Fatigue in adults with Marfan syndrome, occurrence and associations to pain and other factors

INTRODUCTION

Marfan syndrome (MFS) is a rare, autosomal dominant genetic connective tissue disorder caused by mutations in the fibrillin 1 gene. It is diagnosed using using diagnostic criteria; the Ghent 1 criteria from 1996 [De Paepe et al., 1996], and the Ghent 2 criteria from 2010 [Loeys et al., 2010]. MFS can affect several organ systems [De Paepe et al., 1996]. Clinical symptoms vary both between and within families, and tend to evolve with age [Loeys et al., 2010]. The most serious complication relates to the cardiovascular system with risk of dilatation and dissection of the aorta and other large vessels [Loeys et al., 2010]. Many have skeletal signs with long limbs, hypermobile joints, chest deformities, and scoliosis [De Paepe et al., 1996]. Some describe chronic pain [Peters et al., 2001a]. Visual problems are common due to lens dislocation, which entails risk for retinal detachment [De Paepe et al., 1996]. To reduce the risk of aortic dilatation and lens dislocation, many patients are advised to refrain from contact sports and to limit their physical exertion [Loeys et al., 2010]. This may lead to inactivity and a sedentary lifestyle [Rand-Hendriksen et al., 2010].

MFS patients described how fatigue limits their daily life. Few studies, however, examined the occurrence of fatigue and its possible associations in adults with verified MFS. Increased knowledge is imperative to understand fatigue in MFS patients and to design intervention strategies. Fatigue is a multifaceted concept covering physiological and psychological aspects. It is often described as an “overwhelming sense of tiredness, lack of energy and feeling of exhaustion, mental, physical or both” [Dittner et al., 2004]. Severe fatigue is common in the general population with 22% prevalence [Loge et al., 1998; Bültmann et al., 2002a; Lerdal et al., 2005]. Fatigue is associated with having a chronic health problem [Lerdal et al., 2005], occupational status [Loge et al., 1998], psychological distress [Pawlikowska et al., 1994], and low physical activity [Bültmann et al., 2002b], and is reported as a debilitating symptom in many different diseases [Dittner et al., 2004].

We identified only four studies exploring fatigue in MFS, including 260 patients total [Peters et al., 2001a; Percheron et al., 2007; Rand-Hendriksen et al., 2007; van Dijk et al., 2008]. One study found that 89% of their respondents with self-reported MFS experienced fatigue, that the experience of fatigue significantly heightened the respondent's perception of their condition's severity, and that it was significantly associated with the use of cardiovascular medication [Peters et al., 2001a]. The other three studies included participants with MFS verified by diagnostic criteria; and all report higher fatigue scores compared to healthy controls on different instruments [Percheron et al., 2007; Rand-Hendriksen et al., 2007; van Dijk et al., 2008]. Fatigue was associated with psychological distress (in women) [Rand-Hendriksen et al., 2007] and orthostatic intolerance [van Dijk et al., 2008]. The studies didn't use multivariable analyses. Methodological differences make further comparison difficult. Given the complexity of MFS, we expect that several factors, such as Marfan-related health problems, may be associated with fatigue. Our study aims to explore how fatigue affects MFS patients in their daily lives by examining the level of fatigue and prevalence of severe fatigue in adults with verified MFS.

MATERIALS AND METHODS

This cross-sectional, postal questionnaire based study is part of a larger study about challenges in education, work, and daily life for adults with MFS. The study has been approved by the Data Protection Officer at Oslo University Hospital and the Regional Ethics Committee for medical and health research ethics in eastern Norway. Permission was given to collect and analyze anonymous questionnaire data.

Participants and Procedure

In spring 2010, we examined the patient journals of all patients age 20 and above (n = 180), registered with MFS at TRS National Resource Centre for rare disorders in Norway. All patients with documentation confirming that they fulfilled the Ghent 1 criteria (the available criteria at the time) (n = 117) were invited to participate in the study and received a consent form and questionnaire by post. After 6 weeks patients who had not responded received a reminder with a new copy of the questionnaire. Seventy-three persons returned the questionnaires (response rate of 62%). One respondent's questionnaire missed all items on the FSS, and was omitted from this part of the study. Figure 1 shows a flow chart of the recruitment of participants.

RESULTS

Of the 72 respondents, 41 were women (57%). Table I displays respondents socio-demographic characteristics, prevalence of Marfan-related health problems and chronic pain.

Non-respondents (n = 44) were not significantly different from respondents regarding gender (29 women, 67%), or age (mean = 41.4, range 20–76). The FSS item with highest mean score was, “My motivation is lower when I am fatigued,” for which 86% of respondents scored ≥5. Sixty percent of respondents scored five or higher on the item, “Fatigue interferes with my work, my family, or social life” (Table II).

