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Rethinking cognitive function in multiple sclerosis: a nursing perspective.

Abstract: Cognitive impairment is a common problem in multiple sclerosis (MS); up to 65% of patients exhibit some neuropsychological dysfunction during the course of their disease. It is a major contributing factor to unemployment, accidents, impairment of daily functioning, and loss of social activity in those affected by MS. The areas of cognition typically impaired are memory, attention, information processing, executive functions, and visuospatial skills. Cognitive dysfunction is independent of disease duration and level of disability; cognitive decline may begin in the earliest stages of MS before patients become even mildly disabled. Structural brain imaging studies show a positive correlation between the extent of brain atrophy and cognitive dysfunction. Despite its prevalence in MS, cognitive dysfunction often goes undiagnosed or is misdiagnosed as depression, stress, stubbornness, lack of intelligence, or psychosis. Because nurses play such an important role in the care of patients with MS, they are in a position to identify patients with cognitive dysfunction, educate patients and their families on ways to cope with cognitive deficits, and counsel patients on available treatment options. Practical guidelines help nurses identify and care for cognitively impaired MS patients.

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Cognitive dysfunction affects up to 65% of patients with multiple sclerosis (MS; Rao, Leo, Bernardin, & Unverzagt, 1991). There are only modest correlations between cognitive function and disease duration, disease course, and level of physical disability (Beatty, Goodkin, Hertsgaard, & Monson, 1990; Rao, Leo, Bernardin, et al.; van den Burg, van Zomeren, Minderhoud, Prange, & Meijer, 1987); cognitive deficits can be present even during early stages of the disease when there is little to no physical disability.

Although the patterns of cognitive deficits vary considerably among MS patients (Ryan, Clark, Klonoff, Li, & Paty, 1996), certain cognitive domains are more susceptible than others. The cognitive domains most affected by MS are information processing (e.g., distractibility, slowing of mental process, difficulty performing multiple tasks) and verbal and visual memory (e.g., forgetfulness, especially delayed recall of recently learned information; Rao, Leo, Bernardin, et al., 1991). The severity of impairment can range from clinically undetectable to global and severe.

The cognitive symptoms associated with MS appear to be similar to those of patients with other types of brain damage (Ryan et al.). Although little is known about the natural history of cognitive impairment in patients with MS, evidence suggests that, once present, it is unlikely to remit; the degree of impairment either remains stable (Jennekens-Schinkel, Laboyrie, Lanser, & van der Velde, 1990) or deteriorates (Amato et al., 1995; Bernardin et al., 1993; Kujala, Portin, & Ruutiainen, 1997).

The effects of MS-related cognitive impairment can be devastating to patients and their families. Cognitive decline can severely affect activities of daily living (ADLs) and, in turn, quality of life. Patients who experience cognitive impairment are significantly less likely to be employed or engaged in social activities and more likely to need assistance with personal care and household management than cognitively intact MS patients with comparable physical disability (Amato et al., 1995; Rao, Leo, Ellington, et al., 1991). In many instances, families grieve for the loss of the person who is physically present but emotionally and cognitively absent. In other situations, when the family does not recognize that this is a symptom of MS and not deliberate on the patient's part, there are reports of family breakup, abuse, and neglect.

Cognitive dysfunction is difficult to diagnose in patients with MS because it may not be evident upon routine neurologic examination. Conventional measures of neurologic disability are not sensitive enough to detect the subtle MS cognitive impairments (Rao, 1995). In addition, areas of impairment easy to assess at the bedside, such as orientation, simple attention span, language, and immediate recall, are relatively preserved in most cases (Rao, Leo, Bernardin, et al., 1991). Patients are quite conversant and often unaware of the nature and extent of their problems. Therefore, in the absence of formal neuropsychological testing, cognitive dysfunction often goes undiagnosed or is misdiagnosed as stress, depression, or psychosis.

Nurses play a pivotal role in the care of patients with MS and, hence, are in a position to identify patients with cognitive dysfunction, educate patients and their families on ways to cope with cognitive deficits, and counsel patients on available treatment options. Some disease-modifying medications that are effective in treating the physical symptoms of MS (e.g., relapses, disability progression) have recently been shown to improve function in the cognitive domains most commonly affected in patients with MS (Fischer et al., 2000). Because a large proportion of MS patients experience cognitive dysfunction, which appears to be independent of physical disability and progressive in nature, it is important to treat patients as early as possible in the disease. In fact, recent studies have shown that early treatment with disease-modifying medication can delay the onset of clinically definite MS in high-risk patients (Comi et al., 2001; Jacobs et al., 2000).

This article reviews current knowledge on the nature of cognitive impairment in MS, the relationship between brain atrophy and cognitive symptoms, and evidence of beneficial effects of available disease-modifying medications on cognitive function. Practical guidelines are provided to help nurses identify and care for their MS patients with cognitive dysfunction.

History

The recognition of cognitive dysfunction in MS has evolved over time. In 1877, Charcot described a phenomenon in MS patients that he referred to as "marked enfeeblement of the memory," which was generally attributed to hysteria (Charcot, 1877). Because the incidence of MS is higher in women than in men, this "hysteria" was thought to be a female characteristic rather than a symptom of the disease. Several case reports published in the early 1900s also described dementia in MS patients and suggested dementia was a potential symptom of the disease (Dercum, 1912; Hunt, 1903; Kaplan, 1904; Rao, 1986; Ross, 1917).

