Non‐motor symptoms in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, which is a leading cause of disability among young adults worldwide. Since the disease-modifying drug (DMD), interferon-b (IFNb), was first approved in 1993, many other DMDs, such as glatiramer acetate, fingolimod, natalizumab and dimethyl fumarate, have become available. In accordance with the development of these DMDs, the prognosis of patients has markedly improved in terms of disease severity assessed by the Expanded Disability Status Scale (EDSS). Thus, the motor disability usually assessed by the EDSS has improved, whereas issues regarding non-motor symptoms are increasingly drawing attention. Many patients with MS feel decreased quality of life and retire from employment early, even in the mild-severity disease period, as assessed by the EDSS. Fatigue, cognitive dysfunction, depression and anxiety occur in MS patients, with prevalence rates between 25% and 95%, and these so-called non-motor or non-physical symptoms are assumed to contribute to the decline in social activities and to early retirement. We have not paid enough attention to the non-motor symptoms of MS so far, because the end-points to evaluate the effects of DMDs used in the most clinical trials are frequency of relapse, magnetic resonance imaging (MRI) findings or the progression of physical severity assessed by the EDSS. In addition, it is not easy to assess non-motor symptoms in daily clinical practice, because many neurologists are not accustomed to the methods used for assessing non-motor symptoms and they also take time to carry out. Niino and Miyazaki reviewed cognitive impairment (CI), which is the most important non-motor symptom in patients with MS. They also reviewed the methods used to assess cognitive function. Information processing speed, memory, attention, executive functions and visual perceptual functions are impaired in 20–50%, 33–65%, 12–25%, 17–19% and up to 25% of MS patients, respectively. Although all clinical phenotypes of MS show CI, progressive-type MS shows a stronger deficit than relapsing–remitting MS. The batteries used for the assessment of dementia, such as the Mini-Mental State Examination, are not appropriate due to the subtle deficit in cognition among patients with MS. Niino and Miyazaki showed and compared three neuropsychological tests commonly used for MS: the Brief Repeatable Battery of Neuropsychological tests (BRB-N), Minimal Assessment of Cognitive Function in MS and Brief International Cognitive Assessment for MS. BRB-N had a sensitivity of 71% and specificity of 94% in discriminating cognitively impaired from cognitively intact patients with MS. Minimal Assessment of Cognitive Function in MS is a valid and reliable measure of CI in MS. Whereas the BRBN and Minimal Assessment of Cognitive Function in MS are well-defined tests, they are difficult to use in daily clinical practice, because they takes 45 and 90 min to carry out, respectively. Therefore, they recommended the third method, Brief International Cognitive Assessment for MS, to evaluate cognition in MS, which is composed of three modalities, Symbol Digit Modalities Test, the second edition of the California Verbal Learning Test and the Brief Visuospatial Memory Test-Revised. As this method takes only approximately 15 min, it is easier to practice. Ochi reviewed clinical trials for MS in regard to CI. He summarized recent reports about correlations between CI and brain imaging, and clinical trial data of DMDs on cognition. Regarding conventional MRI, there is a correlation between CI and overall lesion burden, as well as brain atrophy quantified by conventional MRI. Recent cross-sectional studies showed that the strength of the association between brain MRI measures and CI was relatively low in patients with low disease burden (i.e. short disease duration, young age, low physical disability, low MRI lesion load and low brain atrophy), whereas it was high in those with a high disease burden (i.e. long disease duration, old age, high physical disability, high MRI lesion load and high brain atrophy). He also mentioned the recent reports utilizing nonconventional brain imaging, such as magnetizing transfer imaging and diffusion tensor imaging. These techniques revealed lesions, and atrophy in gray matter shows a stronger correlation with cognitive decline than white matter lesion load. Furthermore, gray matter atrophy, especially in mesial temporal and thalamic atrophy, is the most frequent structure associated with CI. Regarding clinical trials, outcome