A comparison of mean FSS scores for the study sample to reported values from previously published studies of the general Norwegian population, other MFS studies, and other patient groups is shown in Figure 2. The mean FSS score for the study group (4.72, SD 1.40) is significantly higher than for the general Norwegian population [Lerdal et al., 2005] and for patients with RA [Mancuso et al., 2006], not significantly different from the MFS study by Rand-Hendriksen et al. [2007], but significantly lower than for the other MFS group [Percheron et al., 2007], for patients with EDS-HT/JHS [Celletti et al., 2013] and patients with PD [Hagemans et al., 2007] (Table III).

Forty-two percent of respondents had a mean FSS score of five or higher (indicating severe fatigue), while 29% had a score between four and five (indicating borderline fatigue) and 29% had a score equal to or under four (indicating non-fatigue). In initial bivariate analyses, FSS scores had a significant but weak positive correlation to age (r = 0.25, P = 0.03) but not to age when diagnosed with MFS (r = 0.11, P = 0.35). FSS scores were significantly associated with gender, employment status, and chronic pain but not to other variables (Table IV).

In multivariable regression analyses we first included age, gender, education level, chronic pain, and employment status. After controlling for age and gender, only chronic pain and employment status remained significant. Persons with chronic pain had higher levels of fatigue than persons without chronic pain. Participants with disability benefits had higher fatigue scores than those working or under higher education. The final multivariable regression model (Table V) explained 24% of the variance in FSS scores (adjusted R² = 0.24).

DISCUSSION

This study found that many adult MFS patients experience fatigue interfering with daily activities. Levels of fatigue and prevalence of severe fatigue are higher in these adult MFS patients compared to the general Norwegian population [Lerdal et al., 2005], suggesting that fatigue significantly impacts their daily live.

Single-item distribution analysis revealed that 60% and 57%, respectively, had a mean score ≥5 for the items, “fatigue interferes with my work, family, and social life” and “fatigue is among my most debilitating symptoms.” This underscores that fatigue interferes with daily life for adults with MFS, and that it is important to address fatigue in clinical settings. Interestingly, the question “exercise brings on my fatigue” is the item with lowest mean score, and only 39% had a mean FSS score ≥5. In comparison Hagemans et al. [2007] found that 84% of patients with late onset PD had a mean FSS score ≥5 on this item. Late onset PD entails weakness of the skeletal and respiratory muscles and possibly more severe physical disability than MFS. The disparity in findings may therefore be explained by differences in physical disability. However, one might ask if this is related to the advice on physical restrictions given to many MFS patients to prevent medical complications. One hypothesis is that many MFS patients perform only low intensity exercises, as reported by Peters et al., [2001b], and thus do not experience that exercise brings on fatigue. It is important to note that the item “fatigue interferes with my physical functioning” has the second highest mean in the MFS group and 78% have a mean FSS score ≥5. This shows that physical functioning may be troublesome and connected to fatigue.

Our participants report significantly higher fatigue compared to the general Norwegian population [Lerdal et al., 2005] and patients with RA [Mancuso et al., 2006]. These differences also exceed MCID values proposed for other patient groups [Goligher et al., 2008; Pouchot et al., 2008], indicating that the differences are clinically relevant. However, our participants have lower mean FSS score than patients with PD [Hagemans et al., 2007] and EDS-HT/JHS [Celletti et al., 2013]. The latter, also a connective tissue disorder, is associated with hypermobility and musculoskeletal pain [Rombaut et al., 2010], but not with life-threatening complications. Therefore it is somewhat surprising that patients with EDS-HT/JHS have significantly higher fatigue scores than MFS patients. This might indicate that factors other than disease severity contribute to fatigue.

Forty-two percent of the participants reported severe fatigue [FSS mean score ≥ 5], which is higher than in the general Norwegian population (23%) [Lerdal et al., 2005] and for patients with RA (30%) [Mancuso et al., 2006]. By contrast, 67% of patients with late onset PD reported severe fatigue [Hagemans et al., 2007]. However, the variance in fatigue scores in adults with MFS are large, and approximately one third (29%) of participants reported non-fatigue (FSS mean score ≤ 4) compared to 53% in the general Norwegian population [Lerdal et al., 2005].

