Clinical manifestations

Presentation and course

Although cough syncope may affect women and children, patients with cough syncope are predominantly muscular, obese, middle-aged men, who are current or ex-smokers and tend to overindulge in alcohol (53; 01; 10; 68). In one series of 45 patients, the average weight was 96 kg (211 pounds) (10). Although it can occur across a wide age span, the typical patient is a man in his 50s, and more than 95% of cases are male (53; 10). Smoking is common, but not universal, among patients with cough syncope (53; 10), and other factors such as respiratory tract infections and postnasal drip can cause or contribute to syncope even in the absence of smoking. The vast majority have a chronic cough, bouts of severe coughing, and evidence of obstructive lung disease. Syncope follows bouts of severe involuntary coughing (which is much more forceful than voluntary coughing) and may occur within 3 to 5 seconds of the onset of coughing. However, many bouts result only in pre-syncope with associated visual grey-out, tunnel vision, etc. (53; 71). The face may be congested, and there may be evidence of acral or perioral cyanosis followed later by pallor (53). Cough syncope may occur while either upright or supine. There may be associated brief jerking or rhythmic movements (ie, convulsive syncope) but generally no associated incontinence, tongue biting, or postictal state. Recovery usually occurs within seconds without vasomotor or other sequelae. Patients typically remember a bout of coughing, sometimes with photopsias but are amnestic for the period of lost consciousness. Cough syncope may occur dozens of times a day (14).

Prognosis and complications

The long-term prognosis of cough syncope depends largely on the prognosis of the underlying condition, but cough syncope itself can result in severe bodily injury, including vertebral artery dissection (10; 93; 62). In the absence of underlying significant heart or pulmonary disease, the main risk of syncope is related to the potential for physical harm (98). A “malignant episode of syncope” is defined as “an episode of syncope that occurs with little or no warning and results in a significant injury or property damage, eg, a car accident” (98).

Although the risk of a car accident related to syncope is relatively low (45; 63; 103), previous traffic accidents, injuries, and fatalities have resulted from cough syncope (53; 100; 36; 30; 70; 87) and for that matter from other causes of syncope (75; 48; 88; 65; 59; 106). McCorry and Chadwick reported four heavy goods vehicle drivers involved in serious crashes in the United Kingdom (3 of which were fatal), all of whom avoided prosecution from dangerous driving based on the diagnosis of cough syncope (70). In a review of 40 cases of cough syncope, only one person was reported to have had an episode while driving a car, which resulted in injury to himself (53).

Guo and colleagues reported a series of six occasions involving motor vehicle drivers in serious crashes (including six deaths), and cough syncope was cited as the cause; an alternative cause leading to the crash could be identified in each case (34). Most of the cases were very similar: (1) obese, middle-aged men driving alone; (2) either drifted off the road or collided with a stationary object or an oncoming car; (3) a prior or current history of cough syncope could not be established following the crash. In all cases (except a case of vehicular homicide resulting in three deaths), pathological sleepiness was considered highly likely to have contributed to the crash. Therefore, cough as a cause of syncope-related car crash should be a diagnosis of exclusion and used with great caution as a medico-legal defense (34). Guo and colleagues suggested criteria for diagnosing cough syncope following a vehicular accident that are applicable to medicolegal and clinical situations, and Dr. Douglas Lanska has modified the following table (see table 1).

Table 1. Criteria for Establishing Cough Syncope as a Potential Cause of a Vehicular Accident

Guidelines indicate that a person with recurrent syncope, including “situational syncope” (a category of syncope that would include cough syncope) (103a; 103b), should not drive until a cause has been identified and the symptoms controlled with appropriate therapy.

Biological basis

Pathophysiology

Cough is a defensive mechanism designed to remove mucous and foreign material from the airways. A cough begins with a spontaneous deep inspiration that increases lung volume and decreases intrathoracic pressure. Then the thoracic and abdominal wall muscles contract with the glottis closed (ie, Valsalva maneuver), greatly increasing intrathoracic pressure without changing lung volume. When the glottis opens, an explosive decrease in both intrathoracic pressure and lung volume occurs.

