Multiple Sclerosis and Mild Cognitive Impairment

Multiple Sclerosis and Mild Cognitive Impairment What are the cognitive impairments in MS and why are the terms dementia and Mild Cognitive Impairment (MCI) rarely used?

By Ronald Devere, MD

ognitive impairment (CI) in Multiple Sclerosis quently used office cognitive testing assessment, (MS) has been recognized for over 130 years was mainly designed as a cognitive screen in the since described by Charcot in the late nine- elderly and is being used regularly in the MS pop- Cteenth century.1 He used the terms “weaken- ulation. This test has been found to be very insen- ing of memory, slow conceptual thoughts and a sitive in detecting CI in MS and has been shown to blunted affect and intellectual life” in his 1877 lec- miss severe neuropsychological proven CI in 20 tures.1 The last 70 years have seen numerous percent of cases.11 papers published on this topic, partly due to • Patients with MS who are complaining of cog- improved neuropsychological testing, which is nitive difficulties or are recognized by family and essential in evaluating CI.2-4 friends to have CI (memory loss, slow comprehen- Some degree of CI is common in MS. Using sion, and personality change), should undergo neuropsychological testing it affects upward of 45 thorough neuropsychological evaluation to deter- percent of community dwelling populations.4,5 Self- mine cognitive limitations, functional capacity, and reported CI has been noted, not surprisingly, to be emotional status. higher in up to 58 percent of the MS population in • Duration of MS is generally considered a poor recent studies in Australia.7,8 Summarizing the cur- indicator of the presence of cognitive impairment. rent status of cognitive impairment in MS is as fol- • Severity of CI does not usually correlate with lows: severity of MS. CI can be a significant symptom in • Cognitive impairment is relatively mild on up to 50 percent of recently diagnosed MS and has neuropsychological testing in most people with been well described in the clinically isolated syn- MS.9,10 drome12,13 or initial presentation of disease.14,15 • The most common cognitive impairments • Cognitive impairment does not correlate over- involve complex attention, speed of processing all with physical impairment in this disease.4,16 information, short-term memory loss, complex • Cognitive impairment has not shown a consis- visual-spatial processing, abstract reasoning, and tent correlation with white matter burden on problem solving.9,10 MRI.5 However, this is changing because new MRI • Basic attention, routine social skills and gener- techniques can show cortical gray matter lesions al language skills, except mild word finding, are not seen on routine MRI. Massimiliano et al. usually normal or mildly involved, even if other showed that cortical lesions on MRI obtained on areas of cognition are more impaired. As a result double inversion recovery sequences and cortical of spared routine social and language skills, more atrophy strongly correlated with CI.6 Future stud- cognitive impaired individuals can go undetected ies looking at cerebral cortical MS lesions may during brief or superficial social interactions.9,10 well change some of the current cognitive informa- • Mini-mental testing (MMSE), the most fre- tion in this disease.

