multiple sclerosis ( ms ) is an autoimmune disease of the central nervous system that causes myelin destruction and axonal damage in the brain and spinal cord .
it is the leading cause of nontraumatic neurological disability among young adults and is associated with a variety of debilitating symptoms , including fatigue .  
fatigue is the most common symptom experienced by persons with ms , affecting up to 90% of patients at some point in their disease course [ 13 ] .
fatigue imposes significant socioeconomic consequences , including loss of work hours and employment , and is a prominent cause of diminished quality of life among individuals with ms . despite its prevalence in ms as well as other medical conditions , there is no unified definition for fatigue .
consequently , there is potential for considerable overlap between fatigue and other subjective terms commonly used by ms patients to describe lack of energy or alertness , including sleepiness .
however , many subjects in the general population who have sleep disorders such as obstructive sleep apnea report that problems with fatigue , tiredness , or lack of energy supersede problems with sleepiness   and experience improvement in these symptoms when their apnea is treated .
nonetheless , little is known about the most common symptoms experienced by ms patients with obstructive sleep apnea and other sleep disorders , or ways in which ms patients may differ from non - ms patients in how they describe symptoms that could be attributable to sleep disorders . research to clarify the relationship between sleep disorders , fatigue , and related symptoms in ms could help clinicians identify which ms patients are most likely to benefit from sleep evaluations and facilitate early treatment for common underlying sleep disorders . the purpose of this study was to assess the relationship between polysomnographic findings and the frequency of self - reported daytime symptoms ( fatigue , tiredness , lack of energy , and sleepiness ) , among ms patients referred for clinical polysomnography ( psg ) , compared to referred controls without ms .
this retrospective data analysis was approved by the university of michigan institutional review board .  
demographic , clinical , and polysomnographic ( psg ) data were assembled from the university of michigan ( u - m ) sleep disorders center database and medical records for n = 48 patients , 18 years or older , who had an established diagnosis of ms based on the mcdonald diagnostic criteria and had completed a clinical overnight psg between march 1999 and june 2010 .
only patients who had completed the university of michigan sleepiness impact assessment ( umsia ) at the time of psg ( n = 30 ) were considered eligible for the analyses .   control subjects without ms ( n = 30 ) who had also completed at least 2 out of 4 categorical responses of interest on the umsia were selected from more than 8,000 adult patients referred for diagnostic sleep studies .
controls were matched to each ms patient in a 1  :  1 ratio for paired analyses , based on age ( 5 years ) , gender , and body mass index ( 2  kg / m ) .
matched controls were also selected based on date of study , after or before january 1st , 2008 , to control for minor changes in psg scoring criteria that took place following january 1st , 2008 .  
the following variables were extracted from the sleep database : psg date , gender , age , body mass index ( bmi ) , psg diagnosis , apnea - hypopnea index ( ahi or rate of apneas and hypopneas per hour of sleep ) , percentage of sleep time spent in stage 1 sleep ( n1% ) , percentage in stage 2 sleep ( n2% ) , percentage in stage 3 ( slow wave ) sleep ( n3% ) , percentage in rem sleep ( rem% ) , arousal index ( number of arousals per hour of sleep ) , number of sleep stage shifts , sleep latency , sleep efficiency ( se , ratio of time spent asleep to the amount of time spent in bed ) , the periodic leg movement index ( plmi ) , and epworth sleepiness scale ( ess ) scores .
the epworth sleepiness scale is an eight - item questionnaire that asks the patient to rate , on a likert scale , the likelihood of dozing in a variety of sedentary situations .
medical records were reviewed to confirm eligibility and extract additional data regarding ms - specific variables .
individuals with concomitant diseases that could increase the risk of sleep apnea or influence fatigue level , including cancer , severe cardiopulmonary disease , pregnancy , major depressive disorder ( within 6 months of psg ) , or neurologic diseases other than ms , were excluded . for ms subjects ,
additional variables recorded included ms subtype ( relapsing - remitting versus progressive ) , disease duration at time of psg ( years ) , use of disease modifying therapy ( dmt , defined as glatiramer acetate or beta - interferon use at the time of psg ) , and estimates of disability ( defined as an edss score of less than 6.0 ( low disability ) or greater than or equal to 6.0 ( high disability ) ) . developed in 1996 by one of the investigators ( rc ) ,
the university of michigan sleepiness impact assessment ( umsia ) is a self - administered questionnaire that allows patients to rate , in a parallel manner , the frequency that sleepiness and associated symptoms affect their daily life using 5-point likert scales . for our study , categorical responses regarding the frequency of problematic sleepiness , fatigue , tiredness , and lack of energy ( rated as  never  = 1 ,  seldom  = 2 ,  occasionally 
full , laboratory - based polysomnography ( psg ) and scoring followed existing standards before 2008 , and then slightly different , newly published standards from that point forward . the main relevant change concerned use of nasal pressure to identify hypopneas and rules employed to score them .
