Sitcom Syncope:

Syncope is a common clinical problem, accounting for 3.5% of emergency department visits and 6% of hospital admissions annually.¹ Syncope can be subdivided by cardiogenic and neurally mediated mechanisms. Neurally mediated syncope is the most frequently diagnosed cause of syncope, accounting for 21.2% patient diagnoses after being evaluated for loss of consciousness.¹ Neurally mediated syncope may be further subdivided into vasovagal, carotid sinus hypersensitivity, and situational syncope.^1,2 Situational syncope is composed of tussive, postmicturition, defecation, swallowing, and Valsalva-induced syncope. Gelastic syncope, also known as laughter-induced syncope, is a subtype of situational syncope that has been rarely reported in the literature.³ The mechanism of gelastic syncope is not well understood. We report 3 cases of gelastic syncope that have had an extensive cardiac evaluation. These observations provide some insight into the mechanism of this unusual phenomenon.

We evaluated 3 patients who reported loss of consciousness during vigorous laughter. All patients were hospitalized and underwent a thorough evaluation to search for possible causes of syncope. This included a complete history and physical examination, 12-lead echocardiogram, chest radiograph, and routine blood analysis. In addition, all patients underwent transthoracic echocardiography, Holter monitoring, carotid duplex study, stress testing (nuclear or echocardiographic), polysomnography, and head-up tilt table testing.

Head-up tilt table testing with laughter provocation was an integral part of each patient’s evaluation and performed in a manner reported previously.⁴ Blood pressure, heart rate, and respiratory rate were recorded every 2 to 3 minutes. Laughter provocation was attempted in patients with normal initial tilt table studies. After 20 minutes of tilt table testing, while in the upright position, a comical video clip was shown to the patient with the intention of inducing vigorous laughter. Patients were asked to rate their maximum intensity of laughter during this time interval on a 0-to-10 scale (0 being no laughter and 10 being the most intense laughter they had ever experienced).

The 3 patients in our cohort (age range, 51–74 years) experienced a total of 7 syncopal events. Friends or family members witnessed all events. Three of these events occurred during vigorous laughter. In all cases, structural heart disease and cerebrovascular disease was excluded by noninvasive testing. The extensive medical evaluation for each patient is summarized in Table 1.

Underlying electrical disease of the heart was uncommon. One patient had electrocardiographic (ECG) evidence of left anterior fascicular block on the admission ECG. All patients underwent extended periods of in-hospital and outpatient continuous ECG monitoring. We did not observe any instances of bradyarrhythmia, tachyarrhythmia, or heart block. All patients underwent exercise stress testing and were found to have a normal chronotropic response to exercise. One patient with known coronary artery disease demonstrated a mild reversible apical wall motion abnormality on exercise stress testing without clinical angina pectoris. No patients had evidence of sleep apnea on polysomnography. Following the confirmation of structurally normal or near normal hearts, all patients underwent tilt table testing. Figures 1 to 3 depict the individual hemodynamic recordings for each patient during the testing period.

View: Figure 1
Patient 1 experienced a mixed vasovagal syncope at minute 18 of tilt table testing. The patient experienced classic prodromal symptoms. They were similar symptoms as experienced during previous syncopal events.

View: Figure 2
Laughter induced a blood pressure decrease from 144/80 mm Hg to 119/75 mm Hg at minute 12 of gelastic provocation. Heart rate remained near 70 bpm. The patient remained asymptomatic and rated peak laughter as 6 out of 10.

View: Figure 3
Laughter induced a blood pressure decrease from 140/73 mm Hg to 116/74 mm Hg. Heart rate remained unchanged. The patient remained asymptomatic and rated peak laughter as 5 out of 10.

