multiple sclerosis - disabled persons - fatigue - disorders of excessive sonnolence
esclerose múltipla - pessoas com deficiênica, fadiga - distúrbios do sono por sonolência
excessiva
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central
nervous system marked by multiple exacerbations and remissions. It is considered an
autoimmune disease with a varying course and uncertain prognosis[1]. Fatigue is a common and disabling symptom of MS. Some MS investigators have defined
MS fatigue as a feeling of physical tiredness and lack of energy[1], distinct from sadness or weakness[2],[3]. Others have described it as extreme tiredness and the need to rest. The causes
and mechanisms of fatigue in MS remain poorly understood, and are likely to be multifactorial[3]. Physiological fatigue has been demonstrated in MS and seems to be central in origin,
muscular dysfunction has also been reported and may result from inactivity. However,
there is no correlation between the degree of physiological fatigue, and the amount
of fatigue[4].
Sleep disorders are frequent in patients with multiple sclerosis, interferes with
daytime wakefulness, affects daily functional performance[5], usually their disorders are associated with psychological or motor symptoms[6], disease duration, clinical presentation and disruption of the sleep cycle[4], and may cause marked fatigue[7].
Fatigue is a common complaint in multiple sclerosis, and impairs quality of life[7],[8]. Its pathophysiology is not fully understood, but it seems to be influenced by different
factors[1]. Patients often describe fatigue as the most disabling symptom even when compared
to weakness or spasticity[3]. Fatigue is usually induced by excessive physical activity and relieved by rest[2],[9].
Fatigue is often mistaken for excessive daytime sleepiness (EDS). However, EDS is
defined as a decrease in physical and/or mental work capacity with incomplete relief
at rest. Even though these are distinct clinical symptoms[1],[8], they frequently coexist in the same patient and may be associated with sleep disorders[10].
Some studies have tried to correlate fatigue and EDS in patients with MS[4], but it is difficult to differentiate between them since both may be related to
sleep disorders and may occur concomitantly[11],[12].
The objective of this study is to assess the correlation between fatigue, excessive
daytime sleepiness and the degree of disability in patients with MS.
METHOD
We conducted a retrospective analysis of the medical records of patients with MS followed
up at the neuroimmunology clinic over the period 2006-2008. The study was approved
by the University’s Research Ethics Committee.
All selected medical records met the following inclusion criteria: male or female
patients aged 20-71, with relapsing-remitting or progressive multiple sclerosis based
on McDonald’s 2001 and 2005[13] diagnostic criteria, neurological disability measured by EDSS (Expanded Disability
Status Scale) score up to 7.0[14], with fatigue and sleep complaints assessed by fatigue scales and sleep disorders
assessment questionnaires. In addition, patients should have been under clinical follow
up for at least one year and treated with any disease modifying drugs. Incomplete
medical records, records from patients suffering from acute demyelinating encephalomyelitis
(ADEM) or neuromyelitis optica (NMO), and from patients with multiple sclerosis and
other concurrent conditions, such as hypertension, diabetes mellitus, hypothyroidism
or orthopedic, cardiac or rheumatic disorders that might cause sleep disturbances
or result in neurological disability and fatigue were excluded from the study.
The presence of fatigue was assessed using the Fatigue Severity Scale (FSS): the scale
includes nine (9) items, and the scores range from 1 (absence of fatigue) to 7 (fatigue
present), a minimum of 28 points suggests the presence of fatigue and higher scores
indicate more severe symptoms[15],[16]. Depression was assessed using the Beck’s depression inventory, a self-administered
questionnaire where higher scores indicate more severe depression[17]. EDS was assessed using the Epworth scale, consisting of questions about the possibility
of dozing off in eight different situations; scores equal to or higher than 10 indicate
excessive daytime sleepiness[18].
Medical records from 912 patients were reviewed. From these, 122 have met the inclusion
criteria: 82 (67%) patients had relapsing-remitting multiple sclerosis (RRMS), 15
(12%) had primary progressive disease (PPMS) and 25 (21%) had secondary progressive
multiple sclerosis (SPMS) ([Figure]).
