Cognitive Issues in Multiple Scelorsis
Jiong Shi, MD, PhD–Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona; Seema Khurana, DO–University of Miami, Miller School of Medicine, Miami, Florida
Multiple sclerosis (MS) was first described by a French neurologist Jean-Martin Charcot (1815-1893) who identified the typical symptoms of MS. In France, MS continues to be called Charcot’s disease in memory of his pioneering work. At the time Dr. Charcot gave a rather grave description of the cognitive symptoms associated with MS: â€œIn most of the patients affected by multi-locular sclerosis whom I have had occasions to observe . . . there is marked enfeeblement of the memory; conceptions are formed slowly; the intellectual and emotional faculties are blunted in their totality. The dominant feeling in the patients appears to be a sort of almost stupid indifference in reference to all things.â€ This was a remarkably accurate description of advanced cognitive impairment in MS, but did not address the impact of early symptoms. Fortunately issues relating to cognitive impairment are much better understood and managed today. This article describes the cognitive and emotional aspects of MS-related impairment that we frequently encounter in our clinical practice.
Prior to 1985, there were three common misconceptions about cognition in MS. It was believed that 1) it occurred in less than five percent of patients with MS, 2) it occurred late in the course of the disease, more than 15 years after the diagnosis, and 3) cognitive issues were related to the severity of physical illness. None of these assumptions are true. The following case, for instance, provides an example of a 44-year-old woman who had MS with cognitive problems early on in the disease course: The patient reported that she had developed headaches, dizziness, and blurry vision in 2002. These symptoms gradually worsened. A MRI consistent with MS was done in September 2004. She stated that from 2004 to 2006 she has become more forgetful, had trouble wordfinding, and has gotten lost in the middle of a conversation. She also complained of having trouble concentrating and having unexplained bouts of laughing and crying spells. She is easily frustrated and becomes irritable quickly. She feels tired throughout the day. She used to work in an insurance company and later as a financial counselor. In December 2004 she was asked to quit because of poor job performance. This year was the first time that she had to hire help to complete her tax returns. Scenarios such as the one described above are not uncommon in persons with MS. Thus, it is important to recognize that certain cognitive functions can be affected early on in the course of the disease and to learn to manage these symptoms effectively.
Prevalence of Cognitive Dysfunction in MS
Since the 1980s several studies have focused on cognitive function in MS. As seen in Table 1, cognitive dysfunction has been identified in 43% to 80% of persons with MS. A community-based study that recruited only patients with MS who did not have concerns about their memory revealed that over 40% of them had some level of cognitive impairment as measured by objective testing (Rao, Leo, Bernardin, & Unverzagt, 1991a). Cognitive dysfunction isnot uncommon in patients even in the early stages of MS (Amato, Ponziani, Siracusa, & Sorbi, 2001). The burden of cognitive dysfunction on the social and occupational life of patients, however, is under recognized because MS is widely viewed as a disease that causes primarily motor and sensory deficits. Yet, the extent of cognitive decline, more than the degree of physical impairment, has proven to be a significant and independent predictor of handicap in a patient’s work and social activity (Rao, Leo, Ellington, Nauertz, Bernardin et al., 1991b; Amato, Ponziani, Pracucci, Bracco, Siracusa et al., 1995). As the disease advances, neurological and cognitive deficits tend to converge (Amato et al., 2001). Cognitive deficits, together with neurological disability, constitute the principal determinants of a patientâ€™s handicap.
Cognitive functionality has six distinct domains:
1. Attention and orientation (one has to pay attention and be oriented to being, place, and time to form a memory)
2. Learning and memory
4. Visuo-spatial functioning (visualperceptual, visuo-spatial, and constructional abilities)
5. Intelligence and problem-solving (frontal lobe function that requires memory and ability to make sense of the context of the memory)
6. Psychopathology and personality
There are many tests that can be used to screen for cognitive dysfunctions in persons with MS. Many readers may be familiar with the Mini Mental State Examination (MMSE) which takes about ten minutes to complete. It examines the different cognitive domains and typically people with MS perform quite well in this test scoring at 90 percent level on the average. Since this screening test is not very sensitive, however, further assessment in each of the six functional domains is typically required. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) (Rao, 1990), is composed of four neuropsychological assessments covering the cognitive domains typically impaired in MS (learning and memory, processing speed/working memory, attention/concentration, visual-spatial processing, and word retrieval). The battery includes four separate tests: selective reminding test, paced auditory serial addition test (2 seconds), 7/24 spatial recall test, and a word list generation. A more recently developed test battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), has proven to be fast and easy to administer. This test battery is currently considered the most suitable for testing cognitive functions in the MS population (Benedict, Cookfair, Gavett, Gunther, Munschauer et al., 2006).
