Evidenced-Based Cognitive Rehabilitation for Persons With Multiple Sclerosis: A Review of the Literature

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Evidenced-Based Cognitive Rehabilitation for Persons With Multiple Sclerosis: A Review of the Literature Amanda R. O’Brien, PhD, Nancy Chiaravalloti, PhD, Yael Goverover, OT, PhD, John DeLuca, PhD ABSTRACT. O’Brien AR, Chiaravalloti N, Goverover Y, DeLuca J. Evidenced-based cognitive rehabilitation for persons with multiple sclerosis: a review of the literature. Arch Phys Med Rehabil 2008;89:761-9. Objectives: To conduct evidence-based review of cognitive rehabilitation intervention research conducted in persons with multiple sclerosis (MS), to classify level of evidence, and to generate recommendations for interventions in this area. Data Sources: An open (no year limits set) search of Medline, PsychInfo, and CINAHL (eliminating repetitions) using combinations of the following terms: attention, awareness, cognition, cognitive, communication, executive, executive function, language, learning, memory, perception, problem solving, reasoning, rehabilitation, remediation, training, and working memory. Reference sections of articles found through the sites were also searched. Study Selection: Studies were chosen based on criteria from previous evidence-based reviews such that articles are excluded from the review if (1) the study was not an intervention, (2) it was a theoretic article, (3) it was a review article, (4) detail was lacking to fully evaluate the intervention, (5) it was not MS-specific, (6) it included a pediatric sample, (7) it was a case report without empirical data to evaluate outcomes, (8) it was not peer-reviewed (also excludes book chapters), (9) it was a pharmacologic intervention, or (10) it was not available for review in English. Data Extraction: Articles were categorized into interventions for attention, learning and memory, executive functioning, or nonspecified/combined cognitive domains. There were 4 reviewers in the current study. All articles were reviewed independently by at least 2 persons and abstracted according to predetermined criteria. There was a final total of 16 articles, which underwent a full review and classification of a level of evidence based on previously published peer-reviewed methodology used for evidence-based reviews. Data Synthesis: The current review yielded 16 studies of cognitive rehabilitation for persons with MS, including 4 class I studies, 5 class II studies, 2 class III studies, and 5 class IV studies. Two intervention methodologies in the area of verbal

From the Neuropsychology and Neuroscience Laboratory, Kessler Medical Rehabilitation Research and Education Center, West Orange, NJ (O’Brien, Chiaravalloti, Goverover, DeLuca); Departments of Physical Medicine and Rehabilitation (O’Brien, Chiaravalloti, DeLuca) and Neurology and Neuroscience (DeLuca), UMDNJ-New Jersey Medical School, Newark, NJ; and Department of Occupational Therapy, Steinhardt School of Culture, Education, and Human Development, New York University, New York, NY (Goverover). Supported in part by the National Institutes of Health (grant no. R01 HD 38249) and the National Multiple Sclerosis Society (grant no. RG3837A1/T). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprints requests to Amanda R. O’Brien, PhD, Kessler Medical Rehabilitation Research and Education Center, 1199 Pleasant Valley Way, West Orange, NJ 07052, e-mail: [email protected]. 0003-9993/08/8904-00447$34.00/0 doi:10.1016/j.apmr.2007.10.019

learning and memory received support for a practice guideline and practice option, respectively. Conclusions: Cognitive rehabilitation in MS is in its relative infancy. More methodologically rigorous research is needed to determine the effectiveness and efficacy of various cognitive rehabilitation interventions. Specific recommendations for future research are given. Key Words: Cognition disorders; Cognitive therapy; Multiple sclerosis; Practice guideline; Rehabilitation; Review [publication type]. © 2008 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation ULTIPLE SCLEROSIS (MS), a progressive disease of the central nervous system, is characterized by the proM duction of widespread lesions, or plaques, in the brain and spinal cord. As a result of the widespread nature of the myelin plaques and axonal injuries, MS results in a wide symptom array, including motor, cognitive, and neuropsychiatric problems,1 with high variability in presenting symptoms and disease course.2 Reaching a definitive diagnosis of MS can be challenging and is done through various procedures including taking medical history, description of symptoms, neuroimaging of the brain and spinal cord, cerebrospinal fluid collection, and measurement of evoked responses. To be given a diagnosis of MS, a person must have had at least 2 distinct episodes of symptomatology separated by at least 1 month and must have lesions in more than 1 area of the brain or spinal cord. It is challenging to diagnose MS with certainty because of the variety of symptoms involved and the varying disease courses. Because the physical symptoms are most often focused on for diagnosis, cognitive functioning may less frequently be assessed or included in an immediate focus of treatment. Cognitive impairment is common in MS, with current prevalence rates ranging from 43% to 70%.3,4 MS has been shown to negatively affect various aspects of cognitive functioning including attention,5,6 information processing abilities5,7 (including processing speed8-11), new learning,12,13 and memory functioning.1 Cognitive impairments are associated with reduced functional status in MS.14,15 Cognitive impairment often has a deleterious impact on someone’s personal, occupational, and social functioning, as well as overall quality of life (QOL).15 For example, Rao et al16 found that people with MS who have cognitive impairments—as opposed to those with a purely physical disability—were less likely to be employed, were engaged in fewer social and vocational activities, had greater difficulties in carrying out routine household tasks, and were more vulnerable to psychiatric illness. Given the significant effect that deficits in cognitive functioning have on the QOL of persons with MS, the alleviation of such deficits should be a major goal of MS research and practice. Cognitive and behavioral rehabilitation are designed to enhance a person’s capacity to process and interpret information and to improve his/her ability to function in all aspects of Arch Phys Med Rehabil Vol 89, April 2008

