Clinical predictors to cognitive impairment in multiple sclerosis patients

Cognitive dysfunction is increasingly recognized in multiple sclerosis, even in the early phase of the disease. Multiple sclerosis patients with even mild cognitive deficits may experience greater difficulties in social contact and daily activities, irrespective of physical handicap. This study aimed to estimate clinical predictors of cognitive dysfunction in a sample of Egyptian people with MS. Significant worse performance in assessed cognitive scales was observed in people with MS as compared to controls. This was related to low educational level, long disease duration, initial cerebellar and motor attacks, progressive course, frequent relapses, and immunosuppressive medications. Cognitive assessment scales were significantly negatively correlated with disability measured by Expanded Disability Status Scale (EDSS) scores. Predictors of cognitive impairment in people with MS were low educational level, longer disease duration, type of initial attack, frequent relapses, progressive form, higher clinical disability, and immunosuppressive treatment.


Introduction
Cognitive dysfunction is reported in 45 to 70% of people with multiple sclerosis (MS) [1]. Attention, recent memory, verbal fluency, and informationprocessing speed are the frequently impaired cognitive domains. Executive dysfunction is less frequently reported [2]. MS-related cognitive decline may be related to MS subtype, disease duration, gender, race, and cognitive reserve [3]. People with progressive MS have more frequent and severe cognitive dysfunction than relapsing MS. Moreover, people with MS who have high levels of cognitive reserve are unlikely to practice cognitive dysfunction [4,5].
Previous studies have discussed that immunomodulatory drugs have a beneficial effect on MS cognitive functions. These drugs may decrease the progression of brain atrophy [6].
This study was designed to investigate clinical parameters that may contribute to cognitive impairment in people with MS.

Methods
This is a case control study done on forty-five people with MS and forty-five healthy subjects matched for age, sex, and educational level. Patients were recruited from the Neurology Department and an outpatient clinic. An informed consent was obtained from all participants prior to inclusion in the study. The study was approved by the ethical committee of the Neurology Department (blinded for peer review).
This study included clinically definite MS patients according to the revised McDonald criteria 2017 [7]. Their age ranged from 20 to 45 years, educated with at least primary level of education to be operative in performing the cognitive scales with Mini Mental State Examination (MMSE) score ≥ 26 and Hamilton depression scale score (HDS) ≤ 6. Control subjects were selected to be age, sex, and educationally matched This study excluded patients who are in relapse and receiving pulse steroids; patients with severe motor disability; patients with severe visual impairment; patients with diseases that may affect cognitive functions such as hypertension, diabetes mellitus, connective tissue disorders, thyroid disorders, renal or hepatic impairment, and major psychiatric illness; and patients on tranquillizers or antidepressants.
Patients were submitted to the following: Through neurological examination, assessment of clinical disability using Expanded Disability Status Scale (EDSS) [8], and cognitive assessment using Arabic version of Addenbrooke's Cognitive Examination (ACE-III), we used the validated Egyptian-Arabic ACE-III to evaluate orientation, attention, memory, language, verbal fluency, and visuospatial abilities [9]; paced auditory serial addition test (PASAT 3) to evaluate working memory and information-processing speed [10]; and trail making test (part B) to evaluate executive functions [11].

Statistical analysis
The collected data were coded, tabulated, and statistically analyzed using IBM SPSS statistics (Statistical Package for Social Sciences) software version 22.0, IBM Corp., Chicago, USA, 2013. Descriptive statistics were done for quantitative parametric data as the range as well as mean ± SD (standard deviation) using independent t test, paired t test, and ANOVA test, then post-hoc test was used for pair-wise comparisons. While for qualitative data as number and percentage, inferential analyses were done using chi-square test and Fisher's exact test. Correlations were done using Pearson correlation. P values less than 0.05 were considered statistically significant.

Results
MS patients in our study were 23 males (51.1%) and 22 females (48.9%). Their age ranged from 25 to 40 years with a mean age of 32.9 ± 4.1 years. The control subjects included were 27 males (60%) and 18 females (40%), and their age ranged from 25 to 45 years with a mean age 34.6 ± 5.9 years. Seventeen patients (37.8%) received primary level of education, nineteen patients (42.2%) received secondary level of education, and nine patients (20%) received university education. Disease duration ranged from 2 to 10 years with a mean of 5.1 ± 1.8 years. EDSS score ranged from 2 to 6.5 with mean 4.3 ± 1.3. Clinical characteristics of people with MS are illustrated in Table 1.
As compared to controls, people with MS experienced significant worse performance in all cognitive assessment measures (P ≤ 0.05) Table 2.
Regarding the scores of the cognitive scales, there was no significant difference between male and female patients.
Concerning the scores of ACE language and PASAT 3, there was a statistically significant difference between population subgroups distributed according to the level of education (P = 0.014 and 0.046) Table 3. Post-hoc  analysis revealed that patients with primary level of education had significant lower scores of ACE language compared to those with secondary and university education (P = 0.023 and 0.007 respectively). Patients with primary level of education had also significant lower scores of PASAT 3 compared to those with university education (P = 0.019). People with RRMS (relapsing-remitting multiple sclerosis) showed significant better scores than those with SPMS (secondary progressive multiple sclerosis) regarding total ACE score (P ≤ 0.001), ACE scores of attention (P = 0.011), memory and language (P ≤ 0.001), PASAT 3 (P = 0.032), and trail making B (P = 0.035) ( Table 4).
Patients with cerebellar and sensory attacks showed significant worse performance in ACE attention than those with motor and visual attacks (P = 0.013). Patients with cerebellar attacks showed the worst performance in ACE language (P = 0.036) ( Table 5).
There was a significant negative correlation between age and total score of ACE (P = 0.046, r = − 0.299).
Moreover, a significant negative correlation was found between EDSS and scores of cognitive scales (P ≤ 0.05) except ACE visuospatial and trail making B tests. Also, there was a significant negative correlation between frequency of attacks/year and scores of ACE attention, memory, and language and total score (P < 0.05). Furthermore, duration of illness was negatively correlated with scores of ACE memory, language, and total score (P < 0.05) ( Table 7).

