Reflex syncope (neurally-mediated syncope) …

Douglas J Lanska MD MS MSPH

General Neurology

Updated 05.01.2024
Released 10.21.1993
Expires For CME 05.01.2027

Reflex syncope (neurally-mediated syncope)

Author: Douglas J Lanska MD MS MSPH

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Reflex syncope (neurally-mediated syncope)

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Introduction

Overview

Reflex syncope is one of the main causes of fainting. Cardiac and cerebrovascular regulatory mechanisms are both involved in its pathogenesis. Patients often describe specific triggers, such as sudden postural changes, upright position, extreme emotional stress, pain, or trauma. Most cases of reflex syncope, particularly in the dominant subgroup of vasovagal syncope, do not require pharmacotherapy or extensive evaluation. Prevention remains the best management. Reflex syncope is associated with psychological distress, which may be more salient to the patient than the number of syncopal episodes experienced.

Key points

	• Syncope denotes loss of consciousness secondary to inadequate blood supply to the brain.
	• Reflex syncope is a neurally mediated transient loss of consciousness that occurs when the body inappropriately reacts to certain triggers, such as intense emotion, the sight of blood, extreme heat, dehydration, a long period of standing, or intense pain.
	• Usually, no focal neurologic symptoms are observed during and after these attacks unless the patient has a preexisting neurologic deficit.
	• Almost all cases of reflex syncope occur in the standing position.
	• Pharmacological agents can cause or exacerbate reflex syncope.
	• Most cases of reflex syncope, particularly in the dominant subgroup of vasovagal syncope, do not require pharmacotherapy or extensive evaluation.

Historical note and terminology

The term “syncope” (derived from synkope, the Greek word that means “cutting short”) is now used for describing the symptom of loss of consciousness resulting from insufficient blood flow to the brain (03).

Neuroanatomical connections between the brain and heart have been known since the time of Galen of Pergamon (129 AD-c. 200) (107). Persian physician Ibn Sīnā (ca. 980-1037), known in the West as Avicenna, was the first to note carotid sinus hypersensitivity, which presents with vasovagal syncope following compression of the carotid artery (135).

Galen

Posthumous engraved “portrait” of Galen by G. P. Busch. (Courtesy of the Wellcome Collection. Creative Commons Attribution 4.0 International License.)
Ibn Sīnā (Avicenna)

Posthumous engraved “portrait” of Persian physician Ibn Sīnā (Avicenna). (Courtesy of the Wellcome Collection. Creative Commons Attribution 4.0 International License.)

In the late 18th and 19th centuries, various authors—eg, Denis Diderot, Jane Austen, Charles Dickens, Gustave Flaubert, George Eliot, Fedor Dostoyevsky—wrote fictional accounts of vasovagal syncope, establishing that this phenomenon was already well-recognized, even outside of medical circles (117). Review of these early accounts shows that the phenomenon was recognized as occurring in both sexes but much more frequently in women, and further that venesection was a potent trigger of the phenomenon (117).

One early fictional account was given by French philosopher, art critic, and writer Denis Diderot (1713-1784) in The Nun (1796):

Denis Diderot

Painted portrait of Denis Diderot (1713-1784) by Louis-Michel van Loo (1707–1771). (Courtesy of The Louvre, Paris. Public domain.)

I moved towards the superior with my arms held out in supplication and my body leaning backwards, swooning. I fell, but it was not a heavy fall. In such fainting fits when one's strength abandons one, the limbs seem to give way and as it were fold up unawares; nature, unable to hold up, seems to try to collapse gently. I lost consciousness and the sense of feeling, and merely heard confused and distant voices buzzing round me; whether it was real speech or a singing in my ears, I could make out nothing but this continual buzzing.

Another fictional account of reflex syncope, in this case triggered by venesection, was given by French novelist Gustave Flaubert (1713-1784) in Madame Bovary (1856-1857):

So Bovary ordered a bandage and a basin, and asked Justin to hold it. Then addressing the peasant, who was already pale—

"Don't be afraid, my lad."

"No, no, sir," said the other; "get on."

And with an air of bravado he held out his great arm. At the prick of the lancet the blood spurted out, splashing against the looking-glass.

"Hold the basin nearer," exclaimed Charles.

"Lor!" said the peasant, "one would swear it was a little fountain flowing. How red my blood is! That's a good sign, isn't it?"

"Sometimes," answered the doctor, "one feels nothing at first, and then syncope sets in, and more especially with people of strong constitution like this man."

At these words the rustic let go the lancet-case he was twisting between his fingers. A shudder of his shoulders made the chair-back creak. His hat fell off.

"I thought as much," said Bovary, pressing his finger on the vein.

The basin was beginning to tremble in Justin's hands; his knees shook, he turned pale.

"Emma! Emma!" called Charles.

With one bound she came down the staircase.

"Some vinegar," he cried. "O dear! two at once!"

Gustave Flaubert

Painted portrait of Gustave Flaubert (1821-1880) by Eugène Giraud (1806-1881). (Courtesy of the collection of the Palace of Versailles. Public domain.)

In 1907, British neurologist Sir William R Gowers MD FRS (1845-1915) described a hodge-podge of disorders under the umbrella of “vagal and vaso-vagal attacks,” while trying to relate these to epileptic seizures (62; 63; 106).

Sir William R Gowers

Portrait of British neurologist Sir William R Gowers. Photogravure after Maull and Fox. (Courtesy of the Wellcome Collection. Creative Commons Attribution 4.0 International License.)

These events, as Gowers understood them, were prolonged (typically more than 10 minutes in duration, and often more than 30 minutes) and not associated with loss of consciousness. For Gowers, the descriptor vagal was “a purely descriptive term to characterize the gastric, respiratory, and cardiac symptoms, which included the sense of epigastric oppression or fullness, respiratory distress, difficulty breathing, cardiac discomfort and pain, and the sense of impending death” (106). Gowers suggested further that the term vaso-vagal be used for attacks characterized by the vasomotor symptoms of coldness and pallor.

During World War I, Canadian cardiologist Thomas Forrest Cotton (1884-1965) was selected to be part of the group that Welsh-born British cardiologist Sir Thomas Lewis CBE FRS (1881-1945) was assembling to study “soldier’s heart syndrome” at the Military Heart Hospital at Hampstead, England (08; 16; 125).

Sir Thomas Lewis

Photographic portrait of British cardiologist Sir Thomas Lewis. (Courtesy of the Wellcome Collection. Creative Commons Attribution 4.0 International License.)

In 1918, Cotton and Lewis published their observations on “fainting attacks due to inhibitory cardiac impulses” based on observations of soldiers with vasovagal syncope during World War I (41). In 1932, Lewis took issue with Gowers’ vague descriptive characterization of “vasovagal attacks” and instead advocated calling Gowers’ constellation of symptoms “Gowers’ syndrome” to avoid confusion with how Lewis wished to redefine use of the term “vasovagal” (91). Lewis coined the label “vasovagal syncope” to encompass brief loss of consciousness with hypotension and bradycardia. Lewis recognized common precipitants of such attacks:

In healthy people, completely at ease, the provocation may be adequate without arousing feelings either of disgust or dread. In these instances, there is usually an element of surprise, as when a subject sees blood flow into a syringe from his own arm, the arm redden in reactive hyperemia, or a sphygmograph lever begin to move on his own wrist.

Lewis also recognized key clinical features and used these to propose pathophysiological mechanisms underpinning the syncopal episodes. In particular, Lewis recognized the bradycardia, correctly determined that it was vagally mediated, and he also correctly inferred that it alone could not readily account for syncope.

The slow pulse in the attack is due, as has been shown polygraphically, to a slowing of the whole heart; irregularity, a common feature of vagal slowing, is often displayed. The proof that slowing is vagal is given by atropine, which promptly drives the rate to usual levels under atropine.

The slowing of the heart to 50 or 40, exceptionally to 30 beats per minute, is insufficient to induce unconsciousness; such rates are frequently seen in cases of heart-block that are without symptoms. The idea that, because the vagus is responsible for the slowing, the force of ventricular contractions will be weakened, is open to serious doubt. Appreciable weakening of the beats from this cause has not been demonstrated in mammals; in dogs, the heart rate may be reduced to one half by vagal stimulation without altering the mean blood pressure materially.

Instead, Lewis concluded that the vasodepressor component was more fundamental than the cardioinhibitory component. Undoubtedly the main cause of the fall in blood pressure in these attacks and the enfeeblement loss of pulse is independent of the vagus and lies in the blood vessels. Although atropine raises the pulse rate to and beyond normal levels during the attack, it leaves the blood pressure below normal and the patient still pale and not fully conscious. Attacks in which the blood pressure sinks without a lowering of the pulse rate and the patient verges on unconsciousness whenever the pressure reaches certain low levels have been encountered. Thus, the cause of the syncope is mainly vasomotor and not vagal; however, the vagus adds impressively to the clinical picture by inducing conspicuous slowing of the heart and gastric manifestations.

In 2011, Dutch internist Wouter Wieling and colleagues coined the term “prolonged post-faint hypotension” for a severe variant of vasovagal syncope that had been described as early as 1918 by Cotton and Lewis and subsequently was observed most often during blood donation and tilt tests (41; 154). Patients with “prolonged post-faint hypotension” characteristically experience bradycardia and marked hypotension, along with weakness, malaise, and nausea. Wieling and colleagues proposed that sustained high vagal outflow results in pronounced bradycardia and decreased cardiac contractility, resulting in loss of cardiac output and a marked drop in systemic blood pressure (154).

Clinical manifestations

Presentation and course

	• The modern classification of syncope recognizes the following major types: cardiac syncope, orthostatic syncope, and reflex or neurally mediated syncope.
	• Reflex syncope is a neurally mediated transient loss of consciousness that occurs when the body inappropriately reacts to certain triggers, such as intense emotion, the sight of blood, extreme heat, dehydration, a long period of standing, or intense pain.
	• Reflex syncope is a heterogeneous group of disorders mediated by cardiovascular reflexes that are inappropriately triggered, producing vasodilation or bradycardia, with a resultant fall in blood pressure and cerebral perfusion.
	• Reflex syncope is usually classified based on the efferent pathway most involved, ie, sympathetic or parasympathetic.
	• The term “vasodepressor type” is used if hypotension predominates due to a loss of upright vasoconstrictor tone, whereas the term “cardioinhibitory type” is used when bradycardia or asystole predominate, and “mixed type” is used if both mechanisms are present.
	• Reflex syncope may also be classified by the afferent pathway or trigger as either vasovagal, situational, carotid sinus, or atypical.
	• Vasovagal syncope is the most common form of reflex syncope and includes the common faint.
	• Vasovagal syncope typically occurs in situations of orthostatic stress and is often triggered by emotional distress.
	• Classical vasovagal syncope typically begins in adolescents and young adults as an isolated episode.
	• Carotid sinus syncope occurs rarely in a spontaneous form, triggered by mechanical manipulation of the carotid sinuses, and carotid sinus syncope occurs in a more common form, in which no mechanical trigger is identified, and is instead diagnosed by carotid sinus massage.
	• Onset may be abrupt or may rapidly follow warning symptoms like fatigue, nausea, dizziness, sweating, pallor, blurred vision, abdominal discomfort, headache, pins-and-needles, lightheadedness, rapid heart rate, or impaired hearing.
	• Complete loss of consciousness in reflex syncope lasts no longer than 20 seconds.
	• Witnesses typically report that the face of affected individuals turns ashen-gray, the extremities often get cold, and brief myoclonic jerks can appear, which can be misdiagnosed as epileptic seizures.
	• Full recovery after an episode of reflex syncope may take some hours.
	• Many people with reflex syncope develop adaptive habits to avoid fainting, including crossing their legs, walking around instead of standing, frequently tightening their leg muscles, or sitting or lying down when they experience warning symptoms.