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family and community life.17 Despite the need for cognitive rehabilitation services as a standard of care, there is a paucity of research studies designed to investigate treatment approaches or their effectiveness in persons with MS.18-20 The few existing cognitive rehabilitation programs within MS have been aimed at improving attentional deficits,21 communication skills,22 and memory functioning.23-25 However, most of the existing studies suffer from significant methodologic flaws including small sample size, short follow-up periods, and lack of specific outcome criteria to determine improvement. As a result, researchers and clinicians experience difficulty drawing firm conclusions regarding effectiveness,26 and evidence of effectiveness is ambiguous and controversial.27 Although some studies24,25,28-30 exist showing a benefit of cognitive rehabilitation for persons with MS, others31,32 have failed to show a benefit. An expert review panel recently underscored the need for cognitive rehabilitation interventions for persons with MS27 and recommended strategies such as cognitive structuring, substitution strategies, use of compensatory devices, and mnemonic approaches. The current study is the first, to our knowledge, to conduct a comprehensive evidence-based review of the existing cognitive rehabilitation intervention literature specifically within MS. To date, most of the work on rehabilitation techniques for cognitive impairments has been done with stroke or headinjured patients.26 The current clinical environment requires that therapeutic interventions be supported by class I evidence (eg, randomized controlled trials).33 The current study reviews the existing cognitive rehabilitation literature in MS to accurately describe the current status of the field, offering practice guidelines for clinicians and spurring interest and providing direction for ongoing MS research. METHODS We conducted a comprehensive review of research studies that have focused on cognitive rehabilitation interventions for persons with MS, and as such, relevant literature was identified and reviewed. We implemented methodology used in previous evidence-based reviews.34,35 As such, open-dated literature reviews were conducted in Medline, PsychInfo, and CINAHL using the combination of the search terms, which included attention, awareness, cognition, cognitive, communication, executive, executive function, language, learning, memory, perception, problem solving, reasoning, rehabilitation, remediation, training, and working memory. Reference sections of selected articles were reviewed to identify any additional relevant studies. The literature search and reference section review yielded an initial list of 224 citations. Articles were eliminated according to previously published criteria.34,35 Specifically, a study was eliminated if (1) it was not an intervention, (2) it was a theoretic article, (3) it was a review article, (4) detailed empirical outcomes were not available for evaluation of intervention, (5) the article included populations other than MS, (6) it included a pediatric sample, (7) a case report did not include empirical data to evaluate outcomes, (8) it was not peer-reviewed, (9) it was a pharmacologic intervention, or (10) the article was not available for review in English. On initial review of the citations, 19 articles were identified as research interventions studies of cognitive rehabilitation in MS. The 19 articles were randomly assigned to the 4 reviewers who conducted this study. No one reviewed a study on which he/she was an author. Each study was reviewed independently by 2 people who rated it for level of evidence and completed a review table (1) to characterize important elements of each study, (2) to describe the cognitive domain(s) targeted, (3) to Arch Phys Med Rehabil Vol 89, April 2008

Table 1: Levels of Evidence Level

Criteria

Class I

●

Class Ia

●

Class II

● ● ●

●

Class III

● ●

Class IV

●

Well-designed, prospective, randomized controlled trials Well-designed, prospective quasirandomized assignment to treatment conditions (eg, alternating conditions) Prospective, nonrandomized cohort studies Retrospective, nonrandomized case-control studies Clinical series with well-designed controls that permitted between-subjects comparisons of treatment conditions All other controlled studies in a representative population Clinical series without concurrent controls Studies reporting 1 or more case study that used appropriate single-subject methods (eg, multiple baselines) Evidence from uncontrolled studies, case series, case reports, or expert opinion

NOTE. Adapted from Cicerone et al.35 © 2000 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation.

