Cognitive Function in Multiple Sclerosis
Jeffrey G. Portnoy
Frederick W. Foley
Introduction
Cognitive dysfunction is a common and impactful manifestation of multiple sclerosis (MS). For decades, it has been known that, despite the frequency with which cognitive deficits tend to occur in the MS population, cognition is not formally assessed as often as is necessary, leading to under-diagnosis of this critical disabling symptom.1 Estimates of the prevalence of cognitive impairment have fluctuated alongside changes in diagnostic criteria, methodological approaches in research, and instruments used to assess cognitive functioning. Nonetheless, a general consensus has emerged that approximately half of MS patients experience clinically meaningful changes in cognition, with recent appraisals ranging from 40% to 65%.2,3,4
Impaired cognitive ability is one facet of the broader neuropsychiatric symptomatology present in MS, which also includes high comorbidity with depression, anxiety, and other forms of mood disturbance. Multifactorial neuropsychiatric disability is a primary detractor from health-related quality of life in MS patients5,6 and an important consideration when planning treatment around patients’ changes in function and ability to maintain their routines when disease status worsens.
Psychosocial Impact and Quality of Life
Patients and their caregivers frequently describe changes in cognitive function as a particularly intrusive element of the MS disability profile, and its functional consequences can be severe and far-reaching. The trend in diagnosing presence and severity of neurocognitive disorders has shifted to emphasize the impact of cognitive change on the performance of everyday functions. It is therefore important to consider the manner in which cognitive changes may negatively impact patients’ normal activities in order to help them retain high quality of life.
MS patients with cognitive impairment often experience numerous changes in life circumstance that can present additional sources of medical, emotional, and financial hardship. Loss of employment occurs frequently, and although physical disability undoubtedly plays a large role, patients also frequently complain of reduced ability to complete work-related tasks at the cognitive level preceding the onset and worsening of their MS. It may be difficult for individuals to pinpoint what exactly is different about their cognition or when their changes in thinking began. Nonetheless, patients and their families, friends, and coworkers may still implicitly perceive neurocognitive changes. This potential salience of patients’ deficits, despite the uncertainty of their origin or nature, makes them an especially meaningful chronic stressor, particularly when these yield changes in ability to work, engage in normal social activities, or function independently.
Employment
Vocational status holds a central role as an element of patients’ self-efficacy, quality of life, and general sense of well-being. Employment is notably disrupted among individuals with MS, with cross-sectional and longitudinal studies estimating unemployment upwards of 50% and documenting significant trends in loss of employment over time.7,8 Although the complex nature of disability in MS suggests that multiple etiological considerations are in play to explain change in work status, cognition has been shown to be a strong independent predictor of employment among MS patients.
Instruments such as the Multiple Sclerosis Work Difficulties Questionnaire can be used to examine the origin of patients’ employment-related concerns and their risk for change in work status.9 Both subjective and objective measures of cognitive impairment have been shown to predict employment status among MS patients.10 In-depth examination of barriers to maintenance of employment shows that patients relate the changes in their cognitive functioning to specific aspects of their ability to complete tasks at work and follow standard protocols in line with company policy.11 Unemployed individuals perform worse
than their employed counterparts on neuropsychological tests,12,13 and while general increase in age and worsening of disease status are associated with both cognitive decline and loss of employment, the results of cognitive testing exist as independent predictors of change in employment.14 By contrast, patients with relative stability in cognitive functioning and other elements of disease progression show a significant ability to retain employment, even in the context of the numerous life challenges associated with managing a severe disease.15
than their employed counterparts on neuropsychological tests,12,13 and while general increase in age and worsening of disease status are associated with both cognitive decline and loss of employment, the results of cognitive testing exist as independent predictors of change in employment.14 By contrast, patients with relative stability in cognitive functioning and other elements of disease progression show a significant ability to retain employment, even in the context of the numerous life challenges associated with managing a severe disease.15
Social Functioning
Following diagnosis of an incurable disease, patients will have an increased need for coping methods and mentally healthy ways to consider the role of their illness. These new demands can present inherent challenges to the maintenance of interpersonal relationships. Social isolation can occur due to physical and psychological barriers associated with primary and secondary aspects of any chronic illness. In MS, this is further complicated by the presence of cognitive risk factors that may detract from patients’ ability to remain socially involved. Given high rates of depression and the reliance of MS patients on caregivers for functional and emotional support, the consequences of loss of social relationships can be devastating.