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• Secondary progressive MS is an indicator of impairment. This point was stressed in past stud- greater likelihood of CI. Chelune et al.17 found that ies as well.25,29,30 CI is seven times more likely in secondary progressive MS than in relapsing and remitting. Pharmacological Treatment of Once CI becomes clinically apparent, it tends not Cognitive Impairment in MS to remit. The only exception is when it occurs solely Is there any evidence that specific medication is as a temporary symptom during an exacerbation. effective in cognitive impairment in MS? Greene et This form is usually sudden in onset, coinciding al.31 studied Donepezil (Aricept) 10mg over a 12 with the onset of neurological physical symptoms week study in 17 MS cases. It showed statistically and remits when the exacerbation is over.18 significant improvement in attention, memory, and Most studies have suggested a relative stability executive function. Another double blind placebo of cognitive impairment for up to four years.19 randomized control study,32 studied Donepezil Pirasm et al.,20 in a small sample of MS patients, (Aricept) for 24 weeks in 69 patients. There was showed that cognitive deterioration over an eight significant improvement in memory, although the year period was limited to impaired long term patients were only mildly impaired. One double memory and general intellectual function in fifty blind random placebo controlled study33 looked at eight percent with relapsing, remitting MS. Other Rivistigmine (Exelon) for 12 weeks in 60 cases and areas of cognitive function were very stable. Other showed slight but significant improvement in studies have suggested a more predictable very memory in both patients and placebo group. The slow decline, especially those with a progressive conclusion at this time is that the findings suggest form of MS.20 Overall, there is difficulty predicting some possible benefit of Donepezil, less so change in a specific individual over time. Amato et Rivistigmine, in MS cognitive impairment. More al5 concluded that cognitive deterioration in MS long-term studies of these and other medications occurs much more slowly and less consistent than (galantamine, memantine) are needed. in Alzheimer’s disease. This is an important point There are a couple of points to consider regard- because cognitively impaired MS patients are like- ing the above studies. Unlike Alzheimer’s disease, ly to be stable enough or so slowly progress, that there has been no solid pathological evidence that they have been shown to benefit significantly from there is a deficiency of Acetylcholine in MS cogni- cognitive rehabilitation.22-24 tive impairment. It has only been presumed based Now that I have given some of the more impor- on the widespread demyelinating and axonal tant information on MS cognitive impairment, changes in MS plaques. This is not necessarily a another important question is: How does CI really reason not to try these medications in MS. affect the quality of life (QOL) in MS patients? Secondly, the patients enrolled in many of the Most studies have been contradictory.25,26 One above trials were not characterized as dementia or recent study by Glanz et al.27 using a standard cog- MCI and very little activities of daily living infor- nitive evaluation and a self reported QOL ques- mation were presented. This made it very difficult tionnaire in early MS, with depression controlled, to decide what type of cognitive impaired patients found that QOL was weak or negligibly related to were evaluated. In addition the trials were very cognitive function. A more recent study by Baum- short, lasting 12 to 24 weeks. We know from stark et al.28 including all MS subtypes found the amnestic MCI studies, which were over a three- same conclusion. These studies stated that the key year period, that possibly only Aricept might be of point in evaluating cognitive impairment and QOL one to two year(s) benefit in delaying the develop- in MS is recognizing that fatigue and depression ment of AD. We also know from many studies that need to be controlled, because they are independ- the cholinesterase and glutamate inhibitors have a ent predictors of QOL, regardless of the cognitive modest effect on all stages of Alzheimer’s disease.

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Since the conclusion of all the MS studies have B. These deficits cause significant impairment in shown minimal or no benefit of these agents in social or occupational function and represent a sig- cognitive impairment, these studies should be nificant deterioration from the premorbid state repeated with longer durations when proper cogni- C. Deficits are due to direct physiological conse- tive classification is done. quences of a general medical condition (such as MS) Dementia in MS D. Impairments do not occur as a result of delir- Although the majority of patients with MS have ium. mild cognitive changes, many develop more severe changes, as previously mentioned and warrant the It is important to note that the term progressive use of the term “dementia.” Estimates of the rate decline is not mentioned, since many of us know of more severe cognitive impairment varies that most of the degenerative disorders like between five percent and 30 percent.9,34,35 However, Alzheimer’s disease, frontal dementia, Parkinson’s reviewing the titles and contents of many pub- and Lewy body dementia are progressive, unlike lished articles on cognitive impairment in MS, it is many MS moderate to severe cognitive impaired surprising that the term “dementia” was rarely cases, which can remain stable for many years used and the concept of Mild Cognitive despite no specific cognitive treatments. MS cogni- Impairment (MCI), which has become increasing tive impairment rarely develop major language popular over the last 15 years, is non-existent. A impairment or impaired basic orientation. One search for dementia in MS specifically yields a few study4 found that MS dementia acted similar to a articles. In one36 publication, the author states: subcortical dementia like Parkinson’s or “Determining a precise rate of occurrence of Huntington’s disease, which includes personality dementia in MS via review of the scientific litera- change, mood disturbances, slow thinking, ture is difficult, as the term, ‘dementia’ and ‘cogni- decreased attention, problem solving and problems tive impairment’ are used interchangeably. Also with memory retrieval. This was also echoed by other loosely defined terms such as ‘global’ impair- others.37 Others have stated that MS dementia is a ment or ‘severe’ cognitive impairment are fre- form of frontal dementia.38 One article published quently used.” in 2005,39 reported that nursing home residents The definition of dementia is currently undergo- with MS and dementia are usually admitted at an ing changes because the old definition, published older age (10 years) than the non-demented MS in DSM IV 1994, has become outdated in relation- patients and are less likely to have physical impair- ship to the increased information acquired about ments but much more likely to have mood and cognitive disorders and introduction of the term behavioral problems. They suggested these cases MCI in the last ten years. The Alzheimer’s may represent a “cortical variant” of MS character- Association in 2010 proposed new updated criteria ized by progressive dementia and emotional diffi- for Alzheimer Dementia and its relationship to culties with late onset of other neurological MCI. These criteria have recently been adopted impairments leading to physical disability. Based after a year review by several research groups and on the excellent review by Longley36 and this liter- should be incorporated in the revised DSM criteria ature review, there are some possible reasons for for dementia. The old DSM-IV criteria for demen- the very infrequent use of the terms “dementia” tia due to other medical conditions are: and “MCI” in cognitive impaired MS patients. A. Development of multiple cognitive deficits: • The term dementia in our society carries a ter- a. Memory impairment rible stigma of a progressive untreated cognitive b. One or more of the following: aphasia, deterioration, with strange and disturbing behav- apraxia, agnosia, impaired executive function ior, ending up in a nursing home to die. This term