describe the sample, and (4) to describe the intervention, outcomes, and evidence of treatment effectiveness. Decisions for level of evidence were based on standards published by the American Association of Neurologic Surgeons36 for classification of research studies and the classifications described by Cicerone et al34,35 (table 1). Final acceptance of evidence classification was based on total agreement between the 2 reviewers. An a priori decision was made that if there was a discrepancy in the level of evidence assigned for each article, a third reviewer, blinded to the judgments of the first 2 reviewers, would evaluate the article to reach a conclusion for assignment of level of evidence. A third-party reviewer was never needed. A closer inspection of the full articles by the reviewers showed that 3 of the initial 19 identified articles did not meet the aforementioned inclusion criteria for this review. Of the 3 eliminated articles, 2 were theoretic articles that described general approaches to cognitive rehabilitation; the other article qualitatively described cognitive rehabilitation approaches used at rehabilitation facility, without any accompanying data or specific outcomes. This resulted in a final total of 16 articles that underwent a full review and classification of a level of evidence (table 2). After review of the article and classification of level of evidence, reviewers then provided recommendations based on the strength of the levels of evidence found in the research as to the feasible and preferable approaches to cognitive rehabilitation. The recommendations were classified as either (1) practice standards, (2) practice guidelines, or (3) practice options, based on the body of evidence available.34,35 See appendix 1 for the guidelines used in deciding on the appropriate recommendation for each domain. RESULTS Attention Two studies focused specifically on the remediation of attention skills. Two additional studies had an attention remediation component in addition to components for other cognitive skills. Of the 4 studies in this area, there was 1 class I study

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EVIDENCE-BASED COGNITIVE REHABILITATION IN MS, O’Brien Table 2: Summary Table of Reviewed Articles

Study

Cognitive Domain Targeted 21

Plohmann et al

Attention

Plohmann et al37

Attention

Solari at al32

Attention and memory

Lincoln at al31

Attention, memory, and executive function (based on impaired domain) Executive functioning

Birnboim and Miller38

Chiaravalloti et al30

Verbal learning and memory

Mendozzi et al39

Memory

Basso et al41

Verbal learning and memory

Chiaravalloti and DeLuca40

Verbal learning and memory

Chiaravalloti et al42

Verbal learning and memory

Allen et al24

Verbal learning and memory Verbal learning and memory Nonspecific/multiple skills Nonspecific/multiple skills

Allen et al23 Mendoza et al43 Jonsson et al25

Foley et al22 Lincoln et al44

Nonspecific/multiple skills Nonspecific/multiple skills

Types of MS Included in Study and Number of Participants

Relapsing-remitting (n⫽16), primary progressive (n⫽1), secondary progressive (n⫽5) Relapsing-remitting (n⫽5), secondary progressive (n⫽5) Relapsing-remitting (n⫽39), “relapsing progressive” (n⫽35), “chronic progressive” (n⫽3) Relapsing-remitting (n⫽107), primary progressive (n⫽19), secondary progressive (n⫽94) Relapsing-remitting (n⫽5), secondary progressive (n⫽5)

Relapsing-remitting (n⫽17), primary progressive (n⫽4), secondary progressive (n⫽7) Relapsing-remitting, secondary progressive (total n⫽60; subtype numbers not specified) Relapsing-remitting (n⫽49), primary or secondary progressive (n⫽17), “unspecified” (n⫽29) Not specified other than “clinically definite” MS (n⫽31), healthy controls (n⫽17) Relapsing-remitting (n⫽21), primary progressive (n⫽18), secondary progressive (n⫽25) Not specified other than “clinically definite” (n⫽8) Not specified (n⫽1)—case study Not specified (n⫽20) Relapsing remitting (n⫽6), primary progressive (n⫽9), secondary progressive (n⫽25) Not specified (n⫽1)—case study Not specified other than “clinically definite” (n⫽29)

Level of Evidence Classification

Technique

III

Computer-assisted program

IV

Computer-assisted program

I

Computer-assisted program

II

Calendars, notebooks, diaries, and lists

IV

I

“Metacognitive” therapy, computer-based strategy games, pen-and-paper exercises to help people understand their problems, practice strategies, and transfer abilities to everyday life Modified SMT

Ia

Computer-assisted program

II

Generation effect

II

Generation effect

II

Repetition effect

III

SMT, face-name technique

IV

SMT

I

Memory notebooks

II

Cognitive training, neuropsychotherapy

IV

Communication skills

IV

Psychoeducation, diaries, calendars, alarms, lists, notes

Abbreviation: SMT, story memory technique

(attention and memory), 1 class II study (attention, memory, and executive function), 1 class III study, and 1 class IV study. For the studies that evaluated remediation programs in multiple

domains, only the attentional component will be addressed in this section. The class I study32 in this area evaluated a computer-aided retraining program for remediation of attention and Arch Phys Med Rehabil Vol 89, April 2008