Research has related self-reported and objectively measured cognitive functioning to various aspects of community integration. Subjective impairment is associated with reduced participation in social activities both inside and outside the home, and poorer performance on tests of cognition has been linked to decreased social involvement.16 Core cognitive deficits in MS have been tied to difficulty participating in important domestic events, such as the preparation of meals.17
The influence of cognitive symptomatology on social functioning is not limited to the patient. Cognitive decline is accompanied by a decrease in maintenance of social contacts and leisure activities, both among individuals with MS and their caregivers.18 Cognitive changes may prompt increased levels of social isolation and lead to dissatisfaction and conflict with family members.19 Social relations can misinterpret patients’ cognitive changes as emotional instability or lack of desire to socially relate. This can be compounded by the genuine neurobehavioral change sometimes found in patients with certain forms of cognitive dysfunction, including diminished motivation.20 The erroneous attribution of decreased social ability to volitional changes in attitude, emotional dysregulation, or altered personality can lead to a breakdown in social connectedness that originates from the social contact rather than the MS patient.
Overt dysfunction of social cognitive processes can also occur, producing an expected set of problems with social relatedness. Social cognitive deficits, such as decreased emotion recognition and theory of mind, can be
a manifestation of MS.21 Deficits of this variety have been associated with disease status and duration,22 raising additional concerns about implications on psychosocial health for more disabled individuals. Alexithymia has been known to occur and progress in MS23,24 and is associated with higher levels of personal distress and emotional reactivity, as well as difficulty relating to others empathetically.25 Alexithymia tends to occur in the presence of poorer performance on other cognitive tasks, further adding to the list of social challenges that cognitively impaired patients with MS may be forced to endure.26
a manifestation of MS.21 Deficits of this variety have been associated with disease status and duration,22 raising additional concerns about implications on psychosocial health for more disabled individuals. Alexithymia has been known to occur and progress in MS23,24 and is associated with higher levels of personal distress and emotional reactivity, as well as difficulty relating to others empathetically.25 Alexithymia tends to occur in the presence of poorer performance on other cognitive tasks, further adding to the list of social challenges that cognitively impaired patients with MS may be forced to endure.26
Independence
The loss of independence associated with MS can be a source of frustration for patients and caregivers, as well as a threat to patient safety. Cognitively impaired MS patients have difficulty completing instrumental activities of daily living (IADLs) in real time compared with healthy individuals and are frequently unable to participate in common daily activities due to cognitive limitations.17,27 Deficits in executive functioning, such as organization and planning ability, directly impact capacity to perform everyday activities and overall functional status.28 Longitudinally, a significant effect of declining cognitive performance emerges as a predictor of functional status independent of physical disability.29
Increased reliance on others is an important social and emotional change. Research has recommended preparing patients and their caregivers for changes in independence through education and awareness to aid transitions in daily living and promote safety by helping patients understand and acknowledge their limitations.30 This includes monitoring of changes in patients’ ability to drive31; clean, organize, and manage the home32,33; handle finances34,35; and make appropriate medical decisions.36
Nature of Cognitive Change
As might be expected in a disease that presents as heterogeneously as MS, patients’ degree and type of cognitive dysfunction varies widely. Many patients, even those who have had MS for many years, may be cognitively asymptomatic. Those with complaints may experience mild changes in a single area of thinking or report significant impairment across multiple domains. While some cognitive functions are more frequently affected than others, the MS disease process and its sequelae have the potential to manifest in the form of cognitive impairment in effectively any area.
There is undoubtedly a connection between central nervous system disease activity and cognitive changes, but the link is not always clear-cut. Patients can have intact cognition even when disease is active in the areas of the brain corresponding to those cognitive domains. By contrast, they can show highly specific cognitive deficits associated with brain regions in
which there is little or no radiological evidence of inflammation, demyelination, or volume loss.
which there is little or no radiological evidence of inflammation, demyelination, or volume loss.
