39.3 Reflex syncope

Reflex syncope, also called neurally mediated syncope, accounts for 56–73% of the aetiologies of syncope, with a balanced incidence over the various age categories. The most common form is ‘vasovagal syncope’ where the trigger is pain, fever, instrumentation, emotion, or orthostatic stress; ‘situational syncope’ refers to syncope triggered by a specific situation, that is, micturition, defecation, swallowing, cough; and ‘carotid sinus syncope’, which may be triggered by carotid sinus manipulation or diagnosed in patients with syncope and positive carotid sinus massage. The term ‘atypical reflex syncope’ is used to describe reflex syncope occurring without an apparent trigger: the diagnosis is mainly based on history, exclusion of other causes of syncope, and a positive head-up tilt test. Although recent developments have prompted new pathophysiological hypotheses, including the adenosine pathway, the diagnostic strategy for reflex syncope remains mainly based on clinical evaluation and very few ancillary diagnostic tests. The pharmacological armament is still very limited while new perspectives have been opened for specific subgroup of patients. Regarding the very rare patients who are candidates for permanent cardiac pacing, a new pragmatic approach may help their selection and the prediction of the effect of pacing.

Reflex syncope, also called neurally mediated syncope, refers to situations in which reflexes normally involved in blood pressure and heart rate control become acutely inappropriate, leading to a sudden drop in cerebral blood perfusion. In large series, they account for 56–73% of the aetiologies of syncope, with a balanced incidence over the various age categories.¹ Reflex syncope may be classified according to the trigger of the inappropriate reflex. The most common form is ‘vasovagal syncope’ (also called neurocardiogenic syncope) where the trigger is pain, fever, instrumentation, emotion or orthostatic stress; ‘situational syncope’ refers to syncope triggered by a specific situation, that is, micturition, defecation, swallowing, or cough; and ‘carotid sinus syncope’, which may be triggered by carotid sinus manipulation or diagnosed in patients with syncope and positive carotid sinus massage. The term ‘atypical’ is used to describe reflex syncope occurring without an apparent trigger: the diagnosis is mainly based on history, exclusion of other causes of syncope, and a positive head-up tilt test.

The classical form of vasovagal syncope usually starts in young subjects as an isolated episode and is distinct from other forms, frequently with an atypical presentation, that start in old age and are often associated with cardiovascular or neurological disorders. The different forms of neurocardiogenic syncope share a benign prognosis but the repetition of the episodes may be disabling in about one-third of the patients. Morbidity is particularly high in elderly patients, ranging from loss of confidence to severe trauma and subsequent hospitalizations. Vasovagal syncope recurrence may occur in 7–46% of the cases at 1 year.

The diagnosis is based mainly on history taking, physical examination, including carotid sinus massage,¹ electrocardiogram (ECG), and any investigation needed for ruling out significant structural heart disease. The integration of information related to precipitating factors, presyncopal symptoms, witness description of loss of consciousness, and post-syncopal recovery and symptoms enables the diagnosis to be strongly suspected in many cases.² Vasovagal syncope is diagnosed on the basis of the association of typical predisposing factors, of prodromes due to the activation of the autonomic system (i.e. feeling warmth, abdominal discomfort, diaphoresis, nausea, pallor) and of a post-syncopal period characterized by severe fatigue and syncope recurrence or severe dizziness when standing up early after the initial episode. Myoclonic movements may occur at the end of the loss of consciousness and should be distinguished from seizure convulsions. Situational syncope is generally easily recognized by the specific situation in which it occurs. Carotid sinus syncope occurs more often in elderly patients; a clear triggering mechanical stimulation of the carotid sinus is often lacking and the diagnosis is based on a positive carotid sinus massage. In elderly patients, the diagnosis of reflex syncope may be difficult since a typical presentation is uncommon and multiple causes of syncope may overlap. In this situation, it often lies on ruling out other causes of syncope and positive responses to the head-up tilt test or carotid sinus massage. In children and teenagers, the high incidence of neurocardiogenic syncope should not obscure the arrhythmic causes of syncope due to channelopathies which should be systematically ruled out.

In a limited number of patients presenting with atypical forms, a final diagnosis will require provocative tests or prolonged monitoring.

The criteria for appropriate indications and interpretation of diagnostic tests are listed in the tables of recommendations of the 2018 European Society of Cardiology (ESC) Guidelines on syncope (see Chapter 39.7).

Despite its benign course, recurrent and unpredictable reflex syncope may be disabling in about a third of patients. The cornerstone of the management of these patients is non-pharmacological treatment, including education, lifestyle modification, and reassurance regarding the benign nature of the condition. Additional treatment may be necessary in unpredictable and frequent syncope. In particular when very frequent syncope alters quality of life; recurrent syncope without, or with very short prodrome exposes patients to risk of trauma; and syncope occurs during high-risk activity (e.g. driving, machine operation, flying, and competitive athletics). It has been evaluated that 14%⁸ of the highly selected population of reflex syncope patients referred to specialized syncope units may need such additional treatment. A proposal for the first approach to therapy of reflex syncope in the more common clinical situations is shown in Figure 39.3.1

The criteria for the choice of the appropriate therapy are listed in the tables of recommendations of the 2018 ESC Guidelines on syncope (see Chapter 39.7).

Education and lifestyle modifications have not been evaluated in randomized studies but there is a consensus for implementing them as first-line therapy in all cases. They comprise reassurance regarding the benign nature of the disease and education regarding awareness and possible avoidance of triggers, and early recognition of prodromal symptoms in order to lie down quickly. If possible, triggers should be addressed directly, such as cough suppression in cough syncope; dehydration and agents that lower blood pressure should be avoided or reduced. A large observational study⁹ evaluated a standardized education protocol in patients with vasovagal syncope. In a pre–post comparison conducted in 316 patients, education significantly reduced traumatic injuries and syncope recurrences. The key is careful avoidance of agents that lower blood pressure, including alpha blockers, diuretics, and alcohol. Increased oral fluid intake is also recommended. Salt supplementation has been proposed¹⁰ for improving orthostatic tolerance.

Isometric muscle contractions have been shown to increase cardiac output and arterial blood pressure during the phase of impending reflex syncope. Physical counter pressure manoeuvres of the legs or the arms have showed that they could allow patients with reflex syncope to avoid or delay losing consciousness in most cases.^11,12,13 A limitation of this treatment is that it cannot be used in patients with short or absent prodromes and that 35% of the patients did not have prodromes long enough to see a benefit in the Physical Counterpressure Manoeuvres Trial (PC-Trial).¹³

In patients with syncope and a positive tilt test, prolonged periods of enforced upright posture (so-called tilt training), either in a medical environment or at home, have been shown to turn the head-up tilt test to negative and to reduce syncope recurrence.^14,15 However, the reported benefit has not been confirmed by the majority of the subsequent studies.^16,17 This treatment is also hampered by the low compliance of patients in continuing the training programme for a long period.

Many drugs have been tested in the treatment of reflex syncope, for the most part with disappointing results. The list includes beta blockers, disopyramide, scopolamine, theophylline, ephedrine, etilefrine, midodrine, fludrocortisone clonidine, and serotonin reuptake inhibitors. While results have been satisfactory in uncontrolled trials or short-term controlled trials, several long-term placebo-controlled prospective trials have been unable to show a benefit of the active drug over placebo with some exceptions. Even for the drugs supposed to be of benefit the evidence is weak and there is some reluctance to propose long-term treatment for occasional symptoms.

Midodrine has proved effective in small studies but a systematic review¹⁸ showed that the confidence in estimates was moderate because of imprecision and publication bias. Side effects (i.e. supine hypertension, pilomotor reactions, and urinary problems) often lead to discontinuation of the drug. Another limitation of midodrine is frequent dosing, limiting long-term compliance.

Fludrocortisone, a corticosteroid with mineralocorticoid effect, may counteract the physiological cascade leading to the orthostatic vasovagal reflex by increasing renal sodium reabsorption and expanding plasma volume. The mechanism of action can be compared to that of saline infusion. Fludrocortisone has been shown to be ineffective in a small, randomized double-blind trial in children.¹⁹ The Prevention of Syncope Trial II (POST 2)²⁰ demonstrated reduction of vasovagal syncope recurrences in young (median age, 30 years) patients with low-normal values of arterial blood pressure and without co-morbidities. The benefit was higher in patients who were tolerant of the drug and achieved 0.2 mg per day dose stabilization at 2 weeks. The half-life of the drug is long and side effects include hypertension, hypokalaemia, nausea, and fatigue.

Beta blockers have been presumed to lessen the degree of ventricular mechanoreceptor activation due to their negative inotropic effect in reflex syncope. This theory has not been supported by the outcome of clinical trials.^21,22,23,24 They may enhance bradycardia in carotid sinus syndrome.

Serotonin reuptake inhibitors, by downregulating central serotonin receptor levels, may interfere with serotonin modulation of blood pressure and heart rate. Paroxetine and fluoxetine were shown to be effective in small studies,^25,26 which has not been confirmed by other studies.

Cardiac pacing plays a small role in therapy for reflex syncope. Treating these patients with a pacemaker entails a cumulative high risk of pacemaker-related complications over many years of expected life, to relieve a non-life-threatening and often self-limiting condition. Therefore, permanent pacing should be considered only in older patients, over 40–60 years old, with unpredictable recurrent syncope.

Carotid sinus syndrome: the evidence supporting the benefit of cardiac pacing in patients affected by carotid sinus syncope is limited to few small controlled trials and retrospective observational studies. In general, with pacing, syncopal recurrence rate during follow-up ranges between 0% and 20%, whereas the recurrence of syncope is always higher in untreated patients who show a rate between 20% and 60%.²⁷ In conclusion, cardiac pacing is effective in preventing recurrences of syncope in patients with carotid sinus syndrome, but syncopal recurrence is expected to occur up to 20% of patients within 5 years. Two variables have been shown to hamper the efficacy of pacing therapy in carotid sinus syndrome: the mixed forms and the association with positivity of tilt testing.