According to guidelines for the diagnosis and management of syncope, the modern classification of syncope recognizes the following major types: cardiac syncope, orthostatic syncope, and reflex or neurally mediated syncope (141; 29). Reflex syncope is a neurally mediated transient loss of consciousness that occurs when the body inappropriately reacts to certain triggers, such as intense emotion, the sight of blood, extreme heat, dehydration, a long period of standing, or intense pain. Collectively, reflex syncope is a heterogeneous group of disorders mediated by cardiovascular reflexes that are inappropriately triggered, producing vasodilation or bradycardia, with a resultant fall in blood pressure and cerebral perfusion. Thus, the predominant mechanism underlying reflex syncope can be assigned to hypotensive or to bradycardic phenotypes (24).

Reflex syncope is usually classified based on the efferent pathway most involved, ie, sympathetic or parasympathetic. The term “vasodepressor type” is used if hypotension predominates due to a loss of upright vasoconstrictor tone, whereas the term “cardioinhibitory type” is used when bradycardia or asystole predominate, and “mixed type” is used if both mechanisms are present (141; 29).

Reflex syncope may also be classified by the afferent pathway or trigger as either vasovagal, situational, carotid sinus, or atypical (141; 29). Vasovagal syncope is the most common form of reflex syncope and includes the common faint; vasovagal syncope typically occurs in situations of orthostatic stress (typically standing but less commonly while sitting) and is often triggered by emotional distress (eg, due to fear, somatic or visceral pain, blood draw) (141; 29). Dental interventions can also predispose patients to fainting due to fear, pain, unusual sights and smells, anxiety, fatigue, and fasting (132). Situational syncope is triggered by specific circumstances (eg, coughing or sneezing, swallowing, defecation, micturition or immediately post-micturition, post-exercise, post-prandial, and weightlifting); situational syncope is often a form of reflex syncope but may not be, and situational syncope can also be multifactorial in causation. Carotid sinus syncope occurs rarely in a spontaneous form, triggered by mechanical manipulation of the carotid sinuses, and carotid sinus syncope occurs in a more common form, in which no mechanical trigger is identified and is instead diagnosed by carotid sinus massage. Atypical or nonclassical forms of reflex syncope include those without apparent triggers or atypical presentations; the diagnosis of atypical reflex syncope does not depend solely on history taking, but instead depends more on the exclusion of other causes of syncope (eg, structural heart disease) and on reproducing similar symptoms with tilt testing (141; 29; 27). In particular, syncope without prodromes in subjects with a normal heart and normal electrocardiogram is classified as nonclassical neurally mediated syncope; this form of syncope is characterized by frequent asystolic syncope, very low adenosine plasma levels, low expression of A2A receptors, a predominance of the TC variant in the single nucleotide c.1364 C>T polymorphism of the A2A receptor gene (27; 47), and excessive plasma release of adenosine at the time of syncope during head-up tilt table test (56).

The term “neurocardiogenic syncope” is variously used to mean either reflex syncope (encompassing vasovagal syncope, situational syncope, and carotid sinus syndrome) or specific subgroups (typically vasovagal syncope, but some apply it instead for situational syncope). Because of the various distinct uses of the term, and because the current guidelines have adopted different terminology, the term “neurocardiogenic” is not the primary term used in this chapter.

In Europe, syncope with little or no prodrome is designated as “malignant,” whereas in North America this term is usually used to describe vasovagal syncope associated with long asystolic pauses (60).

Classical vasovagal syncope typically begins in adolescents and young adults as an isolated episode. Atypical presentations beginning in old age are often associated with cardiovascular or neurologic disorders and may also manifest with orthostatic or post-prandial hypotension. In the atypical forms, reflex syncope develops as a manifestation of an underlying pathological process, particularly with impairment of the autonomic nervous system to activate compensatory reflexes (eg, in autonomic failure) (141; 29). For example, newly acquired reflex syncope has been reported following acute inferior wall myocardial infarction (11; 73; 113). Typical provoking factors of prolonged standing, posture change, and hot environments were also less common in older patients (53).

In a study comparing differences in presentation of vasovagal syncope between older and younger patients, older patients were less likely to report presyncope or palpitations and were more likely to present with unexplained falls (53).

Onset may be abrupt or may rapidly follow warning symptoms like fatigue, nausea, dizziness, sweating, pallor, blurred vision, abdominal discomfort, headache, pins-and-needles, lightheadedness, rapid heart rate, or impaired hearing. Uncommonly, tinnitus, when occurring as an initial symptom of inner ear hypoperfusion, can be a warning sign of impending syncope (121); such premonitory symptoms can last a few seconds or a few minutes. Complete loss of consciousness in reflex syncope lasts no longer than 20 seconds (141; 29). There are no focal neurologic symptoms during and after these attacks unless the patient has a preexisting neurologic deficit or new signs develop from syncope-associated trauma.

Witnesses typically report that the face of affected individuals turns ashen gray. The extremities often get cold. Brief myoclonic jerks can appear and can be misdiagnosed as epileptic seizures. In the supine position, consciousness returns within seconds. Mild tachycardia, diaphoresis, and piloerection can be seen due to autonomic activity. Some older individuals may experience unexplained or nonaccidental falls (09); they may complain of lightheadedness, headache, and malaise. Full recovery may take some hours.

Many people with reflex syncope develop adaptive habits to avoid fainting; these habits include crossing their legs, walking around instead of standing, frequently tightening their leg muscles, or sitting or lying down when they experience warning symptoms.

Patients with vasovagal syncope usually have some psychosocial impairment, especially in the form of anxiety and depression (02).

Prognosis and complications

The lifetime incidence of one or more fainting episodes is approximately 40%. For the most part, these episodes are benign and self-limited, although frequent syncope episodes can be debilitating, and injury may occur from sudden falls.

Many forms of reflex syncope, particularly classical vasovagal syncope, have an excellent prognosis and tend to cease with education and adequate prophylaxis. In an 8-year follow-up study, the long-term outcome of patients with vasovagal syncope was considered excellent, with no deaths during a mean follow-up of 30 months and with most patients not having further recurrences after education on triggers and preventive measures (13).

Recurrences of vasovagal syncope are common, with 20% experiencing recurrences within 6 months and 30% experiencing recurrences over 30 months (13; 14). Although educating patients may help prevent syncopal episodes, the recurrence rate before treatment may influence the effectiveness of therapy. Frequent previous syncopal episodes and a positive result during the early passive phase of tilt table testing were prognostic factors for recurrent reflex syncope in men in their late teens and early twenties (13; 146), but, as confirmed in a long-term follow-up study, the frequency of recent occurrences is a better predictor of an unfavorable prognosis than a positive head-up tilt result (52).

Longer duration of unconsciousness suggests more severe cerebral hemodynamic disturbances during either spontaneous or provoked syncope (159). The occurrence of a cardioinhibitory response and prolonged duration of unconsciousness are associated with longer tilt-down time during induced vasovagal syncope. Tilt-down time does not affect asystolic pause duration (160).

Recurrent syncopal attacks can create significant functional impairment. Six percent of patients having recurrent syncope develop complications such as fractures. Syncope while driving threatens the lives of affected patients and others as well (60). A history of emotionally triggered vasovagal syncope is also independently associated with increased risk of coronary events in later life (161).

Clinical vignette

Case 1. Cotton and Lewis described a classic case of vasovagal syncope in a soldier who developed vasovagal syncope following venipuncture (41):

December the 18th, 1916. The patient was sitting, and a few c.c. of blood had just been withdrawn from a vein in the arm and the needle had been removed. He began to feel queer, as though his “stomach had turned upside down;” he became dizzy; pallor was noticed; his head fell forward to his knees. He was at once placed in a long easy chair and further observed. By this time the pallor was intense and he was restless. The pulse was imperceptible, the heart sounds were distant, the rate of beating being 50 per minute; the action was for the most part regular, a single premature beat being noted. From time to time there were retching movements; the pupils were little; if at all, dilated; he was limp, mentally confused or actually unconscious for several minutes. A heavy sweat broke out over the forehead and spread over the chest and body; the pallor remained extreme; respiration was slow and sighing. The pulse was imperceptible for several minutes; as it returned the systolic blood pressure was registered (palpatory and auscultatory) at 60 mm. Hg. A little later the pressure fell to 55 and then to 50, the pulse varying in rate between 50 and 60. Five minutes after the onset some recovery was noted, the pulse had risen to 64 and the blood pressure to 80.

Case 2. Case 2 describes postprandial hypotension aggravated by antihypertensive medications. A 64-year-old woman was evaluated in an emergency room after an episode of unconsciousness and myoclonic jerks. After having dinner, she stood for a long time and then suddenly dropped to the floor with visible pallor and diaphoresis. She was able to answer questions within a minute and had no confusion or bladder incontinence. She had previous complaints of dizziness and lightheadedness with standing. A year earlier she had been started on an alpha-receptor blocker for her mild but persistent hypertension. Her family history was negative for epilepsy and syncope. Her blood pressure was 110/80 mmHg. Orthostatic blood pressures (supine, on standing, and after standing for 3 minutes) were not assessed but should have been. Cardiac and neurologic examinations and a 12-lead EKG were normal. Complete blood count and liver and renal function tests were normal, but her blood glucose level was slightly high. She also had a normal EEG and cranial computerized tomography scan, although these studies were not indicated based on her history and examination. With a possible diagnosis of vasovagal syncope, she was advised to take fluids and to measure her blood pressure daily to help guide her primary care physician with potential adjustments of her antihypertensive therapy.

Biological basis

	• Reflex syncope encompasses a heterogeneous group of conditions in which cardiovascular reflexes that normally function to control the circulation become intermittently inappropriate in response to a trigger, resulting in vasodilatation or bradycardia and consequently produce a fall in arterial blood pressure and global cerebral perfusion.
	• In reflex syncope, both the quick drop in blood pressure and its low value exceed the capacity of cerebral autoregulation to prevent syncope.
	• Bradycardia may be marked or only “relative” given the severity of systemic hypotension.
	• Between syncopal episodes, patients with neurally mediated syncope have normal blood pressure and orthostatic tolerance.
	• The vasodilation that contributes to the vasodepressor components of vasovagal syncope is caused largely by centrally initiated diminution of sympathetic vasoconstrictor tone (ie, passive vasodilation), but there can also be a sympathetically mediated vasodilatory component resulting from release of nitric oxide.
	• Clustering of vasovagal syncope in some families suggests a genetic component.

Etiology and pathogenesis

Reflex syncope encompasses a heterogeneous group of conditions in which cardiovascular reflexes that normally function to control the circulation become intermittently inappropriate in response to a trigger, resulting in vasodilatation or bradycardia and consequently produce a fall in arterial blood pressure and global cerebral perfusion (148). In reflex syncope both the quick drop in blood pressure and its low value exceed the capacity of cerebral autoregulation to prevent syncope (149). Bradycardia may be marked or only “relative” given the severity of systemic hypotension (18). Both cardiac and cerebrovascular regulatory mechanisms are involved in the pathogenesis of reflex syncope. Between syncopal episodes, patients with neurally mediated syncope have normal blood pressure and orthostatic tolerance (76).

Cerebrovascular hemodynamic changes including cerebral vasoconstriction and loss of autoregulatory function have also been described, but results have been inconsistent, and the role of such changes is not well established (65; 66; 110; 50; 51; 18; 35; 36; 37; 89; 43; 04; 61). Cerebral vasoconstriction (in what has been called “cerebral syncope”) is not a paradoxical phenomenon when it occurs before tilt-induced vasovagal syncope but is instead only the physiological consequence of hyperventilation-induced hypocapnia that occurs commonly in habitual fainters (89).

The pathophysiology of reflex syncope can be approached by considering the afferent and efferent limbs of the reflex, central nervous system processing of signals, and contributions from feedback systems (18).