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memory in 82 participants with mixed subtypes of MS. In this study, participants met twice a week for 45-minute sessions for 8 consecutive weeks. Although a well-designed study with an active control group, there are no details regarding what specific tasks participants engaged in when using the computer remediation program. Improvement, defined as a 20% improvement in at least 2 subtests of the Brief Repeatable Battery of Neuropsychological (BRB-N) Tests was seen in 45% of the experimental group versus 43% of the control group, and the improvement was seen only on a world list generation task. As a result, the intervention was not supported as efficacious for improving attention (or memory) in MS. The class II study31 was an individualized intervention that focused on outpatients in the areas of attention, memory, and executive functioning. Two hundred forty participants with laboratory-supported, clinically probably, or clinically definite MS (further subtyping was not provided) were provided with cognitive remediation according to each participant’s specific impairments. After the assessment, detailed feedback was provided to the patients and their treatment teams, and patients were seen for up to 6 months after the neuropsychologic assessment; average number, length, or frequency of sessions are not noted. Although some detail is provided about memory strategies (detailed in the Memory section of the reviews), there was no specific information regarding the treatment administered for attentional impairments. No change in subjectively reported cognitive impairment (or mood or QOL) was seen as a result of the intervention. The final 2 studies in this area (classes III and IV) were computer-aided intervention programs performed by the same research group. The class III study21 focused on participants diagnosed with clinically definite mixed subtypes of MS who were outpatients at an MS clinic. Twenty-two patients met for twelve 40-minute sessions over 3 weeks during which they used a computer-assisted rehabilitation program that remediates 4 types of attention: selective, divided, sustained, and vigilance. The computer program was designed to include attentional demands that the researchers considered complex enough to approximate attentional situations and demands in everyday life. The researchers found support for their hypothesis that tailoring attentional training to the specific type of attention impairment results in improvements. They found significant improvement for people who received specific (vs nonspecific) training in alertness and divided attention. Participants also self-reported improvements in cognitive functioning in everyday life and QOL. Treatment effects were found to be sustained for 9 weeks. The class IV study37 consisted of participants with mixed subtypes of MS recruited through an MS clinic. Participants were included in the study if they had documented or subjective complaints of cognitive impairment. Participants engaged in six 45- to 60-minute training sessions, 4 times a week. Again, specific details about the attentional remediation components of the computer-aided programs were lacking. The researchers reported preliminary results that stated that there were qualitative improvements from the treatment group; however, no quantitative support was provided for these results. Improvements described included decreased reaction time, decreased task errors, and increased performance on the Paced Auditory Serial Addition Test, 7/24 spatial recall, and Stroop color word interference score. Recommendations. There is only 1 class III study that provides any quantitative support in this area. Overall, the evidence is limited in the area of remediation of attention for persons with MS. As such, no specific recommendations can be made at this time for specific treatments for attention in persons with MS. More research is clearly needed to support cognitive remediation for attention in persons with MS. Arch Phys Med Rehabil Vol 89, April 2008

Executive Functioning Two studies investigated the cognitive rehabilitation of executive functions. Lincoln et al31 (class II) included executive functioning as 1 of 3 domains targeted in their cognitive rehabilitation intervention (described in the Attention section above) and found no significant improvements in their study. In the class IV study,38 10 persons with mixed MS subtypes were seen for twenty-four 1-hour weekly sessions for 6 months. The intervention used computer-based strategy games and pen-andpaper exercises. Patients with relapsing-remitting MS showed a 36% improvement on a strategic application test compared with an approximately 16% improvement in persons with secondary progressive MS. Significant improvements were also reported on neuropsychologic test performance including the Rey Auditory Verbal Learning Test delayed subtest, digit symbol coding, and a fluency task. Recommendations. One class IV study provided support for remediation of impairments in the area of executive functioning. Although promising, there is not enough research evidence to recommend any specific approaches to the remediation of executive functions in persons with MS at this time. Learning and Memory The domain of learning and memory, by far, has received the most attention in cognitive rehabilitation for persons with MS, with 6 studies identified specific to these domains and 2 studies31,32 (as discussed above) that include memory as one of several cognitive domains that is targeted by their interventions. Of the 6 specific studies, one was classified as a class I study, one was classified as a class Ia study, 3 were classified as class II studies, and one was classified as a class III study. The class I study30 was a double-blinded, randomized, placebocontrolled trial of an intervention to improve learning and memory in 28 persons with mixed subtypes of MS. The intervention group was taught to use a modified “story memory technique,” which used context and imagery to improve learning and, therefore, recall. The experimental group met for 8 total sessions, 2 a week for 4 weeks, which lasted approximately 45 minutes to an hour each. The control group met with equal frequency and duration and performed traditional memory exercises in their sessions but did not receive training in context and imagery. Participants who had moderate to severe learning impairments showed a significant improvement in learning abilities (as measured on the Hopkins Verbal Learning Test⫺Revised) in the experimental group versus the control group at immediate follow-up. There was little improvement shown for participants with only mild learning impairments, which may have been a function of a ceiling effect. Self-report for memory function was significantly better for participants in the experimental versus control group as well. Long-term follow-up (ie, 5wk) showed an attenuation of treatment effects in the experimental group. Solari et al32 conducted a class I study that included memory among several cognitive skills that were focused on for intervention. Seventy-seven persons with mixed MS subtypes participated. Solari32 used a computer-aided intervention for remediation of memory and attention that consisted of 16 training sessions over 8 weeks. Improvement was defined as a 20% or more improvement in 2 or more BRB-N subtests at an 8 week follow-up compared with baseline testing. Improvement was found in 45% of the experimental group versus 43% of the control group; this difference was not statistically significant between groups. In the class Ia study,39 60 persons with clinically definite MS, of either the relapsing-remitting or secondary progressive