Several pathophysiologic processes may cause or contribute to cough-related syncope:

Valsalva-induced decreased cardiac output. Cough acts like a strong Valsalva maneuver, increasing intrathoracic pressures by up to 300 mm Hg (92; 105), which causes decreased venous return to the atria with resultant decreased stroke volume, decreased blood pressure, and decreased cerebral perfusion (69; 92; 22). Vasodilatation following intermittent coughing may be due to the stimulation of baroceptors by large arterial cough transients and subsequent reduction in total peripheral vascular resistance (92; 55).

Increased intracranial pressure. Cough-induced increased intrathoracic pressure is transmitted to the cerebrospinal fluid with resultant sudden increased intracranial pressure (37; 38; 71; 111; 05) that may act like a cerebral concussion (54) or may force blood out of the closed cranial vault (71) and cause decreased cerebral blood flow (05) or even transient cerebral circulatory arrest (21; 68).

Cardiac arrhythmias. Cough may produce vagally mediated cardiac arrhythmias (18), including sinus arrest (18; 101) and atrioventricular conduction block (40; 90; 07). Vagal stimulation can also induce ventricular asystole in some patients, particularly if vagal tone has been accentuated by cholinergic agents (eg, acetylcholinesterase inhibitors), hypoxia, hypercapnia, or tracheal suctioning in the setting of respiratory infection (57; 12).

Stimulation of hypersensitive carotid sinus. Cough may stimulate a hypersensitive carotid sinus and cause reflex hypotension or vagally mediated, high-grade, atrioventricular block and syncope (107). Several possible mechanisms have been proposed, including mechanical pressure effects of accessory neck muscles on the carotid sinus during coughing or hypotension induced by the baroreceptor response to acutely elevated arterial blood pressure induced by cough (107).

Cough-triggered neural reflex-mediated hypotension-bradycardia. Many patients with cough syncope exhibit prolonged hypotension in response to cough or Valsalva maneuver, and in at least some cases, this appears to be mediated via a neural reflex mechanism (09; 24; 24; 25).

Laryngospasm. Patients with severe gastroesophageal reflux disease can develop severe laryngospasm and syncope, particularly in association with a recent or concurrent respiratory infection that contributes to protracted cough and an increased amount of refluxate (35; 84; 64).

Tracheal compression. A single case of cough syncope and tracheal compression due to a retrosternal goiter has been reported (26), but the case was confounded by a concomitant pulmonary embolus from a deep vein thrombosis. His symptoms reportedly improved with anticoagulation and then further improved following elective hemithyroidectomy.

Augmentation of left ventricular outflow obstruction. Cough may dynamically augment left ventricular outflow obstruction in patients with idiopathic hypertrophic subaortic stenosis, partly due to reflex sympathetic stimulation (109).

Impaired left ventricular diastolic filling. Cough may augment impaired diastolic filling and produce a marked decrease in cardiac output in patients with constrictive pericarditis (23).

Impaction of a brainstem herniation. Cough or sneezing may cause impaction of a brainstem herniation in the foramen magnum in patients with a Chiari malformation with resulting compression of efferent sympathetic and parasympathetic cardiovascular pathways in the brainstem, dysfunction of the midbrain reticular activating system, craniospinal pressure dissociation, transient increased intracranial pressure, and vertebrobasilar compression with brainstem ischemia (58; 19; 27; 112; 113; 114; 39; 81; 49; 83; 02; 66; 67; 91). Other associated episodic symptoms in such patients can include pre-syncope, visual grey-out, vertigo, drop attacks, enuresis, and headache.

Decreased cerebral blood flow. Cough may further impair cerebral circulation in patients with already compromised cerebral blood flow because of extracranial or intracranial arterial stenosis or occlusion (97; 61; 79). Several factors may act synergistically in such cases, including decreased cardiac output from decreased venous return, increased cerebrospinal fluid pressure, and secondary hypocapnia causing cerebral arterial vasoconstriction (61).