our laboratory had already been using thoracic or abdominal excursion changes , in addition to thermocouple airflow changes ( when any of these were followed by awakenings , arousals , or 4% oxygen desaturations ) to identify hypopneas in a sensitive manner before the aasm 2007 standards were published . the apnea - hypopnea index ( ahi )
was calculated as the number of obstructive apneas , central apneas , or hypopneas per hour of sleep .
the presence of obstructive sleep apnea was defined by an apnea - hypopnea index of at least five episodes per hour of sleep .
umsia responses for each symptom ( fatigue , tiredness , lack of energy , and sleepiness ) were dichotomized into 2 categories : frequent ( for responses of  often  or  almost always  ) and infrequent ( for responses of  never ,   seldom ,  or  occasionally  ) and compared between ms patients and controls using chi - square tests .
two - sample t tests ( for normal continuous data ) , chi - square tests ( for dichotomized data ) , and wilcoxon rank - sum tests ( for nonnormal continuous data ) were used to compare baseline characteristics among ms patients and controls .
spearman correlation tests were used to examine associations between categorical umsia responses ( reported frequencies of problematic fatigue , tiredness , lack of energy , and sleepiness ) , epworth scores , demographic information , and psg parameters of interest ( ahi , sleep efficiency , n1% , n2% , n3% , rem% , sleep latency , arousal index , number of sleep stage shifts , and plmi ) separately within ms and control groups .  
chi - square tests , t tests , and multiple linear regression models were also used to compare dichotomized umsia responses and psg variables between ms subgroups of interest ( relapsing - remitting versus progressive ms , use of dmt and disability status , as defined in section 2.1.3 ) .  
  baseline characteristics for n = 30 ms patients and n = 30 matched controls are shown in table 1 .
no significant differences between ms subjects and matched controls emerged for matched variables ( bmi , gender , or age ) or the other comparators listed , except for number of sleep stage shifts ( p = 0.017 ) . for ms patients ,
seventy percent of ms subjects and seventy percent of matched controls were female , consistent with the gender distributions seen in ms in the united states .
for those with available data , 21 ( 70% ) ms subjects had relapsing - remitting disease , and nine ( 30% ) had progressive disease .
twenty ( 67% ) of the ms patients were on disease modifying therapy ( dmt ) , and ten ( 33% ) were not .
eighty percent of ms patients and 63% of controls met diagnostic criteria for obstructive sleep apnea ( see section 2.3 ) .   
response rates to categorical umsia items and distribution of symptom frequencies for ms patients and matched controls are shown in figure 1 .
when responses were dichotomized , significantly more ms patients than controls reported fatigue , tiredness , and lack of energy to occur often or almost always ( 90% versus 18% , 77% versus 0% , and 90% versus 7% ; chi - square p < 0.0001 for each ) .
conversely , frequent sleepiness as per the umsia was reported similarly by both groups ( 53% versus 65% ; p = 0.3409 ) .
there were strong correlations between fatigue , tiredness , and lack of energy in both groups ( table 2 ) . among ms patients ,
tiredness correlated with sleepiness , ( rho = 0.50 ; p = 0.005 ) , and a trend emerged toward a significant correlation between fatigue and sleepiness ( rho = 0.33 ; p = 0.076 ) . among controls , fatigue correlated with sleepiness ( rho = 0.45 ; p = 0.034 ) .
decreased nocturnal sleep efficiency correlated with fatigue , tiredness , and lack of energy in ms patients ( rho = 0.55 , p = 0.002 ; rho = 0.40 , p = 0.029 ; and rho = 0.36 , p = 0.048 , resp . ) , but not with sleepiness in ms patients or with any symptom among controls .
no significant relationship emerged between mean epworth scores and umsia reports of sleepiness among ms patients or controls , although trends suggested a positive correlation between epworth score and fatigue , and between ess score and tiredness in the ms group ( table 2 ) .   a trend toward a significant increase in ahi among ms patients compared to controls emerged in regression models , after adjustment for age and bmi ( p = 0.0647 , not shown ) .