Formal methods of assessing cognition in MS will be discussed later in this chapter, but broadly, the neurocognitive profile in MS is often subtle and difficult for the layperson, including the patient, to identify or describe with accuracy.6 Attempts to develop valid self-report measures of cognition have not been successful to this point.37 General intellectual functioning and conversational language ability are relatively preserved, emphasizing the need for increased awareness and vigilance on the part of patients, clinicians, and family members toward the possibility of cognitive changes. When dysfunction is suspected, formal neuropsychological evaluation is the best way to rule out or clarify the nature of cognitive dysfunction. Examples of patient complaints in relation to types of cognitive dysfunction are shown in Table 18.1.
TABLE 18.1 COMMON SYMPTOMS REPORTED BY PATIENTS IN RELATION TO COGNITIVE DOMAINS AFFECTED BY MULTIPLE SCLEROSIS (MS) | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Processing Speed
Information processing speed is the rate at which patients can apply cognitive ability in real time. Dysfunction in processing speed has implications for functional ability across many areas of cognition.38 Over the course of an individual’s life, he or she naturally develops an internal cognitive rhythm that enables effective employment of cognitive processes. Even slight changes in the rate at which individuals can think or react in certain areas can give the patient the feeling of considerable alteration in overall cognition. In many respects, decreased processing speed is the core cognitive deficit in MS, where demyelination and reduced white matter integrity directly affect the speed of neural signal propagation and transduction.39,40,41
While many individuals with MS will endorse reduced speed of thinking when it is presented as an option, few will consider this independently as an explanation for changes they have noticed or volunteer it in discussions with a clinician. More often, patients may report the functional cognitive symptoms that exist secondary to slowed processing, including the following: difficulty sustaining attention, as patients can no longer keep pace with externally presented information at their prior level of ability; memory problems, which can occur in the context of diminished attention and learning of information; difficulty understanding others, as normal rate of speech is now faster than they can adequately process and comprehend; or trouble
finding words, as the formation of a thought process representing an idea is no longer occurring in lockstep with the retrieval of words and formation of language output. This loss of synchronization is of particular relevance in MS given the presence of focal white matter changes, which can manifest such that cognitive slowing does not occur evenly throughout the brain.42
finding words, as the formation of a thought process representing an idea is no longer occurring in lockstep with the retrieval of words and formation of language output. This loss of synchronization is of particular relevance in MS given the presence of focal white matter changes, which can manifest such that cognitive slowing does not occur evenly throughout the brain.42
Attention
Simple attention can be disrupted in MS, with some patients endorsing changes in their ability to focus either in short bursts or for extended periods of time. Patients also may complain that they have become easily distractible. More typical and specific to MS, however, are changes in complex attention and working memory, defined as the ability to mentally hold and interact with information. Patients may also report difficulty with multitasking that becomes noticeable when engaging in complicated multistep activities, such as driving or cooking. Diminished ability to multitask has been specifically related to patients experiencing difficulties at work.43
MS patients with late-onset changes in attention may not recognize the nature of their deficits and subsequently frame them as novel memory complaints. An individual given a request or new piece of information will not have the opportunity to consolidate that information to memory if attentional processes fail to engage. The patient may subsequently be told by others that they have forgotten something, when in reality they never learned it. Patients who begin an activity but lose focus may also feel that they have forgotten why they intended to do something, although this too is less a genuine memory deficit than a reflection of impaired attention.
Executive Functioning
Executive functions are a broad set of complex thinking abilities, including behavioral initiation, self-monitoring and control, cognitive flexibility, planning, organization, and judgment. Because of the intricacy of these functions, assessing them independent of other MS-related deficits is a challenge. Patients often complain of the functional manifestations of executive dysfunction, although depression and processing speed have been implicated as potential confounding variables.44,45,46 Nonetheless, patients do demonstrate impairments in objective and subjective executive measures, particularly at higher levels of overall disability or in the presence of frontal lobe change.47,48,49 As executive deficits can be reflected prominently in everyday life, they are an important consideration within the cognitive disability profile.
