed and efficiency has been considered to contribute to aspects of the verbal memory impairment observed in patients with MS (DeLuca et al., 1994; Litvan et al., 1988; Rao, St. Aubin-Faubert, & Leo, 1989). Again, the need to utilize cognitively homogeneous research samples of people with MS is alluded to (Kujala et al., 1994). Attention Recent research has shown patients with MS to be impaired on a number of measures of visual and auditory attention (e.g. Litvan et al, 1988; Ron et al, 1991; Rao, Leo, Bernardin and Unverzagt, 1991). The impaired performance of patients with MS on the two highest speeds of the PASAT suggested to Litvan et al. (1988) that patients with MS have impaired attentional capacity on complex tests. Beatty et al. (1996) considered that the poor digit span evident in a number of their MS sample could indicate that the observed memory difficulties were secondary to attentional dysfunction. Employing the sample of their earlier publication, Kujala et al. (1995) examined differences in attentional capacity in people with MS. The cognitively impaired group performed slower on all tests of attention, but did not differ from the other two groups in the error scores of the attention tests. The cognitively preserved group exhibited signs of motor-related slowness and fatigue, while the cognitively deteriorated group also displayed extensive cognitive slowness. Assessment measures that rely on vocal responses rather than motor ones, and accuracy as opposed to speed, provide a purer estimate of attention in patients with MS, given their physical impairments (Beatty and Scott, 1993).

The Paced Auditory Serial Addition Test (PASAT) is purported to be a sensitive measure of impairment in information processing efficiency. Litvan et al (1988) found that patients with MS were deficient in information processing in the two fastest rates of presentation of the PASAT DeLuca et al. (1993) found that the performance of patients with MS was poorer than that of controls on all speeds of the PASAT DeLuca et al. (1994) found a significant correlation between processing efficiency as measured by the PASAT and the number of trials that it took patients with MS to learn a verbal memory task. Diamond et al. (1997) compared information processing across the auditory and visual domains. They employed the PASAT, and a visual analogue of the PASAT called the Paced Visual Serial Addition Test (PVSAT). Patients with MS were significantly impaired on both tasks. No disproportionate modality-specific impairment in processing was observed, indicating comparable levels of impairment in both the auditory and visual domains. Furthermore, the authors concluded that as the performance of the patients with MS was characterized by a stable decline as opposed to a steadily increasing decline, processing efficiency or speed may not be the critical determinant in accounting for their poorer performance on these tests. Grafman et al. (1991) found that patients with MS performed the same as control subjects on measures of automatic processing, but significantly poorer than the controls in effortful processing (i.e., procedures requiring that material be encoded and then recalled or recognised). Kujala et al. (1994) emphasise the importance of utilising subgroups of patients with MS as opposed to cognitively heterogeneous patient samples. These authors also discuss the need to divide the activity of information processing into qualitatively different stages. They compared 22 patients with MS who had mild cognitive deterioration with 23 patients with MS who had preserved cognitive capacity and 35 normal control subjects. Three stages of information processing were investigated: automatic visual processing, controlled processing, and motor programming. The cognitively impaired group were slower than the other two groups in each of the three stages of information processing that were identified. The MS patients who were considered to be cognitively intact displayed signs of mild slowing in automatic visual processing. Grossman et al. (1995) evaluated sentence comprehension in 20 patients with MS and related it to

Multiple Sclerosis Executive Functioning Executive functions incorporate cognitive abilities such as abstract and conceptual reasoning, and are hypothesized to become impaired when connections between the frontal lobes and subcortical structures are disrupted. However, there is only limited evidence to support this theory as yet. Cognitive inflexibility, similar to that apparent in patients with focal frontal lobe lesions, is frequently seen in people with MS upon testing with the Wisconsin Card Sorting Test (WCST). Patients with the chronic-progressive form of MS perform predominantly worse on this test of abstract concept formation and set shifting than patients with relapsing-remitting MS (Mahler, 1992). Beatty and Monson (1996) compared the performance of patients with MS on the WCST and the more recently developed California Card Sorting Test (CCST), which enables differentiation between impairment in concept formation and perseverative response, when the same incorrect problem-solving strategy is employed. A wide range of error scores was found with the WCST for the MS sample, while fewer were found with the CCST along with no significant difference in the number of perseverative responses. This was considered to reflect that problem-solving difficulties in people with MS results from impaired concept formation rather than from perseveration. Given the different patterns of performance on the CCST by the patients with MS, it is uncertain whether their problem solving deficits can be attributed to frontal lobe damage (Beatty et al., 1996). Beatty, Hames et al. (1995) found that patients with MS performed more poorly than normal control subjects on tests of verbal abstract reasoning and that this could not be attributed to generalized impairment in verbal ability. Both patients who performed well and those who performed poorly on vocabulary ability performed relatively poorly on an abstraction task. Troyer et al. (1996) examined the effect of conceptual reasoning on the relationship between severity of MS-related neurological impairment and delayed free recall. They found that conceptual reasoning had a mediating effect, reducing the significant relationship between these two factors to insignificance. This same mediating effect was not found when measures of recall were replaced with measures of recognition. The authors conclude that differences in patient performance on complex memory tasks may in part be due to differences in conceptual reasoning.

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The sequencing of activities is another example of an executive function and is commonly found to be impaired in patients with frontal lobe lesions. Beatty and Monson (1994) demonstrated that a group of 30 patients with MS were impaired on a picture-sequencing task compared to 33 normal control subjects, but performed normally on a purely motor-sequencing test. Beatty (1993) reviews the nature of impairment in memory and executive functioning in patients with MS, and discusses the possibility that these deficits stem from impairment at the level of information processing.
Neuroanatomical Correlates of Cognitive Dysfunction

The degree and pattern of cognitive dysfunction has been found to correlate significantly with the amount and location of white-matter disease in the cerebral hemispheres, as evidenced by MRI (Feinstein et al., 1993). This suggests that cerebral lesions result in cognitive dysfunction. Feinstein et al. (1993) conducted biweekly or monthly MRI and neuropsychological assessment on 10 patients with MS over a period of six months. Lesions load was found to increase in 3 of the patients, who correspondingly demonstrated a deterioration on cognitive testing or an absence of a practice effect. Rao, Leo, Haughton et al. (1989) found that total lesion area was predictive of cognitive dysfunction in 53 patients with MS, particularly in the areas of recent memory, abstract and conceptual reasoning, language, and visuospatial problem solving. Size of the corpus callosum predicted cognitive test performance in areas of mental processing speed and rapid problem solving. Huber et al. (1992) found that patients with MS who had severe cognitive impairment had significant atrophy of the corpus callosum compared with mild and moderately impaired patients, and that this might therefore be used as an indicator of extensive cognitive impairment. Ryan et al. (1996) recently examined the MRI profiles of 150 mildly disabled patients with relapsing-remitting MS, and also concluded that lesion sites were associated with cognitive impairment. Lesions in the genu of the corpus callosum were associated with impairment in visual-spatial ability, while lesions in the white matter of the left parietal region were associated with impaired performance on a test of learning and memory. No lesion area evident by MRI was associated with word fluency ability. Pozzilli et al. (1991) reported that periventricular lesion scores and the width of the third ventricle

56
were the most sensitive MRI features in differentiating the more cognitively impaired from the lesser so, in their sample of 17 patients with MS. However Rao, Leo, Haughton et al. (1989) found that ventricular-brain ratio did not independently predict cognitive test performance in their sample. An MRI study conducted by Anzola et al. (1990) found that patients with extensive periventricular demyelination performed worse than patients with discrete lesions on concept formation, nonverbal reasoning, and verbal memory tests. Similarly, Maurelli et al. (1992) reported that the most severe memory deficits observed in their sample were found in those patients with extensive periventricular demyelination, a finding that they say supports the hypothesis that the memory deficits seen in patients with MS result when the prefrontal and limbic structures become disconnected due to lesions lining the white matter fibre pathways. Both Swirsky-Sacchetti, Mitchel et al. (1992) and Arnett et al. (1994) have investigated and confirmed the existence of a relationship between frontal lobe white matter lesions in patients with MS and impaired conceptual reasoning skill as demonstrated using the WCST. Patient variables beyond the disease process can affect overall functioning. For example, psychological dysfunction may be a consequence of some medication usage (e.g., corticosteroids). People with MS frequently have visual and sensorimotor impairments that may influence neuropsychological test performance in the absence of cognitive dysfunction. Performance measures that are timed and require manual dexterity are sometimes inappropriate. Emotional variables may also have an indirect effect on intellectual performance (Peterson and Kokmen, 1989). A neuropsychological test battery for patients with MS needs to be (a) comprehensive, assessing all aspects of cognitive, emotional, and behavioral functioning; (b) sensitive to the types of problems encountered in MS; (c) not totally dependent on sensorimotor functions; and (d) able to be administered in a way that does not cause excessive fatigue in patients (Mahler, 1992). Affective and Behavioral Functioning Depression is a common finding in people with MS, and is sometimes the first or most prominent symptom. Numerous studies have reported no association between cognitive impairment and depression in patients with MS (Clark et al., 1992; Gilchrist and