Formal neuropsychological evaluation to assess cognitive deficits in patients with MS did not begin until the late 1940s, with the use of intelligence tests (Rao, 1986). In the 1950s and 1960s, large epidemiologic surveys began to report cognitive and affective disturbances in patients with MS. However, the prevalence of cognitive deficits was reported to be less than 3% (Kurtzke et al., 1972).

In 1980, Peyser, Edwards, Poser, and Filskov (1980) demonstrated that neurologists were significantly underestimating the number of MS patients with cognitive dysfunction because they were making assessments using the Mini-Mental State Examination (MMSE; Rao, 1986). MMSE was used extensively in the assessment of cognitive dysfunction in patients with MS because of its brevity and ease in scoring. However, MMSE, designed to detect cognitive abnormalities of Alzheimer's disease or vascular dementia, is a gross screening tool for cortical level dementias and is not sensitive to the cognitive dysfunction found most frequently in MS (Beatty & Goodkin, 1990; Rao, Leo, Bernardin, et al., 1991; Swirsky-Sacchetti et al., 1992).

The prevalence of cognitive dysfunction as a symptom of MS has become increasingly accepted over the past 20 years largely due to the work of Rao and colleagues. During the 1980s, Rao and colleagues performed a series of neuropsychological studies that provided detailed documentation of the nature of cognitive decline in MS and differentiated MS-related cognitive dysfunction from that of dementia (Rao et al., 1989; Rao et al., 1985; Rao & Hammeke, 1984; Rao, Hammeke, McQuillen, Khatri, & Lloyd, 1984; Rao, Leo, Bernardin, et al., 1991; Rao, Leo, Haghton, St Aubin-Faubert, & Bernardin, 1989; Rao, Leo, & St Aubin-Faubert, 1989; Rao, St Aubin-Faubert, & Leo, 1989). Since the work of Rao and colleagues, several neuropsychological assessment tools have been developed to measure discrete cognitive functions in MS (see "Formal Evaluation of Cognitive Function in Patients with MS").

Cognitive Domains Affected in MS

Cognitive impairment in MS is typically circumscribed, not global. Rao, Leo, Bernardin, et al. (1991) performed a study using a comprehensive neuropsychological battery to assess cognitive function in 100 community-based MS patients and 100 matched healthy controls. The cognitive domains most often impaired in patients with MS included memory, information processing, attention, abstract/ conceptual reasoning (executive functions), and visuospatial abilities (Rao, Leo, Bernardin, et al.).

Memory

Recent (explicit) memory is one of the most frequently affected cognitive domains in patients with MS; memory impairment was observed in 22%-31% of patients in the study by Rao, Leo, Bernardin, et al. (1991). Deficits in recent or explicit memory refer to difficulty in remembering recent events and conversations. Patients report memory deficits as forgetfulness, especially with recall of recently learned verbal or visual information. Memory deficits make it difficult for patients to follow recipes, read a book, or remember appointments, injection technique, or medications and may cause the patient to lose objects. In contrast to explicit memory, implicit memory, which refers to learning and remembering without conscious awareness, is relatively spared (Fischer, 2001).

Complex Attention/Information Processing

Attention and information-processing deficits also are commonly observed in MS patients; 22%-25% of patients in the Rao, Leo, Bernardin, et al. (1991) study showed impairment in complex attention and information-processing speed. Information-processing deficits result in increased distractibility and/or a slowing of mental functioning. MS patients report that they feel mentally slow and have difficulty thinking quickly and keeping up with conversations (Fischer, 2001). These deficits make it difficult for the patient to focus on more than one task at a time. MS patients also report problems related to attention in that they must exert more mental effort on previously easy tasks, have difficulty filtering out distractions, and have problems multitasking (Fischer).

Executive Functions/Visuospatial Abilities

Executive functions (i.e., abstract/conceptual reasoning) and visuospatial abilities are the next most commonly affected domains. In the Rao, Leo, Bernardin, et al. (1991) study, 12%-19% of patients with MS showed deficits in executive functions/visuospatial abilities. Executive functions are required for decision making and planning, error correction, novel sequences of action, and overcoming of habitual responses (Foong et al., 1997). On formal neuropsychological testing, patients with deficits in executive functions have difficulty developing, testing, and shifting problem-solving strategies. Patients are often unaware of deficits in executive functions (Fischer, 2001). Friends and family report that the patient has difficulty grasping complex concepts and has difficulty planning and adhering to a schedule (Fischer). Patients struggle to complete tasks in an orderly fashion, start several tasks without finishing any one of them, have problems adapting to new situations, and are unable to solve problems.

Visual-perceptual, constructional, and visuospatial skills are affected almost as frequently as executive functions. Patients typically do not complain about visual perception; however, family members report that the patient drives too close to the guardrail on the highway or has had several "near misses" when driving.

Verbal Abilities

MS less commonly affects language (i.e., verbal abilities) and simple attention span. Abnormalities in language were observed in 8%-9% of MS patients in the study by Rao, Leo, Bernardin, et al. (1991). Although few patients present with aphasia syndromes, deficits in language are usually due to dysfunction in other areas of cognition such as slowed information processing (Fischer, 2001). Patients often describe "inattentiveness"; however, they are usually referring to an inability to sustain and focus attention over time, often related to information-processing deficits and more appropriately termed "complex attention." Attention span, which is the simplest form of attention, is usually spared unless there is a severe attention deficit; 7%-8% of patients with MS in the Rao, Leo, Bernardin, et al. study showed deficits in attention span.

