1. Introduction
Walking impairment is a major manifestation of multiple sclerosis (MS) [1]. Also, the cerebellum is one of the most common sites involved in MS; this involvement is associated with symptoms, such as balance, speech, and walking impairments, which are related to a reduced quality of life among these patients [2]. Since walking impairment can indicate disease progression and lead to disability, the evaluation of walking ability and motor state is essential for the treatment and rehabilitation of patients with MS [1]. These impairments are often objectively evaluated using performance-based instruments, such as T25FW and 6MW [3]. Moreover, some studies have used validated scales, such as the Rivermead Mobility Index and other well-known scales to examine walking ability [4]. However, these instruments assess a major part of the daily functioning of patients and do not specifically examine the effects of the disease on walking indices. The Multiple Sclerosis Walking Scale-12 (MSWS-12) is a 12-item instrument assessing the walking ability of MS patients, in the past two weeks; this scale is also used for patients with other neurological conditions. Initially, the MSWS-12 was designed and evaluated in the college of neurology [5]. This study aimed to examine the relationship between walking impairment (assessed with MSWS-12) and fatigue; this relationship has not been widely examined, despite the high prevalence of both symptoms. 
Studies have shown that 85% of patients with MS suffer from motor and walking impairments [6, 7]. Besides, about 50% of patients with MS experience disease relapse and progression and lose the ability to walk independently, 15 years after the diagnosis [7]. Fatigue is another prevalent symptom in these patients and is reported in 70% to 90% of MS patients [8]. However, few studies have investigated the relationship between walking and fatigue in people with MS. Moriss examined the changes in walking and fatigue in the time between morning and evening; the results showed that fatigue was increased in the patients with MS, while the walking pattern did not change. Still, the stride length and walking speed were reduced as fatigue increased [6]. In their respective studies, Kelleher and Pearson introduced walking impairment as the outcome of the degree of the severity of some MS symptoms, such as fatigue, spasticity, ataxia, and balance disorders [9, 10]. Also, using 6MW and 12MW scales, Burschka showed that walking speed is significantly correlated with fatigue severity, also, the increase of fatigue severity is associated with the decrease of walking speed in patients [11]. However, no study has examined the relationship between walking impairment (based on Walk-12) and fatigue. Fatigue and walking impairments are considered as key symptoms affecting the quality of life and independence of MS patients, thus, the present study explored the relationship between walking impairment and fatigue. 

2. Materials and Methods
Design and participants
This descriptive cross-sectional study was part of a research project on the translation and localization of the Comprehensive Fatigue Assessment Battery for Multiple Sclerosis [12]. The study sample included 60 patients with MS who had visited the Neuromuscular Rehabilitation Research Center, Semnan City, Iran, from 2014 to 2015. The patients had received a definitive diagnosis of MS, based on the McDonald diagnostic criteria; aged 18 to 60 years; and had the minimum required literacy skills. Also, the exclusion criteria were the score of over 22 on the Mini-Mental State Examination (MMSE), ie, mild cognitive impairment; the MS relapse experience in the course of the study; and the existence of any diseases (neurological, rheumatological, or orthopedic) with fatigue as a symptom. Based on the estimations of previous studies, the sample size for the main study was estimated at 54, considering a 95% confidence level, a test power of 85%, and the minimum correlation of 0.4. Considering the risk of attrition, a sample of 60 patients was included in the present study. 

Measures
The questionnaires used were a demographic information questionnaire (age, sex, marital status, occupation, the level of education, the type of the disease, the duration of the disease, comorbidities, and medications), the Walk-12, the Hospital Anxiety and Depression Scale (HADS), and the Modified Fatigue Impact Scale (MFIS).
The Walk-12 is a 12-item scale. Each item includes five options and receives a score of 1 (“not at all”) to 5 (“extremely”). Higher scores indicate the higher impact of the disease on walking. Finally, the score of walking ability falls into a 48-point range with the minimum and maximum scores of 12 and 60, respectively [5]. Walk-12 can be a valuable and useful guide for the evaluation and treatment of walking in patients with MS [13] and has been validated in Iran [14].
The MFIS has been developed based on the Fatigue Impact Scale and includes 21 questions in three dimensions of physical, cognitive, and social [15]. The questions are scored based on five items, ranging from 0 (“never”) to 4 (“almost always”). A total score of 0 shows the absence of fatigue, and the maximum score of 84 indicates severe fatigue. The Persian version of MFIS is structurally and conceptually sound and has optimal validity (total scale content validity index of 0.85) and reliability (internal consistency with a Cronbach’s alpha of 0.953) [16].
The HADS evaluates psychiatric disorders and parallelly assesses depression and anxiety in out-patients. The reliability and validity of this scale have been examined in adult out-patients with severe medical pathology; the results have confirmed the good internal consistency of the subscales [17]. Each subscale comprises seven questions. Each question includes four options and is scored on a four-point ordinal scale from 0 to 3, with higher scores indicating more severe mood disorder. Also, the score ranges of 0 to 7,  8 to 10, and 11 to 21 indicate the lack of depression (normal mood level), borderline case, and depression, respectively [17]. The reliability and validity of HADS have been examined on 261 Iranian patients with depression and anxiety. The findings showed that HADS has optimal reliability, validity, and internal consistency (r=0.81, P<0.001; alpha=0.91), and holds sufficient validity for use in the Iranian clinical population [18].
The MMSE is a practical instrument for the evaluation, documentation, and follow-up of patients’ cognitive functioning throughout their lifetime. The reliability and validity of the Persian version of MMSE have been investigated in the elderly population [19]. This test includes 30 questions in six domains of orientation, registration, attention and calculation, recall, language, and the ability to follow simple commands [20].