Brassington and Marsh Creed, 1994; Krupp, Sliwinski et al., 1994; Moller et al., 1994; Rao, Leo, Bernardin and Unverzagt, 1991). Shnek et al. (1995) investigated depression in 80 patients with MS. Depression in their sample was found to be unrelated to disability or disease activity, but was significantly correlated with measures of learned helplessness and cognitive distortions and lower scores on a measure of perceived self-efficacy. Multiple regression analysis revealed that only learned helplessness predicted depression after demographic and disease-related variables were controlled for. Moller et al. also found depression to be unrelated to EDSS status, illness duration, age, or gender in a sample of 25 patients with MS. Clinical course was not found to influence affective or cognitive state in their sample. A number of self-administered questionnaires are available to detect and rate the severity of a wide range of emotional symptoms. The Beck Depression Inventory and the Minnesota Multiphasic Personality Inventory (MMPI) have been the most frequently used in research on depression in MS (Minden and Schiffer, 1990). Investigations of personality changes in patients with MS have also employed the MMPI, with elevations being recorded on scales 1, 2, and 3hypochondriasis, depression and hysteria, the socalled neurotic triadand scale 8schizophrenia (Meyerink et al., 1988). This MMPI profile is a common occurrence in nonpsychiatric patients with CNS disease, and is considered to be an artefact of the test items and scale composition. Meyerink et al. conclude that physical illness needs to be considered as an independent factor that can influence the validity of MMPI interpretations. Peyser et al. (1980) described five types of MMPI profiles in a sample of patients with MS. The classic 1,2,3 pattern usually occurred in patients who had relatively intact cognition, but moderate physical disabilities. Patients high on scales 1 and 3 but lower on scale 2 had intact cognition but few physical symptoms. Patients high on scale 8 tended to show a great deal of cognitive loss. Neuroanatomical Correlates of Affective Dysfunction.

George et al. (1994) recently reported a positive correlation between the occurrence of clinical depression in patients with MS and lesion load in the left hemisphere cortical white matter. While tentative about drawing conclusions from the results, the authors note that clinical depression has previously been found to be more likely to occur following a

Multiple Sclerosis stroke of the left hemisphere than one of the right. However, MRI findings were unable to distinguish depressed from nondepressed patients with MS in the study by Moller et al. (1994). Feinstein, du Boulay, and Ron (1992) found a trend for psychotic patients with MS to have a greater number of lesions particularly around the periventricular areas, and a later onset of psychosis than that of psychotic patients without brain disease. Ron and Logsdail (1989) have reported that psychotic patients with MS tend to have a greater lesion load around both temporal horns than nonpsychotic patients matched for disease characteristics. Other researchers have investigated the possibility that the frontal lobes may become isolated from other cortical and subcortical areas in some patients with MS, resulting in the development of behavior characteristics seen in frontal lobe syndromes (e.g., Grisby et al., 1993). Other Functional Assessment Measures A variety of new assessment measures have been developed and evaluated using samples of people with MS. Many have addressed the need for more ecologically valid tools to assess salient issues such as patient quality of Me. Granger et al. (1990) evaluated the ability of four functional assessment scales to predict the satisfaction of people with MS with life in general. The Functional Independence Measure (FIM), Incapacity Status Scale, Environmental Status Scale, and Barthel Index (BI) were all found to be predictive of the patients physical care needs. However, the FIM was the strongest clinical tool to use in the assessment of patients with MS. All but the BI also predicted the patients satisfaction with life in general. Marolf et al. (1996) conducted a similar study, comparing the FIM, an extended BI (EBI) and the EDSS. A high correlation and equal sensitivity was found between the EBI and FIM so the authors recommended use of the EBI for its simpler rating system and user friendliness. Brosseau and Wolfson (1994) found the FIM to be both a reliable and valid tool for use with patients who have MS, describing it as a more sophisticated version of the BI, with the addition of a social and cognitive skills section and a more refined scoring system. Schapiro (1994), on the other hand, found the FIM to be unhelpful for measuring quality of life in people with MS. Both measures appear to be clinically useful to assess the impact that MS has on the lives of people who have it.

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Doble et al. (1994) employed the Assessment of Motor and Process Skills (AMPS) to measure functional competence in patients with MS, in relation to their usual activities of daily living (ADL). The AMPS is an observational measure designed to overcome the limitations of self-report or proxy-report measures of ADL. Motor skills were defined as the observable actions that relate to the underlying posture, mobility, coordination, and strength capabilities of the person, while process skills related to attention, organization, conceptualisation, and adaptation. Doble et al. found that 12 out of 22 patients experienced both motor and process skill impairment. Four patients experienced difficulties on the basis of process skill impairment alone, possibly as a result of underlying cognitive impairments. The authors concluded that a number of people with MS who would not be expected to have ADL difficulties based on their neurological impairment rating may still experience impairment in ADL performance, as demonstrated by the AMPS. Both Cella et al. (1996) and Pfenning et al. (1995) have designed quality of life questionnaires specifically for use with people who have MS. Vickrey et al. (1995) also provide a quality of life measure. Their MS Quality of Life-54 Instrument has 12 scales including physical health, pain, energy, cognitive functioning, social functioning, and sexual functioning. Schwartz, Coulthard-Morris, Zeng, and Retzlaff (1996) have developed a measure of self-efficacy for use with patients with MS. They define self-efficacy as "one's degree of confidence in one's ability to perform behaviors or management strategies related to a specific situation or condition" (p. 394). The prolific development of these new measures is evidence of the changing emphasis of research, with its increasing focus on how impairments meaningfully impact on patients' lives.

CONSEQUENCES The way in which a person reacts to MS does not necessarily relate to the severity of the disease. A person who is only mildly affected can be psychologically distraught, while someone who is severely handicapped may cope very well. Many factors play a part in determining the individual's response. These include the effect of the disability on someone's normal way of life, previous methods and patterns of coping, and the extent of support received

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from others. Wineman (1990) found that adaptation to MS was directly related to the person's perception of support and inversely related to functional disability and perceptions of nonsupport. In a review of psychosocial adaptation to disability by people with MS, Antonak and Livneh (1995) note the consistent absence of a linear relationship between chronicity and adaptation in studies of people with MS. This contrasts with studies of people with other impairments. Antonak and Livneh suggest the existence of a complex curvilinear relationship resulting from the cycles of exacerbations and remissions imposing variations in disability and renewed life crises. However, in a sample of 125 people with MS, Eklund and MacDonald (1991) noted that the majority reported having successfully adapted to the disease. The variability and inconsistency of MS tends to compound the difficulties experienced by patients and their families. Anxiety can be prominent in the early stages of the disease when there is uncertainty about diagnosis and prognosis (Gordon el al., 1994). Initial symptoms can be confusing for both patients and doctors. A patient may initially be dismissed as neurotic (White et al., 1992). A psychiatric label can lead to physical symptoms going unnoticed or being underestimated. Even when MS is suspected it can take some time before a definite diagnosis is reached as there is no absolutely reliable diagnostic test. Consequently, a definite diagnosis can almost come as a relief for some patients. O'Connor et al. (1994) followed 172 inpatients with suspected MS who were undergoing a clinical workup to confirm or deny the MS diagnosis. Beneficial changes in patients' health perceptions were observed irrespective of the diagnostic outcome. Distress over diagnostic uncertainty decreased significantly for the patients given a definite diagnosis, and unambiguous statements regarding diagnosis were most preferred by the patients. The study found no justification for health professionals to evade or deny a diagnosis of MS when it is necessitated. Similarly, 59 of the 62 patients with MS studied by Mushlin et al. (1994) felt that they were better off after receiving diagnostic information following their clinical workup. However, it was found that the beneficial effects of diagnostic information were dependent on what the diagnosis was (i.e., a "negative" finding actually resulted in a tendency for patients to become more anxious) and how definitely it was made (Mushlin et al., 1994). Adjustment can sometimes be more difficult when symptoms are mild; people with MS can be un-