Most episodes of reflex syncope are associated with specific triggers that act via specific afferent pathways (eg, vasovagal syncope associated with severe pain may be mediated by peripheral pain receptors, and vasovagal syncope associated with severe hemorrhage may be mediated by cardiac and cardiopulmonary mechanoreceptors) (18). For reflex syncope accompanying endoscopic instrumentation or following micturition, other organ systems receptors (eg, within the gastrointestinal and genitourinary tracts) are thought to be contributory. However, vasovagal syncope can also be triggered by emotional upset or fear, indicating that the “afferent” neural signals may, in some cases, originate solely within the cerebral cortex (18).

In patients with carotid sinus syndrome, signals from the carotid sinus baroreceptor axons travel within the glossopharyngeal nerve. Older adults with vasovagal syncope have exaggerated arterial baroreflex sensitivity at baseline (96). Enhanced baroreflex sensitivity is also a characteristic of young subjects with tilt-induced vasovagal syncope (74; 122). Nevertheless, there has been a longstanding debate on whether the peripheral baroreceptor is “hypersensitive” or whether there is a central problem in the processing of the afferent signals (142; 18). Carotid sinus syncope has been attributed to a central dissociation of afferent signals arising from the carotid baroreceptor and the ipsilateral sternocleidomastoid muscle (142).

In patients with reflex syncope, stretch-sensitive mechanoreceptors in the left ventricular wall increase vagal tone when the cardiac return is decreased, which can lead to “paradoxical” reflex peripheral vasodilatation, bradycardia, and syncope (60). However, the observation that reflex syncope can be seen in patients with deafferented hearts, ie, after orthotopic heart transplantation, forced a reconsideration of the role of cardiac and cardiopulmonary mechanoreceptors, which had previously been considered as responsible for most cases of vasovagal syncope (130; 54; 18).The efferent limb of the vasovagal reflex incorporates neural (eg, mediated through enhanced vagal tone), humoral (eg, particularly epinephrine, but also others, including vasoactive peptides), and peripheral aspects (18).

The vasodilation that contributes to the vasodepressor components of vasovagal syncope is caused largely by centrally initiated diminution of sympathetic vasoconstrictor tone (ie, passive vasodilation) (18), but there can also be a sympathetically mediated vasodilatory component resulting from release of nitric oxide (68).

Low creatine kinase activity levels were associated with a 73% higher incidence of fainting in a random population sample, a finding deemed biologically plausible because creatine kinase enhances cardiovascular and skeletal muscle contractility and salt retention (23). The clustering of vasovagal syncope in some families suggests a genetic component (100; 109; 12; 85; 84; 83; 133; 90). Overall, about one third of patients with recurrent neurally mediated syncope have a family history of syncope (90). Children of a parent with vasovagal syncope are more likely to faint than those without a parent with vasovagal syncope, and the likelihood of fainting is further increased in those with two fainting parents or a fainting twin (133). Twin studies, highly focused genome-wide association studies, and copy number variation studies all suggest there are loci in the genome that associate with vasovagal syncope, although the responsible genes, pathways, and proteins are still unknown (133). A multigenerational kindred candidate gene study identified three genes that associate with vasovagal syncope, providing the best evidence to date for central signaling genes involving serotonin and dopamine (133). Familial vasovagal syncope may infrequently be inherited as an autosomal dominant trait and has similar features to sporadic vasovagal syncope (85; 84; 83). A Portuguese study demonstrated a familial history for reflex syncope in 40% with positive tilt test results and in 25% of those with negative tilt test results (12). There is also some evidence of sex-specific penetrance (19). Polymorphisms of angiotensin converting enzyme alone are not associated with increased risk of vasovagal syncope (108).

Pain plays a key role in triggering vasovagal syncope following venipuncture, and this effect is mediated through reduced capacity to achieve maximal sympathetic activation during orthostatic stress (71). Consequently, topical anesthetics (eg, EMLA) may reduce the frequency and severity of vasovagal syncope during procedures requiring needles and intravascular instrumentation.

Epidemiology

	• Young and middle-aged women are more affected by vasovagal syncope than men.
	• Among adult patients with syncope admitted to the emergency department of a university hospital who were prospectively evaluated for one year, approximately two thirds (63%) had neurally mediated syncope syndromes.
	• In the Framingham Heart Study, vasovagal syncope had a benign prognosis, whereas patients with cardiac syncope were at increased risk for death from any cause and from cardiovascular events, and persons with syncope of unknown cause were at increased risk for death from any cause.
	• The most common type of syncope is reflex syncope.
	• In young patients, syncope is typically vasovagal, whereas in older adults reflex syncope represents a much smaller proportion of syncope cases.
	• Vasovagal syncope accounts for 30% to 50% of syncopal spells in outpatient populations of older adults.

Epidemiological estimates of prevalence of vasovagal syncope vary widely, from 1.3% to over 40%, depending on the country, study population, and methods used to determine whether a subject has the condition (128).

In the UK armed forces, the overall syncope case rate in healthy young men subject to potential triggers (eg, orthostasis and heat) was 10.5 per 1000 person-years (115). In those with syncope, orthostasis (61%) and heat (35%) were the most common precipitating factors (116). The most common interventions used by soldiers were to maintain hydration (59%) and purposeful movements when at attention (predominantly "toe wiggling," 55%). Nearly one third (30%) of participants who had previously fainted did not seek medical attention. A history of migraines and headaches significantly increased the risk of reflex syncope (odds ratio: 8.9), whereas a history of antihistamine prescription (odds ratio: 0.07), non-white ethnicity (odds ratio: 0.03), and male sex (odds ratio: 0.3) were protective.

Young and middle-aged women are more affected by vasovagal syncope than men (06).

Among adult patients with syncope admitted to the emergency department of a university hospital who were prospectively evaluated for one year, approximately two thirds (63%) had neurally mediated syncope syndromes (21). Other epidemiological studies showed similar results (129).

In the Framingham Heart Study, vasovagal syncope had a benign prognosis, whereas patients with cardiac syncope were at increased risk for death from any cause and from cardiovascular events, and persons with syncope of unknown cause were at increased risk for death from any cause (136).

Overall, the most common type of syncope is reflex syncope, followed by orthostatic syncope and cardiac syncope (150). In young patients, syncope is typically vasovagal, whereas in older adults, reflex syncope represents a much smaller proportion of syncope cases (given that orthostatic syncope and cardiac syncope are much more common categories of syncope in this age group). In addition, in older adults with reflex syncope, carotid sinus syndrome and some forms of situational syncope (eg, micturition and cough syncope) represent significant proportions of cases along with vasovagal syncope (78).

Among 677,956 phlebotomies performed in outpatients, there was an overall incidence of vasovagal syncope of 0.004% (157). Use of more than five blood collection tubes and a waiting time of more than 15 minutes were associated with a higher risk of vasovagal syncope, with corresponding odds ratios of 8.1 (95% CI 3.8-17.5) and 3.7 (95% CI 0.9-15.6), respectively (157).

Among 35,134 blood donors at a university hospital in Malaysia, 159 (0.45%) had vasovagal reactions. Dizziness or mild vasovagal reactions were the most frequently observed adverse reactions, accounting for approximately half (55%) of all adverse reactions. In a multivariate regression model, vasovagal reactions were significantly associated with age, female gender, first-time donors, and 450 ml volume of blood collected.

In a Chinese study, vasovagal reactions after plasma donation occurred 737 times in 120,448 plasma donations (0.66%) (158). Gender, season, donor status, weight, pulse, duration of donation, and cycle were significant independent risk factors for vasovagal reactions.

In a Japanese study involving 577,325 blood donations split into a model training group and a testing group, the most important variable was the donor status (ie, first-time donors, repeat donors with no history of reaction, and repeat donors with a history of reaction), followed by age, estimated blood volume, and height (70). These variables were integrated into a scoring system. Based on scores of 0 to 6, vasovagal reaction rates varied from 0.09% to 3.11%.

Vasovagal syncope has been documented in a high proportion of patients with migraine (45).

Although vasovagal syncope was initially felt to primarily affect younger patients (46), tilt table testing has uncovered a bimodal distribution for this condition (147). Vasovagal syncope accounts for 30% to 50% of syncopal spells in outpatient populations of older adults (40; 147).

An association between vitamin D deficiency and vasovagal syncope has been demonstrated in a systematic review and meta-analysis (81). Patients with vasovagal syncope had significantly lower vitamin D serum levels compared with cases without vasovagal syncope. Moreover, the rate of vasovagal syncope occurrence was significantly higher in vitamin D–deficient individuals (odds ratio 5.43).

Prevention

	• Walking, taking a short and cool shower, avoiding hot baths or saunas, and avoiding alcohol and excess caffeine intake are some practical strategies for prevention.
	• It is better to walk instead of standing still.
	• Crossing legs and muscle tensing can also abort or delay impending faints.
	• Appropriate fluid intake is important during the hottest hours on summer days.
	• Water ingestion increases peripheral vascular resistance.
	• Cognitive behavioral therapy may result in dramatic improvements in severe symptoms.

In spite of the complex pathophysiology of reflex syncope, careful application of preventative maneuvers can minimize syncopal events and greatly enhance patients’ ability to tolerate their illness. Walking, taking a short cool shower, avoiding hot baths or saunas, and avoiding alcohol and excess caffeine intake are some practical strategies for prevention. It is better to walk instead of standing still. Crossing legs and muscle tensing can also abort or delay impending faints (86). Appropriate fluid intake is important during the hottest hours on summer days. Additionally, water ingestion increases peripheral vascular resistance; up to 30 mm Hg blood pressure increases occur after ingestion of two cups of tap water (at room temperature) 5 minutes before head-up tilt test (95). If vasoactive agents are needed for vascular problems, salt intake or drug regimens may require adjustment.

Because patients with reflex syncope often have a significant degree of psychological distress, simple psychological interventions such as cognitive behavioral therapy may result in dramatic improvements in severe symptoms, and it may be that those with milder symptoms could also benefit (64).

For individuals undergoing pain procedures in a pain clinic, a higher systolic blood pressure was significantly associated with lower odds of having vasovagal syncope (75). An adequate dose of a vasopressor (eg, ephedrine) can be used to prevent a vasovagal event from happening (75).

A randomized controlled trial performed on 4320 whole blood donors found that water ingestion and applied muscle tension were significantly more effective in vasovagal reaction prevention compared to controls or to individual interventions (102). Controls experienced the highest rate of vasovagal reaction (2.5%), whereas the combined treatment group experienced the lowest rate (0.9%).

Differential diagnosis

Confusing conditions

Syncope is a very common presentation with a wide differential diagnosis and equally wide prognostic implications. An accurate history and physical examination are essential for diagnosis, prognosis, and treatment (87). An accurate diagnosis of syncope is also essential for prevention of recurrences.

The differential diagnosis of reflex syncope first requires distinguishing reflex syncope from other categories of syncope (ie, orthostatic syncope and cardiac syncope) and then determining the type of reflex syncope. The history and examination (including assessment of orthostatic blood pressures, palpation of the pulse, and cardiac auscultation) are essential in making these distinctions.

Seizures, sleep disturbances, accidental falls, and some psychiatric conditions such as anxiety attacks and hysterical reactions are sometimes confused with syncope. Syncope and seizures share certain clinical features that may represent diagnostic challenges (33; 69). Patients with complex partial epilepsy may have symptoms that mimic the syncope prodrome, but postictal confusion is notably absent in reflex syncope. Reports of “convulsions” from observers would support a diagnosis of seizure, but one must be careful not to confuse the simple myoclonic jerks seen in syncope with a convulsion (77); unfortunately, syncope followed by brief myoclonic jerks is not infrequently misdiagnosed as epilepsy (127).

In patients with a recent loss of consciousness and abnormal movements, serum CK concentration is a useful, practical, and relatively accurate parameter to assist in the differentiation of epileptic seizures from either vasovagal syncope or psychogenic nonepileptic seizures (120).