Figure Flowchart of selected medical records.
Statistical analysis was performed. The Student’s t-test, the Pearson’s chi-square
test, and the Spearman correlation were used to analyze the different clinical forms,
namely relapsing remitting multiple sclerosis, primary progressive multiple sclerosis,
and secondary progressive multiple sclerosis, comparing the following variables: age,
excessive daytime sleepiness, level of disability, depression and fatigue. The significance
level admitted was p < 0.05.
RESULTS
The patients’ clinical characteristics are summarized in [Table 1]. Fatigue was present in 51 (64%) patients with RRMS, 14 (93%) patients with SPMS,
and 19 (66%) patients with PPMS. Patients with RRMS and SPMS who experienced fatigue
also complained of moderate to severe depression and we observed a correlation between
fatigue and depression, r = 0.417 and 0.638, respectively. However, such correlation
was not found in patients with PPMS. Among RRMS patients who reported fatigue, 80%
(n = 41) had an EDSS score lower than 6, on the other hand, patients with PPMS and
SPMS who reported fatigue had EDSS scores higher than 6 ([Table 2]).
Table 1
Patient demographics and disease characteristics.
|
|
N
|
%
|
Median
|
25%
|
75%
|
|
Gender
|
|
Male
|
41
|
33.6
|
-
|
-
|
-
|
|
Female
|
81
|
66.4
|
-
|
-
|
-
|
|
EDSS
|
|
< 6 (0–5,5)
|
80
|
65.6
|
-
|
-
|
-
|
|
> = 6 (6–7)
|
42
|
34.4
|
-
|
-
|
-
|
|
Clinical forms
|
|
RRMS
|
82
|
67.2
|
-
|
-
|
-
|
|
PPMS
|
15
|
12.3
|
-
|
-
|
-
|
|
SPMS
|
25
|
20.5
|
-
|
-
|
-
|
|
FSS - Fatigue
|
|
No
|
38
|
31.1
|
-
|
-
|
-
|
|
Yes
|
84
|
68.9
|
-
|
-
|
-
|
|
EDS - Sleepiness
|
|
No
|
78
|
63.9
|
-
|
-
|
-
|
|
Yes
|
44
|
36.1
|
-
|
-
|
-
|
|
Beck - Depression
|
|
No
|
32
|
26.2
|
-
|
-
|
-
|
|
Yes
|
90
|
73.8
|
-
|
-
|
-
|
|
Age, yrs.
|
44
|
33
|
51
|
|
FSS
|
-
|
-
|
41
|
24
|
57
|
|
EDSS
|
-
|
-
|
3.5
|
1.5
|
6.0
|
|
BECK
|
-
|
-
|
10
|
7
|
18
|
|
EDS
|
-
|
-
|
7
|
4
|
11
|
EDSS: expanded disability status scale; RRMS: remitting recurrent multiple sclerosis;
PPMS: primary progressive multiple sclerosis; SPMS: secondary progressive multiple
sclerosis; FSS: fatigue severity scale; EDS: excessive daytime sleepiness; Beck: Beck’s
depression inventory.
Table 2
Correlation between fatigue, disability and depression using the corresponding assessment
questionnaire.
|
|
FSS
|
EDSS (> = 6)
|
BECK
|
|
RRMS
|
|
r
|
-
|
0.208
|
0.417*
|
|
p
|
-
|
0.060
|
0.001**
|
|
N (82)
|
51
|
10
|
15
|
|
PPMS
|
|
r
|
-
|
0.369
|
0.463
|
|
p
|
-
|
0.176
|
0.082
|
|
N (15)
|
14
|
11
|
5
|
|
SPMS
|
|
r
|
-
|
0.394
|
0.638*
|
|
p
|
-
|
0.051
|
0.001**
|
|
N (25)
|
19
|
10
|
13
|
FSS: fatigue severity scale; EDSS (> = 6): expanded disability status scale; Beck:
Beck’s depression inventory; RRMS: remitting recurrent multiple sclerosis; PPMS: primary
progressive multiple sclerosis; SPMS: secondary progressive multiple sclerosis; *r
< 0.01 statistically significant for Spearman coefficient; **p < 0.05 considered as
statistically significant.