Studies have revealed certain patterns in the type of cognitive deficit observed during the course of the disease. Evidence of early deficits in verbal memory and fluency have been described, followed by a decrease in visuospatial learning, delayed recall, and later prolongation of attention and information processing speed. Memory deficits are the most susceptible to longitudinal decline (Rao et al., 1991a; Piras, Magnano, Canu, Paulus, Satta et al., 2003).
Working Memory in MS
Working memory is crucial for effective functioningâ€“â€“a simple memory by itself is not adequate. Working memory consists of a network that integrates attention, learning, memory, retrieval of memory, and manipulation of information in a timely fashion.
There are four stages to a working memory. First, we must pay attention, second, we have to learn the information to remember it, third, we must be able to retrieve the memory from storage, and fourth be able to act on it. Problems with the working memory are among the most common cognitive deficits seen in persons with MS. The current understanding is that impaired working memory is mainly due to reduced information processing speed.
Cognitive Fatigue in MS
Cognitive fatigue is comprised of decreased concentration and attention, memory impairment and difficulties in executive functions not in the context of cognitive decline (Barak & Achiron, 2006). Based on our experience, it is not uncommon for a patient with MS to say that they cannot perform the mental test being presented. This may happen not only because of their problems with memory, but because they are constantly tired. Furthermore, the tiredness may be not only physical, but also mental. We have found that under mentally challenging conditions, such as Paced Auditory Serial Addition Test (PASAT), patients with MS often show objective cognitive fatigue (defined as a greater decline in performance over time on task as compared to controls). They do much better under less challenging conditions, such as when being asked what they have done over the last day. Patients with MS do not show greater decline over time in the latter situation. In fact, under these conditions the performance of both patients with MS and controls can improve to a similar degree with practice.
Subjective cognitive fatigue is commonly cited by patients as an important reason for their premature retirement from the workforce. A recent study comparing the level of cognitive fatigue in people with MS before and after their retirement did not reveal any difference (Barak & Achiron, 2006). Nevertheless, it has been shown that during employment a person with MS will do better in a relaxed work environment with relevant accommodations (Krupp & Elkins, 2000).
Emotional Disturbance in MS
Emotional disturbances in MS include major depression, euphoria, pathological laughing/weeping, and bipolar affective disorders. It has been suggested that depression in MS could be partially linked to immune system deregulation (Mohr, Goodkin, Islar, Hauser, & Genain, 2001). Mohr and colleagues conducted a study on IFN-gamma, an important pro-inflammatory cytokine. They found that it declined when depression was treated through therapy and medications. This association is still being investigated.
Disease modifying agents (DMAs) such as Avonex®, Betaseron®, Rebif®, and Copaxone® are considered safe to use even when a patient is depressed. If a patient develops depression while on one of these medications, however, the depression should be treated. Typically it is not necessary to stop the use of DMA. Depression can worsen cognitive dysfunction and therefore is important to treat (Arnett, Higginson, Voss, Bender, Wurst et al., 1999).
Pseudobulbar Affect Disorder
The term pseudobulbar refers to signs that appear to be caused by a bulbar lesion (damage in a specific structure in the brainstem) although the lesion is actually located in the cortical or subcortical region of the brain. Laughing and crying responses are generated in the brainstem and are normally controlled by the motor cortex. The frontal and temporal lobes provide relevant cognitive or social context for behavior and emotions. The cerebellum uses this information to fine tune emotional displays, such as laughing or crying. Having a lesion in any of these areas may lead to pseudobulbar affect disorder. Clinically stated, pseudobulbar affect disorder is a disinhibition syndrome that results from a loss of cortical inhibition. Lesions throughout the cortex and subcortical areas may disrupt circuits involved in regulation of emotion.
Is there a genetic risk factor for cognitive impairment? Studies investigating cognitive deficits in MS and the relationship to genes have been lacking. There is only one published cross sectional study of 89 patients investigating the possible association of the APOE genotype with neuropsychological function in multiple sclerosis, which yielded negative results regarding the E polymorphism (Olivieri, Cittadella, Sibilia, Manna, Valentino et al., 1999). Preliminary results of our study that recruited as many as 190 patients, however, has shown a significant association between APOE 4 and cognitive deficits in learning and memory in patients with MS.
