Fatigue is significant in vasovagal syncope and is associated with autonomic symptoms

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1 Europace (2008) 10, doi: /europace/eun164 Fatigue is significant in vasovagal syncope and is associated with autonomic symptoms Henrietta Legge, Michael Norton, and Julia L. Newton* Falls and Syncope Service, Institute of Cellular Medicine, Newcastle University, Newcastle, UK Received 21 January 2008; accepted after revision 23 May 2008; online publish-ahead-of-print 10 June 2008 KEYWORDS Vasovagal syncope; Fatigue; Autonomic nervous system Aims To quantify the prevalence of fatigue and its severity in vasovagal syncope (VVS) and to examine whether fatigue severity associates with symptoms of autonomic dysfunction. Methods and results All vasovagal syncope patients diagnosed between September 2004 and March 2006 were included (n ¼ 140). Fatigue was quantified using the fatigue impact scale (FIS) and severity and type of autonomic symptoms by the composite autonomic symptom scale (COMPASS). Patients were considered a responders if they were no longer experiencing VVS symptoms or non-responders if VVS symptoms were on-going. The VVS cohort was matched, in terms of both age and sex, with a group of community dwelling controls. Ninety-six VVS patients completed questionnaires (response rate 96/ 140, 69%). Compared with matched controls, VVS patients were significantly more fatigued ( vs , P, ) and a significantly higher autonomic symptom burden (COMPASS total score: vs ; P, ). Significant correlations were seen between the total COMPASS score and fatigue severity (r 2 ¼ 0.4; P, ). Non-responders reported significantly higher fatigue and more autonomic symptoms than responders to treatment (P ). Conclusion Fatigue is a significant problem experienced by patients with VVS and is associated with autonomic symptoms, the severity of which correlates with fatigue severity. These symptoms are especially profound in those who have not responded to treatment. Introduction Vasovagal syncope (VVS) is an exaggerated tendency to the common faint that affects all age groups. 1 It is not considered a condition with an increased risk of mortality or morbidity, although there is clearly a risk of injury as a result of loss of consciousness. 2 Vasovagal syncope can, however, be a severely disabling condition with sufferers reporting a significantly reduced quality of life. 3 5 Furthermore, those who remain symptomatic report significantly higher levels of impairment due to syncope, more fear and worry about syncope, and higher levels of psychological distress. 6 Previous studies have characterized the non-syncopal symptoms experienced by those with VVS and found using semi-structured interviews that 71% describe autonomic symptoms and three quarters experience severe fatigue after events, 7 with 21% of the VVS patients (and no controls) fulfilling the symptom criteria for chronic fatigue syndrome (CFS). 8 In contrast, studies report that the prevalence of syncope and/or pre-syncope in those with CFS is between * Corresponding author. Tel: þ ; fax: þ address: julia.newton@nuth.nhs.uk or julianewton@blueyonder.co.uk 40 and 90%, 9,10 with overlap also reported for other VVS-associated symptoms such as light headedness (96% of those with CFS). 9 Furthermore, the treatment of neurally mediated hypotension when found in those with CFS can be associated with an improvement in the symptoms of chronic fatigue, cognitive disturbances, and light headedness. 11 In addition, CFS affects 0.5 2% of the population who comprise a similar demographic group as those who experience VVS. Such a degree of symptomatic and demographic overlap raises the possibility that these two syndromes share a common pathophysiological basis. Studies examining the underlying biological basis of CFS have historically proved complex and contradictory results; however, there is evidence that abnormalities of the vascular system and its regulation by the autonomic nervous system, especially in response to standing, may be a common abnormality in CFS It is this autonomic dysfunction that may link the two disorders in certain patients because this is recognized as a potential contributory factor in the underlying pathophysiology of VVS. 16,17 This study therefore set out to quantify for the first time the prevalence of fatigue and its severity in VVS, and to examine whether, as has been recently found in CFS, fatigue severity associates with symptoms of Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 1096 H. Legge et al. autonomic dysfunction. 18 Our hypothesis being that, as in other diseases characterized by hypotension, fatigue is common in VVS and is associated with autonomic symptoms. Lessons learnt from further understanding the symptoms associated with, and the pathophysiology of, VVS may direct intervention studies in CFS. Methods Participants The study cohort was identified from our VVS database. Subjects were consecutive patients who had been seen in our unit with VVS diagnosed by symptom reproduction associated with haemodynamic change during head up tilt test. 19,20 Head up tilt test is performed in all patients who attend the unit with a clinical history consistent with VVS. The diagnosis is made when patients experience hypotension in response to head up tilt (and/or bradycardia) in association with reproduction of their presenting symptoms of syncope or presyncope. Other causes of syncope had been ruled out. All patients diagnosed between September 2004 and March 2006 were included (n ¼ 140). Symptom assessment tools were sent by post to all patients in May 2007 who were invited to complete and return the questionnaires using a pre-paid envelope. A review of the medical notes and details provided by the patient determined whether they were considered as responders (i.e. following diagnosis, the standardized clinical intervention algorithm was applied and the participant, in response to this clinical interventional algorithm or spontaneously, reported a full recovery) or non-responders (i.e. had on-going VVS symptoms). 