Clinical manifestations

Presentation and course

In some forms of syncope, there may be a prodrome with various symptoms (eg, lightheadedness, nausea, diaphoresis, weakness, and disturbed vision), but in other cases loss of consciousness occurs without warning (171). Stereotyped presyncopal symptoms may be absent in some elderly patients for unclear reasons, but other deviations from this clinical presentation should alert the examiner to consider other entities in the differential diagnosis.

Neurologic symptoms, when present, are brief and often progress in a stereotyped manner, culminating in loss of consciousness (181). The patient initially experiences a sense of "dizziness" or disequilibrium, nausea, and unclear thinking. This is followed by fixation of the eyes in the midline and a “frozen” appearance. Vision narrows followed by graying out of vision. This may progress to complete loss of vision (blacking out), with or without hearing loss. Complete loss of consciousness is associated with the “turning up” of the eyeballs. There is a loss of postural tone, usually with enough time to brace oneself to prevent injury. This process may take as little as 7 seconds in cases of sudden circulatory arrest, viz. abrupt asystole, but in other circumstances, it depends on the rate and depth of cerebral hypoperfusion.

Eye deviation and myoclonus frequently occur ("convulsive syncope"), which may lead to an incorrect diagnosis of epilepsy (85; 10; 108). The myoclonic movements may be prolonged if the patient cannot assume a recumbent position.

Loss of consciousness generally lasts at most 20 seconds in cases of reflex syncope, but it can rarely be longer (171). Rapid restoration of consciousness and orientation follows, with post-return-of-consciousness symptoms caused by mixed vagal and sympathetic outflow (eg, nausea, diaphoresis, and tremor). Postictal confusion is not observed, but fatigue may be present during the post-recovery period (171). Focal neurologic symptoms are absent before and following syncope unless the patient has some preexisting neurologic deficit that may become more pronounced during the spell.

Rarely, epileptic seizures can occur in association with syncope as a result of ictal bradycardia or ictal asystole (105; 176). Cardioinhibition has an important role in most seizure-induced syncopal events, thereby favoring the potential utility of pacemaker implantation in patients with ictal syncope that is difficult to suppress (176). Ictal bradycardia or ictal asystole occur predominantly with partial complex seizures, particularly with left-lateralized temporal lobe seizures. Ictal syncope is associated with EEG signs of brain ischemia and the duration of the cardiac arrhythmia.

Cognitive impairment is common in elderly patients with syncope, with a reported overall prevalence of 58%, comparative to the frequency of cognitive impairment among elderly patients with unexplained falls (51).

Prognosis and complications

In a systematic review and meta-analysis of prognosis after an acute-care evaluation for syncope, the clinical findings most predictive of a short-term, serious event were (1) an elevated blood urea nitrogen level; (2) history of congestive heart failure; (3) initial low blood pressure in the emergency department; (4) history of arrhythmia; and (5) an abnormal troponin value (60). An abnormal electrocardiogram was also mildly predictive of increased risk. Younger age was associated with lower risk.

Significant morbidity results from falls or accidents resulting from syncope. After analyzing 1114 patients with syncope and 139 individuals with a nonsyncopal transient loss of consciousness, Bartoletti and colleagues reported that 365 of those with transient loss of consciousness presented with a history of trauma, classified as severe in 59 cases (26). Among 1115 adults with vasovagal syncope, standing position and female sex were associated with injury, whereas recurrent vasovagal syncope and syncope in the afternoon and evening were associated with lower risk compared with morning hours (170). In a per syncope analysis considering up to three previous episodes, syncope at home and absence of prodromes were associated with injury.

Carotid sinus syndrome and vasovagal syncope, both neurally mediated categories of syncope, have been increasingly recognized as important causes for unexplained falls and syncope in the elderly, though still likely to be underdiagnosed (15). In older patients with unexplained falls and syncope, 20% demonstrate an arrhythmia as the attributable cause for their falls and such patients are at a significantly increased risk of further falls (33). In a nationwide Danish cohort, syncope was associated with a 1.4-fold higher risk of occupational accidents and a 2-fold higher risk of termination of employment compared with the employed general population (117). In a large population-based prospective cohort of 30,399 middle-aged people, those hospitalized due to unexplained syncope and orthostatic hypotension had a significantly increased risk (20% to 42%, respectively) of subsequent fractures (73).

Aggregating the experience of multiple prevention trials for syncope in those with a history of syncope, the 1-year rate of another syncopal event was 14% (75). Of those with recurrent syncope during the year, 30% were injured during a syncopal event, but only 4% sustained severe injuries (eg, fractures, burns, joint pain). Patients with bifascicular block were more prone to injury than others with syncope. Patients with a higher frequency of syncopal events were more likely to be injured than those with fewer faints, but this was attributable to more frequent syncope and not more injuries per faint. In patients with vasovagal syncope, pharmacological therapy significantly reduced the likelihood of an injury due to a syncopal event.

A subsequent meta-analysis (ie, systematic integration of the results of the published studies to provide more accurate and robust estimates) of injury risks associated with vasovagal syncope identified 23 studies with collectively 3593 patients that met inclusion criteria (76). Eighty-two percent had more than two syncopal episodes before enrolment. The weighted mean injury rate was 33.5% [95% confidence interval (CI): 27.3-40.5%]. The likelihood of injury was moderately correlated with population age but not with sex, positive tilt test, or hypertension. Injury rates were 26% in studies with younger and 43% in studies with older patients. Nine studies reported major injuries, with a weighted mean rate of major injuries of 14%.

Conclusion. Injuries due to syncope are frequent, occurring in 33% of patients with vasovagal syncope.

Near-syncope confers risks similar to that of syncope for the composite outcome of 30-day death or serious clinical event (27).

Although patients may harm themselves with falls, neurocardiogenic syncope generally has an excellent prognosis and tends to cease with advancing age. However, it may have a poor prognosis and may be refractory to treatment in patients with left ventricular dysfunction (185).

Autonomic insufficiency secondary to medications may be alleviated by medication change; however, neurodegenerative causes for autonomic insufficiency are more serious and refractory.

The prognosis for various cardiac causes depends on the specific condition. A patient with a normal ECG and echocardiogram has an excellent long-term prognosis, but a patient with heart disease or cardiac dysrhythmia has a more serious prognosis (96). Structural heart disease and electrical dysfunction (eg, long QT syndrome, Brugada syndrome, short QT syndrome) are major risk factors for sudden cardiac death and overall mortality in syncopal patients (171). Patients with aortic stenosis who develop syncope have a smaller aortic valve area, smaller cardiac cavities, and lower stroke volumes than those without syncope, and the syncopal patients also had an increased risk of mortality after aortic valve replacement (61). Implanted automatic defibrillators also improve the prognosis for patients with ventricular fibrillation and non-sustained ventricular tachycardia (17). New-onset syncope of unknown etiology is not an independent predictor of mortality in elderly patients (144).

Cardiac syncope has significantly higher mortality compared with syncope due to noncardiac causes or idiopathic syncope. Nevertheless, among older, diabetic, or hypertensive individuals, a history of either noncardiac or unexplained syncope, even in the absence of an obvious cardiac etiology, is associated with significantly higher all-cause mortality (140).

Although the overall in-hospital mortality rate in patients with syncope is relatively low (less than 2%), patients with syncope coexistent with pulmonary embolism, pneumonia, myocardial infarction, or stroke have a mortality rate exceeding 8%, whereas syncope coexistent with atrial fibrillation has no independent impact on in-hospital mortality (84).

Syncope as a manifestation of acute pulmonary embolism is associated with a higher prevalence of hemodynamic instability and right ventricular dysfunction at presentation, a higher risk of all-cause early death (ie, death either in-hospital or within 30 days), and an elevated risk for early pulmonary embolism-related adverse outcomes (22; 52). Syncope is also a predictor of major bleeding events in patients with pulmonary emboli, even among those receiving anticoagulation monotherapy (98). Among 45,765 patients with acute pulmonary emboli from March 2001 to January 2021, 6760 (15%) had syncope. Patients with syncope and pulmonary emboli had a higher rate of major bleeding than those without syncope. Multivariable analyses confirmed that patients with pulmonary emboli and syncope were at increased risk for major bleeding. The increased risk for major bleeding included patients initially receiving anticoagulant therapy without thrombolytics at 7 days and 90 days.

