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 , with an increased propensity for arrhythmogenic syncope, polymorphic ventricular tachycardia, and sudden cardiac death  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 .
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  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
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
QTc calculated by Bazett’s formula where QTc = QT/✓RR
Resting heart rate below the 2nd percentile for age
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
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
Spontaneous Type of LQTS or Drug (ECG/history) induced VT LQTS 3
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
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 . This was followed by Romano et al.  and Ward et al.  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
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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 . 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)  and results of the LQTS registry (8±7 y) . 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  signifying the delay caused
Indian J Pediatr Table 3 Schwartz diagnostic criteria with calculated Schwartz score Patient
HR (<2nd percentile)
Notched T waves
Syncope (with exertion)
Syncope (without exertion)
F/H (definite LQTS)
F/H (Sudden death)
1 2 3 4 5 6
540 520 510 600 560 610
− − − + − −
+ + − − + +
50 72 58 70 92 74
+ − + − − −
+ − − − − +
− + + − + +
+ − − + − −
− − − − + +
− − − − − −
− − − − + +
7.5 7.0 5.5 5.0 7.0 8.0
by misdiagnosis of LQTS as epilepsy, which reflects the lack of awareness regarding the need for early cardiac evaluation in such patients. In the LQTS registry the risk of cardiac events was higher in males until puberty while females predominated in adulthood . In the present study all the patients were males and none of the affected children were females. This is consistent with the previous studies in which males have earlier onset of symptoms and a higher risk of first symptoms in childhood than females . The mechanism of age and sex related differences in QTc are unclear but androgens in males have shown to blunt the QT prolongation in response to QT prolonging drugs . Similarly in adults, females are affected more as hormonal changes favour QT prolongation and vulnerability to arrhythmias [20, 21]. Family screening is a must in all cases diagnosed with LQTS. Two patients in the present study were siblings. In a study by Garson et al. family history was present in 39 % cases .
Table 4 Demographic variables, ECG parameters and mean Schwartz score Age at diagnