does fatigue occur in ms patients without disability?

International Journal of Neuroscience, 2014; Early Online: 1–9Copyright© 2014 Informa Healthcare USA, Inc.ISSN: 0020-7454 print / 1543-5245 onlineDOI: 10.3109/00207454.2014.909415

ORIGINAL ARTICLE

Does fatigue occur in MS patients without disability?

Helcio Alvarenga-Filho, Regina Maria Papais-Alvarenga, Sonia Regina Carvalho,Heleine Norman Clemente, Claudia Cristina Vasconcelos, and Ricardo Marques Dias

Universidade Federal do Estado do Rio de Janeiro, Neurologia, Rio de Janeiro, Brazil

Background: Motor dysfunction and fatigue are the most common impairments that are associated with multi-ple sclerosis (MS). Walk tests and scales demonstrate the presence of fatigue in patients with MS with differentlevels of disability. Objective: To evaluate objective and subjective fatigue in MS patients without disability. Meth-ods: Were selected MS patients with relapsing remitting clinical course, from 18 to 55 years old and EDSS 0 to1.5; controls were paired for age, gender, body mass index, and physical activity level. Fatigue caused by pul-monary diseases, anemia, diabetes, thyroid disease, psychiatry diseases (except depression), and orthopedicand rheumatologic diseases are excluded. All participants performed the 6-minute walk test (6MWT), the MSFunctional Composite (MSFC), and completed the Modified Fatigue Impact Scale (MFIS) and the Beck Depres-sion Inventory. A multivariate model was applied to identify the variables associated with fatigue. Results: 54individuals were selected (31 patients; 23 controls). In the MSFC and 6MWT, no significant difference was ob-served between the groups. A MFIS total score indicated fatigue in 35% of the patients, 42% in the physicaldomain, 25.8% in the cognitive domain, and 29% in the psychosocial domain, which differed from the controlsin all comparisons. Fatigue was associated with MS, low-physical activity, and mood disorders. Conclusions:Fatigue occurs in patients with MS in the absence of motor dysfunction and is associated with the disease itself,the sedentary lifestyle, and mood disorders. The 6MWT is not useful to demonstrate motor fatigue in subjectswithout neurological disability.

KEYWORDS: fatigue, multiple sclerosis, disability

Introduction

Motor dysfunction and fatigue are the two most com-mon and debilitating impairments that are associatedwith Multiple Sclerosis (MS), an idiopathic inflamma-tory demyelinating disease of the central nervous sys-tem that affects primarily young women. Pyramidal syn-drome occurs in 63% to 100% of patients irrespective ofthe clinical course or ethnicity, and affects the ambula-tion in the long term and may confine the patients toa wheelchair or the bed. [1, 2]. Fatigue is reported by53% to 92% of patients and is often described as themost disabling MS symptom, worse than pain or phys-ical disability that limits routine daily activities and re-duces the quality of life [3, 4].

The recognition of symptom fatigue as a frequentand often serious clinical manifestation of MS only oc-

Received 4 March 2014; revised 9 February 2014; accepted 25 March 2014

Correspondence: Regina Maria Papais-Alvarenga, Universidade Federal doEstado do Rio de Janeiro a, Neurologia, Rua Mariz e Barros 775, Rio de Jan-eiro, Brazil. E-mail: regina [email protected]

curred at the end of the 20th century, possibly dueto the lack of objective instruments for its measure-ment and biological markers for its identification. Onthe scale Functional System/expanded disability statusscale (FS/EDSS), organized by John Kurtzke to ana-lyze the neurological impairment in MS, which has beenwidely used over the last 50 years, only objective signsin neurologic examination are used to score dysfunctionand disability [5, 6]. The MS Functional Composite(MSFC) was introduced by the MS Society to enlargethe neurological evaluation in MS [7]. Both tools do notinclude the assessment of the symptom fatigue. Thus,large series of neurological patients have no data on thefrequency, severity, and impact of fatigue symptom inthis disease. [1, 6].

