We described in detail the clinical features and prognosis of 10 children diagnosed as VVS with sinus arrest. The most crucial finding was that VVS patients with sinus arrest were younger and had good prognoses without pacemakers.
Epidemiological surveys showed that the age of onset of syncope has two peaks at teenage and ༞ 60 years. VVS is the most common underlying cause of neurally mediated syncope and is more prevalent in females than males. In our research, the foundation was different from above due to the younger median age of patients, and lack of gender difference. A previous study showed that the risk of syncope is inversely related to the BMI of college students and the morbidity of VVS significantly increases when BMI <18.5 kg/m2 [8]. No related study reports on the BMI characteristics of preschool and school-age children. In our study, it was showed that 90% cases’ BMI was in normal range. Therefore, the physical examination of children with syncope should be noticed, and the likelihood of VVS diseases shouldn’t be ignored in normal BMI children.
Since the mechanism of intra-sinus wandering pacemaker may be related to high vagal tone, the result above suggested that the vagal tone of 50%(5/10) cases was higher; but this finding contradicted the conclusion of Stanczyk’ study[9], in which the VVS children had increased sympathetic nerve impulses and decreased vagal tones. Even so, no significant difference was found between the baseline heart rate variability (HRV) of asymptomatic VVS patients and healthy children[10]. Previous studies had shown that HRV varies with age and is related to sex and race[11, 12], but there is no international recognized reference value. Further studies concerning the difference in autonomic nerve function between VVS patients with or without sinus arrest under rest stage are still needed.
In our study, premonitory signs and symptoms were consistent with previous studies among pediatric VVS patients. The ECG, the cardiac functions, and the lung functions were normal, despite the chest tightness as the main precursor in case5 and the repeated palpitation during syncope in case10. Thus, it seems that children with chest tightness and palpitations should also be distinguished from VVS. Nausea and vomiting was presented before losing consciousness in four cases and after recovery of consciousness in three cases. This clinical feature is consistent with the results of Heyer’s studies, which stated that the gastric dysrhythmia during tilt-induced syncope consisted of a high amplitude bradygastria with a tachygastria component that began well before syncope and continued for several minutes during recumbent recovery, followed by attenuation of amplitudes. This is because the nausea is temporally associated with changes in gastric myoelectrical activity as well as increased serum concentrations of vasopressin and epinephrine. [13]The time of losing consciousness in this study was recorded mainly based on the information provided by witnesses, but this information may be inaccurate, because the onset of syncope only lasts for several seconds, and in a stressful state, the time of losing consciousness is usually described as the time of the entire syncopal episode. Children who did not provide detailed information may be associated with a short period of syncope, which wasn’t observed or valued.
As for treatment, all children were given health education and basic treatments. But not all children had good patient compliance. In this paper, the children’s drug treatment referred to the clinical studies for recurrent syncope. A trial in adults showed that metoprolol is effective for preventing recurrence of malignant VVS in adults[14]. Although metoprolol may be effective in children[15], the mechanisms of action of metoprolol in malignant VVS in children and the prognosis of treated patients remain unclear. In our study, 2 of 10 cases took metoprolol, and one of them occurred prodromal symptoms during the follow-up period. In addition, a previous study in our center indicated that platelet 5-hydroxytryptamine(5-HT) is higher in HUTT-positive VVS children, which suggested that the central serotonergic system might be involved in the pathogenesis of VVS. Sertraline hydrochloride was proved to be effective in preventing recurrent neurocardiogenic syncope in children with refractory VVS with recurrent syncope. Likewise, a previous trial showed that selective serotonin reuptake inhibitors (SSRIs) were effective and well-tolerated in the treatment of recurrent refractory VVS in adults[16]. Also, adult depression and anxiety are proved to be independent risk factors for VVS patients[17], which provided a rationale for using SSRIs in the treatment of VVS. Even so, the effectiveness of SSRIs in children with malignant VVS is still uncertain. In this study, 5 of 10 cases took sertraline hydrochloride, no one developed syncope during the follow-up period. Lastly, studies on adult malignant VVS proved that pacemakers are effective in elderly patients. A recent study found that in patients aged 40 years or older, who are affected by severe recurrent vasovagal syncope and tilt-induced asystole, dual-chamber pacemaker with closed-loop stimulation(CLS) is highly effective in reducing the recurrences of syncope.[18] Studies on the treatment of VVS children with cardiac arrest remain elusive, we found only two reports on the use of pacemakers in children with neurally mediated syncope complicated by sinus arrest. The number of cases of the two articles was 12 and 11, respectively. In the study of 12 children aged 2~14 years (median age: 2.8 years), patients had 10~40s sinus arrest in cardiac monitoring and the symptoms improved after pacemaker installation[19]; in the other study about 11 pediatric patients (0.8~17 years, median age: 2.7 years) with sinus arrest(11.2~21s), cardiac pacing also reduced syncope episodes [20]. Both studies showed that the installation of a pacemaker reduces the incidence of neuro-mediated syncope with sinus arrest in children.[18, 19] But neither of these studies classified syncope, and VVS children with sinus arrest were not analyzed. In a case report of a 17-year-old boy with severe cardioinhibitory VVS, the installation of a pacemaker reduced the incidence of syncope.[21] In another case report, however, a 16-year-old boy had recurrent syncope caused by blood-injury phobia, which was improved with cognitive behavioral therapy and did not require a pacemaker.[22] In the current study, children diagnosed VVS and sinus arrest were included without pacemaker installation, and only one child has once syncope occurred during the follow-up period. Based on the evidence above, pacemakers should be carefully installed in syncope patients with incomplete autonomic nerve development and children with VVS with sinus arrest.
Of note, case 10 had an early age of onset and was misdiagnosed as epilepsy due to the presence of stiffness of the limbs during syncopal episodes and the occasional trembling of the limbs; these symptoms were not improved by 6 years of anti-epileptic treatment. The patient was diagnosed as malignant VVS after implementation of HUTT. Therefore, children with epilepsy who respond poorly to drug treatments should be recommended to use HUTT to identify VVS. Also, attention should be paid to the differential diagnosis of children with syncope at a young age of onset. Further research is warranted to strengthen our understanding of underlying mechanisms of VVS, which may be associated with abnormal Bezold–Jarish reflex, dysfunction of the autonomic nervous system, neuro-humoral factors, etc.
Limitations of the study include the small number of patients and the short time follow-up. In addition, the present study was retrospective and observational, and the medical treatments of cases were different. Consequently, the efficacy of drugs on prognosis needs to be studied further by randomized controlled trials.