EVIDENCE-BASED COGNITIVE REHABILITATION IN MS, O’Brien

types, were eligible for participation. The first 30 participants were randomly assigned to treatment or control groups, and the final 30 persons were assigned to the experimental or control conditions based on age, sex, and education to stratify these variables equitably across the experimental and control groups. There were 3 groups in the study, a control group and 2 intervention groups: a nonspecific training group and a specific training group. Participants met for 15 biweekly sessions that were approximately 45 minutes in length. The intervention was a computer-assisted memory retraining program that included 12 levels of difficulty. Neuropsychologic evaluation was performed preintervention and approximately 40 days postintervention. The specific training group significantly improved (defined as 25% improvement over baseline performance) on 4 memory criterion measures, the nonspecific group improved on one, and the control group did not improve on any of the criterion measures. The researchers concluded that the specific memory training was superior to both the nonspecific training and the no-training conditions. There were 3 class II learning and memory interventions. In the first study,40 participants included 31 persons with clinically definite MS (subtypes not specified) and 17 age- and education-matched healthy controls. All participants completed preintervention neuropsychologic testing, participated in a selfgeneration protocol, and completed follow-up immediately posttesting and 1-week postintervention. In the generated condition, participants were presented sentences in which they had to generate the final word of the sentence (using cues from the sentence). In the provided (control) condition, participants were shown sentences in which the last word was underlined. After a letter-cancellation distractor task, participants were tested for recall of the words from both conditions. Both the healthy control and MS groups recalled and recognized significantly more words from the self-generated condition at the immediate and 1-week follow-up testing sessions. Basso et al41 used a similar paradigm but extended the Chiaravalloti et al30 study by including more severely cognitively impaired persons and assessing learning of information related to activities of daily living. The study consisted of 95 persons with mixed MS subtypes. Basso41 presented a paired-associate learning task of daily living information (name-faces pairs, object location, appointments) in both generated and provided conditions and tested recall for the learned information immediately and 20 minutes postintervention. Basso41 reported a significant improvement in recall for information learned in the self-generated conditions in both groups and concluded that the benefits of self-generation are clinically meaningful even in persons with MS with moderately to severely impaired learning and memory. In another class II study,42 64 participants with mixed MS subtypes and 20 healthy controls completed an Open Trial Selective Reminding Test, which consisted of a list of 10 words that participants had to learn and recall. The learning trials were continued until participants reached 100% recall on 2 consecutive trials. The results showed that persons with MS who required more trials to learn the list to the criterion level (ie, had more repetitions of the material) recalled fewer words at follow-up testing than persons who needed fewer trials to learn the list. Chiaravalloti et al42 concluded that persons with MS may not benefit from simple repetition to improve learning and memory and that impaired information processing may interfere with new learning. In addition, they asserted that the more cognitively impaired a person is, the less he/she will benefit from repetition for new learning. As noted above, there was another class II study that focused on several domains, one of which was memory. Lincoln et al31 used an intervention tailored to each participant’s impairments,