no significant difference was noted in mean n1% , n3% , rem% , arousal index , sleep latency , or sleep efficiency among ms patients compared to controls , though a trend toward decreased n2% emerged in the ms group .
there was also a nonsignificant increase in mean plmi among ms patients compared to controls .   
dichotomized frequencies of fatigue , tiredness , lack of energy , and sleepiness ( often or always versus less commonly ) did not significantly vary by ms subtype or disability status .
sleep efficiency and rem% were significantly decreased in progressive ms subtypes compared to relapsing - remitting ms , after adjusting for ahi and age in regression models ( p = 0.0442 and 0.0373 , resp . ) and in subjects with high disability ( edss  6.0 ) compared to those with low ( edss < 6.0 ) disability status ( p = 0.0048 and 0.0061 , resp . ) .
the association between progressive ms and apnea severity ( ahi ) approached significance in regression models , after adjustment for age and bmi ( p = 0.0596 ) .
the presence or absence of disease modifying therapy ( dmt ) also did not influence the frequency of any symptom .
epworth scores , sleep efficiency , sleep stages , and the plmi were not influenced by dmt use , but use of dmt was associated with decreased ahi ( t - test p = 0.0419 ) .
details regarding the relationships between dmt , disease subtype , and ahi in all n = 48 ms subjects with available psg data ( regardless of umsia completion ) , after adjustment for additional variables known to influence ahi , have been described previously   ( see section 2.1 ) .
  this study of symptoms and psg findings among ms patients and non - ms controls shows that ms patients with suspected sleep problems are more likely than controls to emphasize problematic fatigue , tiredness , and lack of energy , as opposed to sleepiness .
furthermore , decreased sleep efficiency correlated with increased symptoms of tiredness , fatigue , and lack of energy in patients with ms .
our findings are particularly surprising given that sleep efficiency itself , objectively assessed on polysomnography , was essentially identical between ms patients and controls .
these data raise important considerations for understanding fatigue and related symptoms among persons with ms .
in particular , our results suggest that patients with ms may exhibit an increased sensitivity to the downstream effects of diminished sleep efficiency compared to patients without ms .
our findings raise the possibility that measures to increase sleep efficiency in ms could improve daytime fatigue , regardless of whether concomitant sleep disorders are present .  
while fatigue has long been recognized for its impact on the health and quality of life of persons with ms , separation of treatable from untreatable causes can be challenging , given the wide range of potential etiologies .
in addition to contributions from cytokine dysregulation , ms - related fatigue may also be influenced by cns lesion burden , medication effects , and other conditions concomitant with ms , including depression , pain , and sleep disturbances .
while validated instruments to quantify fatigue or assess its impact on the function of persons with ms are commonly employed in both clinical and research settings , most of these instruments do not include items to define fatigue or describe it in the context of similar symptoms such as sleepiness .
subsequently , subjects are left to quantify their fatigue on the basis of their own subjective interpretation , which may vary by education , disease - specific biases , or cultural backgrounds .
this ambiguity increases the potential for overlap among terms used to describe symptoms experienced by ms patients with concomitant sleep disorders .
consequently , ms patients suffering from sleep disorders who describe symptoms other than sleepiness may escape formal sleep evaluations , as fatigue and related symptoms are expected consequences of ms itself .
growing evidence suggests that sleep disturbances may be closely linked to fatigue in persons with ms .
a recent prospective psg study in ms subjects and controls suggests that severe obstructive sleep apnea ( defined as an ahi  30 ) is independently associated with fatigue in ms , as defined by the fatigue severity scale .
the nine - response fatigue severity scale ( fss ) assesses the impact of fatigue on multiple outcomes , with a physical focus , using a 7-point likert scale .  
a separate group   found that fatigue , quantified using a french version of the fatigue impact scale ( fis ) , correlated strongly with sleep disturbances as measured by the pittsburgh sleep quality index among individuals with ms .
a similar association was also demonstrated with the fss as the primary fatigue outcome measure . using home psg , veauthier and
colleagues reported an increase in the prevalence of clinically relevant sleep disorders , including sleep disordered breathing , in fatigued ms patients compared to nonfatigued patients as defined by the modified fatigue impact scale .   whereas the above studies highlight fatigue as a potential consequence of sleep disturbances in ms , these and other studies of relationships between fatigue and sleep disorders in ms have relied on instruments that do not allow a direct comparison between sleepiness , fatigue , and related symptoms in a systematic manner .