Interestingly, we found no significant associations between fatigue scores and Marfan-related health problems (i.e., aortic dilatation, aortic dissection, aortic surgery, and visual impairment due to lens dislocation or retinal detachment). We expected these factors to be of importance. Since the group without aortic dilation was small, this result should be interpreted with caution. We found no significant associations between fatigue and the use of blood pressure medication. The mean FSS score was not significantly different in the group using blood pressure medication (4.72), compared to the group who did not (4.70) (Table I). This contrasts the results from Peters et al. [2001a, 2001b], who found significant associations between cardiovascular medication use and fatigue. The discrepancy might derive from methodological factors; such as inclusion criteria, disease characteristics, and use of different questionnaires. Since questions about type and dosage of blood pressure medication were not included in our study, differences in fatigue levels related to types and dosage of the medications cannot be analzyed. Further comparison with results from the study by Peters et al. [2001a, 2001b] is also difficult.

It has been an accepted fact that there is a correlation between use of beta-blockers and fatigue [Ko et al., 2004]. Two systematic review studies dispute this view [Ko et al., 2002, 2004]. Meta-analyses showed no absolute risk of fatigue associated with beta-blocker therapy in patients with heart failure [Ko et al., 2004], and only a small increase in patients with myocardial infarction [Ko et al., 2002]. This underscores the need for studies investigating the association between fatigue and use of blood pressure medications in MFS.

In our multivariable analyses, chronic pain and employment status show significant associations to fatigue. Pain is most strongly associated to fatigue. Sixty-four percent of participants reported chronic pain. This is higher than for the general Norwegian population with 45% reporting chronic pain/stiffness in muscles and joints [Svebak et al., 2006]. In comparison, Peters et al. [2001a] found that 90% of their respondents with MFS experienced pain on a regular basis. This illustrates that the prevalence of pain may vary in different Marfan populations. Pain is also highly prevalent in EDS-HT [Voermans et al., 2010; Rombaut et al., 2011]. EDS-HT shares some signs with MFS, like hypermobility. To our knowledge the association between hypermobility, fatigue, and pain in connective tissue disorders has not been extensively studied.

We didn't find articles exploring associations between fatigue and pain in MFS patients. In other patient groups, such as RA, studies report conflicting results. Mancuso et al. [2006] found significant associations in employed RA patients between FSS scores and pain in bivariate, but not in multivariable analyses. In contrast, Pollard et al. [2006] found pain to be the factor most strongly associated with fatigue in multivariable analyses in a study of RA patients ages 22–91 years. The disparity between the studies may be caused by methodological differences. In patients with ankylosing spondylitis pain was the factor most strongly associated to fatigue in multivariable analyses, and the authors suggest that treatment of fatigue should focus on pain management [Brophy et al., 2013]. In our study, receiving disability benefits was associated with higher mean FSS scores than being employed or enrolled in higher education. This result concurs with that for the general Norwegian population [Loge et al., 1998], in which people receiving disability benefits and being unemployed reported the highest levels of fatigue. Our study was cross-sectional, hence we could not explore causal associations. Future studies should investigate whether either work or disease-specific variables explain why persons with MFS are unable to work and if this is associated to fatigue.

The final multivariable model explains 24% of the variance in fatigue scores. This implies that other factors contribute to fatigue. Given the complexity of fatigue and MFS, this is not surprising. One factor of interest is depression, since association between depression and fatigue has been reported [Ferentinos et al., 2011]. MFS is a disease with possible life-threatening complications, and many may experience psychological challenges. Rand-Hendriksen et al. [2007] found that psychological distress can be associated with fatigue in women with MFS, but argue that their study was too small to conclude with certainty. Peters et al., [2001a] did not find associations between fatigue and depression in MFS patients Thus, current knowledge on fatigue and psychological issues in MFS is diverging.

Other factors possibly associated to fatigue in MFS are sleep disturbance and physical activity. Sleep disturbances are common in patients with chronic pain conditions [Menefee et al., 2000] and associated with fatigue in patients with multiple sclerosis [Kaminska et al., 2012]. Treatment of obstructive sleep apnea has been found effective for treating fatigue [Chotinaiwattarakul et al., 2009]. Sleep disturbances like obstructive sleep apnea are common in MFS patients [Rybczynski et al., 2010], and the possible association between fatigue and sleep apnea should be investigated.

Being physically inactive during leisure time is an important predictive factor for fatigue in healthy male employees [Bültmann et al., 2002b]. The association between physical activity and fatigue has not been explored in MFS patients. This might be important, since MFS patients often are advised to limit their physical exertion. In other patient groups physical activity and training has been found effective for treating fatigue [Neill et al., 2006; Dalgas et al., 2010].

CONCLUSION

This study confirms that fatigue affects persons with MFS by interfering with their daily lives. Their level of fatigue and the prevalence of severe fatigue are higher than reported for both the general population and a study sample of RA patients, but lower than reported for groups of patients with other chronic conditions. Multivariable regression analyses reveal that chronic pain and employment status show significant associations to fatigue. There is need for more research on fatigue in Marfan syndrome.