Cognitive problems can have an impact on everyday life functions in various areas, such as social and vocational activities, employment, household and family activities, driving, sexual functioning, and psychiatric disturbances. Cognitive impairment is known to be one of the most common reasons contributing to unemployment in MS. Persons with MS can be afflicted in early or productive stages of their career. Fortunately, cognitive rehabilitation can significantly improve functioning and quality of life. In our clinic we have had good results with cognitive rehabilitation. We use two separate approaches in cognitive rehabilitation: restorative and compensatory. Restorative cognitive rehabilitation focuses on improving specific cognitive functions and is used, for instance, with people who have trouble with words. Compensatory cognitive rehabilitation focuses on adaptation, such as learning to use memory aids.
The general recommendation for limiting the advancement of cognitive troubles is to treat the MS primarily with one of the disease modifying agents (DMA). Since the development of new cognitive dysfunction may signify active demyelinating disease, the first step in treatment should be to delay disease progression with a DMA (Bagert, Camplair, & Bourdette, 2002). Interferonbeta (IFN-b) has been shown to provide benefit in slowing the onset of cognitive dysfunction. (Fischer, Priore, Jacobs, Cookfair, Rudick et al., 2000; Pliskin, Hamer, Goldstein, Towle, Reder et al., 1996).
Unfortunately no pharmaceutical agent is specifically indicated for the treatment of cognitive impairment associated with MS. Yet, there are medications that are prescribed for other types of dementia: centrally acting cholinesterase inhibitors. They work by increasing the available neurotransmitter acetylcholine in the brain. Examples include donepezil, galantamine, and rivastigmine. These agents are being evaluated for efficacy in the management of cognitive decline in patients with MS (Bagert et al., 2002).
An open labeled study (where the investigators were not blinded in any way) demonstrated statistically significant functional improvement in attention, memory, and executive functioning in seventeen patients with MS. The study participants received donepezil 5 mg daily for 4 weeks followed by 10 mg daily for 8 weeks, as tolerated (Greene, Tariot, Wishart, Cox, Holt et al., 2000). Controlled studies, however, have provided conflicting information, one failing to show a treatment effect of donepezil on cognitive testing after 6 weeks of therapy. Another study showed improvement in learning and memory (by the Selective Reminding Test) in 69 patients selected for baseline memory deficit (Krupp, Christodoulou, Melville, Scherl, MacAllister et al., 2004; Christodoulou, Melville, Scherl, MacAllister, Elkins et al., 2006). It is fair to say that the jury is still out whether cholinesterase inhibitors are effective for MS-related cognitive dysfunction or not. We also don’t know who would be the best candidates to be placed on these therapies that have significant side effects. We have to wait for larger controlled studies to be certain. Other newer medications, such as memantadine, are being used in advanced Alzheimer’s disease; however there are no clinical trial results in MS.
There is currently not enough clinical trial data or safety information to support the use of complementary and alternative medicine. In a double-blind, placebo controlled, parallel group design by Johnson and colleagues, one half of the twenty-two participants with MS received 240 mg per day of gingko special extract while the other half received placebo. The gingko group improved in areas of fatigue, symptom severity and functionality (Johnson, Diamond, Rausch, Kaufman, Shiflett et al., 2006).
Other non-pharmacological interventions include working with occupational therapy (OT), speech language pathology (SLP), and neuropsychologists. The OT and SLP can perform tests to help determine where the cognitive dysfunctions lie and then provide compensatory techniques to aid the patient. Sometimes the patient needs a more detailed assessment for their job; in that case the patient can have a comprehensive neuropsychological screen done. Other lifestyle changes can also optimize cognitive function such as avoiding cigarettes, increasing the amount of restful sleep, getting regular moderate exercise, and following a balanced diet.
Summary and Conclusions
Cognitive impairment is a common problem in people with MS. It can affect various aspects of cognitive function beyond memory. Working memory is typically affected early on during the course of the disease. The neuropathological basis of cognitive impairment is the demyelinating lesion in the central nervous system, but there is also evidence suggesting an underlying neurodegenerative process. Cognitive rehabilitation has shown promising benefits for patients with MS.
Amato, M. P., Ponziani, G., Siracusa, G., & Sorbi, S. (2001). Cognitive dysfunction in early-onset multiple sclerosis: A reappraisal after 10 years. Archives of Neurology, 58,1602â€“1606.
