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Utility of routine neuropsychological assessment for early identification of cognitive impairment in MS.


Multiple sclerosis (MS), a demyelinating and degenerative disease of the central nervous system, causes not only physical disability, but also neuropsychological (NP) impairment. Cognitive impairment affects between 45-60% of patients with MS. (1,2) Depression is equally common (3,4) and influences susceptibility to relapses. (5-7) Affective disorders, such as euphoria and pseudobulbar affect, are less common, but are found in up to about 10% of patients during the course of illness. (8-10) Such symptoms are often missed in routine neurological examinations, as these deficits can be relatively subtle in the context of physical signs and symptoms and impairment of ambulation. (11) However, NP impairment has a significant impact on social functioning, (12-14) overall quality of life (15) and is the most common reason for the discontinuation of employment. (12) Thus, greater attention to NP impairment through routine screening and assessment, and its progression over time is necessary.

NP Defects in MS

In patients with MS, the most frequently observed cognitive impairments are on tests of information-processing speed, working memory, and episodic memory. (16,17) Verbal fluency and executive function can also be involved, but less frequently. (18) In contrast, general intelligence and central language abilities are relatively spared. (1) Defecits in these domains are strongly related to measures of whole brain volume, (19) enlargement of the ventricles, (20,21) and atrophy of the cerebral cortex on magnetic resonance imaging (MRI). (22,23) White-matter atrophy may be more strongly correlated with deficits in processing speed and working memory, whereas grey-matter atrophy predicts memory deficits and neuropsychiatric conditions such as euphoria. (24) Depression has a lifetime prevalence of approximately 40-50% in MS patients, (3,4) and is more common in this disease than in other chronic neurological illness accompanied by comparable physical disability. (25-27) Anxiety is also common in MS patients, often co-occurring with depression, but remains relatively understudied in this population. (28) Although the prevalence of depression is influenced by psychosocial stressors and medication side-effects, mood may also be affected by structural changes due to neuropathology. For example, depression is associated with lesion burden, global atrophy, (29) decreased grey-matter volume and increased cerebrospinal fluid (CSF) volume in the left anterior temporal region. (30)

In contrast, much less is known regarding the underlying pathophysiology of subtle personality changes in MS. Personality broadly refers to individual traits that define the manner in which an individual tends to respond to his or her environment thus, impacting psychosocial functioning. (31) In the context of neurodegenerative MS, the adverse impact on personality has not been thoroughly investigated. Studies have shown that affect disorders are associated with changes in personality traits in MS patients. (9,32) Additionally, personality may impact disease course indirectly by influencing mood states that in turn influence health behaviours and psychosocial support. Research has shown correlations between personality disorder and frontal lobe lesions, (33) as well as with brain atrophy; (34) these studies show a particularly strong association between increasing brain pathology and personality/behavioural changes, particularly disinhibition and irritability. However, in the future, we may find that more subtle changes in personality can be measured in MS and may have an impact on the early course of the illness.

Personality traits can be reliably assessed in medical and psychological research using the NEO Five Factor Inventory (NEO-FFI). (35) This self-report instrument evaluates five personality domains: neuroticism, extraversion, openness, agreeableness and conscientiousness. Neuroticism refers to emotional reactivity and the tendency toward negative mood states and worry. Extraversion is the degree to which a person depends on external stimulation for arousal, and one's inclination toward positive mood states and sensation seeking. Openness is the desire for new or novel knowledge, ideas, and experiences. Agreeableness refers to the desire for social cooperation, honesty, and altruism as opposed to competition. Finally, conscientiousness refers to the degree to which a person is task-oriented, achievement focused, dependable, deliberate, and organized. (35) Benedict et al (36) found significant associations between lower volume of the cerebral cortex and decreases in the traits of extroversion, openness, and conscientiousness. In a separate study, MS patients with cognitive impairment exhibited higher levels of neuroticism and lower levels of extraversion, agreeableness, and conscientiousness than healthy controls. (37) Johnson et al (38) reported that MS patients have significantly higher levels of neuroticism compared with patients with chronic fatigue syndrome. Further research is needed to clarify the potential reciprocal relationship between personality and NP impairment in MS.