Multiple approaches to risk stratification have been developed for the initial evaluation of syncope (101; 47; 148; 135; 49; 171; 39). According to the San Francisco Syncope Rule, the presence of any of the following is predictive of a serious event within 1 week with 98% sensitivity and 56% specificity: abnormal ECG, congestive heart failure, dyspnea, hematocrit of less than 30%, or systolic blood pressure of less than 90 mm Hg (148). According to a study by Martin and colleagues, which I will refer to as the Martin Rule, predictors of severe arrhythmia or arrhythmic death by 1 year include an abnormal ECG, history of ventricular arrhythmia, history of congestive heart failure, and age over 45 years; with each of these factors accorded a score of 1 point, the risk of severe arrhythmia or arrhythmic death by 1 year was 0% with a total score of 0, 5% with a score of 1, 16% with a score of 2, and 27% with a score of 3 or 4 (101). According to the OESIL Rule, predictors of 1-year mortality include an abnormal ECG, history of cardiovascular disease, lack of a prodrome, and age over 65 years; with each of these factors accorded a score of 1 point, the risk of 1-year mortality was 0% with a total score of 0, 0.6% with a score of 1, 14% with a score of 2, 29% with a score of 3, and 53% with a score of 4 (47). According to the EGSYS Rule, there are positive and negative predictors that carry different weights for cardiac syncope and 2-year mortality: (1) palpitations before syncope (4 points); (2) abnormal ECG or heart disease (3 points); (3) syncope during effort (3 points); (4) syncope while supine (2 points); (5) autonomic prodrome with nausea/vomiting (-1 point); and (6) the presence of predisposing or precipitating factors (eg, warm crowded place, prolonged standing, fear, pain, intense emotion) (-1 point) (49). By the EGSYS Rule, 2-year mortality is 2% when the total score is less than 3 and 21% for scores of 3 or more (49).

Syncope among drivers has significant implications for personal and public safety, so consequently, syncope should be carefully considered in assessments of driving fitness (64; 116). The incidence of motor vehicle crashes among patients with syncope is almost double that of the general population (20.6 per 1000 person-years vs. 12.1 per 1000 person-years), with a rate ratio of 1.83 after adjustment for age, sex, socioeconomic position, relevant comorbidities, and pharmacotherapy (116). The 5-year crash risk following syncope is 8% among the population aged 18 to 69 years compared with 5% in the general population (116). Prior hospitalization for syncope is associated with a persistently increased risk of motor vehicle crashes (116). Those with structural heart disease are at an especially high risk of further syncope. Driving recommendations “should not differ, whether or not the syncopal spell occurred while driving” (64).

In a systematic review of the risk of motor vehicle collision in patients with syncope, 11 studies of moderate quality were included (n = 42,972) (45). The prospective motor vehicle collision risk was lower for vasovagal syncope (0.0% to 0.31% per driver-year; three studies; n = 782) and higher for arrhythmic syncope (1.9% to 3.4% per driver-year; two studies; n = 730), compared to the identified risks for the general populations of Canada, the United States, and the United Kingdom (0.49% to 2.29% per driver-year). The results were more variable for syncope that has not yet been diagnosed (0.0% to 6.9% per driver-year prospectively; six studies; n = 41,460). Patients with syncope not yet diagnosed had an almost 2-fold increased motor vehicle collision risk in the largest study, although the smaller studies showed contradictory findings. Patients with vasovagal syncope appear to be at low risk for motor vehicle collisions, which supports current guidelines that do not recommend automatic driving suspension for most of these patients.

A Canadian retrospective cohort study evaluated 9223 patients with syncope visiting any of six urban emergency departments for syncope and collapse and 34,366 age- and sex-matched control patients visiting the same emergency department in the same month for a condition other than syncope (165). At baseline, crude motor vehicle crash incidence rates among both the syncope and control groups were higher than among the general population (12, 13, and 8 crashes per 100 driver-years, respectively). In the year following the index emergency department visit, there was no significant difference in subsequent motor vehicle crash risk. Subsequent crash risk among patients with syncope was not significantly increased in the first 30 days after the index emergency department visit or among subgroups at a higher risk of adverse events after syncope (eg, age > 65 years; cardiogenic syncope).

According to the Task Force for the Diagnosis and Management of Syncope, about a third of syncopal patients have recurrent syncope within 3 years of follow-up (171). Another study reported that the risk of syncope recurrence following an initial emergency department visit for syncope was 9% at 6 months, 12% at 1 year, and 23% at 5 years (21).

The strongest predictor of recurrence is the prior number of syncopal episodes (171). Recurrent syncope is associated with fractures and soft tissue injury in 12% of cases (171). Other significant predictors of syncope recurrence include diabetes mellitus and anemia (21).

Clinical vignette

A 38-year-old man had experienced several episodes of graying of vision and feeling of faintness after weightlifting. He was referred for new-onset seizures because he reported that after lifting a heavy weight, he was observed to fall to the floor and to have jerking movements of his limbs. He rapidly awoke with no confusion but was sweating and nauseous. He was otherwise healthy, and family history was negative for seizures or syncope. His examination showed no postural blood pressure changes. On cardiac auscultation he had a systolic ejection murmur heard best over the left upper sternal border; the murmur increased with Valsalva maneuver. Neurologic examination was normal. The EEG was normal, but his ECG showed left ventricular hypertrophy. A cardiology consultant found idiopathic hypertrophic subaortic stenosis and arranged an electrophysiological study. The myoclonus was interpreted as secondary to cerebral hypoperfusion (ie, convulsive syncope), and antiepileptic drugs were not initiated.

Biological basis

Etiology and pathogenesis

Cerebral perfusion is maintained relatively constant by an intricate and complex feedback system involving cardiac output, systemic vascular resistance, arterial pressure, intravascular volume status, cerebrovascular resistance with intrinsic autoregulation, and metabolic regulation. A clinically significant defect in any one of these systems or subclinical defects in several of these systems may cause reflex syncope.

Cardiac output can be diminished secondary to medications (eg, beta blockers), mechanical outflow obstruction, pump failure, hemodynamically significant arrhythmias, or conduction defects. Systemic vascular resistance can drop secondary to medication-induced vasodilation, vasomotor instability, autonomic failure, or vasodepressor/vasovagal response. Mean arterial pressure decreases with all causes of hypovolemia.

The baroreflex, one of the body’s homeostatic mechanisms, maintains blood pressure through a negative feedback loop: an elevated blood pressure reflexively causes a decrease in heart rate and, thus, blood pressure, whereas a decreased blood pressure activates the baroreflex, causing an increase in heart rate and, thus, a rise in blood pressure. Baroreceptors are located predominantly in the auricles of the heart, the vena cava, the aortic arch, and the carotid sinuses. They monitor the changes in blood pressure and relay them to the nucleus of solitary tract in the brainstem via glossopharyngeal and vagus nerves. Subsequent changes in blood pressure are mediated by the autonomic nervous system (sympathetic and parasympathetic). The stretch-sensitive baroreceptors (mechanoreceptors) become active when the blood pressure rises, resulting in the distention of the aorta and the carotid sinuses. Subsequent activation of the nucleus of solitary tract in turn inhibits the vasomotor center and stimulates the vagal nuclei. The result is inhibition of the sympathetic nervous system and activation of parasympathetic system.

Hyperventilation may cause syncope by reduction in cerebral blood flow from cerebral vasoconstriction. Fear and anxiety may precipitate neurocardiogenic syncope, but both may stimulate central hyperventilation as well. Additionally, patients with conversion disorders or malingering may complain of transient loss of consciousness that may be misdiagnosed as syncope.

Orthostatic vasovagal syncope starts with venous pooling that is reflected in a decrease of stroke volume (175). This is followed by cardioinhibition (ie, a decrease of heart rate that accelerates the ongoing decrease of blood pressure) (175).

Vasovagal syncope has a genetic predisposition, although it is clear that nongenetic factors are also important: (1) vasovagal syncope has a high prevalence in some families; (2) children of a fainting parent are more likely to faint than those without a parent who faints; (3) the likelihood of fainting is increased further if an individual has two fainting parents or a fainting twin; (4) twin studies, highly focused genome-wide association studies, and copy number variation studies all suggest there are genetic loci that associate with vasovagal syncope (156). Strong evidence is provided by the involvement of central signaling genes involving serotonin and dopamine in the genetic predisposition to vasovagal syncope (156). In addition, a case-control study in 157 subjects with a confirmed vasovagal syncope (and 161 subjects without a history of syncope), vasovagal syncope was associated with polymorphic variants of genes involved in neurohumoral signaling pathways, including genes that encode alpha- and beta-adrenergic receptors, catechol-O-methyltransferase, adenosine receptors, and nitric oxide synthase (173).

