Indian J Pediatr DOI 10.1007/s12098-013-1305-3
ORIGINAL ARTICLE
Clinical Profile of Pediatric Patients with Long QT Syndrome Masquerading as Seizures Bhavesh Thakkar & Anand Shukla & Tarandeep Singh & Saurin Shah & Shomu Bohora & Jayal Shah & Tarun Madan
Received: 9 April 2013 / Accepted: 7 November 2013 # Dr. K C Chaudhuri Foundation 2014
Abstract Objective To study the clinical profile of patients with long QT syndrome presenting as seizures. Methods Retrospective analysis of six pediatric patients admitted at authors’ institute between October 2008 and January 2013 with seizures and a presumptive diagnosis of long QT syndrome (LQTS) was done. The diagnosis was made on the basis of updated Schwartz diagnostic criteria. Clinical data, investigation profile and follow up of patients was recorded in a standard format and analysed. Results All the 6 patients in the study were boys with a mean age of 10.3±2.8 y at the time of diagnosis. The lag period between symptom onset and diagnosis was 5.6±3.14 y. All patients had history of seizures with a history of precipitating event in 4 patients. Average baseline QTc interval was 556± 41.31 ms. Mean Schwartz score was 6.66±1.16. Polymorphic VT was documented in 4 patients. After initiating standard treatment with betablockers, nicorandil, spironolactone or pacemaker, all the six patients were asymptomatic at a mean follow up period of 17.5 mo, with no recurrence of seizures. Conclusions LQTS can cause seizures due to prolonged ventricular arrhythmias in high risk subgroup. Children, who present with LQTS and seizures, generally have a precipitating event causing seizures, and they respond well to drug therapy.
Keywords Long QT syndrome . Seizures . Torsades de pointes B. Thakkar : A. Shukla : T. Singh : S. Shah : S. Bohora (*) : J. Shah : T. Madan Department of Pediatric Cardiology, U N Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Asarwa, Ahmedabad 380016, Gujarat, India e-mail: [email protected]
Introduction Seizures in childhood are commonly evaluated by neurologists and often considered idiopathic in nature. Ventricular arrhythmias due to congenital heart disease or genetic causes present as palpitations, syncope and seizures, and may have specific precipitating factors. Prolonged ventricular arrhythmia may result in tonic posturing due to prolonged cerebral hypoxia, which may be difficult to differentiate from seizures. Infants and young children cannot describe symptoms of cardiac arrhythmias accurately. Therefore children who have seizures refractory to medications, with specific precipitating factors and no neurological cause should be evaluated for cardiac arrhythmia. Long QT syndrome (LQTS) is a cardiac channelopathy, caused by mutations in genes coding for cardiac ion channel subunits or channel-associated proteins [1], with an increased propensity for arrhythmogenic syncope, polymorphic ventricular tachycardia, and sudden cardiac death [1] and can present early in childhood. Syncope is one of the common manifestations of LQTS. Pediatric patients with LQTS often present with seizures and are frequently misdiagnosed as having epilepsy [2, 3]. The aim of the present study was to evaluate the clinical profile of pediatric LQTS patients masquerading as seizures.
Material and Methods Retrospective analysis of six pediatric patients admitted at authors' institute between October 2008 and January 2013 with seizures and a presumptive diagnosis of LQTS was done. Symptom history, family history, ECG findings, 24 h Holter monitoring, results from exercise or provocative drug testing using epinephrine and follow up data after initiation of treatment were all evaluated. QTc was calculated by averaging QTc using Bazett’s formula, from the lead II rhythm strip [4].
Indian J Pediatr
ECG of all first degree family members was performed. History of similar complaints or sudden cardiac arrest in other relatives was enquired and further investigation was advised if required. Diagnosis of LQTS was based on updated Schwartz diagnostic criteria [5] with a score greater than 3.5, indicating a high probability of LQTS. (Table 1) Individuals were labelled as having definite, possible or no evidence of LQTS based on the Schwartz score. In the absence of genetic testing, reversible causes of QT prolongation were looked for and excluded in all the patients. Treatment was offered in form of betablockers, nicorandil, spironolactone or pacemaker depending on patient’s diagnosis. Clinical data, investigation profile and follow up of patients was recorded in a standard format and analysed. Ethics committee of authors’ hospital approved the study.