Visual-Spatial Processing
The ability to accurately perceive and interpret visual and spatial information can be disrupted in MS for several reasons. Patients with visual
disturbance originating in the eyes, optic nerve, or ocular muscles may present with visual deficits.50,51 Cortical change, particularly in occipital or posterior parietal regions, can impact navigation, driving ability, visual recognition, or simple visual-spatial perception. Because of the reliance on vision for many daily activities, evaluation of dysfunction in this area is of clear importance.
disturbance originating in the eyes, optic nerve, or ocular muscles may present with visual deficits.50,51 Cortical change, particularly in occipital or posterior parietal regions, can impact navigation, driving ability, visual recognition, or simple visual-spatial perception. Because of the reliance on vision for many daily activities, evaluation of dysfunction in this area is of clear importance.
Memory
Memory complaints are perhaps the most common subjective complaint among MS patients concerned about their cognitive function. This is unsurprising, as there is a strong tendency among patients with neurological conditions to describe changes in cognition in terms of practical memory, which may be most apparent to them and to others. While other cognitive functions can produce what appears to be changes in memory, as has been discussed, organic changes in verbal and visual memory have been observed in MS. Disruption of hippocampal circuitry is heavily implicated in memory dysfunction,52,53,54 although other limbic and frontal lobe connections likely play a role as well.55,56
Language
Many patients describe difficulties with word-finding, particularly in real time, and trouble keeping up during conversations. Processing speed and executive control are thought to be a considerable part of practical language dysfunction. Significant damage to language cortex is not especially pervasive among MS patients, and while isolated cases of aphasic disorders have been observed, they are not considered typical.57 Patients who describe difficulties with speech output should also be evaluated for dysarthria and speech apraxia, which may impact language production but are not necessarily suggestive of a language deficit at the cognitive level.
Case Study
Deficits in Processing Speed and Executive Functioning
A 44-year-old right-handed man with a 13-year history of MS was referred for neuropsychological evaluation owing to progressive cognitive complaints. Specifically, he reported periods of “brain fog” beginning around the time of his MS diagnosis, accompanied by a gradual decrease in his speed of thinking. He also reported difficulty with planning and adapting to changes; he had become confused and flustered by minor deviations from his routine at
work and had difficulty navigating even familiar roads if he needed to adjust his route due to traffic or road conditions. A series of significant errors at his job, dating back several years, was discovered and ultimately resulted in loss of employment.
work and had difficulty navigating even familiar roads if he needed to adjust his route due to traffic or road conditions. A series of significant errors at his job, dating back several years, was discovered and ultimately resulted in loss of employment.
Before his dismissal, he had been told by coworkers that he had become more irritable and abrupt, and his wife reportedly informed him of subtle personality changes and behavior that seemed uncharacteristic for him. Neuroimaging had showed gradual progression of MS, with multiple T2 hyperintensities present in supratentorial white matter at the time of his latest magnetic resonance imaging (MRI).
Several months prior to this evaluation, he had been started on a serotonin and norepinephrine reuptake inhibitor (SNRI), which he reported was of some benefit to his mood. Nonetheless, he presented as anxious, and when queried, he endorsed multiple symptoms of depression and significant fatigue. Speech was of normal rate, rhythm, and volume, and he had no difficulty understanding questions or instructions. However, thought process during the evaluation appeared mildly disorganized, and he was tangential at times.
Estimates of premorbid functioning based on educational background, vocational history, and crystallized ability testing suggested cognition had been well above average at baseline. On neuropsychological testing, aspects of executive functioning were impaired, including planning, complex problem-solving, and pattern recognition. Processing speed was below expectation. Auditory attention and working memory were mildly weak for age. Memory was generally intact; while learning of new information was mildly weak, likely as a consequence of diminished attentional capacity, he was able to accurately recall most of what he had initially acquired. Language functions were broadly normal, but phonemic verbal fluency was considerably weaker than semantic fluency. Simple visuospatial processing was normal.
Commentary: Neurocognitive profiles of the pattern seen in this patient are not uncommon among those suffering from diseases primarily affecting white matter integrity such as MS. In particular, the gradual onset of slowed processing speed and executive dysfunction, accompanied by mild and insidious changes in mood and behavior, is frequently seen in the context of disruption to frontal-subcortical circuitry. A large discrepancy between phonemic verbal fluency (which relies heavily on frontal lobe function) and semantic verbal fluency (which uses many of the same neural pathways, but with greater dependence on functioning temporal cortex) is strongly suggestive of abnormalities in efficient frontal lobe use.
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