Syncope that occurs in the passive phase of the head-up tilt test depends on the cardioinhibitory reaction (193). The cardioinhibitory reaction is associated with a decrease in heart rate, whereas the vasodepressive reaction is associated with a decrease in arterial pressure. Some patients may have a mixed type.

An uncommon but important cause of reflex syncope is glossopharyngeal neuralgia, which may occur, for example, with esophageal carcinoma (111). Patients may have recurrent episodes of syncope associated with prolonged cardiac standstill and arterial hypotension, which, in most affected patients, can be prevented by atropine or cardiac pacing (20). However, in one well-studied case, a 55-year-old man was admitted with recurrent attacks of left glossopharyngeal neuralgia accompanied by syncope; despite cardiac pacing, he still developed profound hypotension (with systolic blood pressure readings below 40 mm Hg) and lost consciousness during attacks (20). In addition, although atropine eliminated bradycardia with triggered attacks, systolic arterial blood pressure still declined from 120 to 60 mmHg. Blockade of the right and then left vagus nerves with lidocaine failed to eliminate cardiac arrest, but blockade of the left glossopharyngeal and vagus nerves prevented neuralgic attacks and eliminated autonomic and EKG changes associated with stimulation of the trigger point. From the results in this case and others, it is evident that two cardiovascular manifestations occur in glossopharyngeal neuralgia: the afferent glossopharyngeal stimulus activates (1) brainstem mechanisms involved in cardiovascular regulation with bilateral efferent responses mediated via vagal discharge and producing cardiac standstill and prolonged delayed ventricular escape, and (2) inhibition of vasomotor centers while producing peripheral vasodilation and pronounced drops in blood pressure, even with cardiac pacing (20).

Syncope or presyncope in patients hospitalized with COVID-19 is uncommon and is infrequently associated with a serious underlying pathology (eg, cardiac etiology) or adverse outcomes compared to those who do not present with these symptoms (119). In another series of 35 cases associated with SARS-CoV-2 onset, affected patients had significantly lower heart rates compared to 68 SARS-CoV-2-positive patients who did not have syncope (42).

Commonly, cardiac syncope is caused by coronary artery disease that may induce ventricular dysrhythmias from transient ischemia or lead to foci of automaticity within the myocardial scar. Therefore, the risk factors for coronary artery disease and atherosclerosis (eg, hypertension, diabetes, smoking, hyperlipidemia, male gender, and advancing age) are all associated with cardiac syncope. Young athletes may also develop syncope from ventricular dysrhythmia. Familial prolonged QT syndrome may present with syncope or sudden death.

Short QT syndrome is an autosomal dominant genetic disorder affecting infants, children, and young adults that is characterized by a short QT interval between 210 and 340 milliseconds. Normally, QT interval lengthens when the heart rate is slow and shortens during fast heart rates. In short QT syndrome, the QT interval changes very little as the heart rate changes. Short QT syndrome is a risk factor for paroxysmal atrial fibrillation, life-threatening ventricular arrhythmias, syncope, and sudden death. Mutations in several genes encoding K+ channels have been identified, explaining the abbreviated repolarization seen in this condition. An intracardiac device is recommended for symptomatic patients, but the therapeutic strategy for asymptomatic patients, especially children, remains uncertain. Quinidine has shown to prolong QT and reduce the inducibility of ventricular arrhythmias.

Brugada syndrome was first described in 1992 as a unique set of electrocardiographic abnormalities associated with sudden death in otherwise healthy adults without structural heart disease (41). Brugada syndrome signs include right bundle branch block or J wave, ST-segment elevation in the right precordial leads (V1, V2, and V3) at least 0.1 mV, and normal QT interval. Brugada syndrome is responsible for a large portion of patients with “idiopathic ventricular fibrillation” (08). High-risk atrioventricular block can occur in patients with Brugada syndrome and various clinical presentations (80). In a study of 203 patients with Bragada syndrome, syncope occurred in 28% of patients (146). In 30% of patients the etiology of syncope was questionable. Because pharmacological treatment does not protect against recurrent events, implantable cardioverter defibrillator implantation is the only effective therapy to prevent sudden death in these patients (08). Lead failures often cause serious secondary complications such as implantable cardioverter-defibrillator shocks or asystole (03).

In patients with acute pulmonary emboli, syncope is associated with hypotension, tachycardia, right ventricular dysfunction, and reduced cardiac output (83). Syncope is positively correlated with the severity of pulmonary emboli (123). Central pulmonary emboli, blood troponin I level, unprovoked pulmonary emboli, and female sex are clinical factors related to syncope in patients with pulmonary emboli (92).

In patients with unexplained syncope, the incidence of first-ever syncope has a bimodal lifetime pattern with peaks at 15 and 70 years (174). Orthostatic hypotension and carotid sinus syndrome are more common in older patient groups, whereas prodromes, vasovagal syncope, and complex syncope are more common in patients with early-onset syncope (174). Complex syncope was defined as the detection of two or more concomitant diagnoses (eg, carotid sinus hypersensitivity / carotid sinus syndrome, vasovagal syncope, and orthostatic hypotension) during carotid sinus massage and head-up tilt table testing that could contribute to syncope episodes.

Epidemiology

Syncope is a prevalent disorder, accounting for 3% to 5% of emergency department visits and 1% to 3% of hospital admissions (160). The age of a first syncopal event shows a sharp peak between the ages of 10 and 30 years before falling to a nadir around age 50 years and then again rising progressively with age, but only 5% of adults have a first syncopal event over 40 years of age (171).

A large international multicenter study considered people 40 years of age or older who presented to the emergency department with a syncopal event within the preceding 12 hours (192). Among 1790 eligible cases, the incidence of recurrent syncope was 20% within the first 24 months. Patients with cardiac syncope or syncope with an unknown etiology had an increased risk for syncope recurrence. Occurrence of more than three previous episodes of syncope was the only independent predictor identified for recurrent syncope. Recurrent syncope carried an increased risk for death (HR 1.87) and major adverse cardiovascular events (HR 2.69) over 24 months of follow-up.

In a Spanish study of 589 consecutive patients with noncardiac syncope referred to a university syncope unit, the recurrence rate after 52 months of follow-up was 37.4%, and mortality was 6.6% per year (25).

Neurologic causes account for approximately 40% of syncope cases (95). Neurologic causes follow a bimodal distribution and occur primarily in younger patients, with autonomic insufficiency developing in the later decades of life. Reflex syncopes are generally the most common form of syncope, representing approximately one fifth of cases (21%) in the general population (based on the Framingham Study results), and a third to half of cases presenting to emergency rooms (171).

Vasovagal syncope is more common in women; compared to men with vasovagal syncope, women with vasovagal syncope are younger at the time of their first syncopal event, experience more post-syncope fatigue, and are more likely to experience recurrent syncope (53).

The incidence of vasovagal syncope with phlebotomy is 0.004% (4 per 100,000); a larger number of blood collection tubes used and a waiting time of more than 15 minutes were associated with significantly higher risks of syncope (188).

Syncope due to orthostatic hypotension represents approximately a tenth of cases (9.4%) in the general population (based on the Framingham Study results) and up to a quarter of cases presenting to emergency rooms (171). It is much more common in the elderly and in those on multiple medications.

Cardiac causes represent 10% to 30% of syncope cases (103). In older adults with syncope presenting to the emergency department, approximately 3% receive a diagnosis of a serious cardiac arrhythmia that is not recognized on initial emergency department evaluation (114). Cardiac causes of syncope most commonly appear after the seventh decade, when coronary disease is most common. However, familial prolonged QT syndrome may cause symptoms at any age, typically in the second and third decades.

Pulmonary emboli represent a surprisingly common cause among patients hospitalized for syncope: indeed, in one study, pulmonary emboli were present in nearly one of every six patients (17%) hospitalized with a first episode of syncope: 13% among those with an alternative explanation for syncope and 25% among those who did not (134). The estimates from this study, though, are significantly higher than other studies in the literature, suggesting a possible side effect, accrual bias, or investigation strategy (121; 11). In most studies, the estimated prevalence of pulmonary embolism in patients presenting with syncope is low (121), particularly among patients presenting to the emergency department (generally 2% or less) (18, 132; 138), but various other studies have reported that 2% to 11% of hospitalized patients with syncope have pulmonary emboli as a cause (11; 18; 132). In addition, the low prevalence of diagnosed venous thromboembolism in patients with syncope and the extremely low 30-day readmission rate with venous thromboembolism suggests that missed diagnoses of venous thromboembolism are uncommon in admissions for syncope (158). Among patients with pulmonary embolism, the presence of syncope at presentation is associated with a more complicated in-hospital course (112).