Results Between October 2008 and January 2013, 6 children with seizures and a presumptive diagnosis of LQTS and with no reversible cause, were included in the study. Table 2 shows the clinical and ECG features, along with the possible type of LQTS based on these characteristics. All the 6 patients in the study were boys with age ranging between 3 to 13 y at symptom onset, with a mean age of 10.3±2.8 y at the time of diagnosis. Two out of six patients were siblings and had congenital sensorineural deafness. All the six patients had history of seizures. Four patients had history of physical exertion preceding seizures. Other two patients had seizures, even at rest, with no specific precipitating factor, of which one of the patients was noted to have a slow pulse rate, with an ECG revealing prolonged QTc interval and a functional 2:1 AV block. Out of six patients, four were on anti-epileptic medications. Neurological evaluation was normal in four patients, while the 2 siblings had congenital sensorineural deafness. All the patients had QTc prolongation at baseline, with 4 patients having broad based T wave. Corrected QT interval was more than 500 ms in all the patients. Functional 2:1 AV block was seen in 1 patient due to QT prolongation (Fig. 1). Spontaneous T wave alternans was seen in one patient (Fig. 2). Polymorphic VT was documented in four patients, one spontaneous and in three patients it was demonstrated on provocative drug testing (Fig. 3). Table 3 shows the Schwartz diagnostic criteria with calculated Schwartz score for the six patients. Holter monitoring in three patients was nondiagnostic with no evidence of sustained or ill sustained arrhythmia or significant VPCs. Table 4 shows demographic variables, ECG parameters and mean Schwartz score of the patients. Five patients were started on oral beta blockers (tab.metoprolol 1 mg/kg twice daily up to maximum tolerated dose of 2 mg/kg
Table 1 LQTS diagnostic criteria [5] (Updated) LQTS Diagnostic Criteria [5]
Points
Electro cardiac findings A QTca >480 ms 3 460–479 ms 2 450–459 ms (in males) 1 B QTca 4th min of recovery from exercise stress test ≥ 480 ms 1 C Torsade de pointsb 2 D T wave alterans 1 E Notched T wave in 3 leads 1 F Low heart rate for agec 0.5 Clinical history A Syncopeb With stress 2 Without stress 1 B Congenital deafness 0.5 Family history A Family members with definite LQTSd 1 B Unexplained sudden cardiac death below age 30 among immediate family membersd a
0.5
QTc calculated by Bazett’s formula where QTc = QT/✓RR
b
Mutually exclusive
c
Resting heart rate below the 2nd percentile for age
d
The same family member cannot be counted in A and B
Score: ≤ 1 point: Low probability of LQTS; 1.5 to 3 points: Intermediate probability of LQTS; ≥ 3.5 points: High probability of LQTS
twice daily) while one patient was started on oral potassium channel opener (tab nicorandil 0.5 mg/kg twice a day) and aldosterone receptor antagonist (tab spironolactone 25 mg once daily). The patient with 2:1 AV block underwent permanent pacemaker implantation with dual chamber pacemaker and continued on beta blockers (tab metoprolol). Table 5 shows treatment offered and post treatment follow up of the patients. All the six patients were asymptomatic on follow up.
Discussion Seizures in childhood are not uncommon and are generally seen and treated by pediatricians and neurologists. Pseudoseizures include benign paroxysmal vertigo, migraine, syncope (cardiac arrhythmia, vasovagal, orthostatic, structural heart disease with outflow tract obstruction), psychogenic seizures or hyperventilation spells. Syncope generally leads to blackout episodes, complicated by abnormal movements, attributable to generalized cerebral hypoxia. Uncommonly, seizures in childhood can be due to prolonged cerebral hypoxia due to ventricular arrhythmia because of cardiac genetic disorders. Differentiation of cardiac vs. non cardiac etiology is important
Indian J Pediatr Table 2 The clinical and ECG features with the possible type of LQTS Patient Symptom
Age of symptom Neurology onset [Age at evaluation diagnosis (years)]
Patient Baseline ECG morphology on anti- HR epileptics
1
Seizures
11 (13)
+
2
Seizures
6 (13)
WNL
+
3 4 5 6
Seizures, syncope Seizures Seizures, palpitations Seizures, palpitations
5 (7) 6 (7) 3 (10) 3 (12)
WNL WNL SN deafness SN deafness
+ + − −
WNL
due to significant mortality associated with cardiac causes of syncope/seizures. Arrhythmic syncope generally is sudden in onset, with patient becoming cold, clammy and cyanosed and may be associated with preceding palpitations. Genetic disorders leading to arrhythmia in children are LQTS, Brugada syndrome, Short QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC), catecholaminergic polymorphic ventricular tachycardia (CPVT) and rare neuromuscular disorders. Familial history of syncope/seizure like episodes should make one suspicious of a cardiac arrhythmic cause. There may be a precipitating factor for ventricular arrhythmia and syncope like physical stress in LQTS and CPVT, during sleep in LQTS and Brugada or sudden noise in patients with LQTS. Long QT syndrome (LQTS) is a potentially life threatening cardiac channelopathy. Jervell and Lange-Nielsen provided
50
Spontaneous Type of LQTS or Drug (ECG/history) induced VT LQTS 3
72
Broad based T wave with 2:1 Yes AV block Broad based T wave Yes
58 70 92 74
T wave alternans Deep inverted—T waves Broad based T wave Broad based T wave
LQTS 1 LQTS 2 LQTS 1 LQTS 1
Not done Not done Yes Yes
LQTS 1
the first complete description of congenital LQTS in 1957 in a family with four deaf-mute children with fainting spells, sudden death, and prolonged QT interval [6]. This was followed by Romano et al. [7] and Ward et al. [8] independently reporting patients with autosomal dominant cardiac disorder identical to JLN syndrome, but without deafness. QTc prolongation is produced by delayed repolarisation due to loss of function of cardiac potassium (K+) currents, (iKr or iKs) or from prolonged depolarization due to an increase in inward current carried by sodium or L- type calcium channel. Congenital LQTS currently is associated with mutations in 13 different genes, with majority of the known mutations located in the first three types: LQT1 (KCNQ1) 42–45 %, LQT2 (KCNH2 ) 35–45 % and LQT3 (SCN5A ) 8–10 % [9, 10]. Though frequently reported in western literature, LQTS is not uncommon in India and several case reports have been described [11–15].
Fig. 1 Electrocardiogram showing a 2:1 functional AV block due to prolonged QT interval
Indian J Pediatr
Fig. 2 Electrocardiogram showing T wave alternans, especially pronounced in the precordial leads
Patients with LQTS usually come to medical attention during initial years of life or early adulthood [1]. The mean age of symptom onset in the index study was 5.6±2.9 y which is comparable to a large international multi-centre study (mean age 6.8±5.6) [16] and results of the LQTS registry (8±7 y) [17]. The major finding in the index study was the long delay
Fig. 3 Provocative drug testing induced torsades de pointes
in identifying this cardiac disorder and being misdiagnosed as seizures. Four out of 6 patients were on anti-epileptic medications with mean lag period between symptom onset and final diagnosis being 5.6±3.14 y. This lag period was significantly longer as compared to other studies in which syncope was the major manifestation [18] signifying the delay caused
Indian J Pediatr Table 3 Schwartz diagnostic criteria with calculated Schwartz score Patient
QTc (ms)
T-wave alternans
Torsades
Baseline HR
HR (
ORIGINAL ARTICLE
Clinical Profile of Pediatric Patients with Long QT Syndrome Masquerading as Seizures Bhavesh Thakkar & Anand Shukla & Tarandeep Singh & Saurin Shah & Shomu Bohora & Jayal Shah & Tarun Madan
Received: 9 April 2013 / Accepted: 7 November 2013 # Dr. K C Chaudhuri Foundation 2014
Abstract Objective To study the clinical profile of patients with long QT syndrome presenting as seizures. Methods Retrospective analysis of six pediatric patients admitted at authors’ institute between October 2008 and January 2013 with seizures and a presumptive diagnosis of long QT syndrome (LQTS) was done. The diagnosis was made on the basis of updated Schwartz diagnostic criteria. Clinical data, investigation profile and follow up of patients was recorded in a standard format and analysed. Results All the 6 patients in the study were boys with a mean age of 10.3±2.8 y at the time of diagnosis. The lag period between symptom onset and diagnosis was 5.6±3.14 y. All patients had history of seizures with a history of precipitating event in 4 patients. Average baseline QTc interval was 556± 41.31 ms. Mean Schwartz score was 6.66±1.16. Polymorphic VT was documented in 4 patients. After initiating standard treatment with betablockers, nicorandil, spironolactone or pacemaker, all the six patients were asymptomatic at a mean follow up period of 17.5 mo, with no recurrence of seizures. Conclusions LQTS can cause seizures due to prolonged ventricular arrhythmias in high risk subgroup. Children, who present with LQTS and seizures, generally have a precipitating event causing seizures, and they respond well to drug therapy.
Keywords Long QT syndrome . Seizures . Torsades de pointes B. Thakkar : A. Shukla : T. Singh : S. Shah : S. Bohora (*) : J. Shah : T. Madan Department of Pediatric Cardiology, U N Mehta Institute of Cardiology and Research Centre, Civil Hospital Campus, Asarwa, Ahmedabad 380016, Gujarat, India e-mail: [email protected]
Introduction Seizures in childhood are commonly evaluated by neurologists and often considered idiopathic in nature. Ventricular arrhythmias due to congenital heart disease or genetic causes present as palpitations, syncope and seizures, and may have specific precipitating factors. Prolonged ventricular arrhythmia may result in tonic posturing due to prolonged cerebral hypoxia, which may be difficult to differentiate from seizures. Infants and young children cannot describe symptoms of cardiac arrhythmias accurately. Therefore children who have seizures refractory to medications, with specific precipitating factors and no neurological cause should be evaluated for cardiac arrhythmia. Long QT syndrome (LQTS) is a cardiac channelopathy, caused by mutations in genes coding for cardiac ion channel subunits or channel-associated proteins [1], with an increased propensity for arrhythmogenic syncope, polymorphic ventricular tachycardia, and sudden cardiac death [1] and can present early in childhood. Syncope is one of the common manifestations of LQTS. Pediatric patients with LQTS often present with seizures and are frequently misdiagnosed as having epilepsy [2, 3]. The aim of the present study was to evaluate the clinical profile of pediatric LQTS patients masquerading as seizures.
Material and Methods Retrospective analysis of six pediatric patients admitted at authors' institute between October 2008 and January 2013 with seizures and a presumptive diagnosis of LQTS was done. Symptom history, family history, ECG findings, 24 h Holter monitoring, results from exercise or provocative drug testing using epinephrine and follow up data after initiation of treatment were all evaluated. QTc was calculated by averaging QTc using Bazett’s formula, from the lead II rhythm strip [4].
Indian J Pediatr
ECG of all first degree family members was performed. History of similar complaints or sudden cardiac arrest in other relatives was enquired and further investigation was advised if required. Diagnosis of LQTS was based on updated Schwartz diagnostic criteria [5] with a score greater than 3.5, indicating a high probability of LQTS. (Table 1) Individuals were labelled as having definite, possible or no evidence of LQTS based on the Schwartz score. In the absence of genetic testing, reversible causes of QT prolongation were looked for and excluded in all the patients. Treatment was offered in form of betablockers, nicorandil, spironolactone or pacemaker depending on patient’s diagnosis. Clinical data, investigation profile and follow up of patients was recorded in a standard format and analysed. Ethics committee of authors’ hospital approved the study.
Results Between October 2008 and January 2013, 6 children with seizures and a presumptive diagnosis of LQTS and with no reversible cause, were included in the study. Table 2 shows the clinical and ECG features, along with the possible type of LQTS based on these characteristics. All the 6 patients in the study were boys with age ranging between 3 to 13 y at symptom onset, with a mean age of 10.3±2.8 y at the time of diagnosis. Two out of six patients were siblings and had congenital sensorineural deafness. All the six patients had history of seizures. Four patients had history of physical exertion preceding seizures. Other two patients had seizures, even at rest, with no specific precipitating factor, of which one of the patients was noted to have a slow pulse rate, with an ECG revealing prolonged QTc interval and a functional 2:1 AV block. Out of six patients, four were on anti-epileptic medications. Neurological evaluation was normal in four patients, while the 2 siblings had congenital sensorineural deafness. All the patients had QTc prolongation at baseline, with 4 patients having broad based T wave. Corrected QT interval was more than 500 ms in all the patients. Functional 2:1 AV block was seen in 1 patient due to QT prolongation (Fig. 1). Spontaneous T wave alternans was seen in one patient (Fig. 2). Polymorphic VT was documented in four patients, one spontaneous and in three patients it was demonstrated on provocative drug testing (Fig. 3). Table 3 shows the Schwartz diagnostic criteria with calculated Schwartz score for the six patients. Holter monitoring in three patients was nondiagnostic with no evidence of sustained or ill sustained arrhythmia or significant VPCs. Table 4 shows demographic variables, ECG parameters and mean Schwartz score of the patients. Five patients were started on oral beta blockers (tab.metoprolol 1 mg/kg twice daily up to maximum tolerated dose of 2 mg/kg
Table 1 LQTS diagnostic criteria [5] (Updated) LQTS Diagnostic Criteria [5]
Points
Electro cardiac findings A QTca >480 ms 3 460–479 ms 2 450–459 ms (in males) 1 B QTca 4th min of recovery from exercise stress test ≥ 480 ms 1 C Torsade de pointsb 2 D T wave alterans 1 E Notched T wave in 3 leads 1 F Low heart rate for agec 0.5 Clinical history A Syncopeb With stress 2 Without stress 1 B Congenital deafness 0.5 Family history A Family members with definite LQTSd 1 B Unexplained sudden cardiac death below age 30 among immediate family membersd a
0.5
QTc calculated by Bazett’s formula where QTc = QT/✓RR
b
Mutually exclusive
c
Resting heart rate below the 2nd percentile for age
d
The same family member cannot be counted in A and B
Score: ≤ 1 point: Low probability of LQTS; 1.5 to 3 points: Intermediate probability of LQTS; ≥ 3.5 points: High probability of LQTS
twice daily) while one patient was started on oral potassium channel opener (tab nicorandil 0.5 mg/kg twice a day) and aldosterone receptor antagonist (tab spironolactone 25 mg once daily). The patient with 2:1 AV block underwent permanent pacemaker implantation with dual chamber pacemaker and continued on beta blockers (tab metoprolol). Table 5 shows treatment offered and post treatment follow up of the patients. All the six patients were asymptomatic on follow up.
Discussion Seizures in childhood are not uncommon and are generally seen and treated by pediatricians and neurologists. Pseudoseizures include benign paroxysmal vertigo, migraine, syncope (cardiac arrhythmia, vasovagal, orthostatic, structural heart disease with outflow tract obstruction), psychogenic seizures or hyperventilation spells. Syncope generally leads to blackout episodes, complicated by abnormal movements, attributable to generalized cerebral hypoxia. Uncommonly, seizures in childhood can be due to prolonged cerebral hypoxia due to ventricular arrhythmia because of cardiac genetic disorders. Differentiation of cardiac vs. non cardiac etiology is important
Indian J Pediatr Table 2 The clinical and ECG features with the possible type of LQTS Patient Symptom
Age of symptom Neurology onset [Age at evaluation diagnosis (years)]
Patient Baseline ECG morphology on anti- HR epileptics
1
Seizures
11 (13)
+
2
Seizures
6 (13)
WNL
+
3 4 5 6
Seizures, syncope Seizures Seizures, palpitations Seizures, palpitations
5 (7) 6 (7) 3 (10) 3 (12)
WNL WNL SN deafness SN deafness
+ + − −
WNL
due to significant mortality associated with cardiac causes of syncope/seizures. Arrhythmic syncope generally is sudden in onset, with patient becoming cold, clammy and cyanosed and may be associated with preceding palpitations. Genetic disorders leading to arrhythmia in children are LQTS, Brugada syndrome, Short QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC), catecholaminergic polymorphic ventricular tachycardia (CPVT) and rare neuromuscular disorders. Familial history of syncope/seizure like episodes should make one suspicious of a cardiac arrhythmic cause. There may be a precipitating factor for ventricular arrhythmia and syncope like physical stress in LQTS and CPVT, during sleep in LQTS and Brugada or sudden noise in patients with LQTS. Long QT syndrome (LQTS) is a potentially life threatening cardiac channelopathy. Jervell and Lange-Nielsen provided
50
Spontaneous Type of LQTS or Drug (ECG/history) induced VT LQTS 3
72
Broad based T wave with 2:1 Yes AV block Broad based T wave Yes
58 70 92 74
T wave alternans Deep inverted—T waves Broad based T wave Broad based T wave
LQTS 1 LQTS 2 LQTS 1 LQTS 1
Not done Not done Yes Yes
LQTS 1
the first complete description of congenital LQTS in 1957 in a family with four deaf-mute children with fainting spells, sudden death, and prolonged QT interval [6]. This was followed by Romano et al. [7] and Ward et al. [8] independently reporting patients with autosomal dominant cardiac disorder identical to JLN syndrome, but without deafness. QTc prolongation is produced by delayed repolarisation due to loss of function of cardiac potassium (K+) currents, (iKr or iKs) or from prolonged depolarization due to an increase in inward current carried by sodium or L- type calcium channel. Congenital LQTS currently is associated with mutations in 13 different genes, with majority of the known mutations located in the first three types: LQT1 (KCNQ1) 42–45 %, LQT2 (KCNH2 ) 35–45 % and LQT3 (SCN5A ) 8–10 % [9, 10]. Though frequently reported in western literature, LQTS is not uncommon in India and several case reports have been described [11–15].
Fig. 1 Electrocardiogram showing a 2:1 functional AV block due to prolonged QT interval
Indian J Pediatr
Fig. 2 Electrocardiogram showing T wave alternans, especially pronounced in the precordial leads
Patients with LQTS usually come to medical attention during initial years of life or early adulthood [1]. The mean age of symptom onset in the index study was 5.6±2.9 y which is comparable to a large international multi-centre study (mean age 6.8±5.6) [16] and results of the LQTS registry (8±7 y) [17]. The major finding in the index study was the long delay
Fig. 3 Provocative drug testing induced torsades de pointes
in identifying this cardiac disorder and being misdiagnosed as seizures. Four out of 6 patients were on anti-epileptic medications with mean lag period between symptom onset and final diagnosis being 5.6±3.14 y. This lag period was significantly longer as compared to other studies in which syncope was the major manifestation [18] signifying the delay caused
Indian J Pediatr Table 3 Schwartz diagnostic criteria with calculated Schwartz score Patient
QTc (ms)
T-wave alternans
Torsades
Baseline HR
HR (