Cognitive Impairment and Brain Atrophy

Moderate correlations have been observed between cognitive function and magnetic resonance imaging (MRI) measures of total lesion burden, brain atrophy, and tissue abnormalities assessed by magnetization transfer ratios (Comi et al., 1993; Edwards, Liu, & Blumhardt, 2001; Filippi et al., 2000; Huber et al., 1992; Rao, Leo, Haghton, et al., 1989; Rovaris et al., 1998; Swirsky-Sacchetti et al., 1992; van Buchem, McGowan, Kolson, Polansky, & Grossman, 1996). Brain atrophy is thought to reflect brain damage as the result of the culmination of several destructive pathologic processes in MS (e.g., axonal loss; Simon et al., 1999). Brain atrophy in MS is irreversible, often extensive, and one of the most likely causes of cognitive impairment in patients with MS (Fischer et al., 2000). A number of specific indicators of brain atrophy have been reported in the literature, including corpus callosum atrophy, increased third ventricle size, and overall decreased cerebral volume.

Corpus Callosum Atrophy

Several studies have found that MS patients with cognitive impairments have significantly more atrophy of the corpus callosum than patients with little to no cognitive impairment (Comi et al., 1993; Huber et al., 1992; Huber et al., 1987; Pozzilli, Bastianello, et al., 1991; Rao, Bernardin, et al., 1989; Rao, Leo, Haghton, et al., 1989; Swirsky-Sacchetti et al., 1992). The extent of callosal atrophy has been specifically related to mental processing speed and rapid problem solving (Edwards et al., 2001; Rao, Bernardin, et al.; Rao, Leo, Haghton, et al.; Swirsky-Sacchetti et al.), verbal fluency (Pozzilli, Bastianello, et al., 1991; Swirsky-Sacchetti et al.), interhemispheric transfer of auditory and visual information (Rao, Bernardin, et al.), and global cognitive decline (Comi et al., 1993; Huber et al., 1987). Patients with extensive periventricular demyelination have been reported to have deficits in concept formation, nonverbal reasoning, and verbal memory (Anzola et al., 1990). In a study by Pugnetti et al. (1993), the combination of confluent periventricular plaques and brain atrophy was associated with a poorer performance on several scales of the Luria-Nebraska Neuropsychological Battery (LNNB), which is a multifaceted measure of higher cortical functions.

Third Ventricle Size

Ventricle size is another measure of brain atrophy that may contribute to cognitive deficits. An increased ventricular size is related to poor performance on tests of learning and memory (Campbell et al., 1992; Comi et al., 1993; Izquierdo, Campy, Mir, Gonzalez, & Martinez-Parra, 1991; Pozzilli, Passafiume, et al., 1991; Rao et al., 1985). Rao et al. (1985) found that poor performance on memory and intelligence tests was related to an increased width of the third ventricle. Finally, data suggest that cognitive decline is directly associated with the extent and severity of diffuse brain damage. Filippi et al. (2000) observed that cognitively impaired MS patients had significantly reduced brain volume compared with cognitively intact patients. Two studies by Zivadinov and colleagues (Zivadinov, DeMasi, et al., 2001; Zivadinov, Sepcic, et al., 2001) showed that cognitively impaired MS patients had higher levels of whole brain atrophy measured by using the Brain Parenchymal Fraction (BPF), which was defined as the ratio of brain parenchymal volume to the total brain volume within the brain surface contour Significant correlations have been observed between total white matter volume and auditory attention, mental processing speed, nonverbal memory, and executive function, as well as global cognitive function (Edwards et al., 2001).

Normal-Appearing White Matter

Microscopic abnormalities of normal-appearing white matter (NAWM) have been shown to contribute significantly to the decline of cognition in patients with MS. Magnetization transfer imaging (MTI) provides information on the microscopic pathological changes that affect normal-appearing brain tissue (NABT) and, in turn, cognitive impairment (Zivadinov, DeMasi, et al., 2001). The magnetization transfer ratio (MTR) is a quantitative measure of tissue disruption within individual MS lesions (Dousset et al., 1992). MTR histogram analyses provide an assessment of both microscopic and macroscopic MS lesion load (van Buchem et al., 1996). The overall disease burden found on MTR histograms has been reported to correlate with the presence and severity of cognitive impairment in patients with MS (Filippi et al., 2000). An MTR histographic analysis in MS patients revealed that patients with cognitive deficits had significantly lower MTR histographic values for all variables compared with cognitively intact MS patients. Average cortical/subcortical brain MTR was significantly associated with cognitive impairment (Rovaris et al., 2000). In a study of early MS, patients with cognitive impairment had less NAWM compared with cognitively intact patients (Zivadinov, Sepcic, et al., 2001). These results suggest that diffuse brain damage via microscopic lesions may be responsible for cognitive decline in the early phases of MS (Zivadinov, Sepcic, et al.).

Diffusion tensor imaging (DT-MRI), an alternative MRI technique that provides information about tissue integrity and organization that is undetectable with conventional imaging, was used to study a large sample of mildly disabled patients with relapsing-remitting MS (Rovaris et al., 2002). Moderate correlations were found between measures of DT-MRI and cognitive deficits in language, attention, and memory. In addition, macroscopic lesions of both NAWM and normal appearing grey matter appeared to contribute to cognitive decline in these MS patients (Rovaris et al.).