Patient 1 reported multiple episodes of observed syncope. Historically, these were connected with periods of vigorous exercise on hot days. Medications in use at the time of outpatient syncope and during the time of tilt table testing included doxazosin 2 mg and ramipril 10 mg daily. On physical examination, pulses were equal bilaterally. There was no evidence of orthostasis when measuring blood pressures and heart rate in the sitting and standing positions prior to tilt table testing. Results of the tilt table study are depicted in Figure 1. The results were distinctly abnormal, with frank syncope occurring after 17 minutes of attaining upright posture. The observed hemodynamic response was typical for a vasovagal mechanism, with progressive hypotension accompanied with bradycardia and loss of consciousness. The patient’s baseline systolic blood pressure was 112 mm Hg, decreasing to 65 mm Hg at the time of syncope. The patient’s baseline heart rate was 73 bpm, decreasing to 32 bpm at the time of syncope. In this instance, it was not necessary to employ laughter as a means of inducing syncope.

Patient 2 had only 1 episode of witnessed syncope, but reported multiple episodes of near syncope while laughing. Physical examination revealed equal pulses bilaterally and no evidence of orthostasis by heart rate and blood pressure assessment in the sitting and standing positions prior to tilt table testing. This patient reported multiple episodes of lightheadedness associated with laughter. He had learned to curtail his laughter to avoid presyncopal sensations. Figure 2 documents this patient’s hemodynamic response to tilt table testing. The patient’s medication was amlodipine 5 mg. This was also in use during the time of tilt table testing. Twenty minutes upright posture was not associated with any significant change in heart rate or blood pressure. Following laughter provocation, however, a significant decrease in systolic blood pressure was noted. The baseline systolic blood pressure was 144 mm Hg, decreasing to 119 mm Hg after laughter provocation. This was not associated with any change in heart rate or symptoms.

Patient 3 had a history of coronary artery disease treated previously with stent deployment to the left anterior descending and left circumflex coronary arteries. The patient had no history of clinical angina pectoris occurring with syncopal events. Prior medications included quinapril 40 mg daily and hydrochlorothiazide 25 mg daily. The patient had taken these medications at the time of her syncopal events as well as on the day of her tilt table study. Physical examination revealed equal pulses bilaterally. There was no evidence for orthostasis when assessing blood pressures and heart rate in the sitting and standing positions. This patient reported multiple episodes of lightheadedness associated with laughter. She had learned to curtail her laughter to avoid presyncopal sensations. Figure 3 depicts the hemodynamic response of tilt table testing for this patient. Eighteen minutes of vertical positioning was not associated with any significant change in heart rate or blood pressure. Laughter provocation was then undertaken and was associated with a gradual decline in systolic blood pressure. The baseline systolic blood pressure was 140 mm Hg and decreased to 116 mm Hg after laughter provocation. The heart rate was noted to transiently rise and then precipitously fall. The baseline heart rate was 90 bpm, rising to 115 bpm after laughter provocation. The final heart rate measured was 78 bpm and was not significantly lower than the baseline heart rate of 90 bpm.

Current understanding of gelastic syncope is derived from a few case reports summarized in Table 2. Cox et al³ were the first to report on an association of syncope with laughter in 1997. Their patient experienced multiple episodes of syncope without prodromal symptoms, including falling face first onto his dinner plate while laughing. He was ultimately found to have brachiocephalic trunk stenosis, which was cured by stenting of the lesion³ and does not fall into the category of neurally mediated gelastic syncope.

Additional case reports of gelastic syncope were published by Totah and Benbadis,⁵ Bloomfield and Jazrawi,⁶ and Braga et al.⁷ Collectively, they identified 11 male patients (age range, 29–69 years) with this condition. Eight of these patients reported the prodromal symptoms of lightheadedness and dizziness prior to their syncopal event and while laughing. No patients reported any instances of chest pain, palpitations, shortness of breath, chronic cough, or sleep disturbances.

Three patients were observed during Valsalva maneuver. One experienced frank syncope after 14 seconds of Valsalva.⁷ Another experienced lightheadedness in response to sustained Valsalva without syncope.⁵ The last of the group showed a hypotensive response to Valsalva without symptoms. Syncope, in response to non-deliberate Valsalva maneuver, was uncommon. Only 1 patient in this group described pre-syncope or syncope in response to micturition and defecation.⁸

There are limited reports of tilt table testing in patients with gelastic syncope. Four of the previously reported patients experienced frank syncope from a classic vasodepressor response during tilt table testing.^7,9 As already noted, 1 patient was found to have brachiocephalic trunk stenosis,³ which was treated by stenting, and after which no further syncopal episodes were reported. Another patient was found to have an ependymoma involving the cerebellar vermis and abutting the floor of the fourth ventricle. In this case, gelastic events resolved following surgical removal of the tumor.¹⁰

There have been limited reports of medical treatments for gelastic syncope. Two patients with recurrent gelastic syncope have been pharmacologically managed and reportedly cured.^11,12 One was treated with bisoprolol 2.5 mg daily.¹² Another remained symptomatic after treatment with propranolol 30 mg daily. Midodrine 8 mg daily was then added to the regimen. Head-up tilt table testing was then performed to test the efficacy of this medication combination. Following the institution of dual medical therapy, syncope could not be induced. The patient remained syncope free for over 2 years of follow-up.¹¹

In our case series, as in a majority of cases in the literature, patients reported the sensation of lightheadedness and prodromal events prior to their gelastic event. Thus, some patients have described the learned behavior of stifling their laughter because of symptoms of lightheadedness.^5,8,13 These observations, together with a positive tilt table test, are suggestive of a neurally mediated origin for the gelastic syncopal events.

One of our patients had recurrent episodes of syncope that were reminiscent of a vasovagal mechanism. This patient experienced frank syncope during tilt table testing. Although laughter provocation was not completed in this patient, the patient’s history of syncopal events while laughing, engaging in public speaking, and bicycling on a hot day suggest that laughter (among other activities) may induce neurocardiogenic syncope in this patient. His inappropriate hemodynamic response was confirmed by his positive tilt table test.

Two patients showed asymptomatic hypotensive responses during laughter provocation. Patient 2 showed a maximal decrease in systolic blood pressure of 25 mm Hg, with 6 out of 10 level of laughter provocation. Patient 3 showed a maximal decrease in blood pressure of 24 mm Hg, with 5 out of 10 intensity of laughter. This hemodynamic change did not induce symptoms in our patients. We speculate sufficiently intense laughter would induce a more significant hypotensive response with perhaps even syncope. We acknowledge that reproduction of laughter in the clinical setting is quite challenging.

The effect of laughter on blood pressure and heart rate has been minimally described in the literature. This may be, as we have learned in our study, inducing laughter in an artificial setting is extremely challenging. A study by McMahon et al¹⁴ in which blood pressure was measured in 16 subjects immediately following laughter provocation found that laughter produces an immediate increase in blood pressure and heart rate. This observation has been corroborated by Fry.¹⁵ They suggest that while the exact mechanism of this response is unclear, hypertension may be potentiated by a bellows action of the thoracic cavity on the vasculature, as well as stimulation from a small catecholamine surge.

In evaluating patients with laughter-related syncope, it is important to distinguish cataplexy from gelastic syncope. As highlighted by Totah,⁵ cataplexy is the sudden loss of muscle tone associated with emotions, especially laughter, anger, surprise, or startle. It is not accompanied by prodromal symptoms. It is sudden in onset and can not be prevented by stifling emotions. Moreover, it is not related to the intensity of laughter. Cataplexy may be associated with narcolepsy or can be associated with cerebral disease, such as Niemann-Pick disease and Norrie’s disease. Familial instances of cataplexy have also been reported.¹⁶