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which for memory impairment included the use of calendars, notebooks, diaries, and lists (see attention domain for further details of this study). No significant benefits were found for improvements in memory or for subjective cognitive impairment, independence, mood, or QOL. In the class III study focusing on learning and memory remediation in MS,24 8 persons with clinically definite MS participated in fifteen 30-minute sessions (2–3 times/wk). The intervention used the ridiculously imaged stories (RIS) technique (which is the original version of the method used in the Chiaravalloti study,30 otherwise know as the story memory technique) and the face-name method to improve learning and memory. The RIS technique teaches participants to use imagery to improve learning, and the face-name method teaches participants to use an association between a face and name to improve learning. There was a nonsignificant increase in the number of words recalled pretreatment versus posttreatment with the RIS; no significant difference was seen in recall after the face-name technique. However, Allen et al24 reported that MS participants performed at similar levels to healthy controls both on the cognitive tasks and the learning of the strategies included in the training. Thus, a ceiling effect likely limited their ability to find any significant effect if indeed there was one. There was 1 class IV case study design study23 that also used face-name association and the RIS technique.24 The patient was seen for 15 sessions. The participant showed improvements in the number of trials required to learn information. In addition, the person’s scores on a visual reproduction task improved from pretreatment to posttreatment, a 100% improvement was seen in the Bushke selective reminding test, a 300% improvement was seen in the recall of personally relevant words, and scores on the Wechsler Memory Scale⫺Revised learning memory I and II and the California Verbal Learning Test were seen from pretreatment to posttreatment. Recommendations. With evidence from a well-designed class I study (as well as support from a class IV study), the use of the modified story memory technique can be recommended as a practice guideline for the remediation of learning and memory in persons with MS. A future study with a larger sample may be able to support this technique as a practice standard. In addition, because the program was most successful with persons with moderate to severe impairments, persons should be screened for level of impairment before implementing this intervention. With support from 2 class II studies, including a range of mild to severe impairment, use of selfgeneration to improve learning and memory in persons with MS is recommended as a practice option. The same computerassisted intervention was used in 2 class II studies but showed improved outcomes in only one of those studies. Therefore, further research is required before this program can be recommended. Nonspecific Cognitive Rehabilitation Interventions There were 4 studies identified that addressed cognitive impairment in MS in a more general or nonspecific manner including 1 class I study,43 1 class II study,25 and 2 class IV studies.22,44 Mendoza et al43 randomly selected 20 participants with clinically definite MS (no subtypes specified) living in a skilled nursing facility who were then randomized into treatment and control groups. There was no criterion that persons demonstrate memory impairment to be included in the study. The intervention consisted of assigning certified nursing assistants (CNAs) to each participant, in-service training of the CNAs, and use of memory notebooks. Persons in the control Arch Phys Med Rehabil Vol 89, April 2008

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condition received no change in their routine care. In addition, the researchers investigated whether the specific attention given to participants by the trained staff and use of memory notebooks would increase feelings of control, which may decrease depression and, in turn, improve cognitive functioning. Although significant improvements in depression scores were seen for the experimental group from preintervention to postintervention compared with the control group, there were no significant improvements seen on any of the cognitive measures. Jonsson et al25 conducted a study with 40 persons with mixed MS subtypes and used 2 components in their intervention: (1) cognitive training, which consisted of teaching compensation, substitution, and direct training and (2) neuropsychotherapy, which consisted of individualized goaldirected treatment that aimed to help participants realize and accept their present cognitive and behavioral levels of functioning. The sessions were conducted 3 times a week for 1 to 1.5 hours each and, when possible, a close relative was involved. There were significant treatment effects seen on visual spatial memory and visuomotor speed (Trail-Making Test, Symbol Digit Modalities Test) and improvement in depression (Beck Depression Inventory) on short-term follow-up. Longterm follow-up at 6 months showed sustained improvements in visuospatial memory and depression. However, the 2 treatment groups differed at baseline on visuospatial memory and visuospatial perception. This did not seem to be controlled for in any way in the subsequent statistical analyses. One class IV study22 consisted of a case study of teaching communication skills (eg, listening, attending, understanding, assertiveness) to a person with clinically definite MS (subtype not reported). The treatment was administered in 3 phases: education, rehearsal, and application. The qualitative nature of the outcomes makes it difficult to conclude how effective this intervention may be in a broader sample of MS patients or the direct impact on cognitive functioning. In the second class IV study44 participants with clinically definite MS (subtypes not denoted) completed diaries for 3 weeks in which they reported any cognitive problems. The diaries were reviewed and strategies and/or assistive devices (eg, diaries, calendars, alarms, lists, notes) were discussed and given (with training) to participants. Psychoeducation in the form of a booklet, Managing Your Memory, was also given to participants. Treatment continued for up to 6 months. The researchers determined that 17 of 29 patients had an improvement in cognition, and more than 50% of patients reported fewer problems in their diaries postintervention. There was a reduction in the mean number of problems reported at baseline (6.4) to postintervention (2.0) for the sample. Recommendations. There are no specific recommendations to be made based on the available evidence for studies in this category. The class II study25 appears promising but lacks detail to know what the active ingredients may be that resulted in the improvements noted. In addition, differences in visuospatial memory or visuospatial perception, which were used as outcomes, were not controlled preintervention. Further research of these methodologies may prove useful for cognitive remediation in persons with MS and should be undertaken. DISCUSSION The current literature review yielded 16 studies of cognitive rehabilitation specific to persons with MS, including 4 class I studies, 5 class II studies, 2 class III studies, and 5 class IV studies. Most studies conducted to date have focused on the remediation of learning and memory, which is necessary and appropriate as these are among the most common cognitive impairments seen in persons with MS.26 The 1 practice guideArch Phys Med Rehabil Vol 89, April 2008