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has in general been used to apply to the older pop- speech/language, personality or visual perception) ulation and has led to very negative reactions in are acceptable under the category as long as they families and patients, because MS occurs in a meet the strict definition of minimal-to-no-impair- much younger population and many who are more ment of activities of daily living. Amnestic MCI cognitively impaired usually articulate well and has been shown to progress to AD in 75 percent of are capable of light social interaction. cases over a five-year period. Non-amnestic MCI • Patients with MS are usually in the early years has been shown to develop into AD in 55 percent, of their careers, looking after young children and but other disorders like Parkinson’s, Lewy body, trying to work or run a household. With the help frontal and multi-infarct dementia can develop in of their physician, they are also trying to manage a others. Some cases remain the same, never progressive or fluctuating degree of physical progress or rarely improve. In 2004, a study41 impairment. The sense of hope in the face of this divided amnestic and non-amnestic MCI into sin- unpredictable neurological disorder is very strong, gle or multiple domain. This was done, so all not supported by the perceived term, dementia. aspects of cognitive function were included (mem- • The management and treatment of MS ory, executive function, speech, language, personal- patients in the past 15 years has become very com- ity, and visual perception. This classification recog- plicated and requires expert knowledge of the dis- nized that individuals with MCI may have more ease and its management. Numerous more poten- than one category of cognitive impairment, with tially toxic medications with significant side effects no effect on ADLs and so they did not meet the are becoming more available. I am not sure how criteria for a diagnosis of dementia. This informa- many general neurologists are treating these com- tion was important to document because multiple plicated patients, but more and more “experts” in domain cognitive impairment was at times more clinical and research MS are available in private likely to progress to dementia in a shorter time and university related practices. period. In my experience the majority of MS patients • The dementia and MCI terminology have been with cognitive disorders, regardless of severity, are very helpful in interpreting cognitive dysfunction, regularly followed and treated by MS specialists ADLs and quality of life, not only for research pur- and many general neurologists. The MS specialists poses but to counsel and educate patients and fam- are doing a lot of the clinical research and publish- ily about the disorder, in decisions on appointing a ing many of the scientific papers. Their overall Durable Power of Attorney (DPOA), and making experience in using the terms MCI and dementia competent financial and estate decisions. in their specialty practice may be limited. The cog- Suggestions and advantages in incorporating cogni- nitive testing in many published articles and in tive abnormalities in MS into the mainstream of ter- everyday practice of MS patients may or may not minology used in other causes of cognitive impair- be done by neuropsychologists who are experts in ment: the terminology of dementia and MCI. • Update clinical and research MS specialists • The term MCI has been recognized for over 10 and general neurologists in the terminology of years.40 It has been predominantly used in the neu- dementia and MCI as it relates to MS and other rodegenerative pre-dementia arena, but the term is causes of cognitive disorders especially also being used in non-degenerative disorders like Alzheimer’s, Parkinson’s, and frontal dementia and multiple strokes.41 MCI is defined as a cognitive how they differ from MS dementia. This can be disorder with little or no impairment of activities done in the various general and MS specialty jour- of daily living, and stands between normal cogni- nals or symposia on MS with assistance from tive function and dementia. Any one or more areas members of the Cognitive and Behavioral section of (impaired memory, executive function, of the AAN. If not already done, reviews by the