Excessive daytime sleepiness was present in 36.1% (44) of the study patients, with
the following distribution: 54% of the RRMS patients (n = 24), 15% of the PPMS patients
(n = 7), and 29% of the SPMS patients (n = 13).
In RRMS patients (n = 24) who complained of excessive daytime sleepiness, we noticed
that EDS was associated with fatigue in 19 patients (79.1%), while 5 patients (21%)
did not reach a score in the fatigue scale to receive such diagnosis, despite experiencing
somnolence. Also, we observed that 18 out of these 19 patients with fatigue and EDS
had lower neurological disability with an EDSS score ranging from 0 to 4 (p = 0.047)
([Table 3]). Among patients with RRMS who experienced sleepiness and fatigue, we found that
63.1% (12) suffered from moderate to severe depression (p = 0.001) and 36.8% (7) had
no mood changes ([Table 3]).
Table 3
Patients with fatigue and excessive daytime sleepiness.
|
|
RRMS
|
PPMS
|
SPMS
|
|
|
|
Fatigue and no sleepiness
|
Fatigue and sleepiness
|
p
|
Chi-square
|
Fatigue and no sleepiness
|
Fatigue and sleepiness
|
p
|
Chi-square
|
Fatigue and no sleepiness
|
Fatigue and sleepiness
|
p
|
Chi-Square
|
|
|
|
|
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
|
Gender
|
|
Female
|
7(21.9)
|
9(47.4)
|
0.058
|
0.522
|
3(42.9)
|
12(63.2)
|
0.577
|
0.361
|
5(55.6)
|
4(40.0)
|
0.488
|
0.782
|
|
Male
|
25(78.1)
|
10(52.6)
|
4(57.1)
|
2(28.6)
|
4(44.4)
|
6(60.0)
|
|
Beck
|
|
No depression
|
29(90.6)
|
7(36.8)
|
0.001*
|
0.002*
|
3(42.9)
|
6(85.7)
|
0.094
|
0.0197
|
5(55.6)
|
4(40.0)
|
0.498
|
0.778
|
|
Depression
|
3(9.4)
|
12(63.2)
|
4(57.1)
|
1(14.3)
|
4(44.4)
|
6(60.0)
|
|
EDSS
|
|
< 6
|
23(71.9)
|
18(94.7)
|
0.047*
|
0.003*
|
2(28.6)
|
1(14.3)
|
0.515
|
0.361
|
4 (44.4)
|
2(20.0)
|
0.252
|
0.598
|
|
> = 6
|
9(28.1)
|
1(5.3)
|
5(71.4)
|
6(85.7)
|
5(55.6)
|
8(80.0)
|
RRMS: remitting recurrent multiple sclerosis; PPMS: primary progressive multiple sclerosis;
SPMS: secondary progressive multiple sclerosis; Beck: Beck’s depression inventory;
EDSS: expanded disability status scale; *p < 0.05 considered statistically significant.
Even though fatigue, excessive daytime sleepiness, depression, and disability were
present in patients with progressive forms of multiple sclerosis, we did not find
any correlation among them.
DISCUSSION
Fatigue is a symptom frequently reported by patients with MS. It is a subjective complaint,
thus imposing challenges to its proper evaluation. In this study, as expected we observed
that fatigue was present in all clinical forms but in RRMS it was not correlated with
greater neurological disability, measured by the EDSS. On the other hand, patients
with progressive forms and fatigue complaints had EDSS higher than 6. Interestingly,
some authors suggested[15],[19],[20] that the motor impairment observed in MS patients might impact their functioning,
requiring excessive effort to carry out their activities; such hypothesis could explain
our results.
