Vagal Asystoles in a Boy With Prader-Willi Syndrome

A 10-year-old boy with PWS presented to our department of pediatric cardiology for evaluation of possible pacemaker therapy after recurrent episodes of arrhythmia.

The patient was moderately obese. His medical conditions included hypothyroidism treated with levothyroxine and arterial hypertension that had been effectively treated with an angiotensin-converting enzyme inhibitor for ∼3 years. During an inpatient admission for pneumonia at an external hospital, monitoring via pulse oximetry had demonstrated arrhythmias. Subsequent inpatient as well as outpatient electrocardiogram (ECG)-monitoring had revealed episodes of bradycardias (∼30 beats per minute) and sinus arrests that lasted up to 6 seconds without syncope, dizziness, or palpitations.

The obese boy (BMI 24.2, 97th–99th percentile) appeared to be in overall good condition. Clinical examination (Table 1), initial 12-lead ECG, echocardiography, exercise testing, and blood analysis (including brain natriuretic peptide) revealed normal results (Table 2) and structural heart disease was excluded.

During 24 hours of inpatient monitoring, the boy was completely asymptomatic while having experienced various bradycardias and asystoles of up to 6 seconds duration (Fig 1, Table 2). Interestingly, these arrhythmias could be provoked by vagal stimulation via drinking fluid (large quantities of apple juice at room-temperature to rule out atrioventricular block caused by drinking cold liquids) or eating hot soup (large gulps) (Fig 2). ECG changes could not be provoked by usual vagal stimuli, such as fast movement of the head, Valsalva maneuver, or massage of the carotid sinus.

A subsequent ambulatory 9-day holter ECG (nuubo) detected multiple asystoles in daily life of 5 seconds or shorter with missing P-waves, followed by restoration of normal sinus rhythm; this only happened while imbibing large liquid boluses (eg, of apple juice). Heart rate and circadian variability were normal, and no tachycardia or other arrhythmias occurred (Table 2). We excluded other likely causes of sinus pauses including hypothyroidism, cardiac inflammation or failure, and drug effects. The most likely diagnosis was deemed to be vagal-induced atrioventricular block (short sinus pause with reappearance of P-waves without atrioventricular [AV]-conduction or escape rhythm and then full AV-conduction [Fig 3]). Because the patient was asymptomatic, no pacemaker therapy was initiated at this point.

After 3 months, the patient presented again after having suffered an unobserved syncope during break time at school, where he had been running around with friends. We suspected an underlying sinus pause, provoked either by drinking fluid at the time of the physical activity or by another mechanism of vagal stimulation, such as fast movement of the head, Valsalva maneuver, or even physical activity itself. His mother furthermore reported several near syncopes (acute impairment of consciousness with absent gaze) when he had rapidly gulped large boluses of fluids.

Because 24 hour-monitoring again showed multiple asystoles (now lasting up to 7 seconds) associated with signs and symptoms, a ventricle-ventricle-inhibition pacemaker with a backup rate of 50 beats per minute was implanted. In consultation with our specialists, no electrophysical examination was performed, because results would not have changed clinical management. Development of syncopal episodes was a clear indication for pacemaker therapy regardless of the location of the blockage. Unfortunately, electrophysical examination could not be performed in the course of pacemaker implantation. Furthermore, no genetic testing or any further diagnostic investigations were performed because we judged that these would not affect treatment.

The patient recovered quickly and was discharged 2 days later. Subsequent examinations 1 and 4 months after the implantation showed adequate function of the device and the patient reported no further syncopal or near syncopal events. Since then, the patient has been monitored biannually by his resident pediatric cardiologist, who will admit him to our department in the event of medical complications or need for a battery replacement.

Our patient presented with asymptomatic arrhythmias while being monitored during an inpatient admission for pneumonia. Because there was no diagnostic evidence of an underlying structural abnormality and ECG changes were not linked to clinical symptoms, there was no initial indication for treatment. When the recurrent pauses and asystoles, which could be provoked by rapidly drinking large amounts of fluid, produced clinical signs and symptoms, initiation of pacemaker therapy eliminated further clinical sequelae.