6 For the purpose of analysis, the total VVS cohort was therefore substratified into those who had on-going symptoms (non-responders to treatment) and those who considered themselves asymptomatic (responders to treatment). The management strategy for this cohort is standardized and consistent, and it initially includes conservative advice, including specific advice regarding counter manoeuvres increase fluid and/ or caffeine intake, followed 3 months later if symptoms persist with the commencement of medication, initially with fludrocortisone, midodrine, or selective serotonin receptor inhibitor (SSRI) as dictated by the clinical situation. Those who had experienced on-going symptoms at the time of completion of the questionnaires (the non-responders) were further substratified into those who were continuing to experience syncope or pre-syncope (sensation of impending syncope). The total VVS cohort was matched, in terms of both sex and age, with a group of community dwelling controls. The control group was recruited from the local population through advertisements by inviting people to participate into research in the autonomic nervous system. No selection was made on the basis of presence or absence of fatigue, VVS, or co-morbidity. Symptom assessment tools Subjects completed a series of symptom assessment tools. All are fully validated for self-completion, and the results were compared with an age- and sex-matched control population. Fatigue impact scale This is a 40-item symptom-specific profile measure of health-related quality of life, commonly used in medical conditions in which fatigue is a prominent symptom. The scale allows patients to rate each item on a scale of 0 4, with 0 representing no problem and 4 representing an extreme problem. Adding the scores for the individual items creates a total score. The higher the total score, the more fatigued the subject is interpreted to be. 21 Epworth sleepiness scale This 8-item scale is designed to evaluate patients general level of daytime sleepiness. This scale is fully validated to assess daytime hypersomnolence. Patients rate the likelihood that they would doze off in a variety of situations, for example, in the car or in front of the television. Zero represents a situation in which the patient feels they would never doze off and three represents a high chance that they would doze off in the given situation. The scores are added together to produce a total score. The greater the total score, the greater daytime hypersomnolence the patient feels. 22 Orthostatic grading scale This 5-item scale evaluates the frequency and severity of orthostatic symptoms, the relationship between orthostatic symptoms and other orthostatic symptoms, and the impact of these symptoms on the daily life of the patients, for example, on daily activities and standing time. Participants rate each item on a scale of 0 4. Zero would indicate that dizziness has no impact on their day-to-day life, whereas 4 indicates that dizziness severely interferes with daily life. 23 Composite autonomic symptom scale A composite autonomic symptom scale is a comprehensive and highly sensitive assessment of the prevalence, degree, and association between symptoms of autonomic dysfunction. The COMPASS has been fully validated against laboratory-based haemodynamic autonomic function tests and has been used effectively in the identification of autonomic dysfunction in a wide variety of conditions. 18,24 The COMPASS consists of 73 questions that are grouped into eight domains relating to individual aspects of the autonomic nervous system. The eight domains relate to orthostatic intolerance, vasomotor, secretomotor, gastrointestinal (further split into the subdomains of autonomic diarrhoea and constipation), bladder, pupil responses (including focusing), sleep disorder, and syncope. The scale also included domains for male erectile dysfunction and ejaculatory problems which were removed due to suspected irrelevance and also in an effort to reduce the length of the questionnaire. Each domain is scored on the basis of existence, intensity, distribution, frequency, and progression of symptoms. The domains that were included were weighted according to their clinical relevance as described in the original derivation paper. The individual scores are then totalled to serve as an indicator of overall symptom burden. In all cases, higher scores were indicative of the greatest symptom load, with 179 being the possible highest total score. Two further scales (understatement and psychosomatic) were incorporated into the assessment and were scored independently