Identification of Cognitive Impairment

Cognitive dysfunction in patients with MS is difficult to diagnose and is frequently misdiagnosed as depression, stress, or psychosis. As with most chronic illnesses, MS is associated with a high incidence of depression. Although the clinical features of depression differ from those of cognitive dysfunction in MS, clinical depression is often associated with deficits in memory and attention (Lezak, 1983), which are hallmarks of cognitive dysfunction in MS. One distinction between depression and cognitive dysfunction is that a depressive episode is usually preceded by a relatively normal cognitive state and the cognitive decline associated with the depressive episode is typically abrupt in onset (American Psychiatric Association, 1994). When evaluating depression in patients with MS, one should keep in mind that standard depression rating scales were designed for primary depression and not for depression related to diseases such as MS (Moller, Wiedemann, Rohde, Backmund, & Sonntag, 1994).

Other symptoms and conditions, such as depression, fatigue, steroid psychosis, sleep deprivation, pain, fever, and medication side effects, may mimic the symptoms of cognitive dysfunction. Drugs such as anticholinergics, antispasticity medications, pain medications, tricyclic antidepressants, and antiepileptics can produce side effects that may complicate the evaluation of cognitive dysfunction. Table 1 provides examples of common medications with potential side effects that may exacerbate or mimic the cognitive deficits observed in MS.

Studies have shown that there are weak correlations between cognitive dysfunction and physical disability, disease course, gender, age, or disease duration (Beatty et al., 1990; Patti et al., 1995; Rao, Leo, Bernardin, et al., 1991). There fore, cognitive dysfunction must be measured independently of other disease symptoms. Independent of the degree of physical disability, illness duration, course of the disease, and demographic variables, patients with MS-related cognitive deficits experience a reduction in ADLs that may include a loss of interest in social and vocational activities, difficulties in maintaining personal hygiene, sexual dysfunction, and the inability to maintain employment (Amato, Ponziani, Siracusa, & Sorbi, 2001; Rao, Leo, Ellington, et al., 1991). Cognitively impaired MS patients also may exhibit more psychopathology (e.g., apathy and confusion), divorce/family isolation, loss of self-esteem, and loss of self-efficacy than cognitively intact MS patients (Rao, Leo, Ellington, et al.).

As the healthcare professionals who spend the most time with the patient, nurses have more opportunities to recognize signs of cognitive impairment. Signs that should raise suspicion of cognitive impairment are shown in Table 2. Nurses should also observe the patient carefully for changes in personality or unusual behaviors. Nurses may help identify whether the patient is cognitively impaired by asking the patient the following questions:

* Do you get lost more frequently when driving?

* Are you having difficulty balancing your checkbook?

* Do you have difficulty performing ADLs such as cooking?

* Have you had suicidal thoughts?

* Are you having any problems at work/school?

In addition, it is useful to interview family members or other caregivers for corroborating evidence, if appropriate. A recent screening study demonstrated that caregivers who spent more than 3 days per week with MS patients were more aware of an existing problem involving cognitive impairment than the patients themselves (Benedict et al., in press).

The Nurse's Role

As key members of the healthcare professional team, nurses must be aware of the various ways in which cognitive dysfunction may manifest itself in patients with MS. Nurses have a unique and critical role in the care of MS patients, because they have more direct contact with patients and their families than other healthcare providers (HCPs). The nurse's role in caring for MS patients is multidimensional, with physical, emotional, and spiritual components; hence, nurses are in a position to detect subtle changes in patients' behavior over time.

Prompt identification of cognitive impairment in patients with MS is important because there is a strong correlation between quality of life and cognitive impairment. The following case studies illustrate what can happen to patients whose cognitive decline is unrecognized for an extended period of time.

Case Studies

Case 1. MG was a 45-year-old female executive who presented with symptoms of cognitive dysfunction but no physical disabilities. These cognitive symptoms had affected her performance at work and eventually resulted in her termination from employment. Subsequently, she underwent MRI screening and was diagnosed with MS. It was determined that she most likely had MS at the time that she was terminated, and therefore, she was able to receive retroactive disability pay.

Case 2. CD was a 47-year-old female with a 15-year history of MS who had been treated with interferon beta-1b since 1993. She also had a 1 1/2-year history of depression and was being treated with Zoloft 100 mg daily and psychotherapy. During her professional career, she had several nurse management positions, including her current position for a visiting nurse association.

She contacted her HCP office distressed about a 3-week history of reduced ability to deal with complicated situations and to organize information at work. She reported that she had recently been reprimanded by her supervisor. Although she had been known as an easy going person, after one particularly demanding work weekend, she challenged her direct manager in the presence of others. She was concerned about losing her job because of changes in her organizational skills, personality, and temperament.

This patient was divorced, had custody of her 14-year-old daughter, and lacked a positive emotional support system. She had also experienced significant weight gain and loss of interest in personal care. Although, on the surface, this patient appeared to be managing her life-working in her profession and taking care of her home and daughter--she was actually on the verge of no longer being able to cope with her daffy responsibilities.

Nursing Interventions

Once the nurse suspects that a patient with MS is cognitively impaired, the following interventional steps are recommended: (a) ensure the immediate safety of the patient and other family members, particularly children; (b) acknowledge the problem with the patient and/or family; (c) report the problem to other members of the healthcare team; (d) adjust patients' care regimens to compensate for cognitive deficits; and (e) refer the patient to a clinical neuropsychologist or other professional skilled in evaluation and rehabilitation.

Ensure the immediate safety of the patient and other family members. Safety is an important issue for MS patients with cognitive dysfunction, and it is the primary goal of the nurse to ensure the immediate safety of the patient and their families. Patients with cognitive decline often lack insight into their ability to solve problems and avoid dangerous situations. This makes them particularly vulnerable to dangers in driving, cooking, caring for small children, and other common daily tasks. For example, the patient may be unable to quickly assess traffic signals due to slowed information processing. In addition, patients with MS who are cognitively impaired are particularly vulnerable to mental, physical, and sexual abuse because they may not be able to identify inappropriate behavior. Nurses should be mindful of the inherent dangers of cognitive decline in their patients and inform the healthcare team when action is necessary to protect the patient, their families, and caregivers.