An increased risk for cardiovascular morbidity and mortality, including sudden death, is well established in adult patients with PWS. Among adults, cardiovascular conditions are mainly attributable to obesity and diabetes mellitus, such as early onset of coronary artery disease with myocardial infarction.^6,9 

Although we could not find reports of children with pediatric cardiac malformations or diseases directly attributable to PWS, evidence is accumulating about subclinical structural and functional abnormalities in children with PWS at an early age.^7,10,13  Although conventional echocardiography does not show substantial functional or structural alterations,^10,13  Marcus et al identified significant subclinical systolic myocardial dysfunction in children with PWS by strain imaging.¹⁰  Patel et al furthermore determined elevated hs-C-reactive protein levels in pediatric patients with PWS compared with healthy controls, which are a potential marker of early coronary artery disease.¹³  Kobayashi et al recently confirmed these subtle abnormalities in young adults with PWS, suggesting that these changes might begin at an early age.⁷ 

In our patient, the asymptomatic sinus arrests followed by syncope could only be provoked by imbibing exceptionally large boluses of fluids. The phenomenon of vagotonia has long been described in healthy children, some of whom suffer syncopal episodes associated with physical exercise, falls, or even temper tantrums.¹⁴  Swallow syncopes in particular are a rarely described phenomenon, resulting from an exaggerated cardio-inhibitory vagal reaction to esophageal distension that most commonly produces atrioventricular blockage or sinus node dysfunction.¹⁵  Sinus arrests are, however, more common in patients older than 60 years with mainly gastrointestinal conditions, but may also occur in the context of obesity, arterial hypertension, and diabetes mellitus. To date, no case has been associated with a syndromic disease such as PWS.¹⁵  Cardiac autonomic imbalances in patients with PWS have, however, been described and underline an increased cardiovascular risk even in childhood. These imbalances are presumed to be because of parasympathetic deficiency with impaired baroreflex.^16–18  Furthermore, Marcus et al found potentially arrhythmogenic ECG alterations, such as first degree atrioventricular block and prolonged QT-intervals, in some patients with PWS.¹⁰  Patel et al described a similar case of a 15-year old boy with PWS and incidental asymptomatic sinus pauses lasting nearly 5 seconds during their examinations, which were subsequently treated with pacemaker therapy. In contrast, the sinus pauses were shorter than in our patient (4.8 seconds vs 7.4 seconds) and were not described as provocable or reproducible. The boy described by Patel et al was diagnosed with sinus node dysfunction (SND). Whereas we did not perform electrophysical examination so as to exclude SND with full confidence, results of the routine ECG did not suggest SND and the ECG abnormalities documented cannot be explained by SND alone. Vagal stimulation induced the short sinus pauses, followed by returning sinus function with reappearing P-waves and normal AV-conduction shortly thereafter. This suggests sinoatrial and/or atrioventricular block as contributing factors to the underlying pathology.^13,14  We could not find literature that addressed potential mechanisms of vagal asystole specifically among PWS patients. These patients seem to be at high risk because their eating disorder is characterized by ingestion of very large boluses of various foods. Hyperphagia results in rapid intake of solid food and liquid. Pharyngeal muscle hypotonia in patients with PWS may facilitate ingestion of large sequential boluses of solid food and liquid that are more likely to cause extensive distension and accentuate a vagal reaction. Reports of unexplained sudden deaths among children with PWS suggest the possibility of cardiac etiologies such as arrhythmias. The risk of possible cardiac disorders such as arrhythmias among children with PWS is not well appreciated among clinicians.^4,5,8,11,12 

Our case suggests that patients with PWS may have an increased risk of cardiovascular morbidity and mortality at an early age. In addition to early and aggressive therapy of known cardiovascular risk factors including obesity and diabetes mellitus, we suggest that screening of children with PWS for risk of significant arrhythmias using noninvasive and cost-efficient diagnostic tools (Holter monitoring, vagal provocation and stimulation) should be evaluated.^7,10 

• Patients with PWS are at an increased risk of cardiorespiratory morbidity and mortality compared with healthy controls.

• There is evidence not only for subtle structural and functional cardiac alterations but also the occurrence of subclinical arrhythmias in childhood.

• Autonomic dysfunction including abnormal vagal reaction to swallowing may exist in patients with PWS and eventually manifest as syncopal episodes.

• In addition to aggressive treatment of obesity and obesity-related cardiovascular risk-factors, we suggest the evaluation of the value of periodic cardiologic assessment of children with PWS (including long-term ECG and vagal provocation and stimulation) for risk of significant arrhythmia.

AV

atrioventricular

ECG

electrocardiogram

PWS

Prader-Willi syndrome

SND

sinus node dysfunction