of the COMPASS score itself. These scales were included in order to detect a tendency for participants to over or under report the symptoms they have. These validity scales served as indicators of whether the participant had actively engaged in the completion of the questionnaire. Procedure All patients who were included in the VVS cohort were sent the combined questionnaires for self-completion, which were returned in a pre-paid envelope. In an attempt to increase the sample number, a second set of the same questionnaires was sent out to all those who had not replied after 2 months. Consent for the use of data was implied by the return of questionnaires. The study was approved by the Local Research Ethics Committee. Data analysis Data were analysed using the Graph Pad-Prism statistics package. All total scores and COMPASS domains were found to be normally distributed, and comparisons were therefore made between the VVS patients and the control group using parametric unpaired t-tests. The only domains that were found to be skewed were the understatement and overscoring domains of the COMPASS scale; comparisons were made using non-parametric analyses. Correlations using appropriate parametric and non-parametric tests were then conducted to assess the relationship between the fatigue severity and

3 Fatigue in VVS 1097 Table 1 Demographics and mean + SD of symptom assessment tools in the vasovagal syncope cohort compared with the control population Controls VVS P n ns Age ns Male 20 (22%) 20 (22%) ns FIS < ESS < Orthostatic tolerance < Vasomotor Secretomotor < Gastrointestinal Autonomic diarrhoea Constipation Bladder Pupils Sleep disorder < Syncope < Underscoring < Overscoring Total < Statistically significant results after corrections for multiple testing (P, 0.001) are shown in bold. ESS, Epworth sleepiness scores; FIS, fatigue impact scores. each of the other questionnaires. Corrections were made for multiple testing (Bonferroni) and, therefore, a statistically significant result was considered to be when P, Results Ninety-six patients with head up tilt (HUT) confirmed VVS-returned questionnaires (response rate 96/140; 69%). However, five were incomplete and therefore excluded from further study, leaving 91 (65%) complete questionnaires which were included in the analysis. In the VVS group, 44 (48%) patients presented with syncope, 14 (16%) with pre-syncope alone, and 33 (36%) with both syncope and pre-syncope. The demographics of the patient and control groups are shown in Table 1. The prevalence of fatigue, daytime sleepiness, and autonomic symptoms in vasovagal syncope Vasovagal syncope patients were significantly more fatigued t(172) ¼ 3.6; P ¼ (Figure 1) and also reported significantly higher levels of daytime sleepiness t(172) ¼ 5.3; P ¼, (Figure 2) when compared with the matched control population. Patients were twice as fatigued as controls and experienced more than twice the average daytime hypersomnolence of the control group (Table 1 and Figure 1). Vasovagal syncope patients reported a significantly higher number of autonomic symptoms than the control group (Figure 3). This is seen clearly from the COMPASS total score, which is significantly higher for the VVS patients than for the control population, t(170) ¼ 7.4, P, In fact, patients autonomic symptom burden is almost triple that of the symptoms experienced by the control groups. This increase in autonomic symptoms was significant in all of the COMPASS domains, except autonomic diarrhoea, bladder, pupils, and over-scoring. These findings suggest that VVS is associated with a substantial burden of symptoms Figure 1 Fatigue impact scores for the control group compared with vasovagal syncope patients. relating to autonomic dysfunction. As with previous CFS literature, which describes abnormal-dynamic responses to standing, one of the greatest differences seen between VVS patients and the control group relates to the orthostatic tolerance domain, t(169) ¼ 7.4, P, Vasovagal syncope patients had mean orthostatic tolerance scores more than three-fold higher than controls. The COMPASS also contains subscales which are designed to assess understatement and overstatement of symptoms severity. Vasovagal syncope patients were interestingly significantly less likely to understate their symptoms as assessed in this way than the population controls. Overstatement scores were slightly higher in VVS patients when compared with controls, although scores were below one in both groups (potential range 0 10), indicating very low overall impact from overstatement of symptoms. The difference here was non-significant. The relationship between increasing fatigue, daytime sleepiness, and autonomic symptoms in vasovagal syncope In order to explore the associations between increasing fatigue, daytime sleepiness, and autonomic symptoms,