Internal jugular vein valve insufficiency. Cough syncope can result from transient increases in intracranial pressure and consequent reduction in cerebral blood flow due to abnormally high internal jugular vein pressures transmitted from the thoracic cavity because of incompetent internal jugular vein valves (99).

Seizure. Rarely, cough and its associated changes in cerebral blood flow or other pathophysiologic processes may actually trigger a seizure with resultant loss of consciousness followed by a postictal state (78; 102; 56). No cases of documented seizures on electroencephalography associated with cough-induced loss of consciousness have been reported.

Differential diagnosis

Confusing conditions

Cough syncope may be confused with epilepsy, particularly as the syncopal attacks may be associated with secondary arrhythmic convulsive jerks of the extremities (ie, convulsive syncope) (53; 52; 21; 42; 32; 56). However, there is generally no associated aura, postictal confusion, tongue biting, or incontinence. Furthermore, the syncope improves or resolves with treatment of the cough and underlying pulmonary disorder without recourse to anticonvulsants. Rare patients with cough-associated syncope may have interictal epileptiform activity on electroencephalograms, postictal symptoms, and apparent control of syncope with anticonvulsants (78; 102), and in such rare cases, cough-triggered changes in cerebral blood flow or other factors may actually trigger a seizure.

Associated or underlying disorders

The cause of cough in patients with cough syncope is variable but most commonly is associated with chronic obstructive pulmonary disease. Several factors may contribute to cough and cough-related syncope:

Several factors may increase the likelihood that cough will produce syncope:

TUBB3 E410K syndrome (ie, due to a heterozygous c.1228G >  A [p.E410K] mutation in the TUBB3 gene) has been reported to cause cough syncope and a clinical picture resembling Moebius syndrome with congenital extraocular ophthalmoplegia sparing abduction and facial nerve palsy; other clinical manifestations include osteoporosis because of hypogonadotropic hypogonadism, borderline intellectual disability, cyclic vomiting, and hyposmia (76).

Premature ventricular contractions (PVCs) have been reported in association with chronic cough and cough syncope (96; 46). Premature ventricular contraction-induced cough happens due to the cardiopulmonary reflex (96).

Premature ventricular contractions may trigger the cough reflex by (1) stimulating sympathetic innervation in the right ventricular outflow tract or pulmonary artery (96); (2) inducing hemodynamic changes in the pulmonary circulation (77); or (3) transiently augmenting pulmonary blood flow (ie, following premature ventricular contractions) and, thus, triggering the cough reflex, either by activating C-fibers in the left ventricular wall or distending the pulmonary artery (41).

Diagnostic workup

The diagnostic workup varies by the clinical circumstances and the clinically suspected etiologies of cough syncope. Lung function, cardiac function, blood pressure, and blood volume should be assessed clinically. Pulmonary function studies, a chest x-ray, and an electrocardiogram should be obtained. Holter monitoring can help identify associated cardiac arrhythmias, particularly during bouts of coughing. In some patients with suspected vagally mediated arrhythmias, vagal maneuvers can be considered to determine if increased vagal tone can precipitate related clinical outcomes (eg, sinus arrest, atrioventricular block, hypotension, or syncope); such maneuvers can include carotid sinus massage and eyeball compression, but many reported cases of cough syncope did not have abnormal findings on such maneuvers (40; 18). More sophisticated cardiac electrophysiologic studies are rarely needed. Echocardiography may be needed in cases of suspected pericarditis or cardiac outflow obstruction. Coughing during head-up tilt is a useful diagnostic test in patients suspected of having cough syncope but in whom the history is inconclusive (73). Extracranial and intracranial cerebrovascular patency can be assessed with magnetic resonance angiography or cerebrovascular ultrasound studies, including carotid duplex and transcranial Doppler ultrasound studies, if indicated clinically. MRI is not routinely indicated but can help demonstrate a Chiari malformation. Depending on the clinically suspected underlying etiologies identified, some cases may require consultation by a pulmonologist, gastroenterologist, cardiologist, neurosurgeon, or vascular surgeon.