In a Korean study, 2.2% of patients with influenza experienced syncope (115). None of the affected patients had severe cough, hypotension, or dehydration. Patients experienced frequent episodes of dizziness before syncope. A long duration of loss of consciousness occurred more commonly among those with a high fever or orthostatic hypotension.

Approximately one third of syncope remains unexplained (95; 96; 168). The frequency of residual idiopathic syncope after evaluation has not changed much over the past 20 years.

In patients with unexplained syncope, first-ever syncope incidence has a bimodal lifetime pattern with peaks at 15 and 70 years (174). Most older patients present only recent syncope, and orthostatic hypotension and carotid sinus syndrome are more common in this group, whereas prodromes, vasovagal syncope, and complex syncope are more common in patients with early-onset syncope.

In children with "syncope," the most common causes are neurocardiogenic (vasovagal, 63%), "pseudosyncope" (13%), cardiac (10%), neurologic (10%), and indeterminate (3%) (104).

Differential diagnosis

Confusing conditions

Some patients have an incorrect diagnosis for more than 10 years, and such misdiagnosed patients are often excessively investigated, inappropriately treated, and have unnecessary restrictions placed on driving and employment (77).

Syncope is likely when loss of consciousness is complete and of rapid onset and short duration, associated with loss of postural tone, and spontaneous and complete recovery without sequelae (171). If some of these features are not present, other forms of transient loss of consciousness should be considered and excluded (171).

Syncope must be distinguished from disorders with transient loss of consciousness but without global cerebral hypoperfusion, including seizures, metabolic disorders (eg, hypoglycemia, hypoxia), vertebrobasilar transient ischemic attacks, and intoxication. Syncope must also be distinguished from disorders that may be associated with falls but that occur without impairment of consciousness, including cataplexy, drop attacks, psychogenic pseudosyncope, and anterior circulation transient ischemic attacks (171; 39).

Unfortunately, patients with convulsive syncope (eg, occurring vasovagal syncope) are commonly misdiagnosed as epilepsy. A misleading diagnosis of epilepsy may be detrimental for the patient, with inappropriate and expensive diagnostic testing and prescription of inappropriate, unhelpful, and potentially harmful medications, when, in some cases, other serious underlying causes for syncope (eg, Takayasu arteritis) are unaddressed (85; 36; 190; 127; 04; 32; 122; 102; 28; 154; 124; 136; 02; 09).

A stereotyped prodrome followed by loss of consciousness and rapid return of sensorium supports the diagnosis of syncope. Reflex syncope can be commonly mistaken for a seizure. If the patient is unable to recall events just moments prior to postural collapse, syncope may still be the correct diagnosis, but one must consider seizure. The presence of postictal confusion and reports of convulsion from observers would support a diagnosis of seizure, but one must be careful not to misattribute the myoclonus of convulsive syncope to an epileptic convulsion.

Ischemia in the distribution of the posterior circulation may cause transient loss of consciousness; there is a selective decrease in perfusion to the posterior circulation rather than a global decrease, and the return of consciousness is slow. Transient loss of consciousness associated with transient posterior circulation hypoperfusion often produces visual field impairments, diplopia, ataxia, and dysarthria prior to collapse. Following reperfusion, the patient may manifest transient disconjugate gaze, hemiataxia, hemianopsia, and dysarthria with or without good recall of the event.

Variants of migraine, particularly basilar migraine, may produce transient loss of consciousness with or without head pain. Basilar migraine is more frequent in children but may rarely present in adulthood. The presence of migrating sensory symptoms before or after the event suggests migraine. Other forms of migraine may also have an association with syncope, but in such cases, migraine and syncope do not occur simultaneously or in close temporal succession (171).

Metabolic causes of transient loss of consciousness may include hypoglycemia and hypoxemia, but the mechanism of loss of consciousness is not a decrease in global cerebral perfusion, and the alteration in consciousness is rarely of sudden onset and offset.

Unlike syncope, episodes of pseudosyncope (or “psychogenic nonsyncopal collapse”) are not associated with compromised cerebral circulation (68). Pseudosyncope is usually a manifestation of conversion disorder and, as such, shares many features with pseudoseizure (31). Psychiatric disease and age of less than 45 years are risk factors for pseudosyncope (171). Some patients may have a combination of tilt-induced vasovagal syncope and psychogenic pseudosyncope (35): such individuals are more likely to have a high attack frequency (including multiple attacks in a single day), delayed recovery following apparent transient loss of consciousness, episodes without prodromes, lacking or atypical triggers, eye closure and especially forced eye closure with attempted passive eye-opening by the examiner (the eyes are typically not closed during epileptic seizures and syncope), apparent loss of consciousness lasting longer than 1 minute (affected patient may lie on the floor for 15 minutes or longer), and tearfulness associated with fainting (171; 35; 68). It is important to note that physical injury does not exclude pseudosyncope (171).

Associated or underlying disorders

The most common cause of syncope in paced patients is cardiovascular autonomic dysfunction (186). In a study of 39 paced patients with syncope, orthostatic hypotension (41%) and vasovagal syncope (31%) were the most common diagnoses; there were no cases of pacemaker dysfunction (186a). Predictors of syncope recurrence and fall-related injury after pacemaker implantation include treated hypertension, renal failure, and atrial fibrillation (186b). Recurrent syncope after pacemaker implantation is associated with increased mortality risk (186b).

Diagnostic workup

Children and adolescents. Syncope is a common and a typically benign clinical problem in children and adolescents (139). Most tests ordered in otherwise healthy pediatric patients presenting with syncope have low diagnostic yield (109; 172; 100). Nevertheless, children with syncope often undergo expensive and unnecessary cardiac and neurologic testing (139; 172; 182; 100).

A diagnostic approach to vasovagal syncope in children that is more cost-effective than the traditional approach has been proposed (94; 149; 182). In the new diagnostic approach, the first steps are the history, physical examination, supine and upright blood pressure, and a standard ECG (94). Echocardiography and electrocardiogram monitoring are recommended only when necessary to exclude other diseases, and it is more cost-effective to refer concerning patients to a pediatric cardiologist than to order the transthoracic echocardiograms alone (172). The head-up tilt test is recommended only in patients with frequent and severe episodes of unexplained syncope after the other studies mentioned above. Other authors have since questioned even the utility of performing blood glucose determinations and an electrocardiogram in the outpatient evaluation of previously healthy children who present to an emergency department with a clinical diagnosis of benign syncope (63).

Unfortunately, many patients undergo extensive unnecessary testing and hospitalization when their risk is very low (182; 100). A quality improvement initiative for pediatric patients with syncope and presyncope substantially reduced medical charges to patients, unnecessary testing, and emergency room visits with no change in the incidence of cardiac arrest, hospitalization for syncope, or referral to pediatric electrophysiologists (182).

Initial evaluation of adults. Current evaluation strategies in common use for syncope in adults are expensive and lack diagnostic value (78; 109). The syncope work-up should be tailored to the patient's presentation. When considering clinical evaluation and diagnostic studies, history, physical examination, and electrocardiography have the greatest utility in evaluating syncope and should be the key components of an initial evaluation for syncope (07; 39). Additional testing should be guided by history and physical examination. Evaluation results indicating a need for further work-up include a history of cardiac or valvular disease (ie, ventricular dysrhythmia, congestive heart failure), abnormal EKG, anemia or severe volume depletion (eg, from a gastrointestinal bleed), syncope while supine or with effort, report of palpitations or chest pain, persistent abnormal vital signs, or family history of sudden death (07). Note, though, that in children with syncope, the diagnosis is primarily clinical; laboratory investigations add little to the diagnosis in children, especially in those with neurocardiogenic syncope (159).

A detailed history with careful review of medications and family history is often diagnostic. Physical examination should include blood pressure measurement in each arm, orthostatic blood pressure measurement (three sets of pulse and blood pressure: after supine for 5 minutes, on standing, and after standing for 3 minutes), neck auscultation, cardiac examination, examination of the extremities for swelling, and examination of cranial nerves and motor function (12; 13; 14). Overall, a diagnosis can be established in 25% to 50% of patients with history and examination alone (96; 171).

