Patient Description
Ms. C, a 48-year-old, right-handed white woman, was diagnosed with multiple sclerosis (MS) at age 43, although she recalls right numbness at age 13, with recurrence at age 16. At age 21, she experienced tingling on her right side and has had recurring transient sensory abnormalities since then. At age 43, when she experienced episodes of imbalance, memory deficits, word-finding difficulties, slurred speech, and difficulty concentrating, she underwent neurologic evaluation and testing, which led to the diagnosis.

She worked as an occupational therapist until 2 years ago when she was asked to leave. She believes this was because her performance suffered due to MS. Currently, she does light office work—answering phones 4 days per week for 4 hours per day—which she calls "no-brain work." In addition, she performs household duties, such as laundry and cleaning, exercises when she can, and tries to remain active, although sometimes she stays home instead of going to social functions because she does not like to be dependent on others for mobility. She has recently stopped driving because she does not trust herself "to press the brakes when I need to press the brakes." Although she has many friends who offer to drive her places, she is reticent to accept help from anyone. She laments her use of a walker and reports that she spends much of her time ruminating over whether her symptoms are "real, or in my head." She has three grown children, and grandchildren. She lives with her husband of 28 years.

Upon presentation to her neurologist, Ms C. was neatly dressed and appeared her stated age. She was ambulatory with the assistance of a cane. She reported being frequently tired, and sleeps approximately 6 hours per night. Her medical history was also significant for surgery for each of three childbirths. She denied any use of recreational drugs or alcohol. She has one brother with MS; five brothers and two sisters are healthy.

The neurologist conducted cognitive screening using the Symbol Digit Modalities Test (SDMT). The patient's score was 28 (0.1 percentile).

Ms. C was referred to a neuropsychologist and was seen as an outpatient for a comprehensive neuropsychologic evaluation.

Clinical Decision Point 1: Making a Neuropsychologic Referral

Question 1: Which of the following is the most significant factor on which to base this patient's referral for neuropsychologic evaluation?

1. The patient's self-report of problems with cognition and everyday life functional activity
2. The SDMT result
3. Driving difficulties described by the patient
4. None of the above; referral for full neuropsychologic evaluation should be based on results of the Paced Auditory Serial Addition Test (PASAT)

Discussion
(b) No single test can screen for the vast array of cognitive problems that can be observed in humans. In the MS literature, however, there is consistent and substantive evidence suggesting that impaired processing speed is the primary cognitive deficit in MS,¹ and that the SDMT is an excellent screening test to identify this deficit.² Thus, the SDMT can be used in clinical practice to identify patients with MS and a processing speed deficit for whom a full neuropsychologic evaluation is indicated.

A full neuropsychologic evaluation comprises a battery of comprehensive tests that assess a patient's strengths and weaknesses in multiple cognitive domains.³ Because a full evaluation is expensive and should be done by a specialist, typically a neuropsychologist, it is neither practical nor necessary for all patients with MS to be referred for such an evaluation. An objective screening measure is a tool that the practicing neurologist can use to identify which patients should be referred. Currently, two tests of processing speed have been suggested for use as in-office screening tests—the PASAT and SDMT (Table 1).⁴

Table 1. Screening Test Descriptions⁴

The cognitive component of the Multiple Sclerosis Functional Composite (MSFC) battery, the PASAT is widely used in clinical practice.⁵ The test evaluates both processing speed and working memory and has been shown to be sensitive to early cognitive impairment in patients with MS.⁶ The utility of the test is limited, however, by several factors. First, the test requires that the patient perform mathematical calculations, which creates anxiety in patients as well as in healthy volunteers, thereby confounding test findings.⁶ Second, practice effect—meaning that a patient's improvement in test performance may be attributed to either cognitive improvement or the fact that the patient is simply better at taking the test due to repeated practice-is common, whether due to the fact that many patients have taken the test numerous times or the nature of the test.^3,4 Finally, the test is not specific for processing speed impairment, but also evaluates working memory.³

The SDMT is easier for the patient and quicker to administer compared with the PASAT, and it requires no mathematical calculations by the patient.⁶ Importantly, compared with the PASAT, the SDMT is more sensitive to MS-related cognitive impairments,⁷ and is a better measure of processing speed because it makes fewer demands on working memory.^3,6 Use of the SDMT as a screen for cognitive impairment has been supported by a validation study that showed the test had a sensitivity of 82%, specificity of 60%, positive predictive value of 71%, and negative predictive value of 73% when correlated with the Minimal Assessment of Cognitive Function in MS (MACFIMS).² Furthermore, a longitudinal study that monitored changes in cognitive function in patients with early relapsing-remitting MS found that the SDMT was the most sensitive test to detect cognitive decline over a 3-year period.⁸ The better predictive value and greater ease in administration suggest that the SDMT could replace the PASAT in the MSFC, and this was confirmed with data from a study enrolling 400 patients with MS.⁴ Even with retesting over five monthly assessments, the SDMT showed minimal practice effect, with larger effects with the PASAT.⁴ Other advantages of the SDMT include the ability to predict impairment even in early stages of MS,⁹ and correlation with markers of MS-related brain injury.¹⁰ It is important to note, however, that the SDMT may be confounded by the presence of visual disturbances.^3,6