4 1098 H. Legge et al. Figure 2 Epworth sleepiness scores in (A) vasovagal syncope compared with controls and in (B) non-responders vs. responders. Figure 3 Relationship between autonomic symptoms measured by the total composite autonomic symptom scale score and fatigue (B) in responders, (C) non-responders. Table 2 Correlations between fatigue impact scale and the other symptom assessment tools in the vasovagal syncope group FIS vs. r r 2 P ESS < Orthostatic tolerance domain < Vasomotor Secretomotor < Gastrointestinal Autonomic diarrhoea Constipation Bladder Pupils < Sleep disorder Syncope Underscoring Overscoring Total < Statistically significant results after corrections for multiple testing (P, 0.001) are shown in bold. ESS, Epworth sleepiness scores; FIS, fatigue impact scores. the fatigue impact scale (FIS) scores were then correlated with the Epworth sleepiness scores (ESS), orthostatic grading scale (OGS), and each of the COMPASS domain scores (Table 2). Fatigue significantly correlated with the ESS and the OGS scores. A significant correlation was seen between the total COMPASS score and fatigue severity, as assessed using FIS (Figure 3). Such a correlation further indicates the relevance of autonomic symptoms in VVS patients. The prevalence of fatigue and its associations in those who continue to experience vasovagal syncope symptoms compared with those who have responded to treatment The total VVS patient group was subdivided into those who had responded to treatment (i.e. were now asymptomatic) and those who had not (i.e. continued to experience the symptoms of VVS despite treatment). The two groups were then compared for each of the different questionnaire scores and the separate COMPASS domains. Fatigue and daytime sleepiness were significantly greater in the nonresponding group when compared with the group where the treatment had been effective and symptoms were resolved (Table 3 and Figure 4). Non-responders reported significantly more autonomic symptoms than those who had responded to treatment, t(89) ¼ 7.1; P ¼, (Table 3). A large significant difference was found between responders and non-responders,

5 Fatigue in VVS 1099 Table 3 Comparison in symptom assessment tools between responders to treatment and non-responders Responders (n ¼ 44) Non-responders (n ¼ 47) P FIS < ESS Orthostatic tolerance < Vasomotor < Secretomotor Gastrointestinal Autonomic diarrhoea Constipation Bladder Pupils < Sleep Syncope Underscoring Overscoring Total < Statistically significant results after corrections for multiple testing (P, 0.001) are shown in bold. ESS, Epworth sleepiness scores; FIS, fatigue impact scores. Figure 4 Fatigue impact scale scores for the non-responders, subdivided into those with syncope or pre-syncope. especially within the orthostatic tolerance, t(89) ¼ 7.6; P ¼,0.001, and vasomotor domain of the COMPASS questionnaire, t(88) ¼ 4.0; P ¼, In order to determine the contribution of each symptomatic group to fatigue severity in VVS, each of the questionnaire and domain scores for the responder and non-responder groups were then correlated with the patients FIS. Table 4 reports the correlations for the nonresponding to treatment group. None of the correlations for the responding group were significant. It is, therefore, only the results of the non-responder group that influence the overall relationship. The strength of the correlation between FIS scores and the ESS, OGS, and the total COMPASS score was equal for the non-responders (Table 4). The greater fatigue impact scores reported by the nonresponders to the treatment correlated with an increased number of autonomic symptoms reported in the COMPASS questionnaire (Figure 3). Those patients who had responded to the treatment tended to have lower FIS scores and subsequently fewer autonomic symptoms. Determining whether syncope or pre-syncope contribute equally to the symptom burden in vasovagal syncope In order to further explore the difference between the symptom burden in those with syncope and from those Table 4 Correlation between fatigue impact scale scores and each of the other symptom assessment tools in the non-responders r r 2 P ESS Orthostatic tolerance Vasomotor Secretomotor Gastrointestinal Autonomic diarrhoea Constipation Bladder Pupils Sleep Syncope Underscoring Overscoring Total Statistically significant results after corrections for multiple testing (P, 0.001) are shown in bold. with pre-syncope, the non-responders to treatment were further divided into those who were currently suffering syncope (with or without pre-syncope) and those who suffered from pre-syncope alone. Syncope patients presented

6 1100 H. Legge et al. with slightly higher fatigue impact scores, however, the difference was not significant (Figure 4). Discussion This study has confirmed that fatigue is a significant problem experienced by patients with VVS and as in other clinical situations, is associated with autonomic symptoms and excessive daytime sleepiness, and the severity of which correlates with fatigue severity. This study quantifies fatigue and other symptoms for the first time in VVS. The prevalence and severity of these symptoms suggest that VVS is a symptom complex that is not only associated with syncope but also with other symptoms that may arise due to similar or identical pathophysiology. These findings would support our hypothesis that the drop in blood pressure, which is the characteristic of VVS, not only impairs cerebral perfusion, leading to the symptom of syncope/pre-syncope, but may also affect perfusion of other organs, which manifest as the symptom of fatigue, and a wide range of other associated symptoms. The findings of this study are consistent with the previous studies. 