In the elderly, it is often difficult to distinguish syncope from unexplained or accidental falls (126; 129). Valvulopathy and the number of antihypertensive drugs are both significantly related to syncope in this group.

In a retrospective monocentric study of 100 patients aged 65 years or older who were admitted with a diagnosis of fall-related trauma, patients were categorized into three groups according to the identified cause of falls: (1) transient loss of consciousness, 36%; (2) unexplained fall, 37%; and (3) definite accidental fall, 27% (129). Of patients with a transient loss of consciousness, a probable origin was identified in 91%: (1) orthostatic hypotension, 53%; (2) a cardiac disturbance, 27%; (3) reproduced vasovagal syncope, 6%; (4) severe anemia, 6%; and (5) severe hypothyroidism, 3%. Patients with transient loss of consciousness were older and more clinically complex than the other groups.

Syncopal events with high-risk features suggesting a serious underlying condition include: (1) new-onset chest discomfort, breathlessness, abdominal pain, or headache; (2) syncope during exertion or while supine; (3) sudden onset of palpitations, immediately followed by syncope; (4) severe structural heart disease or coronary artery disease (ie, heart failure, low left ventricular ejection fraction, or previous myocardial infarction); (5) unexplained hypotension with systolic blood pressure of less than 90 mm Hg; (6) evidence of gastrointestinal bleeding (eg, on rectal examination); (7) persistent bradycardia (40 bpm or lower) while awake in the absence of physical training; and (8) an unexplained systolic murmur (39). In those with structural heart disease or an abnormal ECG, the following are also high-risk features: (1) absence of warning symptoms prior to syncope, or a short prodrome (lasting less than 10 seconds); (2) a family history of sudden cardiac death at a young age; and (3) syncope occurring in the sitting position (39).

The occurrence of tongue biting in seizure has a sensitivity of 24% and a specificity of 99% for the diagnosis of generalized tonic-clonic seizures (30). Tongue biting, particularly if it is along the lateral aspect of the tongue, is highly specific to generalized tonic-clonic seizures. Among the 45 patients with syncope, in only one was the tongue lacerated, and this was at the tip. Lateral tongue biting was specific to generalized tonic-clonic seizures.

Hyperventilation syndrome can be diagnosed by having the patient hyperventilate voluntarily to see if symptoms are reproduced (69; 87). This often requires strong and persistent encouragement by the examiner.

Syncope is frequently associated with acute principal diseases of varying severity, most of which are not life-threatening. In one study, a syncope-associated, underlying acute principal disease was diagnosed in 27% of 1279 patients presenting to an emergency room (118). In most cases, the cause was an acute noncardiovascular condition (67%), most of which were non-life-threatening, including infectious diseases (34%) and acute diseases with pain, fluid loss, or hypotension (24%). Severe, acute cardiovascular conditions were much less frequent (4%). Cardiogenic syncope, no previous history of syncopal episodes, atypical clinical features, alterations of vital parameters, and laboratory abnormalities were also independently associated with syncope-associated acute principal diseases.

Reflex syncope. Diagnosis of reflex syncope is supported by a long history of recurrent syncope (with onset before the age of 40 years), evidence of typical triggers (eg, after prolonged standing or an unpleasant sight, sound, smell, or pain); occurring in crowded or hot places; occurring during a meal; occurring with head rotation or when pressure is placed on the carotid sinus from tumors, shaving, or tight collars; or evidence of autonomic activation prior to syncope (eg, pallor, sweating, or nausea/vomiting), absence of heart disease (171; 39). A clear history consistent with reflex syncope with an appropriate stimulus and a typical progressive prodrome (ie, pallor, sweating, or nausea) requires no further workup; all other patients should receive an electrocardiogram (95).

Prodrome duration can be helpful in distinguishing arrhythmic and reflex syncope. A prodrome duration of 5 seconds or less suggests arrhythmic syncope, whereas a prodrome duration of more than 10 seconds in the absence of structural heart disease suggests reflex syncope (06; 39).

Vasovagal syncope is diagnosed if syncope is precipitated by emotional or orthostatic stress and is associated with a typical prodrome (171; 39).

Situational syncope is diagnosed if it occurs during or immediately after specific triggers such a coughing/sneezing, hiccupping, swallowing, defecation, visceral pain, micturition, exertion, or after eating (171; 39; 191).

To develop a personalized treatment strategy in patients with severe recurrent episodes of reflex syncope, the mechanism of reflex syncope should be evaluated. Documentation of bradycardia/asystole during a syncopal episode does not exclude the possibility that a preceding or concurrent hypotensive reflex plays an important role (40). Even when a hypotensive mechanism is established, the possibility of an associated cardioinhibitory reflex should be investigated. Diagnostic tests for the hypotensive phenotype include office blood pressure measurement with active standing test, wearable blood pressure monitoring, 24-hour ambulatory blood pressure monitoring, and tilt table test. Diagnostic tests for the bradycardic phenotype include carotid sinus massage, tilt table test, and prolonged ECG monitoring.

Orthostatic hypotension. Orthostatic hypotension is the likely basis for syncope if syncope and presyncope are present during standing, absent while lying, and less severe or absent while sitting. Sitting or lying down must alleviate the symptoms of presyncope. Orthostatic hypotension is often most symptomatic on arising in the morning and may be aggravated immediately after exercise, after meals, or in high ambient temperatures.

Although orthostatic hypotension is a very common cause of syncope, it is often overlooked, and orthostatic blood pressure measurements are often overlooked during the initial evaluation of syncope in the emergency department (67). Nevertheless, it should be emphasized that demonstration of orthostatic hypotension does not, by itself, indicate the reason for syncope. In particular, orthostatic blood pressure measurements do not, in isolation, reliably diagnose or exclude orthostatic syncope, nor do they rule out life-threatening causes of syncope (eg, cardiac syncope) (151).

Orthostatic hypertension is defined as a sustained fall in systolic blood pressure of at least 20 mm Hg (at least 30 mm Hg in those with supine hypertension), or diastolic blood pressure of 10 mm Hg, or a decrease in systolic blood pressure to less than 90 mm Hg within 3 minutes of standing or head-up tilt to at least 60 degrees on tilt table testing (57; 58; 39). The 90 mm Hg threshold for orthostatic hypotension was added with the 2018 guidelines from the Task Force for the Diagnosis and Management of Syncope (39). An isolated diastolic blood pressure drop is rare, the diastolic criterion is seldom used, and in any case its clinical relevance is doubtful.

Orthostatic hypotension is not defined or determined by the heart rate response to standing. With neurogenic orthostatic hypotension, the increase in heart rate with standing is blunted or absent, whereas with anemia or hypovolemia the orthostatic heart rate response is increased or exaggerated (39). An orthostatic heart rate increase of more than 30 bpm, or to a rate of more than 120 bpm, within 10 minutes of active standing, without a drop in blood pressure, is indicative of postural orthostatic tachycardia syndrome (or POTS) and should not be labeled as orthostatic hypotension.

Diagnosis of syncope due to orthostatic hypotension is supported by the following (1) an appropriate triggering situation (eg, a history of syncope on or shortly after standing, with prolonged standing, with standing shortly after exertion, or after meals); (2) a temporal association with starting or changing dosage of medications known to cause orthostatic hypotension; and (3) a history of autonomic neuropathy or parkinsonism (171; 39).

In a prospective cohort study of patients with suspected (pre)syncope presenting to the emergency department of a tertiary care teaching hospital, orthostatic blood pressure was measured during the active lying-to-standing test with a continuous noninvasive finger arterial pressure measurement device, and then orthostatic blood pressure recovery patterns were assessed (177). Classic orthostatic hypotension was the most prevalent abnormal blood pressure pattern (19%), but only half of the patients received a final diagnosis of orthostatic hypotension. Initial orthostatic hypotension and delayed blood pressure recovery were present in 20% of the patients with (pre)syncope, of whom 45% were diagnosed as unexplained syncope.

Cardiovascular syncope. Diagnosis of cardiovascular syncope is supported by the presence of structural heart disease, a family history of unexplained sudden death or channelopathy, occurrence during exertion or while supine, occurrence of syncope following palpitations, and specific ECG findings suggesting arrhythmic syncope (171; 39).