Vasovagal syncope: several randomized trials of pacing for vasovagal syncope have been performed and they have shown conflicting results.¹ Importantly, in these trials, the patients were selected for pacemaker therapy when some form of bradycardia was observed during the head-up tilt test and, actually, careful analysis of these randomized trials, both blinded and unblended, suggests that the primary mechanism of benefit from permanent pacemaker therapy in reflex syncope was an expectation response.²⁸ The ISSUE 2 study²⁹ opened a new era in the understanding of the possible role of cardiac pacing in vasovagal syncope, showing that spontaneous asystole, and not bradycardia provoked during the tilt test, should form the basis for patient selection for pacemaker therapy. The ISSUE 3 study, a randomized double-blind trial of patients aged 40 years and older with recurrent reflex syncope and implantable loop recorder-documented asystole, confirmed the effectiveness of pacing therapy in this situation.³⁰ During follow-up, the 2-year estimated syncope recurrence rate was 57% with the pacemaker off and 25% with the pacemaker on, with a relative risk reduction of 57%.

Recently, the SUP2 (Syncope Unit Project 2) trial, a prospective multicentre observational study evaluated a pragmatic approach, shown in Figure 39.3.2, using three tests sequentially in order to detect patients with asystolic responses who might benefit from dual-chamber pacing.⁸ In a highly selected population of patients referred to syncope units for recurrent unpredictable reflex syncope, carotid sinus massage was performed first, followed, if negative, by tilt testing followed, if negative, by implantation of an implantable loop recorder. At each step, the patients received a dual-chamber pacemaker in case of documented asystole or received the subsequent test. The patients who received a pacemaker had an actuarial syncope recurrence rate of 9%, 15%, and 20% after 1, 2, and 3 years, respectively. This was significantly lower than the 22%, 37%, and 43% recurrence rates observed in the unpaced patients. A sub-analysis of ISSUE 3³¹ and the long-term analysis of SUP2³² showed that the benefit of cardiac pacing was maximum in tilt-negative patients. These observations generated the hypothesis that tilt positivity is indicating an associated hypotensive susceptibility to reflex syncope rendering cardiac pacing less effective. It was hypothesized that tilt testing should be regarded as a risk stratification tool rather than being diagnostic.

In conclusion, the more adequate candidates for cardiac pacing in reflex syncope are the older patients severely disabled by unpredictable syncope, in whom asystole is provoked by carotid sinus massage, or documented by an implantable loop recorder. Positivity of the head-up tilt test may be indicative of a lower efficacy of cardiac pacing by detecting an associated hypotensive susceptibility.

A new clinical entity has been recently described in a small series of patients who presented with a long history of syncope and in whom paroxysmal atrioventricular (AV) block could be recorded at the time of syncope recurrence.³³ The term ‘idiopathic AV block’ was used because these patients had an otherwise normal heart and no sign of conduction disease at the ECG and electrophysiological study. Over very long periods of follow-up these patients never exhibited permanent AV block. A reflex mechanism involving adenosine was suspected in these patients who had very low plasma adenosine levels and a high induction rate of transient complete heart block during exogenous injections of adenosine. No syncope recurrence was observed after permanent cardiac pacing. Similarly, the entity of ‘low adenosine syncope’ has been recently described in patients who have an otherwise unexplained syncope with sudden onset without prodrome and a normal heart and normal ECG.³⁴ The clinical, laboratory, and biological features of these patients are close to those observed in patients affected by idiopathic paroxysmal AV block. Unlike in vasovagal syncope patients, tilt testing was usually negative.^34,35 No syncope recurrence was observed after permanent cardiac pacing in ten patients who had ECG documentation of asystolic pause due to sinus arrest or AV block.³⁶ The features distinguishing ‘low adenosine syncope’ from vasovagal syncope are summarized in Table 39.3.1.

Theophylline is a non-selective adenosine receptor antagonist potentially effective when adenosine is suspected to be involved in the mechanism of syncope. In a series of case reports, theophylline appeared effective in patients with recurrent sudden-onset (pre)syncope who presented with the common biological characteristic of low circulating adenosine levels.³⁷ Norepinephrine transport inhibitors, reboxetine and sibutramine, lead to a selective increase in sympathetic tone during stress by inhibiting reuptake of norepinephrine in sympathetic neuronal synapses. A mismatch between sympathetic nerve activity and norepinephrine spillover is present in patients with orthostatic vasovagal syncope.³⁸ Reboxetine and sibutramine have been shown to block or attenuate the vasovagal reflex during tilt testing.³⁹ Sibutramine achieved 94% suppression of syncopal episodes at 6 months in a small, open-label prospective clinical study on very symptomatic patients who had not responded to any previous treatment.⁴⁰

Although recent developments have prompted new pathophysiological hypotheses, the diagnostic strategy for reflex syncope remains mainly based on clinical evaluation and very few ancillary diagnostic tests. The pharmacological armament is still very limited while new perspectives have been opened for specific subgroup of patients. Regarding the very rare patients who are candidates for permanent cardiac pacing, a new pragmatic approach may help their selection and the prediction of the effect of pacing.