Influence of age and gender on the occurrence and presentation of reflex syncope
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The clinical history is the cornerstone of diagnosing patients with transient loss of consciousness (TLOC). Reflex syncope is the most common cause of TLOC in patients across all ages. Knowledge of the variation in incidence and clinical features of reflex syncope by age and gender provides important background information to acquire an accurate diagnosis.
In a cohort of 503 patients presenting with TLOC we established a final diagnosis after systematic evaluation and two years of follow-up. The occurrence of prodromal signs, symptoms, and triggers in patients with reflex syncope was analyzed by both age (< 40 yrs, 40–59 yrs and ≥ 60 years) and gender.
Reflex syncope was the most frequently obtained diagnosis (60.2%) in patients of all ages presenting with TLOC. Its occurrence was higher in patients under 40 years (73.4%), than above 60 years of age (45.3%). Pallor (79.9%), dizziness (73.4%), and diaphoresis (63.0%) were the most frequently reported prodromal signs and symptoms. Most triggers and prodromal signs and symptoms were more common in patients under 40 years of age and in women.
Reflex syncope is nearly twice as common in patients under 40 years of age than in patients aged 60 years or above. Typical signs and symptoms of reflex syncope are more common in younger patients and in women. Therefore, age and gender provide important diagnostic information and can help to decide whether additional testing is necessary.
Keywordssyncope diagnosis age distribution sex signs and symptoms
Transient loss of consciousness (TLOC) is a symptom of both benign and potentially lethal clinical disorders . Syncope, epilepsy, psychiatric disorders, and metabolic disorders are the main causes of TLOC . Syncope is characterized by a transient global cerebral hypoperfusion . Reflex syncope is the most prevalent cause of syncope . It is caused by systemic arterial hypotension resulting form reflex vasodilatation, bradycardia, or both . The occurrence of reflex syncope is often preceded by precipitating events (triggers) such as fear, severe pain, or micturition . Though the exact pathophysiological mechanisms by which triggers could lead to the occurrence of syncope are still unknown , reflex-mediated factors, physical factors, or a combination of these are thought to be involved .
The clinical history is the cornerstone of diagnosing patients with TLOC . In particular, it constitutes a powerful diagnostic tool to discriminate between seizures and syncope, and cardiac syncope and reflex syncope [2, 15, 27]. Therefore, knowledge about the occurrence of triggers, signs, and symptoms provides important background information for physicians to optimize and personalize their diagnostic strategy.
The age distribution of syncope in the general population is bimodal with a peak in teenagers and young adults, mainly found in females, followed by a peak in the elderly [13, 26]. Despite this fact, a coherent evaluation of the respective occurrence of triggers, signs, and symptoms of reflex syncope for both age and gender has not been performed.
Therefore, the aim of our study is to explore differences in prodromal signs and symptoms and triggers in patients with reflex syncope by both age and gender.
The data for the present study were derived from the Fainting Assessment Study (FAST), a prospective cohort study designed to assess the accuracy of diagnostic strategies for adult patients presenting with TLOC to different departments (Cardiology, Neurology, Internal Medicine, Emergency Department, or Cardiac Emergency Room) of the Academic Medical Center, Amsterdam, the Netherlands . Attending physicians of the different departments formulated an initial diagnosis based on history, physical examination, and a 12-lead ECG. Additional tests were performed according to an algorithm based upon the ESC-guidelines . After 2 years of follow-up, a final diagnosis was made using the initial diagnosis, results from additional testing and additional diagnostic information from recurrent episodes during follow-up. An expert committee reviewed the case if: a patient’s initial diagnosis was deemed incorrect and changed, the patient died during follow-up, or there was any doubt about the final diagnosis due to findings of additional tests or new episodes of TLOC . The final diagnoses were classified in one of the following diagnostic categories: reflex syncope (including vasovagal syncope, situational syncope, and carotid sinus syncope), orthostatic hypotension, cardiac syncope, neurological disorder, psychogenic pseudo-syncope, metabolic disorder, or no definitive diagnosis . This study is based on these final diagnoses.
In the FAST-study, consecutive patients presenting with TLOC to the Academic Medical Center Amsterdam were eligible for inclusion. TLOC was defined as self-limiting loss of consciousness not due to head trauma, lasting not longer than 1 hour . Patients younger than 18 years of age were excluded. The Medical Ethical Committee of our institution approved the study. All patients gave informed consent.