Brassington and Marsh sure whether to perceive themselves as normal or handicapped. Understandably given the waxing and waning nature of symptoms particularly in the initial stages of the disease, people can develop a preoccupation with physical symptoms. When physical problems become more obvious some patients may find it easier to accept their changed health status. For others, however, it can be very difficult to come to terms with the stigma of disability. Boyle et al. (1991) identified four distinct psychological responses exhibited by people with MS: one characterized by depression, another by denial or euphoria, a third by hysteria or an exaggeration of physical difficulties, and a fourth referred to as the severity response, (i.e., distress regarding the condition matches physical difficulties). A study by Stenager et al. (1992) found that the cumulative lifetime risk of suicide among persons with MS was approximately 2%, about 1/3 higher than that expected in the general population. The risk was found to be highest in young patients and males. Sleep disorder is a consequence that many people with MS have to contend with. Clark et al (1992) reported a prevalence of sleep difficulties three times higher in patients with MS (25.2%) than in a control group (8.2%). Significant increases in levels of depression were found to be associated with the presence of sleep complaints, as were three lesion sites detected by MRI. Clark et al. hypothesize that neurological symptoms of MS, such as spasticity and bladder problems, may disrupt sleep cycles, which in turn leads to increased levels of depression and fatigue. Rudick et al. (1982) examined the quality of life in patients with MS, and compared them to patients with either inflammatory bowel disease or rheumatoid arthritis. MS was found to have a more negative impact on quality of life than either of the other conditions. This was considered to be a result of the multiple distinct problems produced by MSfor example, motor, sensory, and cognitive problems (Rudick et al., 1992). Limitations in the amount of information able to be processed can make it difficult for an individual with MS to retain and process the information necessary to solve complex tasks efficiently. Impaired memory, attention, and concentration faculties, coupled with fatigue, effect the personal organization of people with MS, as well as their vocational functioning and normal family role. Activities of daily living such as grocery shopping and the preparation of meals can present a major hurdle and result in severe

Multiple Sclerosis fatigue. Packer et al. (1994) reported extreme fatigue and lowered activity levels in patients with MS, noting that an inability to take part in activities such as paid employment, domestic work, and child care not only restricts the individual, but places increased demands on families and support networks as well. Rao, Leo, Ellington et al. (1991) investigated the contribution of cognitive dysfunction in the problems of daily living experienced by 100 patients with MS. No significant correlation was found between level of cognitive impairment, physical disability, and illness duration. The patients who were cognitively impaired were less likely to be working, engaged in fewer social and avocational activities, reported more sexual dysfunction, experienced greater difficulty in performing household tasks, and exhibited more psychopathology than cognitively intact patients. These findings suggest that cognitive dysfunction is a major factor in determining the quality of life of people with MS. Similar findings were reported by Wild et al. (1991), who compared 14 patients with MS whose disease activity was primarily cerebral and 11 patients whose disease was predominantly situated in their spinal cord. Despite less motor involvement the cognitively impaired patients were significantly more likely to be unemployed, divorced, and depressed. They were also more likely to experience psychosocial instability and to have psychiatric symptomatology than the p a t i e n t s whose disease was characterised predominantly by motor dysfunction. Sullivan et al. (1990) investigated the degree to which 1180 people with MS, contacted by way of a survey questionnaire, perceived themselves to experience cognitive difficulties. Thirty-eight percent of the sample reported significant cognitive problems in at least one area of information processing, 23% reported difficulties in retrospective memory, 22% had difficulties with attention/concentration, 18% had difficulties with prospective memory, and 17% had difficulties with planning and organization. The use of an external memory aid such as a notepad was the most frequently reported strategy employed to cope with cognitive impairment, along with mental rehearsal, increased effort, requesting assistance, maximizing alertness, avoidance of difficult situations, immediate action, and mental exercise. In part two of their research, Edgley et al. (1991) examined the determinants of employment status in their sample. Of the individuals aged between 18 and 55 years of age, 66% were unemployed at the time of the survey. Significant determinants of employment status included mo-

59
bility problems, perceived cognitive problems, and lower education. Of the unemployed respondents, 78% named symptoms of MS as their primary reason for becoming unemployed. Ambulation and fatigue were the MS symptoms most frequently reported as reasons for leaving work. A somewhat more positive picture was painted by Rodriguez et al. (1994), who examined the functional status of 179 patients with MS using the MRD. While one-third of their sample had marked paraparesis, paraplegia, or quadriplegia, and one quarter required care for bladder dysfunction, few reported any major decrease in cognitive functioning. More than half of the sample were working full time and most reported being able to maintain their usual financial standard without external support. Rodriguez et al. (1994) concluded that the functional status of people with MS is more favorable than previously thought. Several studies have recently investigated the impact of MS on sexual activity. Decreased sexual desire, decreased lubrication, diminished orgasmic capacity, changes in orgasmic quality, anorgasmia, erectile failure, reduced frequency, and satisfaction with masturbation have all been reported (Hulter and Lundberg, 1995; McCabe et al., 1996). In a sample of women with advanced MS, Hulter and Lundberg found that changes in sexual function correlated with neurological symptoms (e.g., bowel and bladder dysfunction, pelvic floor weakness, ataxia, and vertigo), age, EDSS score, and cohabitation. Sexual dysfunction was reported significantly more often by women with lower EDSS scores. McCabe et al. found that only 35.4% of men and 20.4% of women were not experiencing any form of sexual dysfunction, and sexuality was not influenced by length of time since symptoms developed, time since diagnosis or level of disability. Mattson et al. (1995) found no association between sexual dysfunction and disease duration, type of MS, EDSS scores, or the presence of fatigue. Mattson et al. reported an improvement in the sexual functioning of patients following corticosteroid treatment for other problems. Given the retrospective nature of this reporting, however, the authors recommended further investigation of this finding. Gulick (1994) examined the relationship between perceived social support and illness duration, gender, marital status, and ADL level of functioning in people with MS. The importance of the role played by spouses in meeting the needs of people with chronic illness was evident. Low to moderate correlations were found between social support, network size, and

60
the number of ADL functions, particularly for women. Hammond et al. (1996) found a significant association between degree of disability and incidence of separation and divorce between couples. Greater degrees of disability were also associated with lower rates of participation in the paid work force.

Brassington and Marsh For example, Goldstein et al. (1992) demonstrated that gist recall is a preserved feature of the memory functioning of patients with MS, as it is for patients with closed head injury and temporal lobe epilepsy. The pattern of recall exhibited by patients with MS revealed that they retrieved most important story ideas. This area of strength can be utilized in rehabilitation by teaching and encouraging patients with MS to encode and retrieve information according to its meaning, as opposed to focusing on irrelevant details. Given their findings regarding the nature of memory deficits in MS, Minden et al. (1990) suggest that when patients with MS are required to assimilate information, (e.g., about their illness or rehabilitation strategies), sufficient time and repetition be allocated to maximize learning. Bennett et al. (1991) review the types of compensatory strategies that can be developed in the cognitive retraining of patients with MS. The use of lists and other written cues may help to counteract the memory impairment commonly associated with MS. Careful planning and organization of activities into routines will enhance energy conservation, a high priority given the prevalence of debilitating fatigue experienced by many people with MS. Computer programs may be able to assist in the restoration of memory functions, using graded practice on a variety of tasks (Mahler, 1992). Jonsson et al. (1993) examined the short- and long-term effects of cognitive treatment (involving compensation, substitution and direct training) and neuropsychotherapy in 20 patients with mild to moderate cognitive and behavioral impairment associated with MS. Although the treatment effects were disappointing when evaluated with an extensive cogn i t i v e test b a t t e r y , the r e s u l t s of the Beck Depression Inventory provided support for the program. Following treatment the patients rated themselves as significantly less depressed, an effect that remained evident 6 months later. However, the minimal success of actual cognitive rehabilitation lends support to the view of Bennett et al. (1991) that rehabilitation should focus on compensatory strategies to enable people with MS to minimize the impact of cognitive deficits on their lives. Foley et al. (1994) examined the impact of cognitive impairments on fundamental aspects of communication such as accurate listening, making requests of others and making compromises. Their comprehensive guide for the rehabilitation of patients experiencing difficulties in this area was demonstrated to have