The majority of our knowledge regarding the sub-jective experience of fatigue in MS originates from thestudies that applied self-questionnaires [8, 9]. The Fa-tigue Severity Scale (FSS)[8] assesses fatigue using onedimension and the Fatigue Impact Scale (FIS)[9] wasdeveloped later to assess this symptom in a multidimen-sional manner based on three domains: physical, cogni-tive, and psychosocial.

1

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2 H. Alvarenga-Filho et al.

A weak correlation between FIS scores and EDSSlevels was originally observed by Fisk et al. (1994) [9].Later studies reported a relationship of fatigue to higherdisability in certain studies (Colosimo et al., Kroenckeet al., Strober and Arnett, and Pittion-Vouyovitch et al.)[10–13] but not in others (Bakshi et al. and Tellez et al.)[14, 15].

In patients with MS, motor fatigue defined as theloss of the ability to generate force during an exercisehas been analyzed, mainly, by walking tests [16–20]. Areduction in walking speed in the 6-minute walk test(6MWT) has been verified, especially during the lastminute. However, the relationship between motor fa-tigue and perception of fatigue by self-questionnairesshowed contradictory results. A single study found anassociation between FSS scores and objective measuresof fatigability [21].

A significant limitation in all of those studies is thatMS patients evaluated for fatigue had mild, moderate,or even severe disability, most of them with pyramidalsyndrome affecting lower limbs.

It remains unclear whether MS is a determining fac-tor for fatigue. Since the introduction of disease-modif-ying agents for the treatment of relapsing-remitting MS,a growing number of MS patients can fully ambulate.However, there is little evidence of the pharmacologyintervention efficacy against fatigue in MS [22].

To clarify this matter, we selected MS patients with-out neurological impairment and healthy controls andapplied subjective and objective fatigue tests.

Methods

Ethical approval for the present study was granted by theHospital Universitario Gaffree e Guinle Local ResearchEthics Committee.

Participants

Patients with relapsing remitting MS who attended theneurology service of the Hospital Universitario Gaffreee Guinle (Rio de Janeiro, Brazil) were invited to partici-pate. Healthy individuals who were matched by sex, age,ethnicity, body mass index (BMI), educational level andphysical activity were identified among students and thehealth care team.

Instruments

After giving informed consent, each potential partici-pant completed a screening assessment that was appliedby a multidisciplinary team and underwent clinical andlaboratorial investigation to exclude potential causes offatigue according to the protocol proposed by the Centerof Disease Control to investigate Fatigue Chronic Syn-

drome [23]. The clinical and laboratorial data regardingMS were collected from medical charts. Electrocardio-grams, chest X-rays and pulmonary function tests wereperformed using spirography and plethysmography. Aneurological evaluation to analyze dysfunction and dis-ability using the FS/EDSS scale was conducted by thesame neurologist during the month prior to the study.

The following inclusion criteria were applied: age 18to 55 years and an EDSS score between 0 and 1.5.Participants who smoked or who had asthma, heartdisease, or uncontrolled arterial hypertension; abnor-malities in pulmonary function tests, anemia, diabetesmellitus, thyroid disease, psychiatric diseases (exceptdepression), orthopedic, or rheumatologic diseases; theuse of medication for fatigue, depression, or insomniain the 48 h preceding the study visits; an MS attack inthe previous 3 months; corticosteroid therapy less than1 month previously; or a Body mass Index (BMI) > 40were excluded from the study.

Two series of the 6MWT were applied with an in-terval of 1 h. All participants completed the ModifiedFatigue Impact Scale [9, 24], the Beck Depression In-ventory [25, 26], the physical activity index [27], andthe MSFC [28].

Procedures

FS (Functional System)Seven functional (FS) systems were scored from 0 to 6according to the neurological examination: pyramidal,cerebellar, sensory, brainstem, sphincter, visual, andmental functions. A score of 0 corresponded to a nor-mal neurological examination, a score of 1 denoted thepresence of signs without any complaint, and scores be-tween 2 and 6 represented increasing levels of severity.