Management

Management of cough syncope focuses on treatment of cough (eg, bronchodilators and antitussives) and the underlying conditions, but cardiac function, blood pressure, blood volume, reflex-mediated changes, and extracranial vascular patency may all require separate management (25). Smoking cessation is closely associated with decreased symptoms and should be strongly encouraged (53; 97; 10). Avoidance of excess alcohol should also be strongly encouraged (53). In patients with intractable cough, nebulized lidocaine can be helpful (108). Medications that can cause or contribute to cough, such as angiotensin-converting enzyme inhibitors, may need to be discontinued. In some cases, vasoconstrictors may be helpful (107; 15). Patients with syncope that is not medically controlled should be advised not to drive automobiles or other motorized vehicles (36).

There is an anecdotal report of successful use of gabapentin to control cough syncope induced by postnasal drip (03).

Treatment of patients with asthma or chronic obstructive airway disease with a reactive airway component should be directed at aggressive control of bronchospasm (97; 42; 25). Bronchitis should be treated with appropriate antibiotics.

Patients with cough syncope and Chiari malformation may benefit from posterior fossa decompression surgery (58; 27; 112; 114; 39; 49; 83; 91).

Patients with gastroesophageal reflux disease can be effectively treated with proton pump inhibitors (eg, omeprazole, lansoprazole, etc.) and, if necessary, with surgical correction using either a Stretta procedure (a minimally invasive trans-oral endoscopic procedure that delivers radiofrequency energy to the area of the lower esophageal sphincter) or laparoscopic Nissen fundoplication (84; 56; 47). Medical and surgical management of gastroesophageal reflux generally allows patients with resultant cough syncope to return to their premorbid physical and social activities (47).

Patients with cough syncope associated with cardiac arrhythmias may benefit from treatments designed to suppress vagal tone. Such treatments include administration of atropine, procaine block of the vagus nerve in the neck, section of afferent or efferent reflex pathways, or permanent pacemaker implantation (40; 90; 07; 18; 57). In many patients, pacing is considered the safest and most definitive approach. Pacing may prevent symptoms even during paroxysms of severe coughing (90). No randomized controlled trials of pacing have been conducted in patients with cough or other situational syncopes, but results of randomized trials for vasovagal syncope are at best inconsistent (33). Permanent cardiac pacing should generally be reserved for patients with little or no prodrome and significant bradycardia or asystole at the time of syncope who have failed other interventions (72; 33). Other indications can include frequent cardioinhibitory syncope (more than five attacks per year), severe physical injury or accident, and age greater than 40 years (13; 12).

Patients with cough syncope associated with hypersensitive carotid sinus syndrome may benefit from similar treatments to patients with vagally mediated cardiac arrhythmias, including administration of atropine and vasoconstrictors, procaine block of the vagus nerve in the neck, carotid sinus denervation, and in some cases, pacemaker implantation (107). Prevention of the heart rate response by pacing or atropine will not prevent the reflex hypotensive response in patients with both cardioinhibitory and vasodepressor components (107). Some patients with mixed carotid sinus hypersensitivity (eg, with both cardioinhibitory and vasodepressor response patterns) may require treatment with anticholinergic and alpha-adrenergic medications in combination with carotid sinus denervation (107).

Patients with idiopathic hypertrophic subaortic stenosis may benefit from beta blockers through suppression of dynamic ventricular outflow obstruction produced by reflex sympathetic stimulation (109).

Patients with constrictive pericarditis may benefit from pericardiectomy through improvement in diastolic filling (23).

Neurovascular surgery may benefit patients with critical extracranial or intracranial arterial occlusive disease and cough syncope (61).