PSYCHOLOGICAL INTERVENTION Given the variable nature of MS different levels of functional independence are achieved by different people. Needs for lifestyle modification and supportive treatment increase with the progression of the disease. Granger etal. (1990) remarked that although the physical and psychological symptoms of MS and methods of treatment for exacerbations have been well studied, the unique needs of patients with MS for rehabilitative and supportive care in the community remain, to a large extent, unmeasured. Eklund and MacDonald (1991) found that the two areas of need identified by people trying to adapt to MS were for help in accepting the reality of the disease and learning how best to live with it. Mertin (1994) has stressed the importance of neurorehabilitation for people with MS, commenting that this needs to begin at the stage of diagnosis, rather than being considered as a last resort for patients who are severely disabled. While the neurological and neuropsychological deficits caused by the disease frequently lead to inactivity, Mertin described the importance of people with MS being as active as is realistically possible given their physical and cognitive status at the time. Hence, countering diseaseinflicted inactivity is an important component of psychological and physical rehabilitation for patients with MS. Rehabilitative interventions can teach compensatory strategies to alleviate present difficulties and prepare for possible new deficits or the worsening of current ones in future exacerbations (Bennett et al., 1991). Early intervention and long-term planning to prepare for likely increases in disability may also help to sustain motivation and desire for employment (Gordon et al., 1994). Roessler and Rumrill (1994) describe an intervention that employs strategies for enhancing the self-efficacy of people with MS with the aim of promoting career maintenance. Neuropsychological findings regarding deficits can be used to advise patients and their families in areas concerning the patient's cognitive status, and cognitive strengths can be used to offset weaknesses.

Multiple Sclerosis beneficial results. Smits et al. (1994) examined the effects of 4-aminopyridine (4-AP) on cognitive functioning in 20 patients with MS. 4-AP is a potassium channel blocker thought to restore nerve conduction in demyelinated nerve fibers, and has been demonstrated to have a favorable impact on the motor and visual functions of some patients. However, despite subjective reporting by some of the patients of improvements in memory and attention functions, Smits et al. observed no significant effects of 4-AP on the cognitive functioning of their sample. Unlike the cognitive impairments that may accompany MS, the affective symptoms are reversible and can be treated using standard practices. Psychological interventions aimed at treating distress and depression in patients with MS may even have an important part to play in slowing the progression of the disease. Foley et al. (1992) concluded that psychological distress is associated with immune dysregulation in MS. Individual therapy aimed at identifying emotional disturbances and the psychosocial factors that influence them, and teaching active coping skills, can be beneficial. Minden (1992) provides a working guide on psychotherapy for use by professionals working with people who have MS. Psychosocial studies examining concerns related to living with MS have begun to appear in recent years (e.g. Aronson, 1997; Gulick, 1994; Rudick et al., 1992). From 697 responses to a self-completed questionnaire, Aronson found that poor quality of life among people with MS was associated with unemployment, MS symptoms of moderate or worse, fatigue, mobility limitations on stairs, a disease course other than stable and especially interference by MS in social activities. Antonak and Livneh (1995) reviewed the literature on psychosocial adaptation to MS to illustrate a general discussion on the concept of psychosocial adaptation to disability. Wineman et al. (1994) compared the coping strategies of 433 people with MS and 257 people with a spinal cord injury. Individuals in both groups who perceived higher levels of illness uncertainty used more emotion-focused coping behaviors, while problem-focused coping was employed by those without perceived uncertainty. Interventions designed to clarify ambiguous information, provide information on probable disease course, and reduce as much uncertainty as possible are recommended. Warren et al. (1991) found that patients with MS who were experiencing an exacerbation were most likely to resort to emotion-focused coping

61
techniques rather than problem solving or social support. They suggest the use of stress reduction techniques and education in the use of more effective coping strategies regardless of whether stress precipitates MS exacerbations or visa versa. Couple and family therapy may also be appropriate given that the changes brought about by MS can result in considerable family and marital stress. Sexual dysfunction may be an important issue needing to be addressed for some couples. Research on the sexual functioning of people with MS was lacking until relatively recently (Hulter and Lundberg, 1995; McCabe et al., 1996; Mattson et al., 1995). Self-help support groups are often therapeutic in that they provide social interaction, emotional support, the exchange of information and practical advice for people with MS and their families. Eighty percent of O'Brien's (1993) sample of spousal caregivers of people with MS reported seeking information and advice from others as one of their coping strategies. Until recently there has been a notable absence of research assessing the processes and consequences of caregiving for persons with MS. However, in the last few years some studies have come to light. O'Brien (1993) conducted semistructured interviews with 20 caregiving spouses of people with MS, seeking to describe the caregivers' stressors, identify their coping behaviors, and examine the relationship between caregiver stress and caregiver coping behavior. Results demonstrated that the majority of the caregivers experienced moderate levels of stress as a result of their caregiving duties. Problem-focused coping behaviors were reported more often than emotion-focused ones, indicating that the caregivers were actively struggling to meet the demands of the caregiving situation. Changes in personal plans and confinement were found to be the major stressors for the majority of caregivers, indicating that the provision of physical care is less burdensome than restrictions on personal freedom. Financial burden and role constriction were also significant causes of caregiver stress. Knight et al. (1997) found spousal caregivers of people with MS to be experiencing a range of negative effects related to the symptoms of the person with MS, such as motor problems, sudden mood changes, incontinence, pain, and interpersonal conflict. Individual differences in perceived burden by the spouses was associated with satisfaction with social support and satisfaction with ability to cope.

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Table I. Large-Scale Population-Based Studies Providing Estimates of Cognitive and Affective Disturbance in Multiple Sclerosisa Authors Subjects Results Frequency of cognitive dysfunction in general MS population is more than 4 in 10. Cognitive dysfunction not found to correlate with duration of illness, depression, disease course, or medication usage, but was slightly correlated with physical disability.

Rao, Leo, Bernardin and 100 MS: mean EDSS 4.1 39 R/R, 19C/P, 42 C/S Unverzagt (1991) 100 normal controls matched on age, sex, & education Mclntosh-Michaelis et al. 147 MS: mean age 48 years 34 (1991) controls with rheumatoid arthritis, mean age 55 years, matched on sex and education Skegg (1993)
91 MS

Cognitive impairment detected in 46% of MS sample. 34% with memory impairment. 33% failed on tests of frontal lobe function. Physical disability associated with cognitive impairment. Memory impairment more common in those whose MS was of 10 years duration or more. 29 of the 91MS identified in a defined population of 112,000 had been referred to a psychiatrist at least once. However, only 2 were likely candidates for a true psychiatric presentation of MS. While only 3.7% of the MS patients had a severe decrease in mental functioning, disturbance in mentation enough to interfere with everyday activities was reported by 18.6% of patients; 4.3% of patients had mood or thought disturbance that required psychotherapy or hospitalization. Depression prevalence rate in MS patients was significantly lower when measured by mood scale than by the Beck Depression Inventory or Multi-scale Depression Inventory. Inclusion of nonmood symptoms in self-report scales may artificially raise prevalence and severity ratings of depression in MS.

Rodriguez et al. (1994)

179 MS: mean EDSS 3.5

Nyenhuis et al. (1995)

84 MS: mean EDSS 4.7 35 R/R, 28 C/P, 20 C/S, 1 B 101 depressed adults 87 normal controls matched on age, sex, and education

R/R: relapsing-remitting; C/P: chronic progressive; C/S: chronic stable; B: benign.

Aronson (1997) found that poorer quality of life among caregivers of people with MS was associated with being a spouse, longer duration of caregiving, moderate or worse MS symptoms in the care recipient, and especially the care recipient's current disease course unless it was stable. Finances were an area of low satisfaction identified by the caregivers. Only one study is known to have examined the extent of stress or "burden" experienced by relatives in relation to the cognitive deficits exhibited by people with MS (Mclntosh-Michaelis et al., 1991). While no significant relationship was found between these two variables, further research into the area was advocated.

The Need for Large-Scale, Population-Based, Multicenter Collaborative Investigations to Provide Accurate Prevalence Rates for Cognitive and Affective Problems Increasingly, it appears that investigators are employing community-based populations of people with MS for research purposes (Gulick, 1994; McIntosh-Michaelis et al., 1991; Nyenhuis et al., 1995; Rao et al., 1993; Rao, Leo, Bernardin, and Unverzagt, 1991; Rao, Leo, Ellington et al., 1991; Rodriguez et al., 1994; Skegg, 1993). Results from these studies are more representative of the total population of people with MS, and hence more generalizable than those obtained from samples gathered via medical centers, neurology departments, or outpatient clinics. Table I summarises some of the investigations that have provided recent estimates of cognitive and affective disturbance in population-based studies of MS. These studies demonstrate that cognitive impairment is a relatively common occurrence in people with MS. Prevalence rates of approximately 40% have been recorded, somewhat less than that found in studies util-

CRITICAL REVIEW In concluding his 1986 review article, Rao outlined a number of areas encompassing neuropsychological aspects of MS that would benefit from further study. These six areas are now addressed in light of the recent research undertaken in this area.