EDSS (expanded disability status scale)This scale measures disability for 20 items, with scoresfrom 0 (normal neurological examination) to 10 (deathdue to MS). EDSS scores between 1 and 1.5 denotethe presence of neurological signs without dysfunction;from 2 to 4 indicate impairment in one or more FS; 4.5or higher indicate impairment in walking in addition to acertain degree of dysfunction; and 6 and higher indicatethe need of a walking aid, restriction to a wheelchair orto bed. Disability is classified as mild (2–3), moderate(3.5–5.5), or severe (≥6).

MSFC (multiple sclerosis functional composite)The MSFC includes the three following tests: theNine-Hole Peg Test—9-HPT, the Timed 25 Foot-Walk—T25-FW, and the Paced Auditory Serial Addi-tion Task—PASAT. The 9-HPT involves the use of awooden box with nine holes and a container with 15pegs. The patient is instructed to pick up one peg at

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Fatigue and disability in MS 3

a time as rapidly as possible, place them in the holes,remove them from the holes one at a time, and placethem back on the table. The task must be performedinitially using the dominant hand, and both hands aretested twice. The total time to complete the task is mea-sured using a timer.

The T25-FW test measures the time that is requiredto walk a distance of 7.62 m and the time to complete thetask is measured using a timer. Two consecutive trialsare performed.

The PASAT employs a compact disk on which a se-quence of 61 digits repeated every 3 sec is recorded. Thetask consists of adding two consecutively presented dig-its without taking into account the previous sum. Thescore of PASAT is the total number of correct answers,and the maximum score is 60. The total score of theMSFC (Z score) is calculated from the results of thethree tests:

1. Z legs = [individual mean (T25-FW) − group mean(T25-FW)/group standard deviation (T25-FW)]

2. Z arms = [individual mean (1/9 HPT) − group mean(1/9 HPT)/group standard deviation (1/9 HPT)]

3. Z cognitive = [individual mean (PASAT – 3′′) −group mean (PASSAT – 3′′)/group standard devia-tion (PASAT – 3′′)]

4. MSFC = (z bracos − z pernas + z cognitivo)/3

6MWTThe 6MWT is a self-paced field test that is used to eval-uate physical function. The 6MWT was conducted ac-cording to ATS guidelines (2002) [29]. Enright’s [30]predictive values for the 6MWT were used. The subjectswere instructed to walk from one end of a 25-meter hall-way to the other at their own pace while attempting tocover as much ground as possible in the allotted 6 min.Dyspnea and leg pain were measured using the modi-fied Borg dyspnea scale [31], and blood pressure wasassessed at the beginning and the end of the 6MWT.Oxygen saturation (SaO2) and pulse rate were registeredthroughout the test using pulse oximetry.

Beck depression inventory (BDI)

BDI is a structured, self-reported, 21-item question-naire. Each item has four affirmative answers that rangefrom 0 to 3. The total score is classified to be between1–10 (normal), 11–16 (mild mood disorder), 17–20(mild depression), 21–30 (moderate depression), 31–40(severe depression), and >40 (extreme depression).

Physical activity index (PA)

According to the amount of hours dedicated to sportsor physical activities of recreation in the last week, the

participants were classified into four levels: I. less than1 h (sedentary); II: 1 to 3 h; III: 3 to 6 h; and IV: morethan 6 h.

Fatigue scales

The modified fatigue impact scale (MFIS)MFIS is a structured, self-reported, 21-item question-naire that assesses the effects of fatigue in terms ofphysical (MFIS-phys—nine items), cognitive (MFIS-cog—10 items), and psychosocial (MFIS-soc 2 items)functioning. All of the items are scaled, and scoresgreater than 38 indicate an impact of fatigue on a per-son’s activities. In this questionnaire, the physical do-main is affected when its score ≥16, and scores ≥18 and≥8 indicate fatigue in the cognitive and psychosocial do-mains, respectively.

