Interest of non-invasive and semi-invasive testings in asymptomatic children with pre-excitation syndrome

Abstract

Aims To determine the feasibility and the results of exercise testing (ET) and electrophysiological study (EPS) in outpatient asymptomatic children with a Wolff-Parkinson-White (WPW) syndrome.

Methods and results Exercise testing and transesophageal EPS were performed in 55 outpatient asymptomatic children aged 6 to 19 years old (14 ± 3) with WPW. Wolff-Parkinson-White persisted during maximal exercise. Isoproterenol was not required in five children younger than 10 years old, because they developed a catecholaminergic sinus tachycardia. Maximal rate conducted through accessory pathway (AP) was higher in children younger than 16 years old than in teenagers ( P < 0.05). Atrioventricular re-entrant tachycardia (AVRT) was induced in six children; atrial fibrillation (AF) in 12 children. The induction of tachycardias and the dangerous forms (18%) were not influenced by age. After 5 ± 1 years, one child, 12 year old with inducible rapid AF, had a sudden cardiac arrest; two children became symptomatic after ablation.

Conclusions Transesophageal EPS was required to determine the prognosis of asymptomatic WPW in children. The maximal rate conducted in AP was higher in children younger than 16 years old than in teenagers; other data did not differ. AVRT was rare; 71% of children had no inducible arrhythmia and were authorized to resume physical activities.

Wolff-Parkinson-White syndrome, Children, Electrophysiological study, Exercise testing

Electrophysiological study (EPS) has been proved to be an effective method to evaluate the properties of accessory pathway (AP) and the propensity to develop atrial fibrillation (AF) or other tachycardia in Wolff-Parkinson-White (WPW) syndrome, especially when WPW does not abruptly disappear during exercise test. ^1–3 Intracardiac route is the mainly reported technique used to assess WPW, and recent studies ^4–6 were the first to show that asymptomatic young patients with induced tachycardia and short AP refractory period benefit from the preventive ablation of AP. However, it is sometimes difficult to perform an intracardiac study in young asymptomatic patients. In younger children, anaesthesia is required. ⁶ Ten to twenty years ago, authors reported the contribution of esophageal route to study the supraventricular tachycardia in children, ^7–11 but less is known on the long-term follow-up of these groups.

The purpose of the study was to determine (i) the results and clinical consequences of non-invasive and semi-invasive testing, including exercise testing (ET) and transesophageal electrophysiologic study in asymptomatic children with WPW, (ii) the age of feasibility of the technique in outpatients.

Population and methods

Population of study

Fifty-one patients, aged 6 to 19 years old (mean 14 ± 3) were prospectively studied between 1990 and December 2006. All asymptomatic children were consecutively recruited in our centre, except children younger than 10 years old, who were more recently recruited, after the change of our stimulator.

Overt WPW syndrome was present on surface ECG. Wolff-Parkinson-White syndrome was detected on routine ECG before sportive activity ( n = 18) or during a systematic ECG recording ( n = 26) either before anaesthesia or more frequently in the preventive medicine group. In the case of 11 children, WPW syndrome was detected after birth following auscultation of a systolic murmur; only two children had minor Ebstein's anomaly; two girls had a mild pulmonary valve stenosis without enlargement of right ventricle and other children had a normal heart at the age of evaluation.

Methods

Informed and signed consent was obtained from children and their parents. The study was approved by the ethical committee. The children were not treated.

Non-invasive studies were initially performed including the recording of a 24 h ECG Holter monitoring and an ET on bicycle.

Electrophysiological study was performed in the non-sedated state during a consultation, in one of our rooms devoted to electrophysiology, after clear explanation of the technique. We explained that two difficulties would be encountered: at first, the nausea reflex when the catheter is introduced, and, secondly, the oppression or the mild pain provoked by esophageal pacing. For the younger children, invasive procedure was offered as an alternative method of evaluation.