Discussion
Cognitive domains which were observed to be affected in our patients were attention, memory, language, visuospatial, information-processing speed, and executive functions. This proposed that MS can affect both cortical and subcortical cognitive functions. This was in agreement with numerous previous studies which described cognitive dysfunction in people with MS [12][13][14][15]. MS-related cognitive dysfunction results from domain-specific disconnection phenomena. Reduced functional connectivity between cortico-cortical and cortico-subcortical cognitive processing regions results in impairment to specific cognitive domains [16]. Cortical lesions may also responsible for cognitive deficits in people with MS [17].  Intelligence and education are responsible for the formation of cognitive reserve level which can affect the brain's resilience in the presence of insult [18]. In the current study, people with MS who have higher levels of education showed significant better performance in only ACE language and informationprocessing speed compared to those having lower educational level. This was in accordance with Benedict and his colleagues who found that MS patients with a low cognitive reserve at baseline suffered a noteworthy cognitive decline [5]. However, Russo and colleagues [19] found no significant differences in the educational level between patients whose cognition was unimpaired, mildly impaired, and severely impaired.
The current work revealed that people with MS who had high EDSS showed more impairment in attention, memory, language, fluency, informationprocessing speed, and to a lesser extent task switching for executive functions. Amato and colleagues found that MS patients with cognitive dysfunction had higher EDSS score than those without. Also, they found that EDSS score correlate weakly with impaired cognitive functions. Moreover, they revealed that cognitive functions correlates with physical disability and may predict disability levels [20].
People with MS who experienced frequent relapses had significant impairment in attention, memory, and  language. Duration of illness also affected the cognitive performance especially in memory and language as concluded in this work.
The current study showed that MS course has a significant impact on cognitive abilities. People with SPMS experienced significant worse performance in tasks of attention, memory, language, information-processing speed, and executive functions compared to those with RRMS. This agreed with Borghi and colleagues, who concluded that people with progressive MS showed a marked cognitive deficit as compared to those with RRMS and healthy controls [21].
Type of first attack may correlate to cognitive functions in MS. In this study, patients with cerebellar followed by sensory attacks showed the worst performance in attention tasks compared to patients with motor and visual attacks. Patients with cerebellar followed by motor attacks showed the worst performance in language tasks compared to patients with visual and sensory attacks; these findings may direct attention to the role of cerebellum in cognition.
Treatment type may contribute to impairment of cognitive functions in people with MS. We found that attention, memory, language, and informationprocessing speed were significantly better in patients receiving immunomodulatory drugs compared to those on immunosuppressive medications. This agreed with Fischer and colleagues, who reported that interferon Beta 1a had a significant favorable effect on attention, memory, visuospatial abilities, information processing, and problem solving [22]. Available immune-modulatory treatments for multiple sclerosis rapidly inhibit the inflammation and reduce the progression of brain atrophy, and they may also have neuro-protective properties [6].

Conclusion
It could be concluded that cognitive impairment in MS patients affects both cortical and subcortical domains. Low educational level, longer disease duration, type of initial attacks, frequent relapses, progressive course, higher disability, and immunosuppressive medications are correlated with cognitive impairment in people with MS. deviation HE contributed in the data acquisition, data interpretation, and manuscript writing and reviewing. EMF took part in the research idea, data acquisition, data analysis, and interpretation. NME and AMA participated in the data acquisition, data analysis, and interpretation. RSI helped in the manuscript writing and reviewing. The authors read and approved the final manuscript.

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available due to the current Cairo University regulations and Egyptian legislation but are available from the corresponding author on reasonable request and after institutional approval.
Ethics approval and consent to participate An informed written consent was taken from each patient. All data obtained from every patient were confidential and were not used outside the study. The patients have the rights to withdraw from the study at any time without giving any reason. All the costs of the investigations were afforded by the researcher. Our study was approved by the ethical committee of the Department of Neurology, Faculty of Medicine, Cairo University on 15/6/2018 (ethical reference number is not available).