Statistical analysis

A database was constructed in Excel and analyzed us-ing SPSS for Windows, version 20.0. The results arepresented as proportions, means, medians, and stan-dard deviations. The differences between groups wereanalyzed using the Mann–Whitney U-test, and p-values<0.05 were considered to be statistically significant. Thecorrelation was classified as negligible (0.0–0.19), weak(0.20–0.39), moderate (0.40–0.59), strong (0.60–0.79),or very strong (0.80–1.00). In all participants, the out-come fatigue (MFIS) was tested for association withMS, gender, age, IMC, sedentary style and perfor-mance on the 6MWT (total distance and distance at thelast minute). Continuous variables were dichotomizedbased on the median values. The variables with a sig-nificance level of p < 0.05 were entered into a multiplelinear regression model.

Results

Seventy-eight individuals were invited to participate inthe study. Of these, 11 (14.10%) did not accept, nine(11.53%) did not fulfill the eligibility criteria, and four(5.13%) removed the term of informed consent. Thefinal sample consisted of 54 individuals, including 31with MS and 23 healthy controls, all of whom had a uni-versity education. The majority of the participants wasfemale, white, and had paid employment. Of the MSgroup, 48.4% practiced physical activity for less than1 h per week (sedentary), 38.7% did so twice per week,9.7% did so three times per week, and one patient prac-ticed physical activity five times per week; of the con-trols, the levels of PA were 34.8% (sedentary), 34.8%,21.7%, and 8.7%, respectively, with no significant dif-ferences between the groups. Patients and the controlsalso not differed in relation to evaluation of MSFC.(Table 1).

C© 2014 Informa Healthcare USA, Inc.

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Table 1. MSFC: Comparison of the results between patients and controls.

MSFC RRMS patients (N = 31) Controls (N = 23) p-value

25-TFW 1 4.41 ± 0.61 (3.10–5.50) 4.37 ± 0.35 (3.80–5.10) 0.75925-TFW 2 4.30 ± 0.57 4.29 ±0.47 0.704

(3.10–5.20) (2.80–5.20)9-HPTDominant hand

First test 17.73 ±1.86 17.39 ±1.60 0.337(14.10–21.10) (14.50–20.20)

Second test 17.01 ±1.57 16.95 ±1.65 0.440(13.50–19.30) (12.90–19.50)

Nondominant handFirst test 18.68 ±1.67 18.46 ±1.47 0.756

(16.00–24.70) (15.50–22.00)Second test 18.10 ±1.69 18.07 ±1.59 0.304

(13.80–20.80) (14.90–21.30)PASAT “3 47.71 ± 8.60 46.09 ±6.65 0.276

(30–60) (38–60)Z legs −0.008 ± 0.981 (−2.05–1.68) 0.0110 ± 1.02455 (−2.6–2.04) 0.146Z arms 0.020 ± 1.033 (−2.04–1.82) −0.028 ± 0.95217 (−2.15–1.24) 0.436Z cognitive 0.068 ± 1.063 (−2.06–2.09) −0.0919 ± 0.89846 (−1.22–1.94) 0.051Z total 0.324 ± 0.631 (−1.16–1.45) −0.0437 ± −0.53066(−1.03–1.27) 0.436

25-TFW1, Timed 25-Foot Walk; 9HPT, 9 Hole Peg Test; PASAT, Paced Auditory Serial Addition Test.

The clinical profile of MS revealed a mean diseaseonset at 24.87 ± 6.98 years of age and a relapsing re-mitting clinical course. Over a period that ranged from1 to 12 years (mean 5.17 ± 3.71 years), a mean of 4.91± 2.44 attacks occurred per patient (range: 2–12 at-tacks). None of the patients exhibited disability on theFS/EDSS scale [EDSS = 0 in 41.9%; EDSS = 1.0 in45.2%; EDSS = 1.5 in 12.9%]. The majority of patientswere using immune modulators to treat MS, includingbeta interferon (29%), glatiramer acetate (16.1%), andfingolimod (16.1%).

Measures of functional exercise capacity

The analysis of the 6MWT using the best performanceseries is shown in Table 2.

The mean distance was walked within the predictedvalue that was calculated according to the BMI, physicalactivity index, and age for each participant.

A strong positive correlation was observed betweenthe total distance covered and the distance coveredin the final minute in both the patients (rho = 0.740)and the controls (rho = 0.698).