Two of the patients were eating or had just finished such at the time of their syncopal event. The question of postprandial hypotension as a contributing factor to these syncopal events arises. Postprandial hypotension is a reduction in systolic blood pressure > 20 mm Hg or a reduction below 90 mm Hg from a pressure > 100 mm Hg within 2 hours following a meal. There is a normal decrease in blood pressure after consuming a meal. This is ordinarily associated with an increase in heart rate and maintenance of blood pressure. This response is blunted in some patients. Risk factors for such include use of diuretics, hypertension, autonomic dysfunction, Parkinson’s disease, diabetes, and end-stage renal disease.¹⁷ We do not feel our patients experienced postprandial hypotension; these patients lacked the major risk factors. Additionally, they complained of lightheadedness associated with laughter, not food consumption. Nevertheless, because of this association in 2 of our 3 subjects, we acknowledge postprandial hypotension may have contributed.

We believe that our patients had gelastic-induced syncope. Each presented with syncope in the setting of laughter and was accompanied by prodromal features that were atypical for cataplexy. We suggest that gelastic syncope is a unique and separate subset of neurally mediated syncope similar to tussive or micturition syncope. The action of coughing, urination, or laughing produces repetitive short bursts of expiration resulting in a Valsalva-like hemodynamic response. The Valsalva response increases intrathoracic pressure, decreases the return of venous blood from the systemic circulation, and thus reduces stroke volume. The normal physiologic response to a reduction in stroke volume is a compensatory increase in heart rate. Patients with gelastic syncope, much like those with other forms of vagally mediated syncope (tussive and micturation), have an impaired heart rate response and have an uncompensated reduction in stroke volume, and when severe, lose consciousness.

We believe that gelastic syncope is a form of vasovagal syncope and will respond to the usual therapeutic interventions that are used to treat vasodepressor syncope. This includes an assurance of adequate hydration support base (2 L per day), dietary salt supplementation, the use of compression stockings, certain physical maneuvers (gripping of hands and tensing of arms and legs) and treatment with beta-blocking agents. Additionally, the avoidance of situations known to produce vasodepressor syncope, such as prolonged standing and dehydration, have been shown to be effective.^10,12 The combination of adequate hydration and avoidance of dehydration and prolonged standing were effective in preventing additional incidences of syncope in patient 1. Patients 2 and 3 had only one syncopal event associated with laughter and by curbing extreme laughter had managed to avoid any further events.

Based on previous literature, we assert that in patients refractory to these maneuvers, medical therapy may play a role.^10,12 Beta-blocking agents have been shown to be effective. They are thought to work by blunting the parasympathethic rebound that occurs following a sympathetic stimulus by preventing the stimulation of C fibers in the heart. In doing so, beta-blocking agents paradoxically block the bradycardia that is frequently seen. Beta-blocking agents have also been shown to diminish the catecholamine lability seen in patients experiencing syncope.

In patients not responsive to beta-blockade, midodrine may be considered. Midodrine is an alpha-1 agonist that exerts its effect through agonizing alpha receptors on venous and arterial vasculature. It has been shown to produce a 15 to 30 mm Hg increase in blood pressure at 1 hour after administration, with a half-life of 3 to 4 hours. This physiologic effect has been demonstrated to be effective in randomized controlled trials for neurogenic orthostatic hypotension. As with beta-blockers, its use is generally limited to cases refractory to behavioral therapy.^18,19

While the avoidance of precipitating situations may be an effective alternative for other forms of neurally mediated syncope, laughter suppression is impractical, if not impossible, to achieve. Interestingly, the propensity to laugh, as reported by Clark et al,²⁰ may be an independent risk factor for coronary artery disease. Thus, aside from the social implications, the extended suppression may not be advised.²⁰

This case series and literature review suggests that most cases of gelastic syncope are neurally mediated, and as such, may be responsive to common therapies directed towards this mechanism. The resultant loss of consciousness is certainly no laughing matter and can result in significant injury to those affected by this condition. Knowledge of this condition, its mechanism of action, and potential treatments may be of benefit to physicians evaluating patients with syncope.