In patients with pseudo-syncope, physical examination does not reveal any abnormal findings (eg, changes in pulse rate or hypotension) during or immediately after attacks. Hypoglycemia, acute blood loss, drugs, primary autonomic failure, neurodegenerative disorders, and alcohol intake should be considered during evaluation.

Diagnostic workup

	• Medical history, physical examination, and electrocardiography are the core components of the “syncope workup.”
	• Clinical features that suggest or support a diagnosis of reflex or neurally-mediated syncope on initial evaluation include: (1) a long history of recurrent syncope, particularly with onset before 40 years of age; (2) occurrence of syncope after sudden unexpected unpleasant sights, sounds, smells, or pain; (3) occurrence of syncope after prolonged standing or in crowded, hot places; (4) occurrence of syncope during a meal or postprandially; (5) occurrence of syncope after exertion or exercise; (6) occurrence of autonomic activation before syncope, as manifest by pallor, diaphoresis, or nausea or vomiting; (7) occurrence of syncope with head rotation or with pressure on the neck in the area of the carotid sinus; and (8) the absence of heart disease.
	• Clinically, vasovagal syncope is “highly probable” if syncope is (1) precipitated by emotional distress (eg, pain or fear) or orthostatic stress (standing), and (2) associated with a typical prodrome (pallor, diaphoresis, or nausea).
	• Carotid sinus massage is indicated in the initial evaluation of patients older than 40 years of age with syncope of unknown etiology, particularly in those with severe, recurrent, unpredictable syncope.
	• A young, healthy patient who has a single, characteristic episode of vasovagal syncope does not need an extensive investigation, whereas a patient with vasovagal syncope and risk factors for vascular disease, or age beyond the sixth decade, should have a detailed examination and an EKG to establish the diagnosis and eliminate other more significant medical conditions.
	• In patients with vasovagal syncope suggested by clinical evaluation, tilt table testing does not generally provide significant additional information, and there may be a significant number of false negatives.
	• An implantable loop recorder is indicated in an early phase of evaluation in older patients with recurrent syncope of uncertain origin, absence of high-risk criteria, and a high likelihood of recurrence within the battery life of the device.

The medical history, physical examination, and electrocardiography are the core components of the “syncope workup” (93; 29).

Clinical features that can suggest or support a diagnosis of reflex or neurally mediated syncope on initial evaluation include: (1) a long history of recurrent syncope, particularly with onset before 40 years of age; (2) occurrence of syncope after sudden unexpected unpleasant sights, sounds, smells, or pain; (3) occurrence of syncope after prolonged standing or in crowded, hot places; (4) occurrence of syncope during a meal or postprandially; (5) occurrence of syncope after exertion or exercise; (6) occurrence of autonomic activation before syncope, as manifest by pallor, diaphoresis, or nausea/vomiting; (7) occurrence of syncope with head rotation or with pressure on the neck in the area of the carotid sinus (eg, with shaving, tight collars, and rarely with tumors); and (8) the absence of heart disease (141; 29).

Clinically, vasovagal syncope is “highly probable” if syncope is (1) precipitated by emotional distress (eg, pain or fear) or orthostatic stress (standing), and (2) associated with a typical prodrome (pallor, diaphoresis, or nausea) (141; 29). Similarly, situational syncope is “highly probable” if syncope occurs during or immediately after specific triggers: cough, sneeze, gastrointestinal stimulation (eg swallow, defecation, visceral pain), micturition (or postmicturition), post-exercise, postprandial, brass-instrument playing, weightlifting, etc. (141; 29).

Investigating the mechanism of reflex syncope is mandatory in patients with severe recurrent episodes (24). Comprehensive assessment of the mechanisms underlying reflex syncope allows the development of personalized mechanism-based therapy.

Carotid sinus massage is indicated in the initial evaluation of patients older than 40 years of age with syncope of unknown etiology, particularly in those with severe, recurrent, unpredictable syncope (141; 29). The 2009 guidelines considered the following as exclusions for carotid sinus massage: (1) a history of prior stroke or transient ischemic attack within the past three months; and (2) a carotid bruit (unless significant carotid stenosis is excluded by carotid Doppler studies) (141); however, the 2018 guidelines no longer deem the test contraindicated in patients with either stroke in the previous three months or carotid bruits (29; 131). Carotid sinus massage must be performed first in decubitus position and then under orthostatic stress (usually in the tilt table test, unless the test was already positive). Carotid sinus hypersensitivity is established by a ventricular pause lasting for more than 3 seconds or a fall in systolic blood pressure of more than 50 mm Hg with carotid sinus massage; carotid sinus syndrome is diagnosed when carotid sinus hypersensitivity occurs in association with spontaneous syncope, ie, syncope is reproduced in the presence of findings diagnostic of carotid sinus hypersensitivity (141; 29; 131). For a “positive” carotid sinus massage test result, both components (ie, vasodepressor and cardioinhibitory) must be identified. A positive initial test result requires two actions: (1) repeating the test with noninvasive ‘‘beat-to-beat’’ blood pressure measurement after atropine and (2) a tilt table test (29; 131). Detection of a dominant vasodepressor component contraindicates pacemaker implantation. Although carotid sinus hypersensitivity is a common finding in older men, asymptomatic pauses exceeding three seconds (ie, carotid sinus hypersensitivity) have little value in the diagnosis of syncope etiology (29; 131).

Further workup of presumptive reflex syncope is determined by the health and age of the patient and the type of reflex syncope (see below and also see the separate MedLink chapters on cough syncope, micturition syncope, and swallow and defecation syncope for further discussion of the workup of these disorders).

A young healthy patient who has a single, characteristic episode of vasovagal syncope does not need an extensive investigation. A normal examination is reassuring and sufficient to allow conservative treatment in young patients without risk factors. However, a patient with vasovagal syncope and risk factors for vascular disease, or age beyond the sixth decade, should have a detailed examination and an EKG to establish the diagnosis and eliminate other more significant medical conditions (93). In one study, diagnosis based on history alone was possible in only 5% of patients older than 65 years, compared with 26% of younger syncope patients (49). After obtaining a detailed medical history and information from bystanders, examination should include blood pressure measurement in each arm, orthostatic blood pressure measurements (ie, after supine for 5 minutes, on standing, and after standing for 3 minutes), cardiac and neck auscultation, palpation of arterial pulses in all limbs, and detailed examination of cranial nerves and motor function. Recurrent syncope in an older individual with a normal neurologic examination, no orthostatic hypotension, and a normal EKG should raise consideration of a cardiac cause for syncope (94); further neurologic investigations are not useful in this circumstance. Establishing a relationship between symptoms and bradycardia should be the goal of the clinical evaluation of patients with reflex syncope and a normal baseline ECG (29).

In patients with vasovagal syncope suggested by clinical evaluation, tilt table testing does not generally provide significant additional information, and there may be a significant number of false negatives (22; 25; 29). Indeed, tilt testing was positive in only 51% to 56% of patients with atypical clinical features, suggesting a reflex mechanism (124; 15; 119; 55; 57; 118; 29). Consequently, one study concluded that, “In patients with neurally-mediated syncope, clinical characteristics, outcome, and mechanism of syncope are poorly correlated and not predicted by the results of tilt testing... Therefore, these tests are of little or no value in guiding specific therapy” (32). Similarly, current guidelines indicate that “tilt testing offers little diagnostic value in patients for whom it is most needed” (29); in these patients, a positive tilt test reveals a susceptibility to orthostatic stress (137; 29).

Nevertheless, despite the test’s limitations, current guidelines suggest that (1) tilt testing should be considered in patients with suspected reflex syncope, particularly to confirm a diagnosis of reflex syncope in patients in whom this diagnosis was suspected but not confirmed by initial evaluation (79; 80; 104; 17; 15; 114; 29; 138); and (2) tilt testing may be considered to educate patients to recognize symptoms and learn physical maneuvers (29). Tilt testing may also be helpful in (1) separating syncope with abnormal movements from epilepsy; (2) distinguishing syncope from falls; and (3) separating syncope from psychogenic pseudo-syncope (29). In suspected psychogenic pseudo-syncope, the tilt test should be performed together with EEG monitoring (or in the absence of EEG with video recording); a normal EEG helps to confirm the diagnosis (140; 20; 29). Tilt testing should not be used to assess the efficacy of a drug treatment (105; 29).

According to earlier guidelines for tilt table testing issued jointly by the American College of Cardiology and the European Society of Cardiology (17), tilt table testing is warranted for (1) syncope in a high-risk patient, regardless of whether the medical history is suggestive of vasovagal syncope, either in the absence of structural cardiovascular disease or when structural cardiovascular disease is present and other causes of syncope have been excluded by appropriate testing; (2) further evaluation of a patient in whom an apparent cardiac cause has been established (eg, asystole or atrioventricular heart block) when demonstration of susceptibility to reflex syncope would affect treatment; and (3) exercise-induced or exercise-associated syncope. Tilt table testing is controversial in the evaluation of recurrent unexplained falls (especially in the elderly) (156) or recurrent dizziness/presyncope, and in the assessment of therapeutic effectiveness for patients with reflex syncope. Tilt table testing is not indicated in the assessment of a single syncopal episode with clinical features of vasovagal syncope, without associated injury, and not in a high-risk setting. Tilt table testing is also not indicated when an alternate specific cause of syncope has been established and when additional demonstration of susceptibility to reflex syncope would not alter management. Pregnancy should be excluded prior to tilt table evaluation in women of childbearing age.

Reflex syncope should be considered likely if tilt testing reproduces symptoms along with the characteristic circulatory pattern, but a negative tilt table response does not exclude a diagnosis of reflex syncope (29). In patients with syncope of uncertain origin, tilt testing may suggest the presence of a “susceptibility to orthostatic stress” or a “hypotensive susceptibility,” which may exist not only in reflex syncope but also with other causes of syncope, including some forms of cardiac syncope (29; 131). The presence or absence of hypotensive susceptibility plays a major role in guiding the use of pacemaker implantation in patients affected by reflex syncope and in the management of hypotensive therapies, which are frequently present in the elderly with syncope. A positive cardioinhibitory response to tilt testing predicts, with high probability, asystolic spontaneous syncope, which could potentially benefit from pacemaker implantation; conversely, the presence of a positive vasodepressor, a mixed response, or even a negative response does not exclude the presence of asystole during spontaneous syncope (48; 29).

The Valsalva maneuver may be considered for confirming the hypotensive tendency induced by some forms of situational syncope (eg, coughing, brass instrument playing, singing, and weightlifting) (82; 29; 131). A pronounced fall in blood pressure, beyond what is normally expected during forced expiration, with a normal chronotropic response during the maneuver, may occur in patients with some forms of situational syncope, including those precipitated or triggered by coughing, brass instrument playing, singing, and weightlifting (82; 29). In addition, if possible, reproduction of the trigger situation (eg, coughing, swallowing, laughing, bass instrument playing, weightlifting) under beat-to-beat noninvasive heart rate and blood pressure measurement should be performed in patients with suspected situational syncope (29).

An implantable loop recorder is indicated in an early phase of evaluation in older patients with recurrent syncope of uncertain origin, absence of high-risk criteria, and a high likelihood of recurrence within the battery life of the device (29). An implantable loop recorder also should be considered in patients with suspected or certain reflex syncope presenting with frequent or severe syncopal episodes (31; 28; 25; 29). The duration of the prodrome is largely subjective and, therefore, can only be imprecisely estimated; nevertheless, an estimated duration of five seconds or less is characteristic of arrhythmic syncope (eg, due to atrioventricular block or ventricular tachycardia) and distinguishes arrhythmic from reflex syncope (34; 29), although, conversely, in patients without structural heart disease, an estimated duration of more than 10 seconds is characteristic of reflex syncope and can distinguish reflex syncope from cardiac syncope (05; 29). In practice, the prodrome is considered “absent or very short” if it does not allow patients enough time to act (eg, to sit or lie down), greatly increasing the risk of serious injury (29). Sometimes an implantable loop recorder strategy should also be considered in patients less than 40 years of age, though there is not sufficient evidence to guide evaluation (29).