The clinical examination, plus electrocardiography, as part of multivariable scores, can accurately identify patients with and without cardiac syncope (05).

According to the EGSYS Rule, there are positive and negative predictors that carry different weights for cardiac syncope and 2-year mortality: (1) palpitations before syncope (4 points); (2) abnormal ECG or heart disease (3 points); (3) syncope during effort (3 points); (4) syncope while supine (2 points); (5) autonomic prodrome with nausea/vomiting (-1 point); and (6) the presence of predisposing or precipitating factors (eg, warm crowded place, prolonged standing, fear, pain, intense emotion) (-1 point) (49). An EGSYS score of less than 3 is associated with lower likelihood of cardiac syncope: the probability of cardiac syncope is 2% with a total score of less than 3, 13% with a score of 3, 33% with a score of 4, and 77% with a score of more than 4 (49).

Clinical predictors of cardiac syncope include the following, based on systematic reviews (05; 99): (1) age at first syncope of at least 35 years; (2) history of atrial fibrillation or flutter; (3) known severe structural heart disease; and (4) cyanosis witnessed during the episode. Negative predicators of cardiac syncope include the following: (1) age at first syncope younger than 35 years; (2) certain prodromal symptoms prior to syncope, including mood change, preoccupation with details, feeling cold, or headache; (3) mood changes after syncope; and (4) inability to remember behavior prior to syncope (05).

The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology has identified specific ECG findings suggestive of an arrhythmic basis for syncope, which were modified somewhat from 2009 to 2018: (1) bifascicular block (ie, left or right bundle branch block combined with left anterior or left posterior fascicular block); (2) other intraventricular conduction abnormalities with QRS duration of at least 0.12 seconds; (3) Mobitz I second-degree atrioventricular block and first degree AV block with a markedly prolonged PR interval; (4) asymptomatic inappropriate sinus bradycardia (40 to 50 bpm) or slow atrial fibrillation (40 to 50 bpm) in the absence of negative chronotropic medications or athletic physical training; (5) nonsustained ventricular tachycardia; (6) pre-excited QRS complexes; (7) long (greater than 460 ms) or short (less than 340 ms) QT intervals; (8) early repolarization; (9) a right bundle branch block pattern with ST elevation in leads V1 to V3 (Brugada syndrome); (10) negative T waves in the right precordial leads (epsilon waves) suggestive of arrhythmogenic right-ventricular cardiomyopathy; and (11) left ventricular hypertrophy suggesting hypertrophic cardiomyopathy (171; 39).

Arrhythmic syncope is considered highly probable when the ECG shows any of the following: (1) persistent sinus bradycardia or slow atrial fibrillation of less than 40 bpm or repetitive sinoatrial block or pauses of at least 3 seconds; (2) Mobitz II second- or third-degree atrioventricular block; (3) alternating right and left bundle branch block; (4) ventricular tachycardia or rapid paroxysmal supraventricular tachycardia; (5) episodes of polymorphic ventricular tachycardia with either a long or short QT interval; or (6) malfunction of a pacemaker or implanted cardiac defibrillator with resulting cardiac pauses (171; 39). In addition, the presence of premature ventricular contractions closely coupled to the preceding complex with short coupling intervals (usually < 350 ms) on an electrocardiogram recorded shortly after a syncopal event may suggest a malignant origin and serve as a red flag for idiopathic ventricular fibrillation (29).

Cardiac ischemia-related syncope is confirmed when syncope presents with evidence of acute myocardial ischemia (with or without myocardial infarction) (39).

Syncope due to structural cardiopulmonary disorders is highly probable when syncope presents in patients with any of the following: prolapsing atrial myxoma, left atrial ball thrombus, severe aortic stenosis, pulmonary embolus, or acute aortic dissection (39).

Pulmonary embolus as a cause of syncope should be suspected in patients with elevated troponin levels or a dilated right ventricle on echocardiogram (11).

Diagnostic tests to be considered after initial evaluation in adults

Immediate ECG monitoring. Immediate ECG monitoring is indicated when there is suspicion for arrhythmic syncope (171; 39).

Echocardiography. Although echocardiography is considered to be useful for diagnosis and risk stratification, the yield of echocardiography for syncope evaluation is low (39). Given the lack of any favorable impact on mortality and the increased costs, echocardiography in patients presenting with syncope should be limited to evidence-based use (150).

Echocardiography should be performed if there is previously known heart disease, data suggestive of structural heart disease, or syncope secondary to cardiovascular cause (39). More specifically, a transthoracic echocardiogram should be done in patients with syncope who are older than 60 years or have known heart disease or evidence suggestive of structural heart disease or syncope due to a cardiovascular cause (including an abnormal electrocardiogram or an elevated brain natriuretic peptide level) (95; 171; 65).

Two-dimensional and Doppler echocardiography during exercise in the standing, sitting, or semi-supine position is useful to detect provocable left ventricular outflow tract obstruction in patients with hypertrophic cardiomyopathy, a history of syncope, and a resting or provoked peak instantaneous left ventricular outflow tract gradient of less than 50 mm Hg (39).

Carotid sinus massage. Carotid sinus massage may be diagnostic, and traditional recommendations suggest that it should generally be performed in patients over age 40 with syncope of unknown etiology after initial evaluation, although it should be avoided in patients with a history of ventricular tachycardia, recent myocardial infarction, transient ischemic attack, stroke within the previous 3 months, or anterior cervical bruit (unless significant plaque and stenosis have been excluded by carotid Doppler (95; 171; 39). Carotid sinus hypersensitivity is defined as asystole of more than 3 seconds or a drop in systolic blood pressure of more than 50 mm Hg with carotid sinus massage (39). Carotid sinus hypersensitivity is common in older men without syncope (low specificity), but the specificity increases if spontaneous syncope is reproduced during carotid sinus massage (39). Because the response to carotid sinus massage was similar in patients with and without syncope, the utility of carotid sinus massage has been questioned as a “nonspecific and dubious diagnostic method” (184). It is precisely for this reason that a diagnosis of carotid sinus syndrome requires that carotid sinus massage precipitates bradycardia, asystole, or hypotension that reproduces spontaneous symptoms in patients with syncope of unknown origin that is compatible with a reflex mechanism (39). The main complications of carotid sinus massage are neurologic, with transient ischemic attacks or strokes occurring in 0.24% of patients who undergo the procedure (39).

Carotid sinus massage and tilt testing are both useful for identifying patients with the bradycardic (cardioinhibitory) phenotype, whereas carotid sinus massage has a limited value for identifying the hypotensive (vasodepressor) phenotype (38). Carotid sinus massage and tilt testing should both be performed in patients over age 40 years with unexplained but possible reflex syncope (38).

Head-up tilt testing. Head-up tilt testing is recommended when there is suspicion reflex syncope and, in some cases, where syncope is thought consistent with POTS, psychogenic pseudosyncope, or orthostatic hypotension (particularly when orthostatic hypotension is suspected based on history, but when initial evaluation does not disclose orthostatic hypotension) (39). Tilt table testing may confirm the diagnosis of vasovagal or neurocardiogenic syncope and may be useful for a positive cardioinhibitory response to tilt testing predicts, with high probability, asystolic spontaneous syncope, a finding with therapeutic implications when cardiac pacing is considered (62; 95; 39). Tilt table testing may be of further value when establishing a diagnosis of syncope of unknown cause (96; 72). In a retrospective study on presyncope and single and multiple episodes of syncope, tilt table testing was very useful in making the correct diagnosis, especially when there was a well-taken, detailed clinical history (147). There are multiple potential hemodynamic patterns to tilt table testing: among 400 pediatric cases with unexplained syncope, the responses included vasovagal syncope (10%); postural orthostatic tachycardia syndrome, either symptomatic (6%) or asymptomatic (7%); orthostatic intolerance (7%); orthostatic hypotension (2%); and negative response (69%) (189). Tilt table testing has an important role in the evaluation of patients with unexplained syncope and in the differential diagnosis of vasovagal syncope (72).