Information about prodromal signs, symptoms, and triggers of episodes was obtained by a physician using a structured questionnaire. Triggers were defined as those reported situations in which TLOC occurred . Prodromal signs and symptoms were defined as signs and symptoms (e.g. nausea, diaphoresis, and pallor) that offer warning of an impending episode of loss of consciousness . Patient responses to the occurrence of triggers and prodromal signs and symptoms were originally classified as: unknown, absent, sometimes present (<50% syncopal episodes), and usually present (>50% syncopal episodes) . For analysis, these results were dichotomized (not known or absent (0) and sometimes or usually present (1)).
Patients were divided into three different age groups: below 40, 40–59, and 60 years or above. These age groups were chosen to compare symptoms and signs separately in young adults, middle-aged subjects, and older adults/elderly subjects. It is known that the prevalence of episodes of TLOC is markedly different in these patient groups [9, 30, 33]. In the following sections young adults and older adults/elderly subjects will be addressed as younger and older patients.
Continuous data were expressed as mean and standard deviations or median and quartiles. The Student’s t test, Mann–Whitney test, or Kruskal–Wallis test was used to compare groups. We present categorical variables as percentages and compare between groups using the Chi-square statistic or, when appropriate, the Fisher’s exact test.
For each sign or symptom that was associated with both age and gender in univariate analysis (P < 0.1), we performed a multivariate logistic regression analysis to assess whether these effects were mainly age-related, mainly gender-related, or both. The presence of a prodromal symptom or sign was used as dependent variable in these models with gender and age as categorical, independent variables. The strength of the association was expressed as an odds ratio (OR) with a 95% confidence interval (95% CI).
All data were analyzed using SPSS 14.0 (SPSS, Chicago, IL, USA). P < 0.05 was considered statistically significant.
Patient characteristics and final diagnoses by age in patients with TLOC
Carotid sinus syndrome
Psychogenic pseudo syncope
Syncopes last year
Duration TLOC <1 minute
Reflex syncope was the most prevalent cause of TLOC in all age groups (Table 1). The proportion of patients with reflex syncope was highest in the youngest age group (73.4%) compared to the other age groups (62.9 and 45.3%, respectively). The prevalence of cardiac syncope was much higher in patients aged 60 years or above (20.0%), compared to patients under 40 years of age (1.3%). Neurological causes of TLOC were equally prevalent in all age groups (overall 4.2%). In 12.3% of the patients no diagnosis was made after 2 years of follow-up. This percentage was similar in all age-groups.
Signs, symptoms, and triggers in patients with reflex syncope
Signs, symptoms and triggers in patients with reflex syncope by age and gender
P Value age
P Value gender
Syncopes last year
Seeing black spots
Need lying down
Shortness of breath
Number of prodromes
Coughing, micturition, defaecation or swallowing
The most frequently reported prodromal signs and symptoms by patients with reflex syncope (all episodes) were: pallor (79.9%), dizziness (73.4%), and diaphoresis (63.0%). All signs and symptoms, except ‹pallor’, were more prevalent in patients under 60 years of age, with differences reaching statistical significance for nausea, dizziness, seeing black spots, needing to lie down, and palpitations. The median number of different prodromal signs and symptoms that emerged over syncopal episodes was higher in patients under 60 years of age than in those above that age (5 vs. 3; P < 0.01). Additionally, young patients reported more prodromal signs and symptoms that are generally associated with neurological disorders, like muscle jerking (27.6 vs. 15.7%) and postictal confusion (13.1 vs. 8.5%). These differences were, however, not statistically significant. Postictal confusion was shorter than 1 minute in 12.5%, 1–5 minutes in 41.7%, and >5 minutes in 45.8% of the patients. Cyanosis was rare; only in eight subjects (2.6%) a blue color of the face was reported.
All patients reported at least one trigger. The syncope triggers that were more frequently reported by patients less than 40 years of age were prolonged standing (P = 0.01) and venepuncture (P < 0.01).
Women reported more episodes of reflex syncope in the last year (2 vs. 1; P = 0.02) and pre-syncope per month (1 vs. 0; P < 0.01) than men. Women also reported more prodromal signs and symptoms than men (Table 2). These differences were all statistically significant, except for diaphoresis, pallor, and shortness of breath. The median number of different prodromal signs and symptoms over all syncopal episodes was higher for women than men (6 vs. 4; P < 0.01). The occurrence of reflex syncope upon venepuncture and after a meal was more common in women (P = 0.03 and 0.01, respectively).