Multiple Sclerosis izing clinic-based samples (e.g. Rao et al., 1984; Lyon-Caen et al., 1986). The occurrence of pure psychiatric presentations of MS has been demonstrated to be rare (Skegg, 1993). Rodriguez et al. (1994) reported that 4.3% of their community-based sample presented with severe mood or thought disturbance, compared to a global prevalence of psychopathology of 54% in the clinicbased sample studied by Arias Bal et al, (1991). The importance of employing community-based samples to obtain accurate estimates of the prevalence of cognitive and affective disturbance in populations with MS is evident. The Need for More Information on the Range and Severity of Cognitive Deficits in MS, Contrasting This With the Nature of Cognitive Dysfunction Evident in Other Dementing Conditions A large number of recent studies have added to our knowledge base regarding specific areas of cognitive deficit experienced by people with MS. The profile that has repeatedly appeared in the literature on cognitive impairment in patients with MS is characterized by little or no language deficit; impairment in retrieval from long-term memory but normal recognition memory, immediate recall, and rates of forgetting; impaired abstract and conceptual reasoning; slowed rates of information processing; and reduced attentional capabilities. This pattern is consistent with that of subcortical dementia, a concept reviewed by Cummings and Benson (1984) and frequently raised in discussions of the cognitive deficits evident in people with MS. However, recent research has drawn attention to the need to divide research samples of patients with MS into cognitively homogeneous groups to gain a better understanding of the nature and pattern of deficits evident in individual patients (Armstrong et al., 1996; Grossman et al., 1995; Kujala et al., 1994; Ryan et al., 1996). Ryan et al. comment that the subcortical dementia profile evident in patients with MS on neuropsychological testing is the result of group analyses of data from cognitively heterogeneous samples. A cluster analysis of their sample of 177 people with MS revealed no single pattern of cognitive impairment, but rather a variety of specific deficits in one or two areas of cognitive functioning and normal performance in others. Despite the vast array of knowledge gathered from group studies in the last decade, the usefulness of

63
individual analysis or at least cognitively homogeneous samples, to document distinct patterns of neuropsychological functioning in the light of the idiosyncratic positioning of brain lesions should not be forgotten. Inconsistencies across studies employing group analyses may arise from the use of cognitively heterogeneous samples. Ryan et al. (1993) examined this issue further. Four models of cognitive deficit were presented: (a) specific deficit, (b) subgroup deficit, (c) a syndrome dissociation model, and (d) a global function dissociation model. Data from the neuropsychological assessments of 119 patients with mild relapsingremitting MS were then analyzed and reviewed in the context of the four models. The results were supportive of a specific deficit model of cognitive impairment in this sample of patients with MS. However, Ryan et al. caution against making inferences regarding the deficits evident in people with MS from a single sample of clinically mild patients. Many studies have confirmed the absence of a relationship between the extent of cognitive deficits evident in patients with MS and age, severity of physical disability, disease duration, or diagnostic type (e.g. Amato et al., 1995; Beatty et al., 1990; Beatty, Paul et al., 1995; Good et al., 1992; Rao et al., 1993; Rao, Leo, Bernardin, and Unverzagt, 1991). Cognitive impairments have been recorded in patients in the early stages of the disease as well as in those in the more advanced stages (e.g., Klonoff et al., 1991; Ryan et al., 1996). Table II summarises recent research that has addressed previously unexplored areas such as language functioning, information processing, and attention processes; while Table III details the relatively large amount of research that has investigated the specific nature of memory deficits in MS. Comparisons of the cognitive deficits evident in patients with MS and those observed in other dementing conditions have been relatively limited. Recent research has mostly compared patients with MS and patients with Chronic Fatigue Syndrome (e.g. DeLuca et al., 1995; DeLuca et al., 1993; Krupp et al., 1994; Packer et al., 1994). One study utilized people with Postpolio Syndrome as a comparison group (Packer et al., 1994) and another, people who had suffered a spinal cord injury (Wineman et al., 1994). Yet another study compared the cognitive and affective impairments evident in an MS sample with AIDS patients (Morriss et al. 1992). Moulthrop and Nudelman compared patients with MS and patients with

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Table II. Studies Investigating Cognitive Deficits Other Than Memory Impairment in Patients with Multiple Sclerosis"

Authors Rao, St. Aubin-Faubert, and Leo (1989)

Subjects

Results

36 MS: mean EDSS 4.3 Patients with MS exhibited an overall slower reaction time than did 26 normal controls controls, even on a measure of pure cognitive speed. matched on age, verbal IQ, and education 86 MS: mean EDSS 2.08 46 normal controls, matched on age, sex, and education 34 MS: mean EDSS 4.1 18 normal controls, matched for age, sex, and education The groups differed as expected on tests of motor function, but also on some cognitive tests with no motor demands. Cognitive deficits appear to be present even in the mild stages of MS.

Klonoff et al. (1991)

Maurelli et al. (1992)

MS patients performed worse than controls on all WAIS performance subtests. Cognitive deficits were associated with attention processes and information-processing speed impairment.

DeLuca et al. (1993)

11 MS: mean EDSS 4.9; all C/P MS and CFS patients clearly exhibited difficulties in information 12CFS processing compared to controls. 11 controls matched on age and education
4 MS: all C/P mean EDSS 5 or 6 4 normal controls matched on age, sex, and education

Wallace and Holmes (1993)

MS patients performed substantially lower than controls on 5 of the 15 Arizona Battery for Communication Disorders subtests, seeming to identify deficits in language areas not previously studied.

Beatty and Monson (1994)

30 MS: mean AI 5.0 5 R/R, 13 C/P, 12 S 33 normal controls matched on age, sex, and education 45 MS: mean EDSS 5 17 R/R, 22 C/P, 6 P 35 normal controls matched on age, sex, and education 100 MS: mean AI 3.5 32 normal controls matched on age, and education 20 MS: mean EDSS 3.03 17 R/R, 3 C/P 16 normal controls, matched on age, and education

MS patients impaired on the picture sequencing test but performed normally on Luria test of motor sequencing showing a relatively specific deficit in cognitive sequencing to be partially dissociated from impairment in performing simple motor acts.

Kujala, Portin et al. (1994)

22 patients had mild cognitive deterioration, 23 had preserved cognitive capacities. The former were slower in all 3 stages of information processing measured. The latter showed mild slowing in automatic visual processing only.

Beatty, Hames, Blanco, Paul & Wilbanks (1995)

MS patients achieved fewer categories on the WCST, fewer correct sorts on the California Card Sorting Test, and lower scores on the Abstraction scale from the Shipley Institute of Living Scale. A subgroup of patients with MS were consistently impaired to a significant extent across all sentence comprehension tasks, associated with selectively compromised mental information processing speed.

Grossman, Robinson, Onishi, Thompson, Cohen & D'Esposito (1995)

Kujala, Portin, Revonsuo & Ruutiainen (1995)

23 MS: mean EDSS 5.0 9 R/R, 11 C/P, 9 P cognitively preserved 22 MS: mean EDSS 5.5 13 R/R, 6 C/P, 3 P mildly deteriorated 35 normal controls matched on age, and education

The mildly deteriorated group was slower than the other 2 groups on all tests of attention, but did not differ from the other 2 groups in the error scores of the attention tests. The preserved group showed signs of motor & fatigue related slowness, while the mildly deteriorated group also had extensive cognitive slowness, which the attention tests are sensitive indicators of.

Multiple Sclerosis Table II. Continued Authors Subjects Beatty & Monson (1996) 30 MS: mean Al 5.0 5 R/R, 13 C/P, 12 S 33 normal controls Coolidge, Middleton, Griego & Schmidt (1996) 30 MS: mean EDSS 4.7 37.7% R/R 30 normal controls matched on age, educational and IQ 177 MS: mean EDSS 2.0 all R/R 89 normal controls matched on age, sex, and education

65

Results WCST results indicate problem-solving deficits in MS patients resembling those produced by frontal lobe dysfunction. Results from the California Card Sorting Test, however, indicate unique difficulties, possibly due to a deficit in concept formation. Patients with MS displayed significantly poorer recall following short and long delays, and signif icantly poorer cued recall but not recognition memory. Retrieval processes were implicated.