Esophageal catheter (Fiab catheter, Ela medical, France) was introduced through the oral cavity.

The children were leaving hospital after EPS. Those children who had induced atrial arrhythmias were monitored until restoration of sinus rhythm and discharged afterwards.

Our protocol was previously reported. ^12–14

Twelve lead surface electrocardiograms and esophageal electrogram were simultaneously recorded (Midas/Marquette-Hellige and, then, Bard system). Cardiac stimulation was initially performed with a programmable stimulator (Explorer 2000, Ela) which was connected to an Ela pulse amplifier that can deliver pulses of 16 ms duration with a 10–29 mA output (mean 17 ± 5 mA). The biphasic stimulator (Micropace, Bard, France) was then used. Pulses of 10 ms duration were used; output varied from 9 to 20 mA (mean 11 ± 2 mA). The pacing site was defined by the amplitude of atrial electrogram and by research of an optimal esophageal site where tolerance was defined by minimal pain.

Incremental atrial pacing was performed until second-degree atrioventricular block occurred. This pacing was not used in children younger than 10 years old to avoid anxiousness and pain. Programmed atrial stimulation at a basic cycle length of 600 and 400 ms with introduction of one and two extra stimuli was performed. The effective refractory period of AP was determined. When a rapid supraventricular tachycardia was induced, the protocol was stopped.

In the absence of induction of a tachycardia conducted through the AP at a rate higher than 250 bpm and in the absence of a spontaneous sinus tachycardia, isoproterenol (0.02–1 µg/min) was infused in order to increase the sinus rate to at least 130 bpm and the pacing protocol was repeated. ^{15 , 16}

Definitions

• Sustained AF or reciprocating tachycardia was defined as a tachycardia exceeding 1 min.

• Conduction over the accessory atrioventricular connection was evaluated by measuring the shortest atrial cycle length for which there was 1 to 1 conduction over the accessory connection and the shortest atrial tachycardia cycle length for which there was 1 to 1 conduction over the accessory connection.

• The WPW syndrome was considered a risk of sudden death when the following association was observed: the shortest RR interval between pre-excited beats was <250 ms in the control state or <200 ms during isoproterenol infusion ¹⁶ and sustained AF was induced.

Follow-up

Only asymptomatic patients recruited between 1990 and 1995 were followed without treatment; sport recommendations were given. Competition was prohibited. Sport at school was authorized except endurance training. After this date, the ablation of AP was indicated in patients considered to have a form at risk of sudden death (induction of AF with short cycle lengths conducted by AP), except in children of small size or with a possible anteroseptal location of AP; in this last case, the risk of AV block was considered too high in children. They were initially treated medically with flecainide and β-blockers.

Statistical analysis

Data were expressed as the mean ± standard deviation. Statistical analysis used the Student's paired t- test for quantitative data and the χ ² test for discrete variables and ordinal tests. A P -value < 0.05 was considered as significant.

Results

Results of non-invasive studies

The WPW syndrome remained present during ET at the maximal heart rate for all children. For some children, the interpretation of ECG was difficult during maximal sympathetic activation, because the normal atrioventricular conduction was enhanced and the pattern of WPW was less evident. No arrhythmia was induced.

There were no significant changes neither in QRS morphology nor arrhythmias recorded during the 24 h Holter monitoring. Only episodes of sinus tachycardia were noted on Holter monitoring during daily activities.

No clear conclusions could be drawn from these investigations.

Feasibility of esophageal electrophysiological study during a consultation

One 10-year-old child refused the esophageal catheter at the beginning of the study and was not included in the population. In this case, the intracardiac study could be performed only after general anaesthesia. In all other children, the prognosis evaluation of WPW syndrome could be performed by esphageal study. The chest pain provoked by esophageal pacing was rare, but anxiety was frequent. For these children, a significant acceleration of sinus rhythm compared to the ECG recorded before the introduction of the catheter was noted and the sinus tachycardia persisted during esophageal pacing until the end of the study. A mild pain was noted when atrium was paced at high rates, especially when isoproterenol was used. Then, we avoided high rates in the younger children and only used a programmed atrial stimulation.