line that could be generated as a result of this review was in this domain. This guideline was the result of a study from Chiaravalloti et al,30 which produced class I support for the utility of a memory retraining protocol that used context and imagery. Self-generation as a technique to improve verbal learning was supported by 2 separate class II studies and was recommended as a practice option. Despite these practice recommendations, there is still a need for these promising interventions to be investigated further in larger samples. Unfortunately, in the other categories that were investigated (attention, executive functioning, nonspecific cognitive remediation), there were not enough positive results or sufficient quantity of methodologically sound studies that would support making any recommendations for cognitive rehabilitation interventions at this time. A significant omission in the work conducted in MS and cognitive rehabilitation to date is in the area of processing speed. Despite the fact that processing speed is the primary area of cognitive impairment in MS, no interventions were found that focused specifically on this area.45-48 Future studies are needed that either focus on or incorporate processing speed as an aspect of remediation. Overall, it is clear that the MS population has received relatively little attention with regard to the effective rehabilitation of cognitive impairments. When reviewing texts of health professionals such as occupational therapists49,50 and neuropsychologists,51 treatment related to cognitive symptoms of people with MS is scarcely mentioned. Thus, it appears that the current status of the research literature is a mirror of current clinical practices. This is in contrast to the substantial literature that has accumulated on the efficacy of cognitive rehabilitation after traumatic brain injury (TBI). In the most recent reviews of this literature Cicerone et al34,35 reviewed a total of 258 research studies examining cognitive rehabilitation after acquired brain injury (TBI and stroke). Although the difference in the state of affairs between MS and TBI is striking, the dramatic increase in the TBI cognitive rehabilitation literature was seen relatively recently. In 1999, a literature review of cognitive rehabilitation in TBI included only 32 studies,52 which grew to 258 articles by 2005.33 If MS researchers focus their efforts on the identification of effective treatments for cognitive impairments in MS, one could expect to witness similar dramatic advances in the field in a relatively short period of time. It is now well established that cognitive impairment in persons with MS has a deleterious impact on one’s personal, occupational, and social functioning, as well as overall QOL, even beyond that from physical disability alone.14,16,53,54 Given these devastating effects, the amelioration of cognitive deficits may improve everyday functioning in MS, thus greatly reducing the impact of the disease on the lives of people with MS and the overall cost of the disease to society at large. Therefore, efforts to improve cognitive abilities in this population may result in significant improvements in everyday functioning and overall QOL. Although one might argue that MS is a progressive disease and it therefore may not be economically prudent to treat the cognitive deficits such people experience, we would disagree. Specifically, the same argument may be made for treating the physical aspects of the disease. Physical therapy, for example, is routinely prescribed after an MS-related exacerbation, the gains of which may also be lost with disease progression. Given the impact of cognition on everyday life, the real question is, How do we deny cognitive interventions if data exist that they may be beneficial? One method that has been proposed for dealing with such a progressive decline in the aging population is the use of booster sessions after the completion of

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treatment to periodically remind patients of what they learned in therapy.55 Although booster sessions have been shown to be effective in aging populations, to our knowledge they have not yet been applied to MS. Relatedly, some have argued that the progressive nature of MS lends itself better to treatment with either restorative or domain-specific cognitive rehabilitation techniques. Restorative techniques maintain the goal of restoring or improving memory ability across different tasks, whereas domain-specific techniques teach a particular skill.51 In addition to these 2 types of techniques, the use of external memory aids is often taught to facilitate memory abilities (eg, memory books, PDAs), which may fall under either category. We believe that the type of cognitive rehabilitation prescribed for a given patient should be based more on the deficit a person is trying to treat and the result a person is trying to achieve rather than the disease that the person has. Specifically, if a person is trying to treat a relatively circumscribed deficit in verbal memory, a domainspecific intervention may be warranted. In contrast, if a person is struggling with more generalized memory deficit that affects multiple types of memory (eg, verbal and visuospatial), a more generalized or restorative approach may be needed. Although a full discussion on the most beneficial techniques for cognitive impairment is beyond the scope of this review, this review does provide essential information regarding the existing evidence for clinical implementation of particular treatments, regardless of theoretic orientation or approach.

late with actual cognitive impairment in persons with MS.56,57 People are increasingly likely to report cognitive impairment when they are also experiencing depressive symptomatology, which occurs in over half of persons with MS.56 The study by Chiaravalloti et al30 provides a particularly interesting example of the benefits of objectively measuring impairments in the area of the targeted domain of the intervention. In the Chiaravalloti study, all participants were prescreened to include only persons with documented impairments in verbal learning and memory in the intervention. A closer look at the results showed that persons with a moderate to severe impairment in verbal learning and memory gleaned the greatest benefit from the intervention. Future cognitive rehabilitation studies in MS should include objective assessment of pretreatment cognitive skill(s) to ensure that persons who have the most potential to benefit from treatment will be included and the treatment effect will be maximized. Fifth, much more detail about the interventions must be included in published studies. Although the designs of several of the studies reviewed were methodologically sound, an overall limitation of the studies was the lack of detail regarding specifics of the interventions. For many of the studies, it would be difficult or virtually impossible to replicate the interventions because of the lack of details about the administration of the treatment. To appropriately implement and adequately evaluate the interventions, researchers must provide much more detailed information for the reader.