our study is the first to address each of these symptoms separately using parallel phrasing , while relating them to objective psg measures .
while the umsia questionnaire has yet to be validated in patients with ms , our data suggest that ms patients with sleep disorders may share a propensity for terms other than sleepiness to describe their symptoms . furthermore , use of these terms may signal decreased sleep efficiency in this population .
one possible explanation for the strong correlation between fatigue level and sleep efficiency in ms may relate to what is known about the role of cytokine dysregulation in fatigue .
proinflammatory cytokines , produced by autoimmune effector cells , are proposed to contribute to fatigue in ms [ 20 , 21 ] .
it is noteworthy that two of these cytokines , il-6 and tnf - alpha , are also elevated in the serum of individuals with obstructive sleep apnea and sleep deprivation and correlate with fatigue and sleepiness in general population studies [ 2225 ] . while conclusions about a causal relationship between cytokine dysregulation and reported symptoms can not be drawn from our retrospective cross - sectional study , our findings highlight a common immunological pathway between ms and sleep disturbances , which may synergistically amplify fatigue when sleep efficiency is reduced .  
while the lack of correlation between sleepiness and sleep efficiency in both groups may appear counterintuitive , it is consistent with previous reports . despite the traditional clinician emphasis on sleepiness
, many subjects in the general population who have sleep disorders prefer to use terms other than sleepiness to describe their daytime symptoms .
furthermore , previous data from our group have shown little or no association between measured sleep efficiency and either subjective   or objective   daytime sleepiness .
data on potential variables that could influence fatigue and related symptoms in the ms group were not available in a consistent format that could be useful in the analyses .
these include detailed information on depressive symptoms , disease coping strategies , psychosocial factors , and medications ( such as antispasmodics , narcotics , or sleep aids ) that are often used by patients with ms , as well as mri lesion burden and respiratory function , which could influence apnea scores .
subjects whose records indicated severe depression in medical charts were excluded from analyses , but milder depressive symptoms that may not warrant a diagnosis of major depression could not be reliably studied from this retrospective chart review . finally , the number of completed umsia responses for fatigue frequency was by chance slightly lower in the control group , which could theoretically explain the differences in correlation between fatigue level and sleep efficiency among ms patients versus controls .
this is thought to be less likely , however , given the strong differences in correlation between tiredness / lack of energy and sleep efficiency among ms patients versus controls , where the number of completed umsia responses was similar for both groups .   despite these limitations
, our data suggest that ms patients referred to a sleep laboratory are more likely than referred controls to complain of fatigue and related symptoms other than sleepiness , a more widely recognized consequence of sleep disturbances .
our study highlights the importance of considering physiologic sleep disturbance in ms patients who complain of fatigue , tiredness , lack of energy , or sleepiness .
our data suggest that ms patients , in comparison to matched controls also referred for polysomnography , report more fatigue , tiredness , and lack energy , but not sleepiness .
fatigue and significant symptoms other than sleepiness may arise from ms itself or in relation to sleep disturbance as reflected by reduced sleep efficiency in particular , which could offer opportunities for effective intervention .
 
 objectives . to assess the relationship between nocturnal polysomnographic ( psg ) findings and a group of key self - reported symptoms  fatigue , tiredness , lack of energy , and sleepiness  among sleep - laboratory referred patients with and without multiple sclerosis ( ms ) . 
 methods . 
 psg and questionnaire data from n = 30 ms patients and n = 30 matched controls were analyzed retrospectively . 
 associations between symptoms of fatigue , tiredness , lack of energy , sleepiness , and psg variables of interest were examined among ms patients and controls . results . 
 more ms patients than controls reported fatigue , tiredness , and lack of energy to occur often or almost always ( chi - square p < 0.0001 for each ) , but sleepiness was reported similarly by both groups ( p = 0.3409 ) . among ms patients , 
 tiredness correlated with sleepiness ( spearman correlation p = 0.005 ) , and a trend emerged toward correlation between fatigue and sleepiness ( spearman correlation p = 0.076 ) . decreased sleep efficiency on psgs correlated with fatigue , tiredness , and lack of energy in ms patients ( spearman correlation p = 0.002 , 0.029 , and 0.048 , resp . ) , but not sleepiness or any symptom among controls . conclusion . in comparison to controls , ms patients report more fatigue , tiredness , and lack energy , but not sleepiness . 
 fatigue and related symptoms may arise from ms itself or in relation to reduced sleep efficiency . 
1. Introduction
2. Methods
3. Results
4. Discussion
5. Conclusion