Isoproterenol infusion was not used in the case of three children, who had criteria of a dangerous form in basal state (shortest RR interval between pre-excited beats was < 250 ms) and in five children younger than 10 years old. The reason was an anxiety with a spontaneous and permanent sinus tachycardia (from 140 to 160 bpm) during the programmed atrial stimulation in control state.

All children were discharged after the study. However, the injection of flecainide was required for children to whom AF was then induced and persisted for 15 min. Sinus rhythm was obtained and the children were discharged.

The mean time required to evaluate WPW syndrome varied from 3 min to 1 h (mean duration 15 ± 12 min).

No X-rays were used.

Results of electrophysiologic study ( Table  1 )

• The nature of the AP was first assessed. The pre-excitation syndrome was related to an atrioventricular accessory connexion (Kent bundle) in the case of 53 children and was related to a nodoventricular AP for two children.

• The location of the AP was performed in maximal pre-excitation during atrial pacing and on a 12 lead ECG. ^{17 , 18} This was particularly important in the case of children with undetermined location of the AP in sinus rhythm, to detect a possible anteroseptal location. Furthermore, those with a left lateral pre-excitation frequently present minor signs of pre-excitation in sinus rhythm. Atrioventricular AP was left lateral for 9 children, left posteroseptal for 8 children, right posteroseptal for 21 children, right lateral for 5 children, and anteroseptal in the case of 10 children.

• Atrioventricular re-entry tachycardia (AVRT) was induced in the case of six children (11%) ( Figure  1 ). Tachycardia was induced in control state in the case of three children and required isoproterenol infusion in remaining children. The AVRT induced was the same tachycardia felt by four out of six children during sportive activity. Tachycardia was well-tolerated, spontaneously stopped. It was not really possible to be certain if they ever had these arrhythmias.

• Atrial fibrillation lasting more than 1 min was induced in the case of 12 children (22%). Isoproterenol infusion was required in the case of three children. AF less than 1 min was not induced.

• Two children had inducible antidromic tachycardias ( Figure  2 ) after isoproterenol, but they also had induced AF.

• The maximal rate conducted through the AP was 189 ± 59 bpm in the basal state and 240 ± 66 bpm after isoproterenol infusion.

• Ten cases of dangerous APs (18%) associated a rapid conduction in AP (cycle length shorter than 250 ms in control state or than 200 ms after isoproterenol infusion) and the induction of AF. The pre-excitation of the remaining children was considered without risk of severe events.

• Thirty-nine children (71%) had a benign form with no induction of a supraventricular tachycardia and a relatively long effective refractory period of the accessory pathway (>240 ms in control state and >200 ms after isoproterenol infusion).

Figure 1

Determination of accessory pathway refractory period by programmed stimulation. Induction of a re-entrant tachycardia at a coupling interval of 230 ms.

Figure 2

Induction of antidromic tachycardia by premature atrial extra stimulus.

Table 1

Clinical and electrophysiological data of the study group according to the age

	Age
	6–10 year	11–15	16–19
n	10	20	25
Age	8 ± 1	13 ± 1.5	17↑ ± 1
AP location
Right	6	15	15
Left	4 (40%)	5 (25%)	10 (40%)
Male	7 (70%)	8 (40%)	16 (64%)
Sinus CL at the time of EPS	405 ± 65*	610 ± 110**	700 ± 190
AVRT	1 (11%)	3 (16%)	2 (9%)
AF	0	8 (40%)	4 (16%)
Mean CL in AP in CS	332 ± 116 ms	315 ± 107 ms	393 ± 159 ms
Maximal rate in AP in CS	197 ± 54 bpm	207 ± 55 bpm	177 ± 64 bpm
Mean CL in AP after iso	311 ± 70 ms	241 ± 63.5 ms	282 ± 96 ms
Maximal rate in AP after iso	225 ± 79 bpm	262 ± 59 bpm	227 ± 69 bpm
Dangerous form	0	6 (30%)	4 (16%)