Acknowledge the problem with the patient and/or family. Nurses should be prepared to discuss the possibility of cognitive impairment with the patient or the family, or both, realizing that the patient may become defensive. Most patients fear the development of cognitive dysfunction because it can result in an inability to make decisions, remember vital information, and even manage the most elementary responsibilities of daily life. In addition, both the patient and family may be unaware that the patient's new behaviors are due to cognitive decline. Family members frequently state that a patient is "stubborn," "doesn't listen," and is disorganized. Nurses can establish communication about cognitive impairment to help ease the tension that can occur among family members. This is a vital strategy in cases in which the cognitive impairment is subtle.

A primary role of the MS nurse is to educate patients and/or their caregivers about cognitive dysfunction. To facilitate the education process, it is important to establish trust and be empathetic to the fears of patients and their caregivers. Patients and their families must be alerted to the fact that cognitive impairment may put them at risk for harm. Nurses also can instruct patients and caregivers on simple strategies to cope with mild cognitive dysfunction, such as keeping lists of tasks to remind patients of daily activities. In addition, nurses can counsel patients on available medications for the treatment of MS-related cognitive deficits.

Report the problem to other members of the team. The nurse should report potential cognitive deficits to other members of the patient's team. The expert advice of interdisciplinary team members brings insight and creative strategy when attempting to resolve the complex problems that can arise.

Adjust patients' care regimens to compensate for cognitive deficits. Cognitive dysfunction may affect the patient-nurse relationship. As the disease progresses, it may become more difficult to communicate with the patient, which requires the nurse to become increasingly calm and collected. In addition, patients may become more dependent than usual on nurses for care and support. As memory and attention deficits evolve, the patient may have difficulty keeping track of appointments, medications, and myriad small but important everyday items, such as car keys or eyeglasses. Deficits in executive functions will make it difficult for the patient to solve problems and adapt to new situations. Word retrieval problems may cause frustration and embarrassment to the patient.

At some point, the nurse may need to identify a caregiver who can help the patient with ADLs. If a patient's family is unstable or otherwise unable to aid the patient or if the patient is socially isolated, it may become necessary to consider aid from community social services or even a nursing home.

Patients with cognitive impairment need to understand how MS can affect their bodies and how it is treated. Before undertaking an education program, the nurse should try to determine the patient's educational level in order to use appropriate language. For the patient with cognitive impairment, it is particularly important that there are no distractions during the teaching session. The use of visual and verbal cues, consistent repetition and reinforcement, slow speech, and short sentences will help reinforce the information. It also may be helpful to leave related reading material behind for the patient's future reference.

Adapting the patient's care regimen is necessary when dealing with cognitive impairment. Modifications may include the following tasks:

* Ensure that the patient is able to access assistance when needed.

* Organize medications to help establish adherence to treatment. Pill boxes or charts may help patients remember to take medications.

* Instruct the patient in self-care (e.g., self-injection, self-catheterization) to aid in establishing adherence to the regimen.

* Counsel the patient on proper diet to improve overall health and well-being. For example, high-fiber foods and adequate water intake help to prevent bowel complications.

* Conduct reevaluations on a regular basis, usually every 3-4 months.

There is no one pattern of cognitive impairment in patients with MS. Therefore, it may be necessary for nurses to use creative interventions and think "outside of the box" when establishing adaptations to help patients with cognitive impairment manage their ADLs.

Refer the patient to a clinical neuropsychologist, speech/language pathologist, or occupational therapist for evaluation and rehabilitation. Once a cognitive deficit has been identified and addressed with the patient, the nurse may refer the patient to a neuropsychologist for a more formal assessment of cognitive function. Patients who lack sufficient insight into the extent of their cognitive disability may be resistant to hearing that they have a problem. To help these patients, it may be necessary to arrange a family meeting or intervention. The nurse's role as a neutral participant and facilitator helps to assure the patient that the primary concern is for his or her safety and well-being. If possible, the nurse may conduct a follow-up meeting to assess the family's progress. After that, maintaining contact with the patient or family, or both, at regular intervals helps instill a sense of confidence knowing that the nurse is available and cares.

Patients should be referred for additional treatment and testing especially in the early stages of cognitive impairment when signs and symptoms are subtle and may be difficult to distinguish from other disease states or medication side effects. Additional treatment considerations include neuropsychological testing, psychological counseling, occupational therapy (skilled in MS cognition), career counseling, and speech and language therapy.

Nurses can become valuable advocates for MS patients outside of the clinic by helping patients obtain vocational rehabilitation or disability benefits. In addition, they may petition health maintenance organizations and influence those in state and federal legislatures to amend regulations on behalf of patients with MS.

Formal Evaluation of Cognitive Function in Patients with MS

Several neuropsychological tests have been developed to determine the scope and severity of cognitive dysfunction in MS. However, there is a wide range of sensitivity and specificity among neuropsychological tests, and not all are suitable for MS patients. For example, most thorough neuropsychological examinations require 2-6 hours to complete, which is often impractical for patients with MS who easily become fatigued (Peyser, Rao, LaRocca, & Kaplan, 1990). Some tests require motor skills that are beyond the capabilities of more physically disabled patients; this can introduce inaccuracy in assessments of cognitive capabilities (Camp, Thompson, & Langdon, 2001).