There were no differences in the parameters usedto evaluate cardiorespiratory control or in those usedto monitor subjective symptoms during and followingwalking.

MFIS fatigue scale

The frequency of fatigue in the patients and controlswas 35% versus 8.7% in the MFIS total score, 42% ver-

sus 13% in the physical domain, 25.8% versus 4.3%in the cognitive domain, and 29% versus 4.3% in thepsychosocial domain. As shown in Figure 1, the differ-ence between the groups was statistically significant forall comparisons.

The relationship between fatigue and mooddisordersAccording to BID, mood disorders (n = 6) or mild de-pression (n = 1) was observed in seven patients, andmood disorders were also present in two controls (p =0.176). The BDI scores were positively correlated withthe MFIS-physical scores (rho = 0.649).

Association studiesUpon univariate analysis, the MS patients showedhigher scores of fatigue in the physical domain (p =0.002), social domain (p = 0.012), and total MFISscores (p = 0.002). Sedentariness was associated withthe worst score in the physical domain (p = 0.003) andtotal MFIS score (p = 0.010). Patients with poorer per-formance on the 6MWT had poorer scores in the physi-cal domain (p = 0.042). Mood disorders have been asso-ciated with increased fatigue scores on physical, social,and total MFIS scales (p < 0.001). There was no associ-ation between the scales of fatigue according to gender,age, nutritional status, or performance on the 6MWTtest during the last minute. No variable studied was sta-tistically associated with the worst score of fatigue in thecognitive domain (Table 3).

When assessing fatigue using the multiple linear re-gression model, higher scores were observed for MS


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Table 2. 6MWT—comparison of the results between patients and the controls.

RRMS patients (N = 31) Controls (N = 23) p-value

6MWT (meters), mean ± SD (range)Total distance (meters)

631.66 ± 54.90(549 – 743)

643.84 ± 50.45(582.50 – 794)

0.479

Distance in the final minute 109.62 ± 14.84(85 – 142)

112.60 ± 27.52(90.30 – 226)

0.827

Borg scale, mean ± SDLower limbsDyspnea

1.74 ± 1.631.37 ± 1.55

1.58 ± 1.431.10 ± 1.17

0.8020.520

Final arterial pressure (mmHg), mean ± SD 125 ± 1.5; 80 ± 0.7 120 ±1.4; 77 ± 0.7 0.972Heart rate, mean ± SD

During the testFollowing the test

153.16 bpm ± 11.70147.61 bpm ± 12.74

156.26 bpm ± 13.64152.17 bpm ± 15.84

0.1280.372

SO2,% ± SDMaxMin

97.38 ± 0.9090.64 ± 4.29

97.08 ± 1.1790.34 ± 5.44

0.6310.763

6MWT, 6-minute walk test; Borg scale, scale of tiredness in lower limbs and dyspnea following the test; SO2 (mean,maximum, and minimum) during the test.

patients (discrepancy of 8.74 points, p = 0.006), seden-tary lifestyle (difference of 9.92, p = 0.002), and mooddisorders (difference of 25.53, p = 0.001). In the phys-ical domain, higher fatigue scores were observed forMS (discrepancy of 4.31 points, p = 0.010), sedentarylifestyle (difference of 5.68, p = 0.001), and mood disor-ders (difference of 11.11, p = 0.001). When evaluatingthe factors associated with fatigue in the social domain,higher scores were associated with the presence of MS

(discrepancy of 1.02 points, p = 0.035), and mood dis-orders (difference of 2.48, p = 0.001) (Table 4).

Discussion

Fatigue in MS has been described by the Multiple Scle-rosis Council for Clinical Practice Guidelines (1998) asa feeling of tiredness with a lack of physical or mental

Figure 1. Frequency of fatigue in the patients and the controls.


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Table 3 Univariate analysis between selected variables and scores of fatigue (MFIS).