Tilt table testing can sometimes be useful in correcting misdiagnoses of epilepsy in those with convulsive syncope and in identifying rare cases of ictal asystole. Inducing syncope with tilt table testing helps distinguish convulsive syncope from seizures (154). In one study, three patients with normal electroencephalograms who were being treated for epilepsy with anticonvulsants developed bradycardia and prolonged asystole and then typical convulsions during tilt table testing; implantation of permanent pacemakers (atrial/ventricular stimulation, heart rate control) allowed withdrawal of anticonvulsants and prevented further syncope over 2 years of follow-up (72). In another report, a 53-year-old woman presented with episodes of expressive aphasia that were treated with antiepileptic drugs, but then while on therapy, she developed episodes of syncope (89). During a 24-hour EEG monitoring, she had a seizure followed by sinus bradycardia and an 18-second sinus pause, causing syncope and a slowing of cerebral activity that was restored 10 seconds after the return of cardiac activity. This prompted insertion of a dual-chamber pacemaker.

It is worth emphasizing that “seizure-like activities” are commonly precipitated by head-up tilt testing (74). In a study of head-up tilt testing for suspected vasovagal syncope, 47 of 71 patients (66%) showed “seizure-like activities” at the time of syncope during head-up tilt testing: 14 with eyeball deviation but without abnormal limb movements, and 33 with eyeball deviation and abnormal limb movements (eg, myoclonic or tonic-clonic activities) (74). Patients with “seizure-like activities” had a significantly lower heart rate at the time of syncope, and patients with eyeball deviation and abnormal limb movements had a significantly lower systolic blood pressure and cardiac output at the time of syncope.

Tilt table testing can also help establish a diagnosis of pseudosyncope by the constellation of apparent loss of consciousness with loss of motor control, normal blood pressure, heart rate, and electroencephalography (171).

Cardiac stress test. A cardiac stress test should be done if syncope is related to exertion (95).

Holter monitoring. Although Holter monitoring may rarely reveal transient bradyarrhythmias or tachyarrhythmias in patients with syncope (96), symptoms do not recur during monitoring in most patients (39). Holter monitoring for syncope evaluation is expensive in terms of cost per diagnosis and has a true yield as low as 1% to 2% (39). Holter monitoring can be considered in patients with frequent syncope or presyncope (at least one episode per week) (39).

Event recorders. External event recorders are applied by the patient when symptoms occur; they can be useful for evaluation of palpitations but are not useful for evaluation of syncope (39). Patients with recurrent but infrequent syncope can wear a loop event recorder that records their cardiogram just prior to and following a clinical event (46; 125). External loop recorders have a higher diagnostic yield than Holter monitoring and can be useful for patients with relatively frequent syncope (39) and those with recurrent unexplained syncope (130). An implantable loop recorder registers a 1-channel ECG and stores arrhythmic episodes for up to 36 months. These data can be uploaded over standard phone lines and scrutinized for alteration in the cardiac rhythm. Patients with suspected myocardial ischemia should be referred for cardiology evaluation immediately. Based on a systematic Cochrane review of all randomized controlled trials of adult participants (ie, ≥ 18 years) with a diagnosis of unexplained syncope, an implantable loop recorder-based diagnostic strategy increases the frequency of etiologic diagnosis of syncope, although it is not clear that an implantable loop recorder-based diagnostic strategy reduces long-term mortality compared with the standard diagnostic assessment (162). Implanted loop recording is indicated in an early phase of evaluation of patients with recurrent syncope of unknown etiology, who do not meet high-risk criteria for a likely serious underlying problem, and who have a high likelihood of a recurrent event within the battery life of the device (39). Other studies have confirmed that an implantable loop recorder is useful for detecting syncope-correlated arrhythmias in patients with unexplained syncope (91), particularly unexplained, recurrent, traumatic syncope (125). Remote monitoring reduces the time to diagnosis and significantly reduces the risk of traumatic and nontraumatic syncopal relapses. Atrial fibrillation and bradycardia are common diagnostic rhythms identified in older adults with implantable loop recorders for unexplained syncope (16; 70).

Pacemaker or defibrillator interrogation. For patients admitted with permanent pacemakers or implantable cardiac defibrillators, device interrogation is rarely useful for elucidating a cause of syncope without concerning physical examination, telemetry, or EKG findings (48). Interrogation may occasionally document paroxysmal arrhythmias responsible for a syncopal episode, but this rarely alters clinical outcomes (48). Interrogation may be more useful in patients with syncope after recent device placement.

Electrophysiological testing. Electrophysiological testing to determine the threshold for induction of atrial and ventricular dysrhythmias may be diagnostic and potentially therapeutic with radio-ablation or placement of a permanent automatic implanted defibrillator (110; 34). A positive electrophysiologic study suggests that the likely mechanism of syncope is paroxysmal AV block (39).

Neurologic investigations. Neurologic investigations for assessment of patients deemed to have syncope are used widely but are typically of no utility (133; 39; 182). This applies to brain imaging with CT or MRI, ultrasound of neck arteries, and electroencephalography. The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology concluded bluntly that “EEG, ultrasound of neck arteries, and computed tomography or magnetic resonance imaging of the brain are not indicated in patients with syncope” (39).

Indeed, CT or MRI brain imaging are of little value in patients with syncope if the neurologic examination is normal, even if the patient experienced mild head trauma due to syncope (71).

Electroencephalography during a syncopal spell shows initial slowing followed by generalized large-amplitude delta activity and the absence of epileptiform discharges despite clinical convulsion (10; 37). However, electroencephalography is of little diagnostic value in unselected cases (69; 95). Routine electroencephalography has the implicit danger of false-positive abnormalities, especially in children (166). Although electroencephalography is not generally needed in the assessment of syncope, it is appropriate when there is diagnostic uncertainty between syncope and seizures, or in rare cases, suspected ictal syncope (164). Patients with ictal asystole should be diagnosed with concurrent electroencephalogram-electrocardiograph (EEG-ECG) monitoring. Longer term ECG monitoring may be used as a diagnostic aid if ictal asystole is suspected.

Screening for paraneoplastic antibodies and antiganglionic acetylcholine receptor antibodies is recommended in cases of multidomain autonomic failure with an acute or subacute onset (39).

Autonomic testing. Struhal and colleagues applied quantitative sweat testing to assess differences in sudomotor sympathetic activity in relation to the type of reflex syncope (167). They found that in the cardioinhibitory type, sweating started in seven of nine patients after syncope, whereas in vasodepressor type, sweating started in 11 of 12 patients before syncope. In mixed type, sweating started before syncope in 20 patients and after syncope in 10 patients. They also noted that the onset of sweating correlated significantly with the onset of syncope symptoms.

Management

Management of patients with syncope requires careful assessment and appropriate adjustment of medications. Inappropriate prescribing is extremely common for older patients with falls and syncope and is typically persistent and unexplained in medical records (50). The most frequent inappropriate prescribing concerned medications that increased the risk of falls or syncope, specifically vasodilator drugs and benzodiazepines (50).

High-risk patients with syncope require acute hospitalization and urgent, intensive evaluation (171). Features that warrant such evaluation include severe cardiovascular or structural heart disease (eg, heart failure, low ventricular ejection fraction, previous myocardial infarction), a family history of sudden cardiac death, palpitations at the time of syncope, abnormal ECG findings suggesting arrhythmic syncope (see below), or severe comorbidities (eg, severe anemia or electrolyte abnormalities, particularly hypo- and hyperkalemia) (171; 145; 39).

Reflex syncope. Treatment of reflex syncope is generally conservative and consists of reassurance, patient education and instruction in reasonable precautions, avoidance of triggers, isometric counter-pressure maneuvers, and modification or discontinuation of hypotensive drug regimens if possible (86; 90; 145; 39).

Preliminary studies suggest that yoga therapy is a useful lifestyle intervention that can reduce the frequency of syncope and presyncope among patients with recurrent vasovagal syncope (157; 01; 153). In a randomized trial, yoga adjunctive therapy plus standard therapy was superior to standard therapy alone in reducing the symptomatic burden and improving quality-of-life in patients with recurrent vasovagal syncope (153). In another randomized trial of guided yoga therapy for people with recurrent vasovagal syncope, guided yoga therapy was superior to conventional therapy in reducing symptom burden and improving quality-of-life (157). However, higher-quality randomized controlled trials are needed to confirm these results.

Physical counter-pressure maneuvers are very helpful in reducing syncopal recurrences, particularly in patients less than 60 years old who have longstanding, recognizable prodromal symptoms and who are physically able to do them (39; 54). Such maneuvers include forcefully squeezing a rubber ball in the dominant hand, arm tensing in the manner of the Jendrassik maneuver, forceful leg crossing (ie, crossing one leg over the other and squeeze the muscles in the legs, abdomen, and buttocks), and squatting. These maneuvers can transiently increase systolic blood pressure, diastolic blood pressure, and mean arterial pressure, thereby averting syncope (54).