AP location: accessory pathway location: L, left (left lateral or left posteroseptal); R, right (right lateral or anteroseptal or midseptal or right posteroseptal-sided or Mahaim AP); sinus CL at the time of EPS, mean sinus cycle length in basal state during electrophysiological study; AVRT, atrioventricular re-entrant tachycardia; AF, atrial fibrillation; mean CL in AP in CS, mean shortest cycle length conducted by AP in control state; mean CL in AP after iso, mean shortest cycle length conducted by AP after isoproterenol infusion; dangerous form, rapid conduction in AP >240 bpm in control state (CS) (cycle length < 250 ms) or > 300 bpm after isoproterenol (cycle length < 200 ms)+ AF induction.

* P < 0.001, ** P < 0.05.

Differences in protocol and results of electrophysiological study related to the children's age

In most 6–9-year-old children, the protocol was shortened because the children developed a spontaneous sinus tachycardia. Only a basic cycle length of 400 ms (or slightly less) was used and isoproterenol infusion was not required to evaluate the effects of adrenergic tone. Therefore, the duration of procedure was very short.

No statistical differences in the results of EPS between the children of 6 to 10 years old and children older than 10 years ( Table  1 ) were found. However, we could not induce AF in children 6 to 10 years old. The differences with children older than 10 are hardly relevant. We noted a significantly higher maximal rate conducted through the AP in control state in children aged 6 to 15 than in children aged 16 to 19 (204 ± 54 bpm vs. 177 ± 64 bpm, P < 0.05). No significant differences were observed as concerns the induction of arrhythmias and the number of dangerous forms ( Table  2 ).

Table 2

Similar clinical and electrophysiological data in children younger than 16 years old and in teenagers older than 15

	Age
	6–15 year	16–19	P
n	30	25
Age	11.5 ± 2.6	17 ± 1
AP location
Right	21	15	NS
Left	9 (30%)	10 (40%)
Male	15 (50%)	16 (64%)	NS
Sinus CL at the time of EPS	547 ± 85	700 ± 190	<0.01
AVRT	4 (13%)	2 (8%)	NS
AF	8 (27%)	4 (16%)	NS
Mean CL in AP in CS	321 ± 108 ms	393 ± 1598 ms	< 0.05
Maximal rate in AP in CS	204 ± 54 bpm	177 ± 64 bpm	< 0.05
Mean CL in AP after iso	256 ± 69 ms	282 ± 96 ms	NS
Maximal rate in AP after iso	254 ± 63 bpm	227 ± 69 bpm	NS
Dangerous form	6 (20%)	4 (16%)	NS

Follow-up

Follow-up varied from 1 to 10 years (average 5 ± 1).

Accessory pathway catheter ablation was performed in the case of 8 out of 10 children with a potentially dangerous form or inducible AV re-entrant tachycardia. Catheter ablation was not performed in one 12-year-old child, who had been recruited at the beginning of the study. The study had shown a short AP refractory period in control state ( < 200 ms) and AF rapidly conducted through the AP (more than 300 bpm) was induced by two extra stimuli in control state. No re-entrant tachycardia was induced. This patient did not take any drugs and had a sudden cardiac arrest when he was running with other children. He was resuscitated with neurological sequelae; catheter ablation of the AP was performed after this event.

Two asymptomatic boys who risked dangerous arrhythmias became symptomatic after the successful ablation of a left lateral-sided AP. The surface ECG remained without pre-excitation, but they developed atrioventricular re-entrant tachycardias (AVRTs). ¹⁹ Catheter ablation of AP was repeated with success in one of them and the other one refused a repeated ablation procedure.