Neuropsychological Assessment

NP assessment is a clinical procedure involving psychiatric interview, gross mental status examination, and psychometric testing. Psychometric testing is unique to the field of clinical neuropsychology (or psychology) and is a reliable and valid approach to objectively defining cognitive capacity across various domains. (39,40) Specialized testing batteries have been designed and validated for MS, allowing for relatively brief testing sessions. The Brief Repeatable Neuropsychological Battery (BRNB) (41) requires approximately 45 minutes and consists of five tests; the Stroop conflict task (42) may be added as a measure of response modulation. The Minimal Assessment of Cognitive Function in MS (MACFIMS) (43) requires approximately 90 minutes and consists of seven tests. These batteries differ in the tests used to assess auditory/verbal memory and visual/spatial memory. A recent study comparing these batteries found they were comparable in distinguishing MS patients from healthy controls. (4) 4 However, while auditory/verbal assessments demonstrated similar sensitivity across batteries, the Brief Visuospatial Memory Test, Revised (BVMTR), (45,46) which is part of the MACFIMS battery, was more sensitive than the Spatial Recall Test (10/36) used in the BRNB. Both the MACFIMS and BRNB have alternate forms to allow for repeat testing in monitoring cognitive decline.

Value of Early and Routine Assessment

The ideal timing for NP assessment in MS patients is not well established. Currently, many patients are not evaluated until significant deficits are readily apparent. By the time cognitive impairment is appreciated by a patient or caregiver, they may already be experiencing marked changes in instrumental activities of daily living or at the workplace. In our clinical experience we see many patients who have been either dismissed or discouraged from work, circumstances that are contrary to protection guaranteed by the Americans with Disabilities Act. Recent evidence suggests that cognitive impairment may be detectable soon after MS diagnosis, (15,47,48) or even after a single demyelinating episode suggestive of MS. (49-53) Early detection may therefore prevent maltreatment in the vocational sphere and help patients and family members cope more actively and adaptively with this important aspect of neurological disability.

Another way in which early NP testing may be beneficial is in disease-course monitoring. Natural-history studies show that while the course and trajectory of cognitive impairment in MS is more heterogeneous and slower than in, for example, Alzheimer's disease, (8) progression of these deficits are a reliable marker of neurological decline. (15,54,55) A 10-year longitudinal study revealed that, in addition to the presence of cognitive deficits in the initial stages of MS, deficits continued to emerge and progress in patients over time. In the later stages of the disease, neurological and cognitive status are more likely to converge and constitute the strongest predictors of disability in patients with MS. (56)

Finally, there is growing interest in the predictive value of early and/or routine NP assessment. Benign MS (BMS) is classified based on a clinical course of low-level physical and neurological disability for at least 15 years following disease onset. However, evidence shows that even in the context of minimal physical disability, cognitive impairment can be present. (57,58) In fact, Portaccio et al (58) found that the disease course in BMS was predicted by both cognitive impairment and MRI measures of T1 lesion burden at baseline, as the risk of disease progression was predicted by these factors. Rovaris et al (59) proposed that cognitive functioning be considered in distinguishing BMS from other disease courses, as it is clear that evaluating only physical and neurological features is insufficient. Given the potential predictive role of cognitive functioning, Benedict and Fazekas (60) highlight the importance of screening and monitoring for cognitive impairment in detecting early deficits and preventing worsening in patients who appear to be clinically stable. The authors acknowledge that further research is necessary in determining the sensitivity and specificity of repeated assessments in monitoring for decline. At a minimum, there is a clear case for the implementation of a more comprehensive evaluation of MS patients presenting with a benign disease course.

Screening for NP impairment

Despite the numerous benefits of NP assessment, it remains impractical to recommend NP testing for all MS patients. Thus, reliable and valid screening tools for cognitive and neuropsychiatric impairment in MS are needed. Presently, there are no fully validated screening tools available, although there are some promising studies that may guide clinician efforts to triage patients and guide future research.

The Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) (61) is a self-administered, 15-item questionnaire designed to be completed by patients prior to medical appointments, with little need for supervision. The questionnaire has self- and informant-report forms assessing behaviours related to memory, attention, processing speed, executive function, and control of emotion. Higher scores reflect greater degrees of perceived impairment. While the informant-report form is significantly correlated with brain imaging, NP testing, and neuropsychiatric symptoms, (62) the self-report form varies in its correlation with NP testing, and is confounded by depression. (61) Many studies have shown that self-reported impairment is more strongly related to depression than to objective testing in MS patients, potentially due to negative thoughts and self-appraisal, or to misattribution of cognitive difficulties secondary to depression to MS-related change. (62-65) Accuracy of self-reported cognitive impairment increases in non-depressed MS patients and in patients effectively treated for depression. (63)