Fludrocortisone can improve venous volume and may reduce syncopal recurrences in young patients with low-normal blood pressures and without comorbidities (183; 39). Alpha adrenergic agonists, such as midodrine, may help patients with the orthostatic form of vasovagal syncope (183; 39; 155; 93), and it appears (based on uncontrolled retrospective assessment) that midodrine is effective and safe in adolescents with recurrent vasovagal syncope (19). Beta-blocking drugs are not indicated; beta-blockers had previously been thought to decrease the degree of ventricular mechanoreceptor activation, which might lessen the frequency or severity of reflex syncope, but they were found to be ineffective in randomized double-blind controlled trials in patients with vasovagal syncope.

Based on the 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients with Syncope from the American College of Cardiology, the American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society, available evidence does not support the use of pacing for reflex-mediated syncope beyond patients with recurrent vasovagal syncope and asystole documented by implantable loop recorder (178; 179). However, for patients with cardioinhibitory vasovagal syncope aged at least 40 years, with a high burden of syncope (greater than or equal to five episodes, greater than or equal to two episodes in the past year) and a cardioinhibitory head-up tilt test (bradycardia less than 40 beats/min for 10 seconds or asystole greater than 3 seconds), dual-chamber pacing with closed-loop stimulation significantly reduced syncope burden and time to first recurrence by 7-fold (24; 23; 107).

The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology now promotes a broader use of pacing for reflex syncope, noting that the recurrent unpredictable events may be disabling (39). These guidelines now recommend consideration of dual-chamber cardiac pacing to reduce recurrence of reflex syncope when the correlation between symptoms and ECG is established in patients 40 years of age or older who have appropriate clinical features (ie, documentation, by means of an implanted loop recorder, of spontaneous syncope with at least 3 seconds of asystole, or at least 6 seconds of asystole without syncope due to sinus arrest, AV block, or a combination of the 2) (39). These guidelines also now recommend consideration of dual-chamber cardiac pacing to reduce syncopal recurrences in patients affected by dominant cardioinhibitory carotid sinus syndrome with recurrent, frequent, unpredictable syncope (39). The evidence is much less clear for tilt-induced vasovagal syncope with divergent opinions among investigators for patients with cardioinhibitory responses, but pacing was clearly ineffective in patients without an asystolic tilt response (39). Thus, a strong consensus exists that pacing is not indicated in patients without a documented cardioinhibitory reflex, such as patients with noncardioinhibitory tilt-positive responses (39).

Orthostatic hypotension. Treatment of syncope related to orthostatic hypotension includes education and lifestyle measures, ensuring adequate hydration and salt intake, discontinuation or reduction of vasoactive drugs, application of isometric physical counter-pressure maneuvers (see the section above on the management of reflex syncope for an elaboration of physical counterpressure maneuvers), application of abdominal binders and thigh-high moderate-to-high compression support stockings to reduce venous pooling, and head-up tilt sleeping (with the head of the bed elevated more than 10 degrees) (39). Increasing salt intake and oral intake of fluids may be helpful to alleviate orthostatic symptoms.

Medication adjustments may alleviate autonomic insufficiency, even if caused by an underlying neurodegenerative disorder. In particular, syncope and falls are causally related to thiazide use (137). The use of thiazide diuretics should be thoroughly questioned, especially in elderly women who are prone to falls.

Fludrocortisone (0.05 to 0.3 mg once daily) can stimulate renal sodium retention and expand fluid volume and may reduce syncopal recurrences in young patients with low normal blood pressures and without comorbidities (183; 39). Alpha-adrenergic agonists, such as midodrine, may also help patients with postural syncope and the orthostatic form of vasovagal syncope (183; 39), but this may be complicated by problematic nocturnal hypertension.

Cardiac syncope. Cardiac syncope treatment is varied depending on exact diagnosis. Dysrhythmias secondary to myocardial ischemia may respond to endovascular procedures and coronary artery bypass.

Cardiac pacing is indicated for selected patients with syncope due to intrinsic cardiac sinus node dysfunction: (1) with sinus node dysfunction (sick sinus syndrome) and an established relationship between sinus bradycardia and syncope; (2) with intrinsic second and third-degree heart block (persistent AV block, paroxysmal AV block (narrow QRS and bundle branch block), or with atrial fibrillation with a slow heart rate); and (3) with bifascicular bundle branch block with documentation of paroxysmal AV block during prolonged ECG monitoring with an implanted loop recorder or with a positive electrophysiologic study (79; 39).

In patients with unexplained syncope and signs of sinus node dysfunction or impaired atrioventricular conduction on invasive electrophysiologic testing, pacemaker implantation is associated with longer syncope-free survival (59).

In Brugada syndrome an implanted defibrillator is safe, and programming a single, high-rate VF zone is recommended to reduce inappropriate defibrillator discharges, especially supraventricular tachyarrhythmias (180).

Catheter ablation is indicated in patients with syncope due to supraventricular tachycardia or ventricular tachycardia to prevent syncope recurrence.

An implantable cardioverter defibrillator (ICD) is indicated in patients with (1) syncope due to ventricular tachycardia and an ejection fraction of 35% or less; (2) patients with syncope and previous myocardial infarction who have ventricular tachycardia induced during an electrophysiological study; or (3) unexplained syncope and left ventricular systolic function (39). ICD therapy can reduce sudden cardiac death in patients with symptomatic heart failure (NYHA class II–III) and a left ventricular ejection fraction of 35% or less after at least 3 months of optimal medical therapy, who are expected to survive at least 1 year with good functional status (39).

Recurrent ventricular fibrillation responds poorly to medications, and treatment needs to be tailored with electrophysiological studies. Implantation of an automatic defibrillator has been shown to enhance survival and is well tolerated (17).

Pulmonary embolism. Syncope is a frequent presenting symptom in patients with pulmonary emboli but is never the sole clinical feature (141). Available studies do not support or justify routine testing for pulmonary emboli in patients presenting with only syncope or collapse.

Hyperventilation syndrome. Hyperventilation syndrome may respond to rebreathing into a paper bag to normalize arterial pCO₂.

Ictal syncope. People with ictal asystole should have their antiepileptic drugs optimized and should be considered for epilepsy surgery (164). If there are ongoing syncopal episodes with associated ictal asystole lasting 6 seconds or longer, particularly if these persist despite optimized medical therapy, a permanent pacemaker may be considered to reduce morbidity (176; 164).

Psychogenic pseudosyncope. Recurrent syncope, especially without injury, should prompt consideration of a psychogenic pseudosyncope and possibly psychiatric referral. In population-based series of syncope, psychiatric causes (eg, anxiety disorders, panic attacks, and depression) are found in 35% of transient loss of consciousness patients (81).

Special considerations

Pregnancy

Pregnant women typically have a systolic blood pressure in the 90 to 110 mm Hg range, and despite increased plasma and red-cell volume, they may be predisposed to neurocardiogenic syncope. Simple supportive treatment is warranted, and rarely are medications necessary or desired. Impaired venous return by uterine compression of the inferior vena cava may produce syncope in the supine position. Detailed physical examination is mandatory in pregnant patients, especially if they have prior heart disease, dysrhythmias, exertional syncope, or palpitations (95). Recurrent syncope coupled with peripheral edema should raise suspicion for dilated cardiomyopathy.

Syncope occurs in approximately 1% of pregnancies (44). From 2005 to 2014 in the province of Alberta, Canada, 32% of the syncope episodes among pregnant women occurred in the first trimester, 44% in the second trimester, and 24% in the third trimester; 8% of pregnancies had more than one episode of syncope (44).

Pregnant women with syncope, especially with first-trimester syncope, may be at a higher risk of adverse pregnancy outcomes (including preterm birth) as well as cardiac arrhythmia and syncope postpartum (44). The incidence of congenital anomalies among children born to women with multiple syncope episodes during pregnancy is significantly higher (4.9%) compared with children born to women without syncope during pregnancy (44).

Anesthesia

Patients with recurrent neurocardiogenic syncope may be prone to syncope when exposed to blood drawing and anesthetic procedures, as fear and the sight of blood may trigger a spell. The anesthesiologist should be aware of the patient's volume status and the presence of autonomic neuropathy because blood pressure swings may be exaggerated with general or spinal anesthesia. Cardiac status is critical to patient tolerance to general or spinal anesthesia, so careful cardiac examination is essential in a preoperative evaluation.