Another child with a potentially dangerous form and anteroseptal location of AP was treated with flecainide.

One child with negative study had non-sustained paroxysmal re-entrant tachycardias during a pregnancy, 6 years later. The second electrophysiologic study performed after the pregnancy, obtained results, which were identical to the first one. No sustained tachycardias were inducible and the refractory period of the AP was long.

All other patients remained asymptomatic and most of them now practice a normal sportive activity.

Discussion

The evaluation of WPW syndrome is recommended, because some rare cases of sudden deaths were reported as the possible first event of the abnormality. ^20–24 Electrophysiological study was proved as an effective method to evaluate the properties of AP and the propensity to develop AF or other tachycardia in WPW syndrome. ⁷ Furthermore, recent studies ^4–6 reported that asymptomatic young patients with induced tachycardia and short AP refractory period benefit from the preventive ablation of AP.

Classical non-invasive studies, 24 h ECG monitoring and ET, ^1–3 were not useful in our study to evaluate the prognosis of WPW syndrome. Electrophysiological study was required. The study was performed by transesophageal route without hospitalization. Several years ago, these studies were performed by conventional catheterism.

However, the esophageal route offers several advantages. First, the child and the parents can choose an afternoon without school and hospitalization is avoided. Parents can be present. In some other clinics, catheterism can be performed in an outpatient, but this is not the case in our hospital. Such a patient needs at least a day of hospitalization with a higher cost than a consultation. ²⁵ Second, we avoid risks related to anaesthesia and catheterization. X-rays are not used. Sedation used for catheterization can mask the effects of catecholamines on the electrophysiological properties of AP and the induction of tachycardia. ^{15 , 16 , 26} Pappone et al . ⁶ reported catheterism-related complications in 5 of 165 patients (3%). Radiation risk in pediatric cardiac catheterization is high. Third, the laboratories equipped for EPS are now largely used for interventional catheterization, either interventional techniques in congenital heart disease in the case of children or arrhythmias radiofrequency ablation, which are time-consuming. The duration of the esophageal study is shorter than invasive study and study can be performed after invasive studies. Fourth, the quality of data obtained by esophageal study was previously assessed by comparison of both routes of evaluation. ^{12 , 13} Then the results were confirmed in our experience by a second conventional procedure indicated for ablation in the case of children who required radiofrequency ablation of AP. In most cases, AP location is easy by esophageal study and confirmed by ablation. We establish the nature of AP and detect forms at risk of sudden death. The lower incidence of AF induction in the present study than in other studies ⁶ was related to the esophageal route. Atrial fibrillation is easily induced during intracardiac studies by rapid atrial stimulation and is not specific. ¹³

The detection of asymptomatic patients at risk of severe arrhythmic events is important. Previous studies ^{20–24 , 27} have shown that the ventricular fibrillation can be the first event in the history of WPW syndrome. Respectively, < 10, ²⁸ 26, ²² and 53% ²¹ of patients resuscitated of ventricular fibrillation were asymptomatic before this event. Most sudden deaths occur during exercise. ^{20–24 , 27} However, the risk of ventricular fibrillation remains rare in the general population with a WPW syndrome ²⁸ and the methods used to detect these patients should be without risk. Value of intracardiac EPS in asymptomatic subjects was initially reported as low in many studies, ^29–33 but a recent large prospective study of Pappone et al . ⁴ reported the interest of EPS in 212 patients with asymptomatic WPW syndrome aged 7 to 63 with 3 deaths occurring in young adults. For the first time, they also noted the interest of prophylactic ablation of AP ^{5 , 6} in asymptomatic WPW syndrome when atrioventricular reciprocating tachycardia or AF was induced, either on adults ⁵ or on children. ⁶ Catheter ablation was also recommended by Vignati ³¹ but in symptomatic children older than 12.