Patients in whom heart disease is known or suspected, those with exertional syncope, and those with no or only a very short prodrome are at a significantly higher risk for adverse outcomes and should have additional cardiac testing, including echocardiography, stress testing, Holter monitoring, or intracardiac electrophysiologic studies, alone or in combination (93; 29).

Psychiatric referral should be considered if stress is an important trigger for syncope or if the attacks remain unexplained after diagnostic workup and the patient is free of injury after recurrent syncopes (94).

Computed tomography or magnetic resonance imaging of the head, electroencephalography, Doppler ultrasonography, and transcranial Doppler are rarely helpful in the evaluation of patients with reflex syncope unless additional neurologic signs or symptoms are present (93; 139). CT and MRI of the head offer no significant benefit in determining the etiology of syncope (58; 139). In selected patients, electroencephalography and video-electroencephalography may help in distinguishing syncope from epilepsy (33; 29). During reflex syncope, the EEG pattern is characterized by generalized theta slowing initially followed by hypersynchronous delta activity of high voltage; if cerebral hypoperfusion persists, a complete flattening of the tracing may be observed. The EEG activity normalizes quickly after syncope (101). Combined head-up tilt and video EEG may be useful for investigating recurrent unexplained atypical seizure-like transient loss of consciousness, especially in patients with a history of myoclonic jerks or with documented interictal nonspecific EEG abnormalities (111). Changes in the sympathetic modulation of cerebral vasoconstriction may explain the typical paroxysmal EEG findings (152).

Management

	• With appropriate management, one can limit physical injuries, minimize recurrences, and prolong survival in patients with syncope.
	• Conservative management with education, exercise and physical counter-pressure maneuvers, and aggressive volume repletion will control symptoms in most patients with reflex syncope.
	• Patients should be taught physical counter-pressure maneuvers (eg, leg crossing and muscle tensing) that they can perform themselves to prevent syncopal attacks.
	• Despite conservative initial treatment, up to 30% of patients continue to experience regular episodes of vasovagal syncope.
	• Among patients with severe reflex syncope and no or only very short prodromes, implantable loop recorder-guided management is indicated.
	• Permanent pacemaker implantation may be helpful for selected patients with the cardioinhibitory form of vasovagal syncope who are at least 40 years of age with frequent episodes of syncope associated with physical trauma, limited prodromes, and dominant cardioinhibition.

With appropriate management, one can limit physical injuries, minimize recurrences, and prolong survival in patients with syncope (112).

Conservative management with education, exercise and physical counter-pressure maneuvers, and aggressive volume repletion will control symptoms in most patients with reflex syncope (88; 39; 29). In particular, the patient and family should be educated about appropriate lifestyle modifications and ways to avoid situations that trigger syncope (eg, blood drawing, dehydration, prolonged standing). Patients should be taught physical counter-pressure maneuvers (eg, leg crossing and muscle tensing) that they can perform themselves to prevent syncopal attacks (29). Physical counter-maneuvers are effective in reducing or delaying syncopal recurrences in patients younger than 60 years of age who have long-lasting recognizable prodromal symptoms (29). Unfortunately, physical counter-maneuvers cannot be used in patients with a short or absent prodrome and are less effective in patients older than 60 years of age (29). Yoga can also potentially improve the symptoms of presyncope and syncope in young women with reflex syncope (67). Patients should be encouraged to liberalize their fluid and salt intake, unless they have contraindications such as arterial hypertension.

Despite conservative initial treatment, up to 30% of patients continue to experience regular episodes of vasovagal syncope (126). Recurrent and unpredictable reflex syncope can be disabling (29). Additional treatment may be necessary in patients with severe forms of reflex syncope, particularly when: (1) very frequent syncope alters quality of life; (2) recurrent syncope with no prodrome or only a very short prodrome exposes the patient to a risk of trauma; or (3) syncope occurs during a high-risk activity (eg, driving, machine operation, flying, competitive athletics, etc.) (29). Only one in seven (14%) of patients in the highly selected population with reflex syncope who are referred to specialized syncope units need such additional treatment (25). Although there is no generally appropriate therapy applicable to every form of reflex syncope, in those who are receiving hypotensive drugs, the dosages should be reduced, or the drugs should be discontinued (29). The most important discriminant for the choice of therapy is age.

Nonpharmacological interventions

A meta-analysis involving a total of 1130 participants from 18 studies found a significant overall benefit of nonpharmacological interventions versus the control (overall mean effect size was 0.25) (07). Subgroup analysis showed that yoga had the largest effect size (odds ratio: 0.07), whereas physical counter pressure maneuvers were beneficial but had lower effect sizes (counter pressure maneuvers odds ratio: 0.29; tilt training odds ratio: 0.40) compared to the control.

Nonpharmacological interventions show promise in preventing recurrent vasovagal syncope episodes. Yoga, physical counter pressure maneuvers, and tilt training can be considered as viable treatment options.

In patients with prolonged post-faint hypotension, bilateral passive leg flexion and extension can be used by family members during episodes as dynamic tension to improve blood pressure and symptoms (154).

Among younger patients with severe reflex syncope and clear prodromes, counter pressure maneuvers should be considered, and tilt training class may be considered (29). However, although tilt training (eg, by standing and leaning with upper back against a wall and with the feet placed 15 cm away from the wall for up to 30 minutes twice a day) was championed as effective and safe in patients with reflex syncope (01), it showed no benefit in a meta-analysis of randomized trials (153) and was not supported by the review of an expert guidelines panel (29). Indeed, “tilt training has little efficacy in reducing recurrence of syncope in young patients with long-lasting recognizable prodromal symptoms.”

Medications

Fludrocortisone and midodrine. Among younger patients (aged less than 40 years of age) with severe reflex syncope of the “low blood pressure phenotype,” who are unresponsive to education and lifestyle measures, fludrocortisone and midodrine may be considered, although their usefulness and efficacy are less well established by evidence and opinion (29). The “low blood pressure phenotype” applies to patients with chronic low blood pressure values (typically with systolic blood pressure around 110 mmHg) and a clear history of orthostatic intolerance and orthostatic vasovagal syncope (29). The role of midodrine in the management of vasovagal syncope is unclear, with some authors recommending midodrine as a first-line therapy for patients having frequent presyncope or syncope or for those with brief or no prodromes (151; 88), whereas other studies found that midodrine therapy provided no benefit in patients with vasovagal syncope unresponsive to conservative management (126). Midodrine can be used at any age even if existing studies were performed in young patients (29). Fludrocortisone acetate has also considered to be useful, and current guidelines noted, “There is moderate evidence that fludrocortisone may be effective in reducing syncopal recurrences in young patients with low-normal values of arterial [blood pressure] and without comorbidities” (29); however, in the best available study, fludrocortisone did not meet its primary objective of reducing vasovagal syncope by the specified risk reduction of 40% (134). In selected cases, fludrocortisone may be used in patients aged greater than 60 years, but the “Task Force cannot give recommendations due to the lack of sufficient evidence from studies” (29).

Alpha-adrenergic agonists. A meta-analysis found that alpha-adrenergic agonists are effective in preventing vasovagal syncope recurrence (153). However, current guidelines recognize that “there are contrasting results from multiple trials that alpha-agonists may be effective in reducing syncopal recurrences in patients with the orthostatic form of [vasovagal syncope]” (29).

Selective serotonin reuptake inhibitors (SSRIs). A meta-analysis found that SSRIs are effective in preventing vasovagal syncope recurrence (153). A later meta-analysis confirmed the potential benefit of SSRIs: "Serotonin-specific reuptake inhibitors may be effective in preventing syncope induced by head-up tilt testing and in syncope in the community in randomized, double-blinded clinical trials" (123).

Theophylline. Theophylline is effective in preventing recurrences in patients with nonclassical neurally mediated syncope (ie, syncope without prodromes, normal heart, and normal ECG) (27). The benefit was greater in patients with syncope due to asystolic atrioventricuar block.

Beta-blockers. Beta-blockers are not effective based on a meta-analysis in which only randomized studies comparing beta-blockers to nonpharmacologic agents were assessed (97; 99; 153). Consequently, current guidelines state, “There is sufficient evidence from multiple trials that beta-blockers are not appropriate in reducing syncopal recurrences” (29).

Severe and refractory patients

Among patients with severe reflex syncope and no or only very short prodromes, implantable loop recorder-guided management is indicated (29).

A small number of refractory patients may require emerging device-based therapy with pacemakers or radiofrequency ablation (39; 29). However, in a meta-analysis, pacemakers were found to be effective in preventing syncope recurrence when all studies were analyzed, but studies comparing active pacemaker to pacemaker on sensing mode only did not show benefit (153). Careful patient selection is important if other more conservative treatment options are not successful (145).

Pacemaker implantation. Permanent pacemaker implantation may be helpful for selected patients with cardioinhibitory form of vasovagal syncope who are at least 40 years of age with frequent episodes of syncope associated with physical trauma, limited prodromes, and dominant cardioinhibition (ie, in whom clinical features and results of tests suggest that sudden cardioinhibition is mainly responsible for syncope, and particularly if asystole is a dominant feature of reflex syncope) (44; 29; 138; 103). Dual-chamber cardiac pacing should be considered to reduce recurrence of reflex syncope when the correlation between symptoms and ECG is established in patients older than 40 years of age with the clinical features of those in the ISSUE studies (ie, with documentation by means of an implantable loop recorder of syncope with at least three seconds of asystole or at least 6 seconds of asystole without syncope) (29). In selected cases, pacing may be used in patients aged less than 40 years, but there is insufficient evidence to guide recommendations (29). Despite the lack of large randomized controlled trials, dual-chamber cardiac pacing should be considered to reduce syncopal recurrences in patients affected by dominant cardioinhibitory carotid sinus syndrome (29). The estimated benefit of dual-chamber pacing in cardioinhibitory tilt-positive patients is weak, based on the contrasting results of the randomized trials and the divergence of opinion among experts (29; 42); indeed, a systematic review concluded that it is unclear whether pacemaker therapy reduces syncopal burden in cardioinhibitory recurrent vasovagal syncope (42). Pacing is generally not indicated for reflex syncope under either of the following conditions: (1) in the absence of severe, recurrent, unpredictable syncope and age at least 40 years; or (2) for vasovagal syncope of situational syncope in the absence of asystole documented by either tilt testing or implantable loop recording (29). Pacing should not be offered to patients with a noncardioinhibitory tilt-positive response, and further tests (eg, implantable loop recorder) are warranted to document the mechanism of the spontaneous reflex.

Radiofrequency ablation. Bradycardia, in the cardioinhibitory subtype of vasovagal syncope, results from transient parasympathetic overactivity, leading to sinus bradycardia or atrioventricular block. Cardioneuroablation targeting the ganglionated plexi in the heart (ganglionated plexus ablation) is intended to mitigate parasympathetic overactivity by reducing excessive vagal excitation (24; 144; Yarkoni et la 2023; 38).

3D representation of four anatomical ganglionated plexus locations

A three-dimensional representation of four anatomical ganglionated plexus locations. White (anterior) and grey (posterior) circles indicate ganglionated plexus areas within the heart. (1) The right anterior ganglionated plexus ...
Innervation of the heart

Innervation of the heart includes the afferent (sensory) neurons (green) that transmit information from baroreceptors in the heart to the spinal cord and brain, and efferent (motor) neurons that innervate the heart. These effer...

