Really "soft symptoms"? - Medizinonline

Cognitive impairment in MS should be taken very seriously. The everyday relevance of such symptoms is high. For example, patients’ ability to work depends crucially on their cognitive performance. Cognitive status should therefore be assessed in each newly diagnosed patient and documented over time.

Developing multiple sclerosis is a critical life event for those affected. From a psychological perspective, one observes a variety of facets to how the diagnosis is handled. Displacement, complete denial, depression, aggression, sadness, fighting are just some of the possible spontaneous reactions. Very quickly, questions arise about planning for the future in both the family and professional sense. In the end, everything is focused on the most efficient and at the same time most tolerable therapy, so that the patient can continue his or her previous life as long as possible. Their own functionality and the associated quality of life are the top priority for almost all those affected.

In today’s society, maintaining one’s functionality means more than just staying ambulatory and mobile. Mental vitality and performance represent far more weighty factors for those affected in terms of social and occupational functioning levels. Unfortunately, the latter are still dismissed by many neurological colleagues as “soft symptoms” of the disease and are far too seldom considered from the outset, also with regard to therapeutic decisions.

Cognitive disorders in MS

The prevalence of cognitive impairment in MS is reported to be approximately 50% [1,2], with more recent data suggesting closer to 40%. They are among the cardinal symptoms, along with fatigue and emotional affective changes (depression, anxiety disorders), but are referred to as “soft.” From the perspective of those affected, this assessment is flawed because cognitive function decline has far-reaching consequences. For example, it is considered certain that a restriction in cognitive performance inevitably has a negative effect on the ability to work. A recent study on this topic impressively demonstrated that work capacity is a direct function of cognitive performance [3]. This fact not only has a personal significance for those affected, but also a relevance for society that should not be underestimated from the point of view of health economics. A recently published paper estimating the cost burden of MS in Europe makes it clear that symptoms such as cognitive decline and fatigue, which are part of the disease picture from the beginning and independent of the degree of disability, are not to be considered minor, but rather weighty. They represent the very factors that have a significant impact on costs when it comes to frequent absenteeism and early retirement [4].

Facts

Cognitive dysfunction can occur at very early stages of disease and can be detected even in clinically isolated (CIS) [5,6] and radiologically isolated syndrome (RIS) [7] with sensitive testing procedures. The degree of disability does not provide a reliable indication of whether a patient has or will have cognitive problems in the future. Unfortunately, few data are currently available on the longitudinal course of cognitive impairment. However, compared to the temporal development in classical neurodegenerative diseases, these make it clear that the progression is to be classified as rather moderate. There is evidence from longitudinal and cross-sectional studies showing that the most marked progression can be expected in the first five years after diagnosis [8,9]. The “driver” here is considered to be neuroinflammation, which is clearly prominent in the early years.

Which cognitive functions are particularly affected in MS?

MS patients do not complain of global cognitive impairment, but deficits in the following core areas:

Cognitive speed (“red flag” in MS even in the earliest stages).
sustained attention, concentration
Short-term memory and learning
Multitasking.

Cognitive slowing is now considered a “red flag” in MS, as these functional impairments often become apparent early in the disease. Early objectification is important, as affected persons often come to the misconception that they primarily suffer from memory disorders and subsequently become demented. Here, a targeted screening can quickly provide clarity for affected persons, relatives, but also the treating physicians. MS patients may be at risk of becoming conspicuous in their work processes at an early stage due to cognitive slowdown, because – unlike before – they need much more time to deliver good quality.

In addition to just slowing down, there are problems with the ability to concentrate and sustained attention, as well as multitasking (cognitive flexibility). The above-mentioned cognitive domains, which experience a restriction in MS in particular, have enormous relevance to everyday life and represent a burden for those affected at any time of the disease that should not be underestimated.

Measure core deficits and document over time

Since cognitive performance is highly relevant for the patients’ occupation and everyday life, a regular assessment of the cognitive status (once a year) should take place. On the one hand, this documentation serves to make it clear to patients how their therapy affects their cognitive performance; on the other hand, it helps the treating physician to recognize if and when a patient’s cognitive status deteriorates significantly. A clear deterioration of the cognitive status should also always be a reason to critically reconsider the current therapy.

Currently, the most nationally and internationally recommended screening instrument is the BICAMS battery [10]. This screening instrument is composed of three individual tests, the SDMT (Symbol Digit Modalities Test) [11], the VLMT (Verbal Learning and Memory Test) [12], and the BVMT-R (Brief Visual Memory Test Revised) [13]. The execution time for the entire screening battery is approximately 20 minutes. If there is not enough time for this in the clinical routine, it is recommended to perform at least the SDMT regularly once a year. The test takes only 90 seconds to perform and is very informative. Especially the deficit in cognitive speed and working memory can be mapped very reliably with this method.

A screening does not replace an elaborated neuropsychological assessment, but is intended to detect a change in performance compared to the individual pretest at an early stage and to include cognition in the treatment decision process.

Therapy of cognitive disorders

The development on the part of diagnostics can be considered extremely positive, while the treatment of cognitive disorders still presents us with great challenges. Thus, the actual situation must still be rated as unsatisfactory. Effective, evidence-based symptomatic therapy does not exist, so no gold standard can be derived [14,15]. This does not mean, however, that in individual cases one does not decide to use one of the drugs in the sense of a “therapeutic trial and error”.

In the case of course-modifying immunotherapies, the situation has evolved favorably in that pharmaceutical company representatives have recognized that cognition is an important issue in MS and that it may also be advantageous for the placement of new drugs on the market to make a statement about the effect of one’s drug on cognitive performance (this would put a functional aspect in the foreground).