The present study confirms some data. First, sustained AVRT could not be induced in most asymptomatic children. Re-entrant tachycardia was not induced by Milstein et al . ³² and was induced in only 3 out of 40 patients (8%) in our previous study. ³³ It probably explains why these patients were asymptomatic. Similar incidence (15%) was noted by Pappone. ⁴ Recently, Sarrubi et al . ³⁴ reported an unusual rate of AV re-entrant tachycardia induction, which differs from the present study; ³⁴ 33 of 62 children had inducible orthodromic re-entrant tachycardia (53%).

Atrial fibrillation was not induced in children younger than 10, but was induced in 18% of remaining population. Vignati et al . ³¹ reported a highest potential to induce AF in children older than 12 than in those younger than 6. The latter children were not studied in the present survey. AF is easily induced during intracardiac studies by rapid atrial stimulation and is not specific: ¹³ AF is induced in 27%, ³⁵ 41% ³⁶ to 56% ³⁷ of asymptomatic patients and 95% ³³ of those with documented AF. ²⁹ Induction was rarer (from 10 to 30%) with esophageal stimulation and related to the age of asymptomatic patients. ¹⁴ In the case of patients with documented AF, it was possible to induce tachycardia with a sensitivity of 95%. ¹³ Therefore, there is a better specificity without loss of sensitivity than for intracardiac stimulation.

Spontaneous malignant form of WPW syndrome in young children in the literature is rare; two 10-year-old children in the Pappone's study, ⁶ one 10-year-old boy in Pagis's study, ³⁸ and one 12-year-old boy in our study. One sudden death in a 8-year-old boy was reported by Sarubbi et al . ³⁴ Nevertheless, data on clinical condition and electrophysiologic study were unknown in the case of Sarubbi et al . ³⁴ Sudden deaths in young children could also have been missed, because WPW syndrome was unknown.

Sudden death in young children is relatively rare. So, prophylactic ablation in young asymptomatic children remains debatable, ^39–41 because they present higher risks than in the case of adults related to catheterism, ablation, ^42–44 and radiation. ⁴⁵ Adverse events are particularly frequent in those children with anteroseptal AP, with a high risk of iatrogenic complete atrioventricular block. ⁴⁴

Limitations of the study

The age of 10 which was usually considered as the limit for an evaluation by esophageal study without sedation ⁴⁶ could appear debatable. Operator experience was also probably important. Failures of our esophageal studies in the general population occurred in the first recruited patients.

The incidence of inducible atrioventricular re-entry tachycardia could be higher because ventricular pacing was not performed and some inductions by ventricular stimulation could have been missed. However, in a comparison of both routes of evaluation with ventricular pacing performed during catheterism, we did not find any differences as concerns the induction of AVRT by esophageal or intracardiac pacing. ¹³

The study is not a randomized, since it is not possible now to avoid the preventive catheter ablation of the AP when a rapid AF is induced.

Another limitation was the relatively low number of children recruited in our single centre. We therefore could not find any statistical differences in the results of investigations in children younger than 10. But in this short group, no malignant form was found. An inferior limit of age for the indication of systematic EPS clearly remains to debate. There is a very low risk of event.

Children, with a potentially serious form of pre-excitation, required hospitalization to perform in a second time the catheter ablation of the AP. They represented < 30% of this population.

In conclusion, esophageal EPS was performed without sedation during a visit in asymptomatic children since the age of 6; the technique was rapid, cheap, and without risk of catheterism or radiation. Re-entrant tachycardia was rarely induced. Benign forms were identified in 71% of asymptomatic children and sport was authorized. Moreover, some children had misdiagnosed symptoms and the term of asymptomatic should be used carefully in children who frequently had difficulties to differentiate a normal event from a pathological situation. Therefore, we recommend to indicate esophageal electrophysiologic study in all asymptomatic children with WPW syndrome to evaluate the prognosis.

Conflict of interest : none declared.