7 9 This study has also highlighted a constellation of other previously largely unrecognized symptoms that appear to be associated with VVS. The high prevalence of symptoms consistent with autonomic dysfunction suggests that although the prognosis of VVS might be considered good in terms of the syncopal symptoms, there are a wide range of other symptoms that affect these patients. Importantly, the treatment appears to improve not only the syncopal symptoms but also the other associated symptoms, such as fatigue, and the array of autonomic symptoms seen in this study. Vasovagal syncope patients scored higher than the control groups in each of the COMPASS questionnaire domains. In almost all the domains, VVS patients reported significantly more autonomic symptoms than the control group, with the exception of bladder, autonomic diarrhoea, and pupils. Although this is the first study to consider the symptoms of autonomic dysfunction in relation to VVS, our group has recently found that symptoms of autonomic dysfunction were strongly associated with CFS, and it is well recognized that neurally mediated hypotension is a frequent finding in those with CFS/myalgic encephalomyelitis (ME). 18 Interestingly, our recent CFS study revealed a total autonomic symptom burden only slightly greater than the symptom burden for VVS ( and , respectively) with the most significant difference between controls and patients reported symptoms being within the orthostatic intolerance domain. This current study found a very similar profile of autonomic symptoms in VVS compared with that seen in the recent CFS study. This would support the hypothesis that the underlying biological processes that lead to both VVS and CFS may be similar which may provide important insights into the pathogenesis of fatigue, in general, and considering its prevalence (,2% of the UK population) and severity of CFS/ME, in particular. This study was not designed to examine the direction of associations, therefore causation cannot be determined. However, the presence of fatigue and symptoms in VVS are important to consider when managing patients with VVS and as in endpoints in the context of clinical trials for VVS. The strong associations seen in this study between COMPASS domain scores and excessive daytime sleepiness are consistent with the emerging evidence that autonomic dysfunction and daytime hypersomnolence are the significant contributors to the manifestation of the symptom of fatigue. 18 This study is the first to confirm in a syndrome associated with hypotension that the same is in fact true. The finding of increased fatigue severity in those who continue to experience vasovagal symptoms would suggest that fatigue is not a disease-specific phenomenon in VVS but is in fact related to the physiological abnormalities that occur in these patients, i.e. when the underlying abnormalities are treated, the level of fatigue and its associates return to levels comparable with normal controls. This further reinforces the importance for clear, effective advice and treatment for those with VVS, and we would argue emphasizes the importance of making such a diagnosis conclusively. However, it is important to acknowledge that this needs to be tested both in a prospective, longitudinal study, and also taking into consideration the fluctuating symptoms that can be characteristic of the natural history of VVS. The symptom of syncope is frequently considered more catastrophic than that of pre-syncope. However, the findings from our study suggest that both syncope and pre-syncope impact upon the quality of life of patients with VVS and that consideration of symptoms at both ends of the spectrum of VVS is important. There are some limitations in this study. The primary methodological issue seems to be lower than the expected return rate. Only 65% of the patients responded to the questionnaires, despite the sending of a reminder, which may have been related to the number and length of the questionnaires. It could also be argued that symptomatic patients are more likely to respond to questionnaire-based studies, potentially introducing a degree of selection bias. This further reinforces the need to reproduce our findings in an independent cohort of patients where potential confounders such as the presence of depression and/or anxiety are also considered. The study was also a cross-sectional cohort study, and the VVS patients were not prospectively recruited. A further limitation is that VVS was not excluded (either clinically or by head up tilt) in the control group. This and the fact that VVS may develop during their lifetime is a potential confounder. Despite these limitations, we believe that this study raises important findings that will be explored in a prospective study. In conclusion, fatigue appears to play an important role in the poor quality of life experienced by VVS patients. Patients suffer a higher than average amount of daytime sleepiness as well as a range of autonomic symptoms. These symptoms are especially profound in patients who have not responded to the conventional treatment. Such findings have implications for our understanding of the pathogenesis of fatigue and VVS, and how they are both treated in the future, as well as highlighting a need to examine patients presenting with CFS for signs of VVS. Conflict of interest: none declared. Funding This study was supported by a grant from ME Research, UK.

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