Amato, M. P., Ponziani, G., Pracucci, G., Bracco, L., Siracusa, G., et al. (1995). Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up. Archives of Neurology, 52,168-172.
Arnett, P. A., Higginson, C. I., Voss, W. D., Bender, W. I., Wurst, J.M., et al. (1999). Depression in multiple sclerosis: relationship to working memory capacity. Neuropsychology, 13, 546â€“556.
Bagert, B., Camplair, P., & Bourdette, D. (2002). Cognitive dysfunction in Multiple Sclerosis. Natural history, pathophysiology and management. CNS Drugs, 16, 445â€“455.
Barak, Y. & Achiron, A. (2006). Cognitive Fatigue in Multiple Sclerosis: Findings from a two-wave screening project. Journal of Neurological Sciences, 245, 73-76.
Beatty, W. W., Goodkin, D. E., Monson, N., Beatty, P.A. & Hertsgaard, D. (1988). Anterograde and retrograde amnesia in patients with chronic progressive multiple sclerosis. Archives of Neurology, 45, 611-619.
Benedict, R. H., Cookfair, D., Gavett, R., Gunther, M., Munschauer, F., et al. (2006). Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). Journal of the International Neuropsychological Society, 12, 549-558.
Bensa, C., Bertogliati, C., Chanalet, S., Malandain, G., Bedoucha, P., et al. (2006). Early detection of cognitive impairment in relapsing-remitting multiple sclerosis: Functional-anatomical correlations and longitudinal follow-up. Revista de neurologia, 162(12),1221-1231.
Christodoulou, C., Melville, P., Scherl, W. F., Macallister, W. S., Elkins, L. E., et al. (2006). Effects of donepezil on memory and cognition in multiple Sclerosis. Journal of the Neurological Sciences, 245 (1-2),127-136.
Fischer, J. S., Priore, R. L., Jacobs, L. D., Cookfair, D. L., Rudick, R. A., et al. (2000). Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple sclerosis collaborative research group. Annals of Neurology, 48, 885â€“892.
Greene, Y. M., Tariot, P. N., Wishart, H., Cox, C., Holt, C. J., et al. (2000). A 12-week, open trial of donepezil hydrochloride in patients with multiple sclerosis and associated cognitive impairments. Journal of Clinical Psychopharmacology, 20, 350â€“356.
Johnson, S. K., Diamond, B.J., Rausch, S., Kaufman, M., Shiflett, S.C., et al. (2006). The effect of gingko biloba on functional measures in multiple sclerosis: A pilot randomized controlled trial. Explore, 2(1), 19-24.
Krupp, L. B., Christodoulou, C., Melville, P., Scherl, W. F., MacAllister, W. S., et al. (2004). Donepezil improved memory in multiple sclerosis in a randomized clinical trial. Neurology, 63, 1579â€“1585.
Krupp, L. B. & Elkins, L.E. (2000). Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology, 55, 934-939.
Mohr, D. C., Goodkin, D. E., Islar, J., Hauser, S.L., & Genain, C.P. (2001). Treatment of depression is associated with suppression of nonspecific and antigen-specific TH1 responses in multiple sclerosis. Archives of Neurology, 58, 1081-1086.
Oliveri, R. L., Cittadella, R., Sibilia, G., Manna, I., Valentino, P., et al. (1999). APOE and risk of cognitive impairment in multiple sclerosis. Acta Neurologica Scandinavia, 100, 290-295.
Piras, M. R., Magnano, I., Canu, E. D., Paulus, K. S., Satta, W. M., et al. (2003). Longitudinal study of cognitive dysfunction in neuroradiological, and neurophysiological findings. Journal of Neurology, Neurosurgery, and Psychiatry, 74, 878-885.
Pliskin, N. H., Hamer, D. P., Goldstein, D. S., Towle, V. L., Reder, A.T., et al. (1996). Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b. Neurology, 47, 1463â€“1468.
Rao, S. M., Leo, G. J., Bernardin, L., & Unverzaft, F. (1991a). Cognitive dysfunction in multiple sclerosis: I. Frequency, patterns, and prediction. Neurology, 41, 685â€“691.
Rao, S. M., Leo, G. J., Ellington, L., Nauertz, T., Bernardin, L., et al. (1991b). Cognitive dysfunction in multiple sclerosis: II. Impact on employment and social functioning. Neurology, 41, 692â€“696.
Rao, S.M. (1990). A manual for the brief repeatable battery of neuropsychological tests in multiple sclerosis. New York: NMSS.