Also, it is important to highlight that depression and fatigue were present in a smaller
percentage of patients in this sample (RRMS and SPMS) and, in general, both may be
present in patients with reduced mobility[5],[21]. The reduction of daily activities caused by physical limitations can cause depression,
but, in our sample we were not able to determine which symptom came first[5],[21].
Fatigue may be linked to age and has been correlated to cognitive impairment as well[6]. In daily practice, we mainly use scales that predominantly assess motor functions.
The EDSS scale is not appropriate for assessing cognitive dysfunction, and perhaps
this could have explained why we did not find a correlation between fatigue and the
EDSS score in progressive forms of the disease, where cognitive impairment is more
frequent[22],[23]. Also, we did not found an impact of age on the fatigue complaints among patients
with multiple sclerosis of any type.
Excessive daytime sleepiness was present in all clinical forms and it was associated
to fatigue[10] in approximately 25% of the patients with relapsing-remitting MS. In these patients,
we were able to demonstrate that excessive sleepiness was also associated with neurological
disability. Of note, we observed that in this group of patients, the lower the level
of disability, the higher the chance of sleepiness. Interestingly, such findings were
not consistent with what has been described previously [11],[26] and might be explained by the fact that mildly disabled RRMS patients could be more
active.
The differential diagnosis of EDS is initially based on the history of daytime function
and on the analysis of daytime alertness in carrying out routine activities. In a
second moment the sleeping habits should be analyzed and a polysomnography should
be performed[27]. Excessive daytime sleepiness may result from different factors[4], such as disruption of sleep cycles, autonomic dysfunction, and psychiatric disorders[8]; these may favor the onset of EDS and fatigue due to a non-restful sleep[12],[29]. Patients complaining of depression quite often report difficulty in falling asleep,
frequent nighttime awakenings, and early morning wakening followed by fatigue throughout
the day. By using validated subjective scales to measure the degree of daytime alertness,
which has been proven to be effective in the diagnosis of EDS[18], alongside depression and fatigue questionnaires, we were able to demonstrate a
correlation between depression, disability, sleepiness, and fatigue, and confirmed
the notion that these symptoms are frequently concurrent.
Recent studies suggest an association between fatigue and abnormal sleep cycles or
interrupted sleep and interference with the circadian rhythm; however, in this population
we could not address these factors, since we did not assess sleep cycles or performed
polysomnographic studies[5],[12],[26],[29]Usually, most of the studies describe patients with MS divided into subgroups: with
and without fatigue, regardless the clinical presentation[12],[30], therefore reports on the progressive forms are limited. Our study took an alternative
approach, by analyzing the frequency of fatigue and EDS in different clinical forms
of the disease. In this way, we may have missed the comparison between fatigued and
non-fatigued patients, but we added an important piece of information about the different
clinical forms of the disease.
Although it has been demonstrated that cognitive impairment is related to fatigue,
we acknowledge one important limitation of this work which is the lack of neuropsychology
evaluation. The neuropsychology battery tests can only be performed by trained neuropsychologists
and during the period this study was performed, we did not have such specialist available.
Therefore, the lack of correlation between fatigue and EDSS in the progressive forms
may reflect such limitation.
The association between sleepiness and fatigue further supports the assumption that
both are present in MS patients, while showing distinct and unique characteristics
according MS subtypes. When seeing patients with these symptoms, healthcare professionals
should establish a definite diagnosis based on the medical history and on the use
of specific scales to guide the therapeutic approach, since it is possible that initially
by treating fatigue and depression, one can alleviate or eliminate the symptoms of
EDS.
In conclusion, fatigue and excessive daytime sleepiness are frequent in patients with
MS. There was a positive correlation between functional disability, excessive daytime
sleepiness, and fatigue in remitting MS and no association between the degree of disability
and fatigue in patients with progressive subtypes. Also, we noted an association of
fatigue and depression in RRMS and SPMS patients.