Total MFIS Physical MFIS Cognitive MFIS Social MFIS

Variable Median p-value Median p-value Median p-value Median p-value

Multiple sclerosisYesNo

25.6812.04

0.00212.585.96

0.00210.136.30

0.0622.190.83

0.012

GenderMaleFemale

15.1821.07

0.2938.0010.21

0.4276.189.09

0.2531.271.70

0.537

Current age<30 years≥30 years

18.3821.25

0.5279.0810.39

0.5589.507.57

0.3481.192.00

0.142

Overweight (BMI ≥ 25)YesNo

17.0820.67

0.5109.679.79

0.9659.928.10

0.4621.581.62

0.957

SedentaryYesNo

26.4315.00

0.01013.437.03

0.0039.098.06

0.6242.001.32

0.225

Total distance covered<630.75≥630.75

23.5616.19

0.09912.007.52

0.0428.638.37

0.9002.001.22

0.158

Distance covered at last minute<106.00≥106.00

23.3216.87

0.15311.808.00

0.0889.447.69

0.396 2.161.14

0.062

BIDAbnormal (BID <20)Normal

43.1115.22

< 0.00120.007.71

< 0.0018.448.51

0.9813.891.16

< 0.001

MFIS, modified fatigue impact scale: fatigue by total score; BMI, body mass index; BID, beck inventory depression.

energy and may occur in the form of asthenia (fatigueat rest), pathological fatigability (fatigue during physicalactivity), or fatigue during acute events of the disease[32].

The primary purpose of this investigation was to eval-uate fatigue in individuals without neurological impair-ment. The distance that was walked during the 6-minperiod was within the predicted normative values in allparticipants. However, MS patients showed more fa-tigue than the healthy controls in all domains of MFISscale.

The 6MWT revealed significant changes in ambula-tion in MS patients with EDSS ranging from 1.5 to 7.

[17–21]. The test demonstrated, even in patients withmild disability, reduced in total distance covered and onspeed compared to controls [20, 21]. Based on the rec-ommendations of Goldman et al. [20], we applied the6MWT to analyze motor fatigue in patients with MSwith no disability and healthy controls matched by de-mographic features, BMI, and physical activity level. Allof the participants were submitted to pulmonary testsand an extensive clinical investigation to exclude otherfactors that could potentially be the cause of fatigue. Theperformance on the 6MWT did not differ between thegroups. As was previously postulated [20], the 6MWTwas observed to be reproducible, simple, inexpensive,

Table 4 Multiple linear regression model according to MFIS scale

B IC 95% p-valueMFIS total

Multiple sclerosis (yes × no) −8.74 −14.89a − 2.59 0.006Sedentary (yes × no) −9.92 −15.97a − 3.88 0.002Beck classification (abnormal × normal) −25,53 −33.62a − 17.45 < 0.001Physical domainMultiple sclerosis (yes × no) −4.31 −7.56a − 1.06 0.010Sedentary (yes × no) −5.68 −8.87a − 2.48 0.001BECK classification (abnormal × normal) −11.11 −15.38a − 6.84 < 0.001Psycho social domainMultiple sclerosis (yes × no) −1.02 −1.97a − 0.73 0.035BECK classification (abnormal × normal) −2.48 −3.74a − 1.22 < 0.001


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and safe. Nevertheless, the 6MWT did not identify mo-tor fatigue in individuals without disability.

The application of self-questionnaires in the 1990sexpanded the knowledge of the subjective experience offatigue in patients with MS [8, 9]. In the current study,the MFIS scale was applied to patients with EDSS zeroto 1.5 and good performance on the MSFC that analyzefatigue indirectly measuring gait speed (timed-25-foot-walk), the upper limb function (9-Hole-PEG-Test), andcognitive processing speed (Passat Test). Even so, thisgroup differed significantly from controls in differentdomains of fatigue. The impact of fatigue in physicaldomain was perceived by MS patients through a de-crease in the speed of physical activities, less motiva-tion for tasks requiring physical effort, and the feelingof weak muscles and in cognitive domain, by a difficultyin maintaining attention for longer periods of time andthe self-perception of forgetfulness. This description ismissing important information contributing to fatiguein MS, such as the variance of symptoms during the dayand the interference of external factors, primarily theheat. Items on these topics were included in MS fatiguescales that were developed later [33–35].