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legal system should be included in the same ven- • Careful, discrete, and appropriate use of the ues to discuss DPOA for health and estate deci- term dementia has been shown to be at times posi- sions and legal guardianship and how it relates to tive. This term stresses the severity of an individ- cognitive impairment in the younger MS popula- ual’s cognitive impairment. It can reduce the risk tion. that the person’s cognitive impairment may be dis- • Since neuropsychological testing is so impor- missed because of their good initial presentation or tant in the diagnosis of cognitive dysfunction in because of their young age group. MS, it is very important that the neuropsycholo- • The proper use of the dementia term, where gist, who is well trained in this terminology, be appropriate, can help the person obtain retirement reminded that they should use this terminology in benefits, a disability insurance claim, or help col- their summary and final opinion in their reports lect long-term care insurance if previously pur- and help in education. chased. • It is also important that physical impairment not be included in impaired ADLs as it relates to Summary and Conclusion cognitive impairment. Including physical impair- The clinical knowledge relating to diagnosis and ment could under or over diagnose the cognitive treatment of MS has mushroomed in the last 15 effects on ADLs. For example, impaired memory in years. Cognitive impairment in MS has been well the presence of weak and numb arms could mis- studied for many years and is briefly summarized takenly be represented as inability to do finances in this review. Neurology still has a long way to go and reconcile a check book for cognitive reasons. in pharmacological treatment to improve or arrest Memory impairment alone does not usually affect CI in MS. It is time to put cognitive abnormalities important financial and estate decisions, appoint- recognized in MS into a more common, defined ing a DPOA, and only mild cognitive supervision is classified terminology, such as dementia and MCI, normally necessary. MS patients, who meet the instead of the general non-specific terms of “cogni- cognitive and ADL criteria for dementia, will like- tive impairment or global cognitive deterioration,” ly require full time care and supervision and be so we can all better understand our patients’ cog- unable to make decisions in their best interest nitive impairment and capabilities as they relate to regardless of the status of physical impairment. ADLs and make efforts to separate this from physi- • Thorough education is necessary to patients, cal disability. families, other caregivers and MS societies, so they The regular use of this terminology will require fully understand the terms dementia and MCI as it further education of patients, caregivers, MS soci- relates to MS. Attempts should also be made to eties, clinical and research MS specialists and non erase some of the negative stigma or misunder- specialists who continue to treat this disorder. This standing of the term dementia. Longley36 stated a information should be stressed in neurology resi- useful layman’s definition of dementia for use dency training. It will require sensitivity and dis- with individuals with MS: “It is a broad term to pelling myths that are associated with these terms, describe the loss of memory, thinking, some social especially dementia. ■ skills and usually normal emotional reaction. It would also be very helpful to stress the significant Ronald Devere MD, FAAN, is Director of the Alzheimer’s difference in clinical presentation and progression Disease and Memory Disorders Center in Austin, TX. over time, between MS dementia and Alzheimer’s dementia.”36 The legal system should provide edu- 1. Charcot, J. M., “Lectures On The Diseases Of The Nervous System”, London: cation to MS physicians, caregivers, patients and New Sydenham Society, 1877. MS societies as relates to DPOA and legal 2. Jambor, K. L., “Cognitive Functioning In Multiple Sclerosis”, British Journal of Psychiatry, 1969, Vol. 115, pp. 765-775. guardianship. 3. Rao, S. M., “Neuropsychology Of Multiple Sclerosis: A Critical Review”,

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