Overall, however, the data situation is still poor. Interferons and glatiramer acetate have been shown not to adversely affect cognitive performance – on the contrary, patients perform better cognitively on therapy compared with placebo [16–20]. Results are available on natalizumab from two studies documenting improvement in cognitive performance in cognitive domains essential for MS [21,22]. Fingolimod and dimethyl fumarate [23] have been shown to stabilize cognition. A clinically relevant improvement was recently presented for daclizumab in the DECIDE trial [24]. In direct comparison to interferon beta-1a i.m., patients clearly performed better over a 144-week period. In addition, the patients improved in the SDMT to a clinically relevant extent (with three or four points difference from baseline) after the mentioned observation period.

Among nonpharmacological interventions, moderate endurance training on a treadmill has been shown to have a positive effect on cognitive performance [25]. To the not insignificant question of how intensive endurance training should be, the results of a study give the answer that intensive, moderate and light training have an equally positive effect [26]. For the patients, this means that it is primarily important to be physically active at all, they are certainly allowed to challenge themselves physically, but the training intensity can be adapted to the respective form of the day.

In addition to exercise, cognitive training is an additional treatment measure from which patients can benefit [27,28]. Cognitive training, however, should be specifically tailored to each patient’s primary deficits and not be an all-around “a lot of training helps a lot” approach.

Take-Home Messages

Cognitive impairment is an extremely serious symptom in MS with high relevance to everyday life. Cognitive performance is critical to patients’ ability to work.
Cognitive status should be assessed in every newly diagnosed patient.
to be able to document the individual progression over time. The BICAMS battery represents the gold standard for cognitive screening in MS, both nationally and internationally.
Early immunotherapy has a positive effect on cognitive performance.
Significant cognitive deterioration may be a sign of a relapse and should always prompt reconsideration of current therapy.
Awareness of the issue on the part of treating physicians is urgently needed so that the cognitive network can be strengthened by the
use of early immunotherapies and symptomatic therapies is preserved as long as possible.

Literature:

Rao SM, et al: Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 1991; 41: 685-691.
Benedict RH, et al: Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc 2006; 12: 549-558.
Benedict RHB, et al: Benchmarks of meaningful impairment on the MSFC and BICAMS. Mult Scler 2016; 22: 1874-1882.
Kobelt G, et al: New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler 2017. DOI: 10.1177/1352458517694432. [Epub ahead of print].
Khalil M, et al: Cognitive impairment in relation to MRI metrics in patients with clinically isolated syndrome. Mult Scler 2011; 17: 173-180.
Feuillet L, et al: Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 2007; 13: 124-127.
Lebrun C, et al: Cognitive function in radiologically isolated syndrome. Mult Scler 2010; 16: 919-925.
Amato MP, et al: Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol 2001; 58: 1602-1606.
Achiron A, et al: Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study. PLoS One 2013; 8: e71058.
Langdon DW, et al: Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Mult Scler 2012; 18: 891-898.
Smith A: Symbol Digit Modalities Test. Western Psychological Services 1973.
Helmstaedter C, Lendt M, Lux S. Beltz Test GmbH, Göttingen 2001.
Benedict RH. Psychological Assessment Resources Inc, Lutz, FL 1997.
Mäurer M, et al: Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients. Mult Scler 2013 Apr; 19(5): 631-638.
Amato MP, et al. Treatment of cognitive impairment in multiple sclerosis: position paper. J Neurol 2013; 260: 1452-1468.
Fischer JS, et al: Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Ann Neurol 2000; 48: 885-892.
Penner IK, et al: Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis. Mult Scler 2012; 18: 1466-1471.
Patti F, et al: Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis. Mult Scler 2010; 16: 68-77.
Patti F, et al: Subcutaneous interferon β-1a may protect against cognitive impairment in patients with relapsing-remitting multiple sclerosis: 5-year follow-up of the COGIMUS study. PLoS One 2013; 8: e74111.
Ziemssen T, et al: A 2-year observational study of patients with relapsing-remitting multiple sclerosis converting to glatiramer acetate from other disease-modifying therapies: the COPTIMIZE trial. J Neurol 2014; 261: 2101-2111.
Wilken J, et al: Changes in Fatigue and Cognition in Patients with Relapsing Forms of Multiple Sclerosis Treated with Natalizumab: The ENER-G Study. International Journal of MS Care 2013; 15: 120-128.
Morrow SA, et al: Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks. Mult Scler 2010; 16: 1385-1392.
Forsberg L, et al: A Swedish nationwide pharmaco-epidemiological and genetic study (IMSE) of the long-term safety and efficacy of dimethyl fumarate. Poster presented at ECTRIMS 2015.
Benedict RH, et al: Improved cognitive outcomes in patients with relapsing-remitting multiple sclerosis treated with daclizumab beta: Results from the DECIDE study. Mult Scler 2017. DOI: 10.1177/1352458517707345. [Epub ahead of print].
Sandroff BM, et al: Acute effects of walking, cycling, and yoga exercise on cognition in persons with relapsing-remitting multiple sclerosis without impaired cognitive processing speed. J Clin Exp Neuropsychol 2015; 37: 209-2019.
Sandroff BM, et al: Acute effects of varying intensities of treadmill walking exercise on inhibitory control in persons with multiple sclerosis: A pilot investigation. Physiol Behav 2016; 154: 20-27.
Vogt A, et al: Working memory training in patients with multiple sclerosis – comparison of two different training schedules. Restorative Neurology and Neuroscience 2009; 27: 225-235.
Penner IK, et al: Therapy-induced plasticity of cognitive functions in MS patients: Insights from fMRI. Journal of Physiology Paris 2006; 99: 455-462.