In addition to the influence of mood on self-perception of cognitive impairment, part of what might be obscuring the accuracy of self-report screening instruments in identifying cognitive and neuropsychiatric impairment is the frequency of concrete experiences in which such abilities are tested. The workplace is an environment that allows for reflection on relatively concrete and specific behaviours and provides opportunity for error. We tested this hypothesis with 314 MS patients to examine whether vocational status influences accuracy of self-reported impairment. Subjects were classified as 'impaired' or 'unimpaired' based on the MACFIMS criteria; (2) 175 were employed at the time of testing, and 139 were not. Fisher's z statistic revealed a markedly stronger relationship (z = -3.10, P < 0.01) between the Symbol Digit Modalities Test (SDMT) performance and MSNQ in employed versus unemployed patients, and similar results were found with tests of visual/spatial memory and executive function. Asking patients to reflect on their workplace activity might provide more concrete and specific behaviours for consideration, and thus, greater accuracy in self-report of cognitive function. This presents a unique opportunity for the direction of new screening measures for NP impairment in MS with potential for increasing the effectiveness of self-report measures.

In the interim, there is interest in using easily administered brief cognitive performance tests such as the Symbol Digit Modalities Test (SDMT). (64,66,67) The SDMT is a brief test measuring information or cognitive processing speed and is administered by giving the subject 90 seconds to voice the number associated with target symbols based on a grid printed at the top of a page. There are many studies showing that it is highly sensitive when administered to MS patients (2,44,68) and performance on the SDMT is associated with vocational capacity. (69) A decrease on the SDMT of 4 points, or differentiated between MS subjects who remained employed versus those who did not over time. (70) Additionally, performance on the SDMT is strongly associated with lesion burden, (71) ventricle enlargement, (21,72,73) cortical atrophy, (23) deep grey-matter atrophy, (71) informant-reported cognitive problems, (62) and unemployment. (69) Benedict et al (74) recently demonstrated that the SDMT and MSNQ can be reliably administered at monthly intervals with minimal practice effects in MS. Used together, these tests can potentially identify patients at risk for objective NP impairment with higher reliability and validity than when administered in isolation. Additionally, both the SMDT and MSNQ require minimal time, equipment, and training.


NP evaluation remains underutilized in the care of MS patients despite the high prevalence of cognitive impairment and disorders of mood and affect. As cognitive impairment is associated with future problems in work and social function, (14) and can have significant impact on overall quality of life in MS patients and their families, its early identification is clearly important. Additionally, comprehensive NP assessment can provide clarity with regard to psychiatric status and level of functioning in social and vocational domains. In the near future, research regarding personality traits might also provide insight into disease progression, particularly related to cognition, mood, and affect in patients with MS, and perhaps even strategies for preventive care, though more investigation is needed in this area.

As we learn more about potential precipitating and perpetuating factors of cognitive impairment, such as personality traits, and disorders of mood and affect in MS, the benefits of undergoing routine NP assessment will continue to increase. Furthermore, relationships currently under investigation in personality research in MS could increase our understanding of overall neurological disability status and its impact on individual patients. Until then, in the absence of routine NP assessment and prior to readily identifying possible impairment (e.g., through job loss, disruptions in relationships, etc.), patients with MS are vulnerable to undetected NP impairment. Early identification of impairment is particularly important with the advent of new symptomatic and disease-modifying therapies. As such, greater attention is necessary to the development of reliable, valid, and brief screening and monitoring for NP impairment in MS.

Key Points

* Patients with MS are vulnerable to cognitive impairment and disorders of mood and affect, which have a negative effect on many aspects of health-related quality of life.

* Cognitive impairment can be difficult to detect during routine office visits and is often only recognized once the symptoms are severe.

* Despite the high frequency of cognitive impairment in MS, routine NP testing is uncommon; sensitive, brief screening measures are needed.

* Early identification of cognitive impairment is becoming increasingly important with the advent of new symptomatic and disease-modifying therapies for MS patients.

Received:10 November 2009

Accepted: 27 January 2010


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M Hoogs, S Morrow, RHB Benedict

SUNY Buffalo School of Medicine, Jacobs Neurological Institute, Buffalo, New York, USA

Address for Correspondence

Ralph HB Benedict, SUNY Buffalo School of Medicine, Jacobs Neurological Institute, 101 High Street, Buffalo, New York, USA

Tel: +1 7168 591 403

Fax: +1 7168 591 419

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Title Annotation:NP Assessment in MS
Author:Hoogs, M.; Morrow, S.; Benedict, R.H.B.
Publication:The International MS Journal
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2010
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