Data analysis 
The obtained data were analyzed in SPSS V. 20. The distribution of the demographic data was examined by descriptive statistics, including frequency, mean, and standard deviation. The relationships between Walk-12 scores, fatigue, anxiety, depression, and the other variables were assessed with the Spearman correlation test. Besides, a multivariate stepwise backward linear regression analysis was performed to check the relationship between fatigue and walking ability, in the patients. Moreover, the relationship between Walk-12 scores, anxiety, depression, and demographic characteristics (age, the type of the disease, and the duration of the disease) and the fatigue score was investigated. 

3. Results
A total number of 60 patients with MS (52 women and 8 men) complaining of fatigue were included in the study. The Mean±SD age of the study sample was 35±6.68 years. Also, the Mean±SD duration of MS was 5±3.62 years, with the minimum and maximum of 1 and 17 years, respectively. Table 1 presents the demographic characteristics of the participants. 

The walking problems were observed in 46.7% of the participants, based on Walk-12. Also, a significant relationship was found between the Walk-12 score and the severity of fatigue (P=0.001) (Table 2).

Table 3 presents the relationship between the Walk-12 score and the demographic characteristics of the patients. Moreover, anxiety and depression were significantly and directly related to the Walk-12 and fatigue scores, in the patients. Depression was the most important factor affecting fatigue (Table 4).

The other variables, e.g. cognitive status, anxiety, and walking ability were ranked next and showed a significant effect in the statistical analysis.

4. Discussion
The walking ability as a motor index plays a key role in quality of life and affects fatigue status, in patients with MS. Therefore, the severity of walking impairment is a major factor in examining the degree of disease progression. First, Hobart developed the 12-item scale to examine the effect of MS on walking ability and promote the assessment of walking ability in these patients. It is considered as an instrument with optimal validity and reliability [5], and suitable for the examinations of walking ability. Previous studies in Iran have shown that the Persian version of Walk-12 is appropriate for evaluating the walking ability of patients with MS [14]. 
The MSWS-12 aimed to investigate the effect of MS on patients’ walking ability [5]. Kieseier examined walking impairment evaluation in these patients to explore the clinical application of specific measurements of walking in MS. The scores of performance-based tests often used for impairment evaluation are strongly associated with the Walk-12 scores [21]. Researchers do not regard MSWS-12 as an MS-specific measure, because symptoms observed in MS are not limited to MS and appear in many other neurological diseases. Holland examined the suitability of this scale for walking ability measurement in neurological diseases. This researcher stated that other diseases affect the walking ability and cause limitations; he also highlighted that a generalized instrument can provide valuable insights into patients’ perception in clinical studies [22]. Walking ability is a general variable; the 12 items in MSWS-12 examine the walking problems of patients with neurological diseases. 
The present study examined the relationship between Walk-12 and fatigue scores. The fatigue scores are strongly correlated with walking scores in patients with MS; as fatigue is increased, the walking ability is further affected. In other words, the walking ability is a factor affecting fatigue in patients with MS. Few studies have investigated the relationship between walking and fatigue in MS patients. Furthermore, these limited studies have been indirectly demonstrated that motor impairments, including walking impairment, are increased with fatigue, in patients [6, 22]. However, a careful examination of the variables in this study showed that depression, cognitive status, anxiety, and walking ability affect the fatigue severity in patients with MS. Also, depression was the most effective factor in fatigue; this effect has been examined and confirmed in different studies [23, 22, 23, 24, 25]. In some of these studies, the patients’ cognitive status has been also introduced as the second factor affecting fatigue [25]. 
We used the data as a secondary study; all the examined patients suffered from fatigue. It is recommended to examine this relationship in MS patients without fatigue. Also, It is suggested that future studies compare the effect of fatigue on walking ability in other neurological diseases. Thus, measures can be taken for providing more expansive treatment of patients with neurological diseases who have walking impairment and chronic fatigue.

5. Conclusion
This study introduced a walking ability evaluation instrument with high reliability, replicability, and responsiveness to be used by healthcare providers and researchers in Iran. The objective was to assess the relationship between fatigue and walking impairment assessed with this instrument. Based on the results, depression, cognitive problems, anxiety, and walking impairment are among the most important factors affecting fatigue.

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the  Research Ethical Committee of the University of Social Welfare and Rehabilitation Sciences (Code: USWR.REC.1392.161).

Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Authors' contributions
All authors contributed equally in preparing all parts of the research.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
The authors would like to thank all the staff and colleagues of the Neuromuscular Rehabilitation Research Center in Semnan and the MS Association of Semnan.


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