A recent study used functional magnetic resonance imaging (fMRI) to compare the brain networks activated by the PASAT and SDMT, with the hypothesis that the more complex PASAT would activate greater involvement of regions associated with executive function and emotional stress.⁶ The study enrolled 17 healthy right-handed volunteers and evaluated each with versions of the PASAT and SDMT adapted for use with fMRI. Both tests activated the frontal and parietal regions with a clear left-handed predominance, regions anatomically related to attention and working memory functions. (In contrast to these functions, processing speed has no direct anatomic counterpart, but rather is a function of axonal projections that connect brain regions. The PASAT activated more frontal regions compared with the SDMT, including regions associated with the execution of difficult tasks of working memory, maintenance of verbal information, attention, and error detection. As a whole, these findings confirm that the PASAT reflects executive function and working memory more than the SDMT, while the SDMT is more specific to processing speed.

In the absence of an abnormal SDMT result, this patient's self-report alone may or may not be a sufficient basis on which to base the referral. Self-report has not been shown to correlate with everyday life functional activity or cognitive performance, but rather with emotional distress.¹¹ Continued suspicion of cognitive impairment by the patient, an informant or caregiver, or the clinician, even in the absence of a corroborating SDMT result, however, suggests that the patient should be referred for a full neuropsychologic evaluation.

Audio Commentary by J. DeLuca, PhD

Case Continues

Throughout the interview and evaluation, her eye contact was appropriate, and attention and concentration appeared broadly intact. Her speech was slightly pressured, but normal for volume and prosody. While her speech content was mildly tangential, comprehension for task instructions was intact. Her affect was constricted, and mood was stable. Her responses on a self-report questionnaire measuring recent mood indicated moderate symptoms of depression. Overall, she was friendly and cooperative throughout the process, and rapport was easily established and maintained. The results reported in Table 2, therefore, were believed to be a valid estimate of her functioning.

Table 2. Neuropsychologic Evaluation Results

Audio Commentary by J. DeLuca, PhD

Clinical Decision Point 2: Interpreting Neuropsychologic Tests

Question 2: Does the patient suffer from cognitive impairment? If so, what impairments does she display?

1. No; her performance can be explained by her mood
2. Yes; processing speed, learning, memory, language, and executive function
3. Yes; processing speed, learning, and memory, suggestive primarily of temporal lobe involvement
4. Yes; processing speed, which can explain her deficits in all areas of higher cognitive processes

Discussion
(b) Although processing speed deficits are the most common cognitive deficits in patients with MS, this patient's test results identify other areas of cognitive impairment in addition to processing speed. Within the context of an average intelligence, as determined by the WRAT4, the patient clearly exhibited difficulties in processing speed (eg, the SDMT), learning and memory (eg, the CVLT-11 and BVMT-R), language (eg, the Boston Naming Test), and evidence of executive dysfunction (eg, intrusions, perseverations, and false-positive errors, and performance on the Hooper Visual Organization Test). There is no evidence to suggest that a deficit in processing speed alone can account for the higher-level cognitive dysfunction, such as language deficits or observations of qualitative errors during learning, nor is there evidence to suggest that mood impairment alone could account for these areas of cognitive function.

The results of the neuropsychologic evaluation revealed an individual with estimated premorbid functioning in the average range, intact receptive language functions, and intact learning and recall of contextualized verbal material. There was evidence of difficulty on some tasks of basic attention/working memory, but better performance in the context of tasks requiring complex attention and cognitive flexibility. Performance on processing speed tasks was significantly below expectations, however. Difficulties were seen on a word list learning memory task, in which responses were significant for a high number of intrusive responses, many false-positive errors, and a high number of repetitions. This responding style may be reflective of executive/frontal dysfunction, suggesting problems in discriminability and inhibition of response.

The patient's impaired performance on a task measuring memory for nonverbal material was evidence of temporal involvement, as was a striking anomia, for which the patient had adopted the compensatory styles of circumlocutory speech and semantic paraphasias. There was also some evidence of visuospatial difficulties, although such difficulties may be reflective of executive dysfunction (eg, organization of visual material). Finally, her overall profile of mood disturbances on a self-report inventory of depressive symptoms suggested moderate mood disturbance.

Audio Commentary by J. DeLuca, PhD

Case Continues

Findings of the neuropsychologic evaluation were discussed with the patient, including evidence of significant difficulties in the areas of basic attention/working memory and processing speed; expressive language difficulties; memory issues, including difficulties with learning, recall, and recognition of both verbal and nonverbal material; executive dysfunction; and self-reported mood issues. Her cognitive profile is consistent with an individual whose MS has progressed to a point at which it is affecting a number of domains of functioning, including her vocational function, and this is likely causing her to perceive difficulty in doing many things she has always done. These findings support the patient's recent decisions to stop driving, to take a less demanding work position, and to start using a walker more frequently. She expressed some relief at knowing that the symptoms she had been experiencing were indeed disease-related and "not just in her head."