In the late 1980s, the National Multiple Sclerosis Society (NMSS) held its first conference to discuss the state of knowledge about cognitive impairment in MS. A Cognitive Function Study Group was developed to evaluate and make recommendations for improved clinical outcomes assessments for cognitive impairment in patients with MS. The ensuing diagnostic evolution improved the testing of patients through use of MS-specific batteries of neuropsychological instruments.

Comprehensive Neuropsychological Testing

Ideally patients with MS should be assessed for cognitive dysfunction by a clinical neuropsychologist; most MS comprehensive care centers and major medical centers have clinical neuropsychologists on staff. A comprehensive neuropsychological evaluation consists of a diagnostic interview, detailed testing of cognitive functions typically impaired in MS (using a comprehensive neuropsychological battery), and a more brief assessment of cognitive domains less impaired in MS. In addition, the evaluation may also include self-report measures of quality of life, emotional status, and perceived cognitive function (Fischer, 2001).

Table 3 shows an example of a comprehensive neuropsychological test battery. This battery was used by Rao, Leo, Bernardin, et al. (1991) to provide a detailed evaluation of cognitive function in patients with MS. A comprehensive neuropsychological battery is typically administered in two 3-hour testing sessions given on consecutive days. This battery contains several instruments that assess immediate, recent, and remote memory; abstract reasoning; attention and concentration; and language, visuospatial perception, verbal intelligence, and dementia.

Brief Neuropsychological Screening Tools

Unfortunately, it is not practical at this time for all patients with MS to undergo a comprehensive neuropsychological evaluation. However, there are several brief neuropsychological batteries and individual instruments that nurses can use to screen patients who may have cognitive dysfunction to determine whether further testing is appropriate. There are four brief neuropsychological batteries that have been proposed: the Screening Examination for Cognitive Impairment (SESCI; Beatty et al., 1995), the Brief Neuropsychological Battery (Rao, Leo, Bernardin, et al., 1991), the Basso Screening Battery (Basso, Beason-Hazen, Lynn, Rammohan, & Bornstein, 1996), and the Neuropsychological Screening Battery (Franklin, Heaton, Nelson, Filley, & Seibert, 1988). These short batteries take only 15 to 45 minutes to administer (Fischer, 2001). The NMSS Cognitive Function Study Group has proposed the use of a variation of the Brief Neuropsychological Battery, which was originally developed by Rao, Leo, Bernardin, et al. The Brief Neuropsychological Battery yielded a sensitivity value of 71% and a specificity value of 94% in identifying cognitively impaired patients from cognitively intact MS patients (Rao, Leo, Bernardin, et al.).

Patients also can be screened for cognitive dysfunction using a single measure such as the Paced Serial Addition Test (PASAT). The Clinical Outcomes Assessment Task Force of the NMSS developed the Multiple Sclerosis Functional Composite (MSFC) in an effort to create a measure of disability with better reliability and sensitivity than conventional measures such as the Expanded Disability Status Scale (EDSS) (Cohen et al., 2000). MSFC measures ambulation (timed 25-foot walk), arm function (nine-hole peg test), and cognitive function using the PASAT. The PASAT assesses auditory information processing speed and flexibility, as well as calculation ability. Although the test was developed to monitor recovery in patients who had sustained concussions, the test was adapted for use with MS patients by modifying stimulus presentation rates (Rao, St Aubin-Faubert, et al., 1989). In the PASAT 3" test, single-digit numbers are presented at 3-second intervals via audiotape, and patients must add each digit to the one presented immediately before it. The number of correct sums out of 60 possible is calculated as the patient's score.

If patients test positive for cognitive dysfunction on screening tests, they should be referred to a clinical neuropsychologist for comprehensive evaluation. It is important to note that individual tests and screening batteries do not assess all the cognitive domains affected by MS; hence, some patients with MS who have cognitive impairment may test negative.

Treatment with Disease-Modifying Medications

Four disease-modifying agents are currently available for the treatment of relapsing MS: interferon beta-la (IFN[beta]-1a-IM, Avonex, Biogen, Inc., Cambridge, MA); interferon beta-lb (IFN[beta]-1b, Betaseron, Berlex Laboratories, Richmond, CA); glatiramer acetate (GA; Copaxone, Teva Pharmaceutical Industries, Petah Tiqva, Israel); and interferon beta-1a (IFN[beta]-1a-SC, Rebif, Serono Inc., Rockland, MA). Of these agents, IFN[beta]-1a-IM is the only one that has shown significant beneficial effects on cognitive dysfunction in a large well-controlled clinical trial.

The effects of IFN[beta]-1a-IM on cognitive function in patients with relapsing MS were assessed in a subset of patients from the pivotal phase III trial (Fischer et al., 2000; Jacobs et al., 1996). A total of 166 patients completed a comprehensive neuropsychological battery at baseline and after 2 years of treatment and a brief neuropsychological battery every 6 months. Patients were randomized to receive IFN[beta]-1a 30 mcg or placebo administered intramuscularly (IM) once weekly for 2 years. The primary outcome measure was 2-year change in performance on the comprehensive neuropsychological battery, grouped into domains of information processing and learning/memory (Set A; most often impaired in MS), visuospatial abilities and problem-solving (Set B; moderately impaired), and verbal abilities and attention span (Set C; rarely impaired). Results showed that IFN[beta]-1a-IM significantly improved performance on measures of the cognitive domains most vulnerable to MS: information processing and verbal/visual memory (Set A; p = .011). IFN[beta]-1a-IM also slowed the progression of cognitive deterioration by 47% in patients with MS compared with placebo, based on PASAT processing rate (p = .023). In the same study, IFN[beta]-1a-IM reduced the rate of brain atrophy, which is correlated with cognitive dysfunction, by 55% during the second year of treatment (Rudick, Fisher, Lee, Simon, & Jacobs, 1999).