Ryan, Clark, Klonoff, Li & Paty (1996)

MS patients with unequivocal cognitive impairment clustered into groups with specific deficits in 1 or 2 areas of cognitive functioning, and normal performance in others. No single pattern of cognitive impairment was considered characteristic of MS.

43 MS: mean EDSS 5.6 While all subjects performed better on a measure of visual information 42 normal controls processing than auditory information processing, no disproportionate matched on age, education, modality-specific differences were observed between the groups. and verbal IQ a R/R:relapsing-remitting; C/P: chronic progressive; C/S: chronic stable; S: stable; P: progressive; AI: Ambulation Index; CFS: Chronic Fatigue Syndrome. Diamond, DeLuca, Kim & Kelley (1997) depression, seizures, closed head injury, and normal control subjects. The group with MS was significantly slower than each of the other illness groups and the control subjects. Clark et al. (1997) examined the pathological associations and dissociations of functional cognitive systems in patients with MS and Huntington's disease and a nonclinical control group, employing the subtests of the WAIS-R, two motor tests, and the word fluency test. The two clinical groups exhibited a greater degree of association among the tests, and consequently, word fluency was able to be predicted from the tests. The overall predictive power was 7% for the control group, 28% for the group with MS, and 50% for the group with Huntington's disease. The Need for Information on The Rate of Progression of Cognitive Dysfunction in MS The need for longitudinal studies to map the development of cognitive deficits in patients with MS has been addressed by a few researchers (e.g., Amato et al., 1995; Feinstein, Kartsounis et al., 1992), with several more stating that longitudinal studies are currently being undertaken. Feinstein, Kartsounis et al. (1992) tracked 48 patients who presented with the early signs of MS, (i.e., clinically isolated lesions) finding that at follow-up about half the patients had developed clinically definite MS, with memory deficits becoming apparent. Bernardin et al. (1993) presented data from a three year follow-up study involving 84 of 100 patients with MS and 86 of 100 normal control subjects. A significant increase in EDSS scores was noted in the patients with MS, along with statistically significant deterioration in 8 of 29 cognitive measures, including measures of verbal intelligence, memory and visuospatial perception. Performance in the areas of attention/concentration, conceptual reasoning and language did not demonstrate a significant change. The cognitive changes appeared to be independent of illness duration, disease course or changes in physical disability. Conversely, Passafiume et al. (1993) presented the results from 14 patients with MS followed-up after an interval of 31/2 years and found no significant decline in test performance between the initial and follow-up evaluations. Amato et al (1995) traced the evolution of cognitive dysfunction in early-onset MS, in an attempt to identify clinical predictors of cognitive decline. They reported that a patient's initial disability level predicted decreased performance on only 4 of 13 cognitive variables, and while cognitive and neurological deficits did not appear to develop in parallel, cognitive dysfunction was the best predictor of handicap in everyday life. Further research on the

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Table III. Recent Studies That have Examined Memory Impairment in Multiple Sclerosis Authors Subjects 37 MS: mean EDSS 4.3 26 normal controls matched on age, verbal IQ, and education Results MS exhibited deficits on secondary memory and verbal fluency but performed normally on measures of primary memory, recognition memory, and rates of forgetting.

Rao, Leo, and St. Aubin-Faubert (1989)

Minden et al. (1990)

50 MS: mean EDSS 4.2 Significant difference between MS and controls on nearly all 18 R/R, 25 C/P, 7 combined memory tests. Memory impairment related to impairment in other cognitive functions, lower SES, C/P disease course, and 35 normal controls matched on age, sex, and education use of anti-anxiety medication, but not to severity of disability, duration of MS symptoms, or depression. 45 MS: mean Al 3.9 MS patients were impaired on memory for temporal order but not on a concurrent test of content recognition. 12 R/R, 18 C/P, 17 S 22 normal controls matched on age, sex, and education 45 MS: mean AI 3.9 MS patients with impairments in either memory or on the WCST 12 R/R, 18 C/P, 17 S also displayed deficits on some measures of metamemory, but not on others. Self-report by MS patients appraising their own 22 normal controls memory capabilities may prove to be unreliable. matched on age, sex, and education 41 MS: mean EDSS 4.5 45 normal controls matched on age, and education MS patients were significantly impaired on memory measures requiring effort (free and cued recall), but performed normally on automatic measures (monitoring frequency and modality).

Beatty and Monson (1991a)

Beatty and Monson (1991b)

Grafman et al. (1991)

Goldstein et al. (1992)

MS patients recalled fewer total elements over immediate and 12 MS: mean EDSS 4.5 delayed conditions compared to controls. Like the controls, they 10 normal controls recalled more ideas of high rather than low or medium matched on age, sex, and education importance. 34 MS: mean EDSS 4.1 18 normal controls matched for age, sex, and education When compared to the control group, MS patients exhibited learning, short- and long-term memory impairment.

Maurelli et al. (1992)

Rao et al. (1993)

On a working memory task, MS patients showed an exaggerated 46 MS: mean EDSS 4.5 word length effect indicating a deficit in the control process of 14 R/R, 10 C/P, 22 C/S the articulatory rehearsal Normal buildup and release from 47 normal controls proactive inhibition suggests intact semantic encoding. No matched on age, sex, and education difficulty on priming and procedural memory tasks. 23 MS: mean EDSS 5.7 8 R/R, 10 C/P, 4 R/P, 1 S 23 normal controls matched on age, and education
67 MS: 45 R/R, 22 C/P 22 normal controls matched on age, and education

DeLuca et al. (1994)

MS patients required significantly more trials than controls to reach criterion on the task, but the groups did not differ on tests of recall and recognition. Performance was correlated with rate of information processing speed. MS patients demonstrated postencoding negative recency with normal recognition. Word order recall was impaired. This was hypothesized to be due in part to difficulty using temporal order cues in long-term memory. MS patients exhibited 3 distinct patterns of performance on the Selective Reminding Test: 25% performed normally, 22% exhibited severe amnesia-like disturbance, and 53% showed mild to moderate memory impairments.

Armstrong et al. (1996)

Beatty et al. (1996)

99 MS: mean AI 3.5 32 normal controls matched on age, and education

Multiple Sclerosis
Table III. Continued Authors Troyer et al. (1996) Subjects 131 MS: mean EDSS 3.8 55 R/R, 33 C/P, 30 R/P, 13 B Results Neurologic impairment & age each contributed to the prediction of delayed free recall of a word list and Murray (1996)until the effect of conceptual reasoning was accounted for.

67

R/R: relapsing-remitting, C/P: chronic progressive, C/S: chronic stable, R/P: relapsing progressive, S: stable, P: progressive, B: benign.

rate of progression of cognitive dysfunction in people with MS appears warranted. The Need to Correlate Biological Markers of Disease Activity With the Cognitive and Affective Changes Evident in MS There has been a proliferation of literature published in recent years in which the cognitive deficits in MS have been demonstrated to correlate with lesions visible using MRI technology (e.g., Feinstein et al, 1993). Results consistently reveal that the most sensitive indicators of cognitive impairment are the width of the third ventricle, periventricular lesion load, total weighted lesion score, and corpus callosum atrophy (e.g., Anzola et al., 1990; Baumhefner et al., 1990; Clark et al., 1992; Huber et al., 1992; Pelletier et al, 1993; Pozzilli et al, 1991; Rao et al, 1993; Rao, Leo, Haughton et al, 1989; Ryan et al, 1996; Swirsky-Sacchetti, Mitchel et al, 1992). Ryan et al. (1996) detected associations between impairment on neuropsychological measures of visual-spatial ability, learning and memory, with neuropathology evident on MRI. Moller et al. (1994) noted that MRI findings failed to differentiate between the depressed and nondepressed patients in their sample. Table IV summarises recent research which has employed MRI technology. Alongside the increase in studies employing MRI have been a number of studies investigating the relationship between event-related potentials (ERPs) and cognitive impairment in patients with MS (e.g., Honig et al, 1992; Newton et al, 1989; Ruchkin et al, 1994; Van Dijk et al, 1992). In a study of cognitive ERPs, Newton et al concluded that the generation of ERPs is partly dependent on the integrity of the cerebral white matter, and so may indicate subtle degrees of cognitive dysfunction not always detected by standard cognitive measures. These studies are detailed in Table V