Multiple observational studies and one randomized trial have demonstrated the short-term safety and efficacy (improvement in vasovagal symptoms) of cardioneuroablation and its positive impact on quality of life in selected cases (144). Although cardioneuroablation is a promising treatment for patients with recurrent vasovagal syncope and functional bradycardia, large-scale randomized studies are needed to further verify the safety and efficacy of this approach (144). Cardioneuroablation in the management of vasovagal syncope requires more structured and comprehensive studies and patient selection, selection of optimal ablation targets, and ablation endpoints. The long-term pathophysiological consequences of cardioneuroablation have yet to be determined (24; 24; 92; 98; 38). Cardioneuroablation may shift the autonomic balance to a state of sympathovagal imbalance with attenuation of cardiac parasympathetic activity, resulting in higher basal heart rates that are associated with adverse cardiovascular events and increased mortality in healthy populations without cardiovascular diseases (38). Chronic sympathovagal imbalance may also affect the pathophysiology of atrial and ventricular arrhythmias.

Tilt table testing is not useful in monitoring response to treatment (141; 143; 10; 29).

Media

References

01: Abe H, Kondo S, Kohshi K, Nakashima Y. Usefulness of orthostatic self-training for the prevention of neurocardiogenic syncope. Pacing Clin Electrophysiol 2002;25(10):1454-8. PMID 12418743
02: Abuzainah B, Gutlapalli SD, Chaudhuri D, et al. Anxiety and depression as risk factors for vasovagal syncope and potential treatment targets: a systematic review. Cureus 2022;14(12):e32793. PMID 36694488
03: Adams RD. Faintness and syncope. In: Adams RD, Victor M, Ropper AH, editors. Principles of neurology. 7th ed. New York: McGraw Hill, 2001.
04: Albina G, Fernandez Cisneros L, Laiño R, et al. Transcranial Doppler monitoring during head upright tilt table testing in patients with suspected neurocardiogenic syncope. Europace 2004;6(1):63-9. PMID 14697728
05: Alboni P, Brignole M, Menozzi C, et al. Diagnostic value of history in patients with syncope with or without heart disease. J Am Coll Cardiol 2001;37(7):1921-8. PMID 11401133
06: Alboni P, Messop AC, Lauri A, Furlan R. Are women really more affected by vasovagal syncope than men? J Cardiovasc Med (Hagerstown) 2021;22(2):69-78. PMID 32925389
07: Alharbi A, Shah M, Gupta M, et al. The efficacy of non-pharmacological and non-pacing therapies in preventing vasovagal syncope: tilt training, physical counter pressure maneuvers, and yoga - a systematic review and meta-analysis. Auton Neurosci 2024;251:103144. PMID 38181551
08: Anonymous. T.F. Cotton, M.D., F.R.C.P. [obituary]. BMJ 1965;2:367.
09: Anpalahan M. Neurally mediated syncope and unexplained or nonaccidental falls in the elderly. Intern Med J 2006;36(3):202-7. PMID 16503958
10: Arnold AC, Ng J, Lei L, Raj SR. Autonomic dysfunction in cardiology: pathophysiology, investigation, and management. Can J Cardiol 2017;33(12):1524-34. PMID 29102451
11: Ascheim DD, Markowitz SM, Lai H, Engelstein ED, Stein KM, Lerman BB. Vasodepressor syncope due to subclinical myocardial ischaemia. J Cardiovasc Electrophysiol 1997;8(2):215-21. PMID 9048251
12: Azevedo MC, Barbisan JN, Silva EO. Neurocardiogenic syncope and hereditarity. Rev Assoc Med Bras 2009;55(1):19-21. PMID 19360272
13: Baron-Esquivias G, Errazquin F, Pedrote A, et al. Long-term outcome of patients with vasovagal syncope. Am Heart J 2004;147(5):883-9. PMID 15131546
14: Baron-Esquivias G, Gomez S, Aguilera A, et al. Short-term evolution of vasovagal syncope: Influence on the quality of life. Int J Cardiol 2005;102(2):315-9. PMID 15982503
15: Bartoletti A, Alboni P, Ammirati F, et al. 'The Italian Protocol': a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace 2000;2(4):339-42. PMID 11194602
16: Bedford DE. Thomas Forrest Cotton. Br Heart J 1966;28(1):136-8. PMID 5323800
17: Benditt DG, Ferguson DW, Grubb BP, et al. ACC expert consensus document: tilt table testing for accessing syncope and its treatment: American College of Cardiology. J Am Coll Cardiol 1996;28(1):263-7. PMID 8752825
18: Benditt D, Fabian W, Iskos D, Lurie KG. Review article: heart rate and blood pressure control in vasovagal syncope. J Interv Card Electrophysiol 1998;2:25-32. PMID 9869993
19: Bizios AS, Sheldon RS. Vasovagal syncope: state or trait. Curr Opin Cardiol 2009;24(1):68-73. PMID 19102038
20: Blad H, Lamberts RJ, van Dijk GJ, Thijs RD. Tilt-induced vasovagal syncope and psychogenic pseudosyncope: overlapping clinical entities. Neurology 2015;85(23):2006-10. Erratum in: Neurology 2017;88(3):335. PMID 26561288
21: Blanc JJ, L’Her C, Touiza A, Garo B, L’Her E, Mansourati J. Prospective evaluation and outcome of patients admitted for syncope over a 1 year period. Eur Heart J 2002;23(10):815-20. PMID 12009722
22: Bonzi M, Fiorelli EM, Furlan L, Solbiati M. Head-up tilt testing for diagnosing vasovagal syncope: A meta-analysis. Int J Cardiol 2013;168(1):623. PMID 23465235
23: Brewster LM, Mairuhu G, Ganzeboom K, van Dijk N, van Montfrans GA, Wieling W. Low creatine kinase is associated with a high population incidence of fainting. Clin Auton Res 2009;19(4):231-6. PMID 19468786
24: Brignole M. Response to the letter to the editor EUPC-D-23-00318 of Jesús Daniel Martínez-Alday. Europace 2023;25(7):euad178. PMID 37358245
25: Brignole M, Ammirati F, Quartieri F, et al. Assessment of a standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncopes. Eur Heart J 2015;36(24):1529-35. PMID 25825044
26: Brignole M, Aksu T, Calò L, et al. Clinical controversy: methodology and indications of cardioneuroablation for reflex syncope. Europace 2023;25(5):euad033. PMID 37021351
27: Brignole M, Iori M, Strano S, et al. Theophylline in patients with syncope without prodrome, normal heart, and normal electrocardiogram: a propensity-score matched study verified by implantable cardiac monitor. Europace 2022;24(7):1164-70. PMID 34849728
28: Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012;125(21):2566-71. PMID 22565936
29: Brignole M, Moya A, de Lange FJ, Deharo JC, et al. 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J 2018;39(21):1883-948. PMID 29562304
30: Brignole M, Rivasi G, Fedorowski A, Ståhlberg M, Groppelli A, Ungar A. Tests for the identification of reflex syncope mechanism. Expert Rev Med Devices 2023;20(2):109-19. PMID 36814102
31: Brignole M, Sutton R, Menozzi C, et al. Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J 2006a;27(9):1085-92. PMID 16569653
32: Brignole M, Sutton R, Menozzi C, Garcia-Civera R, et al. Lack of correlation between the responses to tilt testing and adenosine triphosphate test and the mechanism of spontaneous neurally mediated syncope. Eur Heart J 2006b;27(18):2232-9. PMID 16864606
33: Britton JW, Benarroch E. Seizures and syncope: anatomic basis and diagnostic considerations. Clin Auton Res 2006;16(1):18-28. PMID 16477491
34: Calkins H, Shyr Y, Frumin H, Schork A, Morady F. The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block, and neurocardiogenic syncope. Am J Med 1995;98(4):365-73. PMID 7709949
35: Carey BJ, Eames PJ, Panerai RB, Potter JF. Carbon dioxide, critical closing pressure and cerebral haemodynamics prior to vasovagal syncope in humans. Clin Sci (Lond) 2001a;101(4):351-8. PMID 11566072
36: Carey BJ, Manktelow BN, Panerai RB, Potter JF. Cerebral autoregulatory responses to head-up tilt in normal subjects and patients with recurrent vasovagal syncope. Circulation 2001b;104(8):898-902. PMID 11514376
37: Carey BJ, Potter JF, Panerai RB. Cerebral vasoconstriction in vasovagal syncope: any link with symptoms? A transcranial Doppler study. Circulation 2002;106(13):e54. PMID 12270874
38: Chakraborty P, Chen PS, Gollob MH, Olshansky B, Po SS. Potential consequences of cardioneuroablation for vasovagal syncope: a call for appropriately designed, sham-controlled clinical trials. Heart Rhythm 2024;21(4):464-70. PMID 38104955
39: Coffin ST, Raj SR. Non-invasive management of vasovagal syncope. Auton Neurosci 2014;184:27-32. PMID 24996861
40: Colman N, Nahm K, Ganzeboom KS, et al. Epidemiology of reflex syncope. Clin Auton Res 2004;14(Suppl 1):9-17. PMID 15480937
41: Cotton TF, Lewis T. Observations upon fainting attacks due to inhibitory cardiac impulses. Heart 1918;7:23-34.
42: da Cunha GJL, Rocha BML, Gomes RV, et al. A systematic review on recurrent cardioinhibitory vasovagal syncope: does pacing therapy break the fall? Pacing Clin Electrophysiol 2019;42(10):1400-7. PMID 31433493
43: Dan D, Hoag JB, Ellenbogen KA, Wood MA, Eckberg DL, Gilligan DM. Cerebral blood flow velocity declines before arterial pressure in patients with orthostatic vasovagal presyncope. J Am Coll Cardiol 2002;39(6):1039-45. PMID 11897448
44: da Silva RM. The current indication for pacemaker in patients with cardioinhibitory vasovagal syncope. Open Cardiovasc Med J 2016;10:179-87. PMID 27651841
45: Daas A, Mimouni-Bloch A, Rosenthal S, Shuper A. Familial vasovagal syncope associated with migraine. Pediatr Neurol 2009;40(1):27-30. PMID 19068250
46: Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med 1982;73:15-23. PMID 7091170
47: Deharo JC, Brignole M, Guieu R. Adenosine and neurohumoral syncope. Minerva Med 2022;113(2):243-50. PMID 33832218
48: Deharo JC, Jego C, Lanteaume A, Djiane P. An implantable loop recorder study of highly symptomatic vasovagal patients: the heart rhythm observed during spontaneous syncope is identical to the recurrent syncope but not correlated with the head-up tilt test or adenosine triphosphate test. J Am Coll Cardiol 2006;47:587-93. PMID 16458141
49: Del Rosso A, Alboni P, Brignole M, Menozzi C, Raviele A. Relation of clinical presentation of syncope to the age of patients. Am J Cardiol 2005;96(10):1431-5. PMID 16275193
50: Diehl RR, Linden D, Chalkiadaki A, Ringelstein EB, Berlit P. Transcranial Doppler during neurocardiogenic syncope. Clin Auton Res 1996;6(2):71-4. PMID 8726090
51: Diehl RR, Linden D, Chalkiadaki A, Diehl A. Cerebrovascular mechanisms in neurocardiogenic syncope with and without postural tachycardia syndrome. J Auton Nerv Syst 1999;76(2-3):159-66. PMID 10412840
52: Domenichini G, Diemberger I, Biffi M, et al. Long-term follow-up of patients with syncope evaluated by head-up tilt test. Ann Noninvasive Electrocardiol 2010;15(2):101-6. PMID 20522049