GA failed to demonstrate significant benefits on cognitive function. As part of the phase III trial of GA, 248 patients were randomized to receive GA 20 mg daily or placebo by subcutaneous (SC) injection (Weinstein et al., 1999). At baseline, and after 12 and 24 months of treatment, patients were administered the Brief Repeatable Battery of Neuropsychological Tests, which included the following measures: sustained attention and concentration, verbal learning and delayed recall, visuospatial learning and delayed recall, and semantic retrieval. No significant treatment effects were observed on any of these measures (Weinstein et al.).

Studies with IFN[beta]-1b have shown inconsistent results. As part of the phase III trial of IFN[beta]-1b, 30 patients were administered neuropsychological tests 2 and 4 years after study entry; 9 patients received IFN[beta]-1b 8.0 MIU, 8 patients received IFN[beta]-1b 1.6 MIU, and 13 patients received placebo SC every other day (Pliskin et al., 1996). The test battery included measures of immediate and delayed recall memory, attention/mental speed, motor function, and depression. Significant improvement was observed on 1 (visual delayed recalled) of 13 outcome variables (8.0 MIU only, p < .003). In another study with IFN[beta]-1b, patients with relapsing-remitting MS were administered 10 verbal memory tests from the Memory Assessment Scales and the Verbal subtests from the Wechsler Adult Intelligence Scale (Selby, Ling, Williams, & Dawson, 1998). Patients who were treated with IFN[beta]-1b for [greater than or equal to] 6 months (n = 94) were compared with patients who were awaiting treatment (n = 73) and with demographically matched healthy controls (n = 112). For all measures, performance of patients treated with IFN[beta]-1b was not significantly better than that of controls.

A small placebo-controlled trial was recently conducted to evaluate the effect of IFN[beta]-1b on cognitive function in patients with relapsing-remitting MS (Barak & Achiron, 2002). Twenty-three patients received IFN[[beta]-1b 8 MIU SC every other day and 23 patients received placebo for 1 year. Cognitive tests assessed verbal learning, delayed recall, visual learning and recall, complex attention, concentration, and verbal fluency at baseline and 1 year. IFN[beta]-1b-treated patients showed significant improvements from baseline in measures of complex attention (p = .024), concentration (p = .004), and visual learning and recall (p = .01; Barak & Achiron). However, there were no significant effects of IFN[beta]-1b on cognitive function compared with the placebo control group; it is important to make comparisons with a placebo control group because patients' performance may improve over time simply due to a practice effect.

In summary, several studies have been conducted to assess the effects of disease-modifying agents on cognitive function in patients with MS; the designs varied widely among these studies. IFN[beta]-1a-IM was the first disease-modifying medication to demonstrate beneficial effects on several measures of cognitive function in patients with MS in a large-scale clinical trial. IFN[beta]-1a had positive effects in the areas of cognition most vulnerable to MS and slowed the progression of cognitive deterioration. Both GA and IFN[beta]-1b have failed to show such beneficial effects in well-controlled trials; there are no reports of the effects of IFN[beta]-1a-SC on cognitive dysfunction.

Studies have shown that intervention with disease-modifying agents early during the disease process in MS is critical. In fact, IFN[beta]-1a has been shown to reduce lesion load and delay the onset of clinically definite MS in high-risk patients (Comi et al., 2001; Jacobs et al., 2000).

Summary

Nurses have the ability to help their MS patients by taking an active role in the identification and management of cognitive dysfunction, which can negatively affect patient quality of life and the ability of patients to perform normal ADLs. It is important to keep in mind that cognitive decline may begin in the earliest stages of MS, even before patients exhibit even mild physical disability. When cognitive dysfunction is suspected, the nurse should immediately ensure the safety of the patient, acknowledge the problem with the patient and family, inform other members of the HCP team, and refer the patient to a neurophysiologist for neuropsychological testing. Nurses are encouraged to adjust the plan of care for their patients according to the level of cognitive deficit. Nurses can also educate their patients on the nature of cognitive dysfunction, its consequences, and current treatment options. New research indicates that disease-modifying medications can have beneficial effects on both brain atrophy and cognitive dysfunction, as well as delay the onset of MS. Therefore, the MS nurse should encourage patients and their families to consider the initiation of disease-modifying therapy early in the course of the disease to alter not only the natural history of MS but also the disabling consequences of cognitive impairment.
Table 1. Medications with Side Effects That May Exacerbate or Mimic
MS-Related Cognitive Dysfunction