Study Limitations Although the articles included in the current review provide a foundation for this work, they are hindered by methodologic limitations that must be addressed for research to move forward. First, the disease subtype of MS must be specifically reported and discussed in any study of cognitive rehabilitation, which was frequently not the case in the studies conducted to date. Different forms of progressive MS can lead to progressive cognitive impairments. In the most common form of MS, relapsing-remitting, cognitive impairments may appear and then remit. The degree of cognitive impairment is typically less severe in relapsing-remitting versus progressive forms of MS.8 The type, course, and time since diagnosis are thus all relevant factors for consideration of research in this area. Future studies should specify disease course and other disease-related variables and analyze how an intervention may affect these different groups. A second issue for consideration in future research is medication effects and the effect of concurrent ongoing treatment for the disease itself. Medications and other medical treatments may have a significant interaction with various cognitive interventions. This factor therefore deserves attention in future research and researchers should specify, as they are able, the medications participants are taking and examine their impact on treatment efficacy. Larger sample sizes are also recommended for future studies. In many of the current studies, smaller sample size prohibited analyses that could have examined the differential impact of interventions on important factors such as disease subtype, age, sex, and duration. Larger sample sizes will allow for greater statistical power and the ability to conduct such relevant analyses. Fourth, in many of the reviewed studies, the criteria used for participants’ inclusion were not clear. For example, inclusion criteria rarely require that participants have a cognitive impairment; when they do, it is often self-reported and not objectively measured. There is a growing body of literature showing that self-reported cognitive impairments do not significantly corre-

Recommendations for the Future of Evidence-Based Cognitive Rehabilitation in MS Review of the current MS cognitive rehabilitation literature yields several recommendations for moving this area of research forward. Future research should use empirically supported cognitive rehabilitation protocols and replicate interventions that have shown effectiveness in other populations who commonly exhibit cognitive impairments (eg, TBI, stroke). MS researchers should compare evidence-based interventions for specific cognitive impairments. For example, does self-generation, use of imagery, or repetition best improve verbal learning and memory for an MS sample? Most studies that were reviewed were designed to remediate a specific impairment. However, there is evidence that a domain-specific approach may not necessarily generalize to other functional domains.58 Therefore, research should also focus on interventions that are more functional and contextual in nature and directly address generalization during treatment. Furthermore, cognitive rehabilitation should not only focus on the impairment level but should also aim to increase participation and reduce activity limitation of the participants. Therefore, future studies should include outcome measures that assess more global functioning to determine what the generalized impact of these cognitive rehabilitation interventions may include for people’s daily lives. Last, there should be a reciprocal relationship between clinical researchers and clinical practitioners, such that each will not only inform but inspire each other by exchanging and generating treatment protocols for investigation. CONCLUSIONS Overall, evidence-based research of cognitive rehabilitation in MS is in its relative infancy. Although several well-designed studies exist and provide a foundation from which to advance the field, relatively few studies have been conducted overall. By far, the most work has been performed in the remediation of learning and memory, and it is the 1 domain in which a practice guideline could be recommended. We offer several recommenArch Phys Med Rehabil Vol 89, April 2008

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dations for future evidence-based research in this area, including (1) increased methodologic rigor; (2) objective assessment of the cognitive impairment to be remediated and documentation of current medications and other ongoing MS treatments; (3) increased sample sizes, which will lead to the ability to determine if specific interventions differentially benefit different types of MS; (4) reporting of the specific disease course and other disease-related information; (5) the reporting of significantly greater details of the methodology of the interventions;

(6) investigation of evidence-based protocols that have been successful in other clinical populations; and (7) investigation of the extent of generalization of treatment to daily life and the resultant impact of cognitive rehabilitation on daily functioning. The existing studies, taken together, hold significant promise for advances in cognitive rehabilitation for persons with MS. It is hoped that this article will generate increased enthusiasm for evidence-based research and practice of cognitive rehabilitation in persons with MS.

APPENDIX 1: DEFINITIONS OF THE 3 LEVELS OF RECOMMENDATIONS Practice Standards

Practice Guidelines

Practice Options

Based on at least 1 well-designed class I study with an adequate sample or overwhelming class II evidence that directly addresses the effectiveness of the treatment in question, providing good evidence to support a recommendation as to whether the treatment be specifically considered for persons with acquired neurocognitive impairments and disability.

Based on well-designed class II studies with adequate samples that directly address the effectiveness of the treatment in question, providing fair evidence to support a recommendation as to whether the treatment be specifically considered for persons with acquired neurocognitive impairment and disability.

Based on class II or class III studies with additional grounds to support a recommendation as to whether the treatment be specifically considered for persons with acquired neurocognitive impairments and disability but with unclear clinical certainty.

NOTE. Reprinted with permission.35

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