53: Duncan GW, Tan MP, Newton JL, Reeve P, Parry SW. Vasovagal syncope in the older person: differences in presentation between older and younger patients. Age Ageing 2010;39(4):465-70. PMID 20444805
54: Fitzpatrick AP, Banner N, Cheng A, Yacoub M, Sutton R. Vasovagal reactions may occur after orthotopic heart transplantation. J Am Coll Cardiol 1993;21(5):1132-7. PMID 8459066
55: Flevari P, Leftheriotis D, Komborozos C, et al. Recurrent vasovagal syncope: comparison between clomipramine and nitroglycerin as drug challenges during head-up tilt testing. Eur Heart J 2009;30(18):2249-53. PMID 19556259
56: Fragakis N, Antoniadis AP, Sotiriadou M, et al. Syncope without prodromes is associated with excessive plasma release of adenosine at the time of syncope during head-up tilt table test. Int J Cardiol 2022;363:43-8. PMID 35716941
57: Furukawa T, Maggi R, Solano A, Croci F, Brignole M. Effect of clinical triggers on positive responses to tilt-table testing potentiated with nitroglycerin or clomipramine. Am J Cardiol 2011;107(11):1693-7. PMID 21420055
58: Gebreselassie AG, Bekele DI, Paul Y, Ngwa JS, Larbi DA. The evaluation of syncope in a predominantly Black population: focus on neuroimaging. N Am J Med Sci 2016;8(7):279-83. PMID 27583235
59: Gibson PS, Powrie R, Pipert J. Prevalence of syncope and recurrent presyncope during pregnancy. Obstet Gynecol 2001;97(Suppl 1):S41-2.
60: Goldschlager N, Epstein AE, Grubb BP, et al. Etiologic considerations in the patient with syncope and an apparently normal heart. Arch Intern Med 2003;163(2):151-62. PMID 12546605
61: González-Hermosillo A, Sierra-Beltrán M, López-Peña U, Kostin A, Hernández-Pacheco G, Lerma C. Cardiovascular and cerebral hemodynamics in asymptomatic healthy subjects with/without abnormal head-up tilt test versus recurrent fainters. J Clin Neurophysiol 2018;35(1):77-83. PMID 29111992
62: Gowers WR. A lecture on vagal and vaso-vagal attacks. Lancet 1907a;i:1551-4.
63: Gowers WR. The border-land of epilepsy: faints, vagal attacks, vertigo, migraine, sleep symptoms and their treatment. England: J & A Churchill, 1907b.
64: Gracie J, Newton JL, Norton M, Baker C, Freeston M. The role of psychological factors in response to treatment in neurocardiogenic (vasovagal) syncope. Europace 2006;8(8):636-43. PMID 16864617
65: Grubb BP, Gerard G, Roush K, et al. Cerebral vasoconstriction during head-upright tilt-induced vasovagal syncope. A paradoxic and unexpected response. Circulation 1991;84(3):1157-64. PMID 1884446
66: Grubb BP, Samoil D, Kosinski D, et al. Cerebral syncope: loss of consciousness associated with cerebral vasoconstriction in the absence of systemic hypotension. Pacing Clin Electrophysiol 1998;21(4 Pt 1):652-8. PMID 9584294
67: Gunda S, Kanmanthareddy A, Atkins D, et al. Role of yoga as an adjunctive therapy in patients with neurocardiogenic syncope: a pilot study. J Interv Card Electrophysiol 2015;43(2):105-10. PMID 25863799
68: Halliwill JR, Dietz NM, Joyner MJ. Active vasodilatation during fainting: a hypothesis revisited. Clin Auton Res 1996;6(4):233-6. PMID 8902320
69: Hart YM. All that shakes is not epilepsy. J R Coll Physicians Edinb 2012;42(2):151-4. PMID 22693702
70: Hashizume T, Kondo G, Ishimaru F, et al. Development and validation of a scoring system to predict vasovagal reaction upon whole-blood donation. Vox Sang 2024;119(4):300-7. PMID 38156553
71: Hockin BCD, Lucci VM, Wu REY, Nicholas M, Parsons IT, Claydon VE. Pain associated with intravascular instrumentation reduces orthostatic tolerance and predisposes to vasovagal reactions in healthy young adults without needle phobia: a randomised controlled study. Clin Auton Res 2023;33(6):673-89. PMID 37589875
72: Huang MH, Roeske WR, Hu H, Indik JH, Marcus FI. Postural position and neurocardiogenic syncope in late pregnancy. Am J Cardiol 2003;92(10):1252-3. PMID 14609615
73: Ilia R. Coronary occlusion post angioplasty associated with vasovagal reaction. Cathet Cardiovasc Diagn 1997;40(3):336. PMID 9062741
74: Julu PO, Cooper VL, Hansen S, Hainsworth R. Cardiovascular regulation in the period preceding vasovagal syncope in conscious humans. J Physiol 2003;549(Pt 1):299-311. PMID 12679368
75: Kamar S, Hallit S, Chamandi S. Vasovagal syncope related to pain procedures in a pain clinic at a tertiary Lebanese hospital between 2016 and 2019. BMC Res Notes 2021;14(1):133. PMID 33849656
76: Kaufmann H. Neurally mediated syncope and syncope due to autonomic failure: differences and similarities. J Clin Neurophysiol 1997;14(3):183-96. PMID 9244158
77: Kempster PA, Balla JI. A clinical study of convulsive syncope. Clin Exp Neurol 1986;22:53-5. PMID 3581511
78: Kenny RA. Neurally mediated syncope. Clin Geriatr Med 2002;18(2):191-210. PMID 12180243
79: Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lancet 1986;1(8494):1352-5. PMID 2872472
80: Kenny RA, O'Shea D, Parry SW. The Newcastle protocols for head-up tilt table testing in the diagnosis of vasovagal syncope, carotid sinus hypersensitivity, and related disorders. Heart 2000;83(5):564-9. PMID 10768910
81: Khalaji A, Behnoush AH, Tajdini M. Association between vitamin D deficiency and vasovagal syncope: a systematic review and meta-analysis. Clin Cardiol 2023;46(7):721-8. PMID 37226313
82: Kim AJ, Frishman WH. Laughter-induced syncope. Cardiol Rev 2012;20(4):194-6. PMID 22314146
83: Klein KM, Berkovic SF. Genetics of vasovagal syncope. Auton Neurosci 2014;184:60-5. PMID 24794249
84: Klein KM, Bromhead CJ, Smith KR, et al. Autosomal dominant vasovagal syncope: clinical features and linkage to chromosome 15q26. Neurology 2013;80(16):1485-93. PMID 23589636
85: Klein KM, Xu SS, Lawrence K, Fischer A, Berkovic SF. Evidence for genetic factors in vasovagal syncope: a twin-family study. Neurology 2012;79(6):561-5. PMID 22869686
86: Krediet CT, van Dijk N, Linzer M, van Lieshout JJ, Wieling W. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation 2002;106(13):1684-9. PMID 12270863
87: Kuriachan V, Sheldon RS. Current concepts in the evaluation and management of syncope. Curr Cardiol Rep 2008;10(5):384-90. PMID 18715535
88: Kuriachan V, Sheldon RS, Platonov M. Evidence-based treatment for vasovagal syncope. Heart Rhythm 2008;5(11):1609-14. PMID 18984541
89: Lagi A, Cencetti S, Corsoni V, Georgiadis D, Bacalli S. Cerebral vasoconstriction in vasovagal syncope: any link with symptoms? A transcranial Doppler study. Circulation 2001;104(22):2694-8. PMID 11723021
90: Lee SH, Park JE, Ki CS, et al. Genetic analysis of cardiac syncope-related genes in Korean patients with recurrent neurally mediated syncope. J Cardiovasc Dev Dis 2022;9(8):265. PMID 36005429
91: Lewis T. A lecture on vasovagal syncope and the carotid sinus mechanism with comments on Gowers's and Nothnagel's syndrome. BMJ 1932;1:873-6.
92: Li L, Po S, Yao Y. Cardioneuroablation for treating vasovagal syncope: current status and future directions. Arrhythm Electrophysiol Rev 2023;12:e18. PMID 37457436
93: Linzer M, Yang EH, Estes NA 3rd, Wang P, Vorperian VR, Kapoor WN. Diagnosing syncope. Part 1: Value of history, physical examination, and electrocardiography. Clinical Efficacy Assessment Project of the American College of Physicians. Ann Intern Med 1997a;126:989-96. PMID 9182479
94: Linzer M, Yang EH, Estes NA 3rd, Wang P, Vorperian VR, Kapoor WN. Diagnosing syncope. Part 2: Unexplained syncope. Clinical Efficacy Assessment Project of the American College of Physicians. Ann Intern Med 1997b;127:76-86. PMID 9214258
95: Lu CC, Diedrich A, Tung CS, et al. Water ingestion as prophylaxis against syncope. Circulation 2003;108(21):2660-5. PMID 14623807
96: Madden KM, Lockhart C. Arterial baroreflex function in older adults with neurocardiogenic syncope. Clin Invest Med 2009;32(3):E191-8. PMID 19480734
97: Madrid AH, Ortega J, Rebollo JG, et al. Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study. J Am Coll Cardiol 2001;37:554-9. PMID 11216978
98: Martinez-Alday JD, Carazo CM, Rodríguez-Mañero M. Regarding 'Clinical controversy: methodology and indications of cardioneuroablation for reflex syncope'. Europace 2023;25(7):euad179. PMID 37363927
99: Mathias CJ. Beta-adrenergic receptor blockers and the treatment of vasovagal syncope: more nails in the coffin! Clin Sci (Lond) 2006;111(3):189-91. PMID 16848762
100: Mathias CJ, Deguchi K, Bleasdale-Barr K, Kinber JR. Frequency of family history in vasovagal syncope. Lancet 1998;352:33-4. PMID 9800748
101: Mecarelli O, Pulitano P, Vicenzini E, Vanacore N, Accornero N, De Marinis M. Observations on EEG patterns in neurally-mediated syncope: an inspective and quantitative study. Neurophysiol Clin 2004;34(5):203-7. PMID 15639129
102: Meher R, Patidar GK, Chaurasia R, Pandey HC, Hazarika A. Prevention strategies for vasovagal reaction in whole blood donors: a quadri-armed randomised control trial. Transfus Med 2024;34(1):20-9. PMID 38165089
103: Morillo CA, Brignole M. Pacing for vasovagal syncope: tips for use in practice. Auton Neurosci 2022;241:102998. PMID 35696879
104: Morillo CA, Klein GJ, Zandri S, Yee R. Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J 1995;129(5):901-6. PMID 7732979
105: Moya A, Permanyer-Miralda G, Sagrista-Sauleda J, et al. Limitations of head-up tilt test for evaluating the efficacy of therapeutic interventions in patients with vasovagal syncope: results of a controlled study of etilefrine versus placebo. J Am Coll Cardiol 1995;25(1):65-9. PMID 7798528
106: Nahm F, Freeman R. Vasovagal syncope: the contributions of Sir William R. Gowers and Sir Thomas Lewis. Arch Neurol 2001;58(3):509-11. PMID 11255458
107: Nahm F, Freeman R. Syncope and the history of nervous influences on the heart. Arch Neurol 2003;60(2):282-87. PMID 12580718
108: Newton JL, Donaldson P, Parry S, et al. Angiotensin converting enzyme insertion/deletion polymorphisms in vasovagal syncope. Europace 2005a;7(4):396-9. PMID 15944101
109: Newton JL, Kerr S, Pairman J, et al. Familial neurocardiogenic (vasovagal) syncope. Am J Med Genet A 2005b;133(2):176-9. PMID 15666305
110: Njemanze PC. Critical limits of pressure-flow relation in the human brain. Stroke 1992;23(12):1743-7. PMID 1448824
111: Ninni S, Kouakam C, Szurhaj W, et al. Usefulness of head-up tilt test combined with video electroencephalogram to investigate recurrent unexplained atypical transient loss of consciousness. Arch Cardiovasc Dis 2019;112(2):82-94. PMID 30600217
112: Ntusi NA, Coccia CB, Cupido BJ, Chin A. An approach to the clinical assessment and management of syncope in adults. S Afr Med J 2015;105(8):690-3. PMID 26543940