Several studies investigated fatigue in MS patientsand its relationship with disability [10–15] and most ofthem reported an association of fatigue with high EDSSlevels. Kroncke et al., found higher FSS scores in pa-tients with primary and secondary progressive diseasethan those with remitting relapsing disease, but, after ananalysis of covariance, this apparent difference was at-tributable almost exclusively to differences in disabilityamong the three subtypes of MS [11].

Our results demonstrated that perception of fatigueoccurs in MS independently of the neurological impair-ment. The physical domain of fatigue was the most com-promised and correlated strongly with the overall MFISscore. Similar results were described by Tellez et al. [15],who applied similar procedures to a large number of par-ticipants and observed that 55% of the patients with dif-ferent levels of disability and 13% of the controls had fa-tigue as determined using the MFIS. There was a weakcorrelation between fatigue and EDSS, an observationthat was originally made by Fisk et al. [9], who stated,“typical clinical factors had little bearing on the impact offatigue: this was reflected by the absence of any correlationbetween FIS scores with current EDSS scores.” The currentstudy supports Fisk’s conclusion.

Some studies showed an increased risk of fatigueassociated with older age [10, 15], depression mood[11–14], and sleep disorders [12,13].

We used a model of multiple linear regression to as-sess the variables that could be associated with the out-come fatigue, such as the disease itself, gender, age,overweight status, sedentary lifestyle, performance on

the 6MWT (total distance and last minute), and BDIscores. Mood disorders, low physical activity, and MSwere independently associated with fatigue. Interest-ingly, none of the participants had clinical depression(BDI ≤ 20), and only 16% had mood disorders or milddepression. However, 42% of all participants had noregular physical activity and were thus ideal candidatesfor future studies using intervention with aerobic andanaerobic workouts [37].

The most important finding of this study is the factthat perception of fatigue occurs in MS independentlyof neurological impairment and that fatigue shows anoverlap with depression mood in fatigued MS patients.Historical reports described a state of excessive tirednessduring the day, disproportionate to the degree of dis-ability seen in some MS patients, denominated “neuras-thenia” which was related to psychological causes[5]. Aclear relationship of fatigue with depression was demon-strated by Bakshi et al. [14] in MS relapsing remit-ting subtype, independently of the physical disability.The authors suggested that brain lesions in specific neu-roanatomic pathways could represent common mecha-nisms for both symptoms.

The origin of primary fatigue in MS is unknown[38, 39] and further studies must elucidate this rela-tionship. Changes in brain activation have been demon-strated by functional MRI [40, 41]. The highest cor-tical activation was correlated with the greater numberof demyelinating lesions, and functional cortical reorga-nization would be an adaptive mechanism that wouldbe required to maintain functional capacity in an in-jured brain, which would need to recruit more areas forthe same function, producing fatigue. A new insight re-garding the physiopathology of fatigue is provided by anemergent theory that is referred to as “failure of energy”.Based on the demonstration of an increase in energydemand during the process of axonal modifications inresponse to demyelination, Paling et al. [42] hypothe-size that soluble proinflammatory cytokines may impairmitochondrial function. Insufficient energy productioncould lead to the accumulation of intracellular sodium,with calcium influx and cell death. New MR techniquescould investigate these pathology driven hypotheses invivo. Although this theory has not been proven, it is un-deniable that the term “lack of energy” is often usedby patients with MS to describe the feeling of fatigue[3, 8, 43].

Conclusions

Fatigue occurs in patients with MS in the absence of mo-tor dysfunction and is associated with the disease itself,the sedentary lifestyle, and mood disorders. The 6MWT


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cannot be used to demonstrate motor fatigue in subjectswithout neurological disability.

Acknowledgments

The authors thank the researchers Luiz Claudio San-tos Thuler and Anke Bergmann from the INSTITUTONACIONAL DE CANCER (Brazil) for the competentadvice on multifactorial analysis.

Declaration of Interest

The authors report no conflict of interest. The authorsalone are responsible for the content and writing of thispaper.

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does fatigue occur in ms patients without disability?

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