The Need to Evaluate the Effect of Cognitive Disturbance on the Patient's Everyday Functioning (i.e. Self-Care, Independent Living, Academic Achievement and Vocational Functioning) Fortunately, in the last decade there has been an increased focus on the practical relevance of the cognitive deficits evident in MS populations. This appears to have followed the identification by many health professionals in the field that this must be the most critical question from the patients' perspective. The combined results of these studies suggest that cognitive decline in individuals with MS can have a detrimental effect on their social functioning, interpersonal relationships, employment status, affective state, and execution of activities of daily living (Amato et al., 1995; Edgley et al., 1991; Gilchrist and Creed, 1994; Rao, Leo, Ellington et al., 1991). The results from recent studies addressing this issue are summarised in Table VI. The Need for Additional Information on the Relationship Between the Cognitive and the Affective Disturbances in MS Rao (1986) identified depression and euphoria as mood states often associated with cases of MS, and the need for more information on the relationship between these states and the cognitive changes evident in patients with MS. Recently there have been a number of studies reporting high levels of depression in MS populations, most noting that the depression does not account for impaired cognitive performance (e.g., Clark et al., 1992; Krupp et al., 1994; Moller et al., 1994). The presence of euphoria has been less well documented in recent years, most probably a reflection of its less common occurrence. Lezak et al. (1990) examined three abnormal characteristics that appeared to occur together and that could be related to reactive emotional changes

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Brassington and Marsh

Table IV. Recent Research Utilizing MRI Scanning to Examine Biological Markers of Disease Activity in Multiple Sclerosis and Their Relationship with Cognitive and Affective Changes" Authors Subjects 53 MS: mean EDSS 3.8 21 R/R, 10 C/P, 21 C/S, 1B Results Total lesion area was a robust predictor of cognitive dysfunction. Size of corpus callosum was predictive of performance on measures of mental processing speed and rapid problem solving. Ventricular-brain ratio did not predict cognitive test findings. Patients with extensive periventricular demyelination had inferior performance on concept formation, nonverbal reasoning and verbal memory tests. Plaque burden in the cerebrum had a strong relationship with neuropsychological functioning.

Rao et al. (1989)

Anzola et al. (1990)

41 MS: mean EDSS 2 41 R/R

Baumhefner et al. (1990) 62 MS:mean EDSS 5.5 62 C/P Pozzilli et al. (1991)

17 MS: mean EDSS 1.7 Greater width of the third ventricle and higher periventricular lesion 17 R/R load were the most sensitive MRI measures in differentiating the 17 normal controls more cognitively impaired patients from the relatively unimpaired. matched on age, sex, and education 34 MS: mean EDSS 4.1 The most severe memory deficits were found in MS patients with 18 normal controls extensive periventricular damage. matched for age, sex, and education
40 MS: 24 R/R, 16C/P

Maurelli et al. (1992)

Swirsky-Sacchetti, Mitchel et al. (1992)

Neuropsychological tests were highly related to all generalized measures of cerebral involvement with "total lesion area" the best predictor of neuropsychological deficit. Left frontal lobe involvement best predicted impaired abstract problem solving, memory, and word fluency, while left parieto-occipital involvement best predicted deficits in verbal learning, and complex visuo-integrative skills. Significant correlations evident between the ventricular measures and cognitive performance in the MS subjects but not in the controls. Lesion area, regardless of distribution, correlated with performance on most of the neuropsychological tests. Patients with severe cognitive impairment had greater lesion area and atrophy of the corpus callosum compared to the 2 lesser impaired groups. There was a trend for the psychotic MS patients to have a higher total lesion score, particularly around the periventricular areas. This trend reached statistical significance in the areas around the temporal horn.

Clark et al. (1992)

123 MS: mean EDSS 2.1 60 normal controls matched for age, and education 35 MS: mean EDSS 3.4

Huber et al. (1992)

Feinstein, du Boulay and Ron (1992)

10 MS: mean EDSS 4.9 psychotic symptoms 10 MS controls mean EDSS 4.6 no psychotic symptoms 31 MS: mean EDSS 4.9 Average age 40 years, average education 14 years 32 normal controls Average age 33 years, average education 17 years 10 MS: mean EDSS 4.6 10 matched controls

Honig et al. (1992)

Long P300 wave latencies evident in MS patients were strongly correlated with demyelinative brain lesions seen on MRI and cognitive impairment, but only weakly associated with the EDSS, which primarily reflects spinal, not cerebral, demyelination

Feinstein et al. (1993)

Lesion load was seen to increase in 3 MS patients over the course of 6 months. These 3 patients also demonstrated deteriorated cognitive performance.

Multiple Sclerosis
Table IV. Continued Authors Pelletier et al. (1993) Subjects 90 MS: mean EDSS 3.9 63 R/R, 27 C/P 25 normal controls matched for age and sex Two individual case studies 43 MS: mean EDSS 3.8 17 R/R, 8 C/P, 17 C/S, 1 B Results Performance on each functional task was predominantly associated with atrophy of one part of the callosum, i.e., left-ear dichotic suppression with the posterior callosal region, alternate finger tapping with the anterior region, etc.

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Fontaine el al. (1994)

Cognitive deficits and visual hallucinations linked to plaques evident in particular neuroanatomical sites. There appeared to be a relationship between frontal lobe white matter lesions in MS patients and impaired conceptual reasoning, which could not be explained by a global deterioration in cognitive functioning. MS patients with comorbid depression had worsen depression with increasing lesions in their left cortex. Lack of MS lesion involvement in the brainstem & cerebellum of nondepressed MS suggest a role of these areas in the etiology of affective illness. MRI findings failed to differentiate between the MS patients who were depressed and those who were not depressed.

Arnett et al. (1994)

George et al. (1994)

16 MS: EDSS < 7

Moller et al. (1994)

25 MS: mean EDSS 3.3

Ryan et al. (1996)

177 MS: mean EDSS 2.0 Lesions evident on MRI scans were associated with 2 lesions sites: all R/R visual spatial ability with the genu of the corpus callosum, and 89 normal controls learning and memory with the deep white matter of the left matched for age, sex, and education parietal lobe.

R/R: relapsing remitting; C/P: chronic progressive; C/S: chronic stable; B: benign.

Table V. Recent Research Utilising Evoked Potentials to Examine Biological Markers of Disease Activity in Multiple Sclerosis and Their Relationship with Cognitive and Affective Changes Authors Newton et al (1989) Subjects 23 MS: mean disease duration: 10 years 19 normal controls matched for age 62 MS:mean EDSS 5.5 62 C/P 10 MS: mean EDSS 5 Controls no information given
30 MS 19 normal controls (described in another paper)

Results 10 MS patients showed abnormalities on cognitive-related ERP components, mainly on the auditory test. ERPs may indicate subtle degrees of cognitive impairment. Visual, auditory and somatosensory evoked potentials seem related primarily to noncerebral plaques in the brain stem and cerebellum. Fatigue in multiple sclerosis was associated with a slowing of performance (reaction time) on memory tasks, but paradoxically brain potentials were unchanged or speeded up in latency. Nonmotor cognitive variables were not significantly abnormal in the MS group. No significant relationship between event-related potential latencies and psychometric tests were found. MS patients exhibited significantly prolonged P300 wave latencies compared to controls. These were strongly correlated with cognitive impairment but only weakly associated with the EDSS.

Baumhefner et al (990) Sandroni et al. (1992)

Van Dijk a al. (1992)

Honig et al. (1992)

31 MS: mean EDSS 4.9 Average age 40 years, Avereage education 14 years 32 normal controls Average age 33 yeaers, Average education 17 years

Ruchkin et al. (1994)

Neuropsychological testing, behavioral performance and ERP data all 10 MS: mean EDSS 3.05 indicate that verbal working memory is especially susceptible to 10 normal controls MS, while visuospatial working memory is less susceptible. matched for age, sex, and education

C/P: chronic progressive.

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Brassington and Marsh

Table VI. Recent Studies That Have Examined the Effect of Cognitive Dysfunction in Multiple Sclerosis on Everyday Lifea Authors Subjects 1180 MS responding to a mailed questionnaire Resutls Mobility problems, perceived cognitive problems, and lower education were significant determinants of employment status.

Edgley et al. (1991)

Rao, Leo, Ellington, et al. (1991)

100 MS: 39 R/R, 19 C/P, 42 C/S Cognitively impaired MS experienced greater disturbance in ADL 52 cognitively intact than cognitively intact MS, despite similar physical disability. The 48 cognitively impaired former were less likely to be employed, engaged in fewer social 100 normal controls and recreational activities, reported more sexual dysfunction, etc. matched on age, sex, and education

Grigsby et al. (1993)

23 MS: mean EDSS 5.1 All C/P 23 normal controls matched on age, and education 24 MS: mean EDSS 4 23 R/R, 1 C/P

MS patients performed more poorly than controls on the BDS. MS scoring low on the BDS showed greater behavior inertia and greater disruption of the ability to regulate purposeful activity in the performance of ADL. Significant cognitive impairment was more frequent in subjects diagnosed as depressed. Depressed MS experienced significantly more stress in the domains of occupation, marriage, and family relationships, but not in money, housing, and social life. MS patients demonstrated significantly poorer motor and process abilities when performing ADL. Process skill impairment may be due to underlying cognitive impairments.