Audio Commentary by J. DeLuca, PhD

Clinical Decision Point 3: Managing Cognitive Impairments

Question 3: What should the patient be told about management options?

1. No proven therapies are available for her present cognitive condition
2. A number of therapies with proven efficacy are available
3. Improvement in symptoms and quality of life can be achieved with a combination of approaches

Discussion
(c) Potential management strategies for MS-related cognitive impairment include pharmacologic approaches, such as disease-modifying therapy, acetylcholinesterase inhibitors, and l-amphetamine; behavioral therapies, such as cognitive rehabilitation and speech or occupational therapy; and supportive psychotherapy. The data for all these options, however are insufficient on which to base any claim of proven efficacy, and more research is needed. Nevertheless, existing data do suggest that one or more of these options may be worth trying and can offer improvement in symptoms and quality of life.

Although the research on the effectiveness of cognitive rehabilitation in MS is in its infancy, there are some data to support a referral for such therapy. An expert review panel conducted a meta-analysis to evaluate the status of research on cognitive rehabilitation in MS and to recommend practice guidelines.¹² Noninterventional and non-peer-reviewed studies, as well as review or theoretical articles, case reports without empirical data, were excluded from the analysis. From an initial list of 224 citations, 16 studies met the inclusion criteria, and most of these focused on learning and memory deficits. Unfortunately, no studies of cognitive rehabilitation in the area of processing speed had been done as of the time of this analysis.

The expert review panel recommended one practice guideline based on a 2005 randomized trial that provided data to support a memory retraining protocol.^12,13 The trial enrolled 29 subjects with MS-related learning deficits and randomized them to either the control group (n = 14) or the experimental group (n = 15).¹³ Both groups participated in 8 "treatment" sessions, which consisted of nontraining memory tasks for the control group and the Story Memory Technique (SMT), which taught the skills of visualization and context to improve learning, for the experimental group.¹³ In subjects with moderately severe impairment, 88% in the experimental group showed significant improvement in learning abilities compared with 38% in the control group (P <.01).¹³ Subjects with mild impairment showed little improvement.¹³ On this basis, the technique used in this study was recommended by the review panel as a practice guideline for the rehabilitation of learning and memory in persons with MS.¹²

The panel also recommended self-generation to improve verbal learning as a practice option based on two studies.^12,14,15 Self-generation as a technique is founded on the concept that an individual better remembers items he or she generated compared with items he or she only read about.¹⁴

Certainly, the evidence of benefits from cognitive rehabilitation in the allied field of traumatic brain injury also supports such a referral.¹⁶ The number of studies of cognitive rehabilitation in the setting of traumatic brain injury rose eight-fold, from 32 to 258, between 1999 and 2005.¹² A similar push in parallel research in the setting of MS is needed, including research in larger populations than were represented in the 16-study meta-analysis and in the area of processing speed.

Data are mixed on pharmacologic approaches to the treatment of cognitive impairment in MS. Of the disease-modifying therapies, only interferon beta-1a has shown positive data, with significant improvement in processing and learning/memory in a subset of patients who participated in the phase III trial,¹⁷ but this finding has yet to be replicated. Initial data on donepezil showed improvement in memory,¹⁸ but this finding was not supported by a more recent and larger trial that showed no effect.¹⁹ l-amphetamine has shown promising data in two trials, although one trial lacked a placebo control²⁰ and the other, a larger randomized controlled trial, reported positive findings on a secondary, rather than primary, outcome measure. These findings need to be replicated.²¹ For all pharmacologic approaches, further randomized placebo-controlled trials are needed.

Audio Commentary by J. DeLuca, PhD

Case Continues

The patient is in the process of seeking supportive psychotherapy from an individual with whom she can develop a good rapport. This will be a critical step for her to take in fully understanding and accepting the changes that she is currently experiencing. Family therapy may be another avenue for her to explore. She is not, however, participating in cognitive rehabilitation.

Audio Commentary by J. DeLuca, PhD

Conclusion

Cognitive impairment in MS is one of the most significant symptoms of MS and must be assessed in practice and clinics for persons with MS. Simple and proven cognitive screening with the SDMT can be used effectively to help make a determination of whether a referral for a neuropsychologic evaluation is warranted.

Despite the lack of research on the benefits of behavioral or pharmacologic interventions for cognitive impairment in persons with MS, there is considerable allied support for the effectiveness of cognitive rehabilitation for persons with MS with cognitive impairment and pharmacologic research is ongoing. With cognitive rehabilitation, supportive psychotherapy, and referral to an appropriately trained and experienced clinician, the person with MS can show considerable improvement in symptoms and quality of life.

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