113: O’Donnell D, Hamer A, Horrigan M. Delayed neurally mediated syncope after inferior wall acute myocardial infarction. Am J Cardiol 2002;90(2):157-9. PMID 12106848
114: Parry SW, Gray JC, Newton JL, Reeve P, O'Shea D, Kenny RA. 'Front-loaded' head-up tilt table testing: validation of a rapid first line nitrate-provoked tilt protocol for the diagnosis of vasovagal syncope. Age Ageing 2008;37(4):411-5. PMID 18586835
115: Parsons I, Ellwood J, Stacey MJ, et al. Reflex syncope in the UK Armed Forces. BMJ Mil Health 2023a;169(5):408-12. PMID 34620724
116: Parsons IT, Ellwood J, Stacey MJ, Gall N, Chowienczyk P, Woods DR. Risk factors for reflex syncope in the British Army. BMJ Mil Health 2023b;169(6):548-53. PMID 35177430
117: Perkin GD. Vasovagal attacks. J Neurol Neurosurg Psychiatry 1994;57(7):789. PMID 8021662
118: Petix NR, Del Rosso A, Furlan R, Guarnaccia V, Zipoli A. Nitrate-potentiated head-up tilt testing (HUT) has a low diagnostic yield in patients with likely vasovagal syncope. Pacing Clin Electrophysiol 2014;37(2):164-72. PMID 23992559
119: Petersen ME, Williams TR, Gordon C, Chamberlain-Webber R, Sutton R. The normal response to prolonged passive head up tilt testing. Heart 2000;84(5):509-14. PMID 11040011
120: Petramfar P, Yaghoobi E, Nemati R, Asadi-Pooya AA. Serum creatine phosphokinase is helpful in distinguishing generalized tonic-clonic seizures from psychogenic nonepileptic seizures and vasovagal syncope. Epilepsy Behav 2009;15(3):330-2. PMID 19383552
121: Pirodda A, Brandolini C, Raimondi MC, Ferri GG, Borghi C. Tinnitus as a warning for preventing vasovagal syncope. Med Hypotheses 2009;73(3):370-1. PMID 19447564
122: Pitzalis M, Parati G, Massari F, et al. Enhanced reflex response to baroreceptor deactivation in subjects with tilt-induced syncope. J Am Coll Cardiol 2003;41(7):1167-73. PMID 12679218
123: Raj P, Lei L, Flevaris P, Raj S, Sheldon R. Serotonin reuptake inhibition for the prevention of vasovagal syncope: a systematic review and meta-analysis. Clin Auton Res 2023;33(6):811-9. PMID 37971641
124: Raviele A, Menozzi C, Brignole M, et al. Value of head-up tilt testing potentiated with sublingual nitroglycerin to assess the origin of unexplained syncope. Am J Cardiol 1995;76(4):267-72. PMID 7618622
125: Roland CG, Fye WB. Thomas Forrest Cotton (1884-1965). Clinb Cardiol 2007;30:366-8.
126: Romme JJ, van Dijk N, Go-Schön IK, Reitsma JB, Wieling W. Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial). Europace 2011;13(11):1639-47. PMID 21752826
127: Ruppert E, Chassagnon S, Chauvin M, Hubbard J, Mutschler V, Bourgin P. Cardioinhibition can be the unique manifestation of epilepsy-like syncope. J Clin Neurophysiol 2015;32(1):e1-3. PMID 25647776
128: Salari N, Karimi Z, Hemmati M, Mohammadi A, Shohaimi S, Mohammadi M. Global prevalence of vasovagal syncope: a systematic review and meta-analysis. Glob Epidemiol 2024;7:100136. PMID 38283939
129: Santini M, Colivicchi F. In-hospital management of syncope: the European perspective. Eur Heart J 2002;23(10):767-8. PMID 12009714
130: Scherrer U, Vissing S, Morgan BJ, Hanson P, Victor RG. Vasovagal syncope after infusion of a vasodilator in a heart-transplant recipient. N Engl J Med 1990;322(9):602-4. PMID 2304506
131: SEC Working Group for the 2018 ESC Guidelines for Syncope, Expert Reviewers for the 2018 ESC Guidelines for Syncope, SEC Guidelines Committee, SEC Working Group for the 2018 ESC Guidelines for the Diagnosis and Management of Syncope, Expert Reviewers for the ESC Guidelines for the Diagnosis and Management of Syncope, SEC Guidelines Committee. Comments on the 2018 ESC guidelines for the diagnosis and management of syncope. Rev Esp Cardiol (Engl Ed) 2018;71(10):787-93. PMID 30243611
132: Sharma PR, Hargreaves AD. Malignant vasovagal syncope. Dent Update 2006;33(4):246-8, 250. PMID 16756240
133: Sheldon R, Gerull B. Auton Neurosci 2021;235:102871. PMID 34474354
134: Sheldon R, Raj SR, Rose MS, et al. Fludrocortisone for the prevention of vasovagal syncope: a randomized, placebo-controlled trial. J Am Coll Cardiol 2016;68(1):1-9. PMID 27364043
135: Shoja MM, Tubbs RS, Loukas M, Khalili M, Alakbarli F, Cohen-Gadol AA. Vasovagal syncope in the Canon of Avicenna: the first mention of carotid artery hypersensitivity. Int J Cardiol 2009;134(3):297-301. PMID 19332359
136: Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of syncope. N Engl J Med 2002;347:878-5. PMID 12239256
137: Sutton R, Brignole M. Twenty-eight years of research permit reinterpretation of tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J 2014;35(33):2211-2. PMID 24980488
138: Sutton R, de Jong JSY, Stewart JM, Fedorowski A, de Lange FJ. Pacing in vasovagal syncope: physiology, pacemaker sensors, and recent clinical trials-precise patient selection and measurable benefit. Heart Rhythm 2020;17(5 Pt A):821-8. PMID 32036025
139: Tajdini M, Khalaji A, Behnoush AH, et al. Brain MRI and EEG overemployment in patients with vasovagal syncope: results from a tertiary syncope unit. BMC Cardiovasc Disord 2023;23(1):576. PMID 37990291
140: Tannemaat MR, van Niekerk J, Reijntjes RH, Thijs RD, Sutton R, van Dijk JG. The semiology of tilt-induced psychogenic pseudosyncope. Neurology 2013;81(8):752-8. PMID 23873974
141: Task Force for the Diagnosis and Management of Syncope, European Society of Cardiology (ESC), European Heart Rhythm Association (EHRA), et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30(21):2631-71. PMID 19713422
142: Tea SH, Mansourati J, L'Heveder G, Mabin D, Blanc JJ. New insights into the pathophysiology of carotid sinus syndrome. Circulation 1996;93(7):1411-6. PMID 8641031
143: Teodorovich N, Swissa M. Tilt table test today - state of the art. World J Cardiol 2016;8(3):277-82. PMID 27022459
144: Traykov V, Shalganov T. Cardioneuroablation for the treatment of vasovagal syncope: current status and impact on quality of life. Curr Cardiol Rep 2023;25(12):1839-49. PMID 37982935
145: Trim GM, Krahn AD, Klein GJ, Skanes AC, Yee R. Pacing for vasovagal syncope after the second Vasovagal Pacemaker Study (VPS II): a matter of judgement. Card Electrophysiol Rev 2003;7(4):416-20. PMID 15071267
146: Uhm JS, Youn HJ, Chung WB, et al. Positive result in the early passive phase of the tilt-table test: a predictor of neurocardiogenic syncope in young men. Korean J Intern Med 2012;27(1):60-5. PMID 22403501
147: Ungar A, Mussi C, Del Rosso A, et al. Diagnosis and characteristics of syncope in older patients referred to geriatric departments. J Am Geriatr Soc 2006;54:1531-6. PMID 17038070
148: van Dijk JG, Sheldon R. Is there any point to vasovagal syncope? Clin Auton Res 2008;18:167-9. PMID 18682890
149: van Dijk JG, van Rossum IA, Thijs RD. Timing of circulatory and neurological events in syncope. Front Cardiovasc Med 2020;7:36. PMID 32232058
150: Vanbrabant P, Van Ouytsel V, Knockaert D, Gillet JB. Diagnostic yield of syncope investigation (initiated) in the emergency department: a pilot study. Acta Clin Belg 2011;66(2):110-5. PMID 21630607
151: Ventura R, Maas R, Zeidler D, et al. A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test. Pacing Clin Electrophysiol 2002;25(5):816-21. PMID 12049374
152: Vicenzini E, Pro S, Strano S, et al. Combined transcranial Doppler and EEG recording in vasovagal syncope. Eur Neurol 2008;60(5):258-63. PMID 18756091
153: Vyas A, Swaminathan PD, Zimmerman MB, Olshansky B. Are treatments for vasovagal syncope effective. A meta-analysis. Int J Cardiol 2013;167(5):1906-11. PMID 22626839
154: Wieling W, Rozenberg J, Schon IK, Karemaker JM, Westerhof BE, Jardine DL. Prolonged post-faint hypotension can be reversed by dynamic tension. Clin Auton Res 2011;21(6):415-8. PMID 21796353
155: Yarkoni M, Rehman WU, Bajwa A, Yarkoni A, Rehman AU. Ganglionated plexus ablation procedures to treat vasovagal syncope. Int J Mol Sci 2023;24(17):13264. PMID 37686062
156: Yiu D, Gieroba Z, Hall K, Mackintosh S, Russell A, Mangoni AA. An early drop in systolic blood pressure predicts a positive tilt table test in elderly patients with unexplained falls or syncope. Age Ageing 2006;35(2):183-5. PMID 16495295
157: Yoshimoto A, Yasumoto A, Kamiichi Y, et al. Analysis of vasovagal syncope in the blood collection room in patients undergoing phlebotomy. Sci Rep 2020;10(1):17933. PMID 33087731
158: Zhao P, Dong D, Dong R, et al. Development and validation of a nomogram for predicting the risk of vasovagal reactions after plasma donation. J Clin Apher 2023;38(5):622-31. PMID 37466252
159: Zysko D, Gajek J, Kozluk E, Agrawal AK, Smereka J, Checiński I. The clinical relevance of the duration of loss of consciousness provoked by tilt testing. Acta Cardiol 2010;65(2):203-9. PMID 20458828
160: Zysko D, Fedorowski A, Nilsson D, et al. Tilt testing results are influenced by tilt protocol. Europace 2016;18(7):1108-12. PMID 26443446
161: Zysko D, Melander O, Fedorowski A. Vasovagal syncope related to emotional stress predicts coronary events in later life. Pacing Clin Electrophysiol 2013;36(8):1000-6. PMID 23614671

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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Former Authors

David Benditt MD
Wade S Smith MD PhD
Kemal Hamamcioglu MD
Jasvinder Chawla MD MBA

Patient Profile

Age range of presentation: 6 to 65+ years
Sex preponderance: female > male
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Reflex syncope (neurally-mediated syncope)

Associated Disorders

Orthostatic hypotension

Differential Diagnosis

seizures
sleep disturbances
accidental falls
some psychiatric conditions
anxiety attacks
- hysterical reactions
- cardiac arrhythmia
- transient ischemic attack
- brainstem stroke
- subarachnoid hemorrhage
- epileptic seizures
- complex partial seizures
- hysterical fainting
- hypoglycemia
- acute blood loss
- drugs
- chronic fatigue syndrome
- postural orthostatic tachycardia syndrome (POTS)
- primary autonomic failure
- multiple system atrophy
- pure autonomic failure
- neurodegenerative disorders
- alcohol intake

Also Relevant

Convulsive syncope
Cough syncope
Drug-induced syncope
Postural orthostatic tachycardia syndrome
Swallow syncope
- Syncope

Reflex syncope (neurally-mediated syncope)

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Nonpharmacological interventions

Medications

Severe and refractory patients

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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