Gilcnrist and Creed (1994)

Doble et al. (1994)

22 MS: mean EDSS 3.6 10 R/R, 8 C/P, 3 R/P 22 normal controls matched on age and sex

Amato et al. (1995)

Cognitive and neurological deficits appeared not to develop in 50 MS: mean EDSS 1.9 44 R/R, 6 C/P parallel but cognitive dysfunction proved to be a predictor of 70 normal controls handicap in everyday life, even .in patients in the incipient phase matched on age, sex, and education of MS.
139 MS EDSS ranging from 1 to 8

Schwartz et al. (1996)

Neuropsychological performance was not associated with fatigue. Fatigue was found to limit social, work, and overall role performance but not physical role performance.

R/R: relapsing remitting; C/P: chronic progressive; C/S: chronic stable; R/P: relapsing progressive. BDS: Behavioral Dyscontrol Scale.

to cognitive inefficienciesnamely, that attentional disorders get interpreted as memory problems by people with MS, verbal retrieval difficulties block their access to stored information, and high scores on the Obsessive/Compulsive (O/C) scale of the Symptom Checklist-90 are evident. Lezak et al. compared 15 patients with MS who were highly impaired on six measures of cognitive efficiency and 10 patients who demonstrated low impairment on these measures. The patients who were highly impaired had more abnormally high O/C scores and no difference was observed between the two groups on the Depression scale. This provides evidence of the impact of cognitive impairment on emotional functioning. Bernardin et al. (1992) compared the influence of possible "endogenous" (structural brain changes

as evidenced by MRI, and cognitive impairment) and "exogenous" (e.g., duration, severity, and course of illness, employment, coping strategies) etiological factors on the severity of emotional disturbance in 100 patients with MS. Endogenous variables were most associated with mood disturbance, suggesting that these changes may be a direct result of the demyelinating process. Recent research examining the relationship between affective and cognitive changes in patients with MS is described in Table VII. In 1990, Peyser et al. also identified areas in need of attention by researchers interested in MS. Some of their suggestions are of the same order as those made by Rao (1986). However, two additional areas identified by Peyser et al. as deserving of research attention are addressed below.

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Table VII. Recent Studies That Have Examined the Relationship Between Cognitive Deficits and Affective Disturbance in Multiple Sclerosisa Authors Lezak et al. (1990) Subjects 25 MS: 15 cognitively impaired 10 cognitively unimpaired 50 MS: mean EDSS 4.2 13 R, 19 OR, 18 P Resutls Cognitively impaired MS patients scored higher on the O/C scale of the SCL-90, but not the Depression scale. Point prevalence of psychiatric morbidity 54%, prevalence of depression 22%, high level of emotional lability shown by 30% of MS patients, 46% showed signs of cognitive deterioration. Endogenous mechanisms (structural brain changes and cognitive impairment) were the most important factors associated with mood disturbance.

Arias Bal et al. (1991)

Bernardin et al. (1992)

100 MS: mean EDSS 4.1 39 R/R, 19 C/P, 42 C/S

Good et al. (1992)

84 MS: EDSS < 6 Both MS patients who were cognitively impaired and MS patients All with R/R who were not, were more depressed than controls, but depression 48 normal controls could not explain the deficits in the cognitively impaired group. matched on age, sex, and education 34 MS: Mean EDSS 4.1 The cognitive deficits evident in the MS patients were not related to 18 normal controls abnormal emotional states. matched on age, sex, and education 123 MS: mean EDSS 2.1 Depression scores were not correlated with either cognitive 60 normal controls performance or ventricular enlargement. Cognitive impairment matched on age, sex, and education appeared related to the disease process but not to depression. 10 MS: mean EDSS 4.9 psychotic symptoms 10 MS controls: mean EDSS 4.6 no psychotic symptoms In each of the 10 cases, neurological symptoms preceded the onset of psychosis. The psychotic group had a later age of onset of psychosis than psychotic patients without brain disease suggesting an etiological association between the pathological process of MS and the psychosis. A large proportion of the depressed MS patients were experiencing both significant cognitive deficits and social stress. MS patients had the lowest mean scores on neuropsychological measures and their cognitive deficits were more widespread compared to CFS patients. Depression was not able to explain the cognitive loss only in the MS patients. Cognitive performance and depression scores were found to be unrelated. Disease course did not influence affective or cognitive state in MS patients.

Maurelli et al. (1992)

Clark et al. (1992)

Feinstein, du Boulay, and Ron (1992)

Gilchrist and Creed (1994) Krupp et al. (1994)

24 MS: mean EDSS 4 23 R/R, 1 C/P 20 MS: mean EDSS 2.3 20 CFS subjects all matched for age, and education

Moller et al. (1994)

25 MS: mean EDSS 3.3

"R/R: relapsing remitting; C/P: chronic progressive; C/S: chronic stable; R; relapsing; B = benign; P: progressive, CFS: chronic fatigue syndrome.

The Need for the Development of a Brief Screening Instrument, to be Used by Neurologists, to Screen for Patients Requiring a More Comprehensive Neuropsychological Assessment A series of studies detailing the interrater reliability of the EDSS have been published in recent years (e.g., Francis et al., 1991; Noseworthy et al., 1990). Unfortunately, a comparison of the results from these studies fails to provide a definite conclusion regarding the usefulness of the EDSS in this

context. Pliskin et al. (1996) report that the EDSS was insensitive to treatment-related changes in a clinical trial of interferon p-1b. The treatment changes were monitored by neuropsychological assessment (i.e., the Trail Making Test-Part B, employed as a measure of sustained attention, psychomotor speed, and cognitive flexibility). The MMSE has been evaluated as a brief screening instrument for cognitive deficits in MS samples, and found to be lacking in sensitivity (Beatty and Goodkin, 1990; Honig et al., 1992). Beatty and Goodkin

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suggested supplementing the MMSE with a brief version of the Boston Naming Test, and increasing the number of items on the verbal free recall, to increase the sensitivity and specificity of the MMSE for identifying dementia. More recently Hohol et al. (1995) have developed a simple assessment tool for use as a brief screening tool by neurologists. This instrument, called Disease Steps, merits further empirical evaluation. Basso et al. (1996) recently developed and tested a 35-50 minute cognitive screening battery. This battery yielded a high degree of effectiveness in detecting cognitive impairment in patients with MS, plus high rates of sensitivity and specificity. The authors concluded that this screening measure is more sensitive than those employed by Rao et al. (1991) and others, due to the broader range of cognitive abilities assessed. Rudick et al. (1996) discuss at length the qualities imperative in optimal assessment tools for multiple sclerosis clinical trials. The Need for More Research into TVeatments for Cognitive Dysfunction in MS One recent study has reported on the effects of neuropsychological treatment with patients who have MS (Jonsson et al., 1993). While no improvement was observed on a neuropsychological assessment battery, lower depression levels, increased self-confidence, insight into and acceptance of neuropsychological deficits were some of the positive intervention outcomes recorded in this study. Smits et al. (1994) found no significant improvement in the cognitive functioning of 20 patients with MS following treatment with 4-AP. Foley et al. (1994) describe a detailed cognitive-behavioral approach for the treatment of communication skills deficits in cognitively impaired people with MS. A case study is provided to illustrate that despite significant difficulties with memory and reasoning, a 57-year-old woman with MS learnt to communicate more effectively with family and friends. The intervention described by Roessler and Rumrill (1994) to increase career maintenance self-efficacy in people with MS incorporates cognitive and behavioral strategies, (e.g., modeling and role playing of socially competent methods for discussing accommodation needs with one's employer). They also provide suggestions on how to evaluate the impact of such an intervention. CONCLUSION

Brassington and Marsh

Significant advances have been made in a number of important areas in the 12 years since Rao (1986) published his critical review on the neuropsychology of MS. Further refinement of the research questions and methodologies to be employed continues unabated. Current research activity demonstrates the dedication of neuropsychologists and other behavioral neuroscientists to understanding and alleviating the plight of the person with MS and their family.

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