Medication (Brand Name) Side Effects

Anticholinergics
 Oxybutin (Ditropan XL) Somnolence, dizziness, insomnia,
 nervousness, confusion
 Tolteradine (Detrol) Dizziness, nervousness, somnolence
Antiepileptics
 Gabapentin (Neurontin) Somnolence, dizziness, fatigue
 Topiramate (Topomax) Somnolence, nervousness, difficulty with
 memory, confusion, depression,
 difficulty concentrating, mood
 disturbances, agitation, aggressive
 reaction, emotional lability
 Phenytoin (Dilantin) Mental confusion, dizziness, insomnia,
 nervousness
Antifatigue
 Amantadine (Symmetrel) Dizziness, insomnia, depression, anxiety,
 irritability, confusion, somnolence,
 nervousness, agitation, fatigue
 Modafinil (Provigil) Nervousness, dizziness, depression,
 anxiety, insomnia, confusion, amnesia,
 emotional lability
Benzodiazepines
 Diazepam (Valium) Drowsiness, fatigue, confusion,
 depression
 Clonazepam (Klonopin) Somnolence, depression, dizziness,
 nervousness
Muscle Relaxants
 Baclofen Drowsiness, dizziness, psychiatric
 disturbances, insomnia
 Tizanidine (Zanaflex) Somnolence, asthenia, dizziness,
 nervousness
Narcotics
 Morphine (MS Contin) Dizziness, sedation, dysphoria, euphoria,
 agitation, insomnia
Tricyclic antidepressants
 Amitriptyline (Elavil) Dizziness, drowsiness, nervousness,
 relentlessness, insomnia, sedation,
 fatigue, anxiety
Steroids
 Prednisone, Prednisolone Euphoria, insomnia, mood swings,
 personality changes, severe depression,
 psychotic manifestations, aggravation
 of emotional instability

Table 2. Signs of Cognitive Dysfunction

Clinic
 Does not keep appointments
 Multiple phone calls to physician's office or clinic
 Problems with grooming or personal hygiene
 Difficulty adhering to medication regimen
 Difficulty relating medical history
 Inability to follow simple instructions
 Weight loss

Home
 Burns
 Car accidents
 Empty refrigerator
 Parenting issues
 Poor organizational skills

Unusual Behavior
 Frustration
 Anger/defensive posture
 Euphoria
 Disinhibited behavior
 Confabulation
 Promiscuity
 Rigidity/stubbornness
 Fear of abandonment
 Insecurity

Table 3. Measures in a Comprehensive Neuropsychological Battery

Cognitive Function Test

Dementia Screen Mini-Mental State Examination
Verbal Intelligence Verbal IQ and subtests from Wechsler Adult
 Intelligence
 Scale-Revised (WAIS-R)
Memory
 Immediate Digit Span
 Brown-Peterson Interference Test
 Recent Buschke Verbal Selective Reminding
 Test (SRT)
 Story Recall Test

 7/24 Spatial Recall Test (7/24)
 Controlled Oral Word Association
 Test (COWAT)
 Remote President's Test

Abstract Reasoning Wisconsin Card Sorting Test
 Booklet Category Test
 Standard Raven Progressive Matrices

Attention/Concentration Simple versus Two-Choice Reaction Time (RT)
 Sternberg Memory Scanning Task
 Paced Auditory Serial Addition
 Test (PASAT)
 Stroop Color/Word Interference Test

Language Abbreviated Boston Naming Test
 Oral Comprehension

Visuospatial Perception Hooper Visual Organization Test
 Judgment of Line Orientation
 Facial Recognition
 Visual From Discrimination

Cognitive Function Reference

Dementia Screen Folstein, Folstein, & McHugh, 1975
Verbal Intelligence Wechsler, 1981

Memory
 Immediate Wechsler, 1981
 Brown, 1958; Peterson & Peterson, 1959
 Recent Buschke & Fuld, 1974
 Caine, Bamford, Schiffer, Schoulson,
 & Levery, 1986
 Rao, Hammeke, et al., 1984
 Benton & Hamsher, 1976
 Remote Caine et al., 1986

Abstract Reasoning Heaton, 1981
 DeFilippis & McCampbell, 1979
 Raven, 1960

Attention/Concentration Benton, 1977
 Sternberg, 1969
 Gronwall, 1977
 Stroop, 1935

Language Caine et al., 1986
 Bayles, Kaszniak, & Tomoeda, 1987

Visuospatial Perception Hooper, 1958
 Benton et al., 1983
 Benton et al., 1983
 Benton et al., 1983

Note. From "Cognitive Dysfunction in Multiple Sclerosis: I. Frequency,
Patterns, and Predictions," by S.M. Rao, G.J. Leo, L. Bernardin, and
F. Unverzagt, 1991, Neurology, 41, p.686. Copyright 1991 by
Lippincott, Williams & Wilkins. Adapted with permission.


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Questions or comments about this article may be directed to: June Halper, MSCN ANP FAAN, by phone at 201/837-0727 or by e-mail at jhalper24@aol.com. She is the executive director of the Consortium of Multiple Sclerosis Centers, Gimbel MS Center, Teaneck, NJ.

Patricia Kennedy, RN CNP MSCN, is a nurse practitioner at Rocky Mountain MS Center in Englewood, CO, and the Jimmie Heuga Center in Avon, CO.

Colleen Murphy Miller, RN NP DNS MSCN, is a nurse practitioner at The Jacobs Neurological Institute, The State University of New York at Buffalo, Buffalo, NY.

Linda Morgante, MSN RN CRRN MSCN, is a director of clinical services at Maimonides Medical Center, Brooklyn, NY.

Marie Namey, MSN RN MSCN, is an advanced practice nurse at the Cleveland Clinic Foundation, Cleveland, OH.

Amy Perrin Ross, MSN RN CNRN MSCN, is a program coordinator of neuroscience at Loyola University Medical Center Maywood, IL.
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Title Annotation:neuroscience research; includes tables
Author:Halper, June; Lawford, Patricia Kennedy; Miller, Colleen Murphy; Morgante, Linda; Namey, Marie; Ross
Publication:Journal of Neuroscience Nursing
Geographic Code:1USA
Date:Apr 1, 2003
Words:9690
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