Relative contribution of age and gender
Multivariate odds ratios showing the independent effect of age and gender on the presence of signs/symptoms among patients with reflex syncope
OR age 40–59 versus <40 years of age
OR age ≥60 versus 40–59 years of age
OR women versus men
Seeing black spots
Need lying down
In this study, the influence of both age and gender upon the frequency and occurrence of triggers and prodromal signs and symptoms of reflex syncope was evaluated. A unique feature of this study is that the occurrence of prodromal signs and symptoms was analyzed for both age and gender in the same patient population. In addition, we used the diagnosis after 2 years of follow-up as the final diagnosis of TLOC. Follow-up data are also available in several studies of Sarasin et al. [24, 25] upon diagnostic evaluation of patients presenting with TLOC, unlike most other studies in which the final diagnosis was obtained after initial evaluation .
Reflex syncope proved to be much more common in young subjects (73%) than in elderly (45%) subjects. The most common subdiagnosis of reflex syncope was vasovagal syncope (82.4% of cases). The diagnosis of carotis sinus syncope was made in 6.5% of patients aged 60 years or above, while none of the patients under 40 years of age had this diagnosis.
Typical prodromal signs and symptoms of reflex syncope were about 50% more common in young patients and women than in older subjects and men. The most important triggers for reflex syncope in our study were prolonged standing, emotion/pain, and increased thoracic pressure (such as coughing, micturition, and defecation).
Our results confirm the high frequency of reflex syncope in patients <40 years (73% in our study) and the predominance of females in this young age group . In the general population approximately twice as many women (50%) than men (25%) are affected by TLOC . Reflex syncope remained the single most frequently observed imminent cause of TLOC in patients aged 60 years or above in our study . Its occurrence (45%) was, however, lower than in younger subjects, while a sharp increase in the occurrence of cardiac syncope and orthostatic hypotension was observed [8, 30]. Surprisingly, the number of patients remaining undiagnosed after 2 years of follow-up was similar in all age-groups. Elderly patients are usually considered more difficult to diagnose because of co-morbid disorders.
Reflex syncope versus epilepsy: similarities and distinctions
In our study, limb muscle jerking was present in 27.6% of the patients in the youngest age group and in 15.7% in the oldest age group. In 2001, Newman et al. also found a high number (46%) of subjects with tonic and myoclonic or twitching muscle activity after vasovagal responses during blood donation . Though the number of blood donations increases until 50 years of age, the number of syncopal reaction rates was highest in patients under 40 years of age . Thus, limb muscle jerking is common in both reflex syncope and epileptic seizures, particularly in young patients.
Urinary incontinence was present in 19.1% of our patients with reflex syncope, confirming earlier findings that urinary incontinence provides no additional evidence for or against the diagnosis of a seizure . The duration of the TLOC was <5 minutes in 73.7% of the subjects in our study. Although Hoefnagels et al.  suggested that a duration of loss of consciousness of >5 minutes and postictal confusion are suggestive of epilepsy, 13.5% of our patients with reflex syncope suffered from prolonged loss of consciousness and postictal confusion was observed in 10% of our patients with reflex syncope. Prolonged periods of unconsciousness or postictal confusion (≥5 minutes) in syncope patients may be explained by continuing hypotension, for instance, when remaining in an upright position during or after the episode. Additionally, since seeing an episode of TLOC can be very stressful to witness, the perceived duration of TLOC could be longer than the actual duration. Thus, an eyewitness’s account about the duration of TLOC will not always be reliable.
Tongue biting was observed in 1.7% of our reflex syncope subjects. However, we did not make the distinction between lateral bites and bites at the tip of the tongue. A lateral tongue bite is highly specific (>99%) to generalized tonic–clonic seizures, while a bite at the tip of the tongue can also occur in syncope .
Thus the distinction between convulsive syncope and true epileptic seizures can be difficult. However, previous studies indicate that a history of pre-syncope with diaphoresis, nausea, and pallor as prodromal signs is strongly suggestive of reflex syncope; while tongue biting, muscle aches, and cyanosis are more often associated with an epileptic seizure [15, 18, 27].
Reflex syncope versus cardiac syncope
Palpitations have been reported earlier as a predictor of cardiac syncope in patients without suspected or diagnosed heart disease . The diagnosis of cardiac syncope was obtained after further investigation in only 4 out of 146 patients without suspected heart disease after initial evaluation. Remarkably, in the same study, palpitations were no predictor of cardiac syncope in patients with suspected heart disease after initial evaluation . Palpitations have also been reported as features of the clinical history predictive of non-cardiac syncope , or as having no predictive value at all . Our data document that palpitations are very common and part of the normal clinical presentations of young (35%) and female (34%) subjects with reflex syncope. A likely explanation is a pronounced postural tachycardia prior to an actual faint .
Prodromal signs and symptoms and triggers of reflex syncope by age
Prodromal symptoms and signs were less prevalent in older patients in our study. This effect of age can be explained by several factors. The activity of the autonomic nervous system and end-organ function decreases with age . When standing up, the most common trigger for all types of neurally mediated syncope , elderly subjects have less postural tachycardia and less diaphoresis, and, thus, less prodromal symptoms than younger patients . In these elderly subjects, standing up is commonly accompanied by straining and an instantaneous brief rise in blood pressure, followed by a fall in pressure [16, 34]. In young patients, a brief rise in blood pressure is absent [16, 34]. It has been reported that the drop in blood pressure during a vasovagal response is more gradual in elderly subjects than in younger subjects . This, in combination with the observation of Lipsitz et al.  that for a given fall in systemic blood pressure the fall in cerebral blood flow velocity is smaller in the elderly, might result in later awareness of the decrease in blood pressure and more time for the cardiovascular system to adapt. Given the relationship between blood pressure decrement and the occurrence of signs and symptoms in syncope , elderly subjects will report fewer prodromal signs and symptoms than younger subjects.
Poor recollection might make it more difficult to discern specific prodromal signs and symptoms in older patients. In older adults, over one-third of fallers do not recall having fallen 3 months after a documented fall . These facts imply that medical history taking in elderly patients is not always reliable.
Prodromal signs and symptoms and triggers of reflex syncope by gender
The median number of prodromal signs and symptoms in our study was about 50% higher in women than men. Most triggers were also observed more frequently among women than men. Similar results were obtained by Ganzeboom et al. .
The reason for the observed gender differences in the occurrence of signs, symptoms, and triggers is not entirely clear. Women have a greater decrease of thoracic blood volume compared to men upon standing , resulting in lower orthostatic tolerance associated with decreased cardiac filling ; this explains the higher number of TLOC episodes in women. Shoulder pain, a clinical feature known to be associated with orthostatic hypotension [10, 23], was reported in our study by 11% of women and 4% of men with reflex syncope (P = 0.02). Shoulder pain is most likely due to muscle ischaemia . This muscle ischaemia is thought to result from a (prolonged) impairment of blood flow in orthostatic hypotension. It is unknown whether this also occurs in patients with reflex syncope experiencing shoulder pain. Therefore, further research is needed to explain the occurrence of shoulder pain in patients with reflex syncope.
Studies on pain perception have reported that women consider pain as more unpleasant and are more sensitive to it than men, because of different sociocultural, psychological, and biological factors . Women appear to have a greater tendency to report pain to health care providers than men and are more open to discuss physical phenomena . It seems therefore reasonable to assume that this tendency may also lend itself to women reporting more prodromal signs and symptoms associated with their syncope than men.
The medical history is a very important tool to discern different causes of TLOC . It is of utmost importance to differentiate between causes with a benign prognosis (such as reflex syncope) and malign prognosis (such as cardiac syncope and neurological syncope) , as appropriate treatment differs markedly for different causes of TLOC. According to the ESC-guidelines, reflex syncope is diagnosed if certain triggers are associated with the occurrence of prodromal signs and symptoms . In this study we showed that signs and symptoms, as well as triggers of reflex syncope, are more often present in women and young people. Since the occurrence of prodromal signs and symptoms is lower in cardiac syncope than in reflex syncope, and cardiac syncope is rare in young women [2, 6, 8], one can be relatively certain about the diagnosis of reflex syncope in the case of a positive history in combination with a normal physical examination and ECG [2, 5]. It will then often not be necessary to perform additional tests. Because men and elderly patients report fewer prodromal signs and symptoms, there will be more uncertainty about the diagnosis. Moreover, the risk of cardiac syncope is increased in these patients. Additional tests need to be performed more often to obtain more certainty about the diagnosis. Thus, the age- and gender-related occurrence of prodromal signs and symptoms could help to decide whether additional testing is required.
On the basis of a 2 year follow-up we have demonstrated that the frequency and type of prodromal signs, symptoms, and triggers in patients with reflex syncope depend on both age and gender, so these factors should be considered in relation to the probability of its differential diagnosis. In addition, information about age and gender could help decide whether additional tests are needed.
Conflict of interest
The study was financially supported by the Netherlands Heart Foundation (numbers NHS 99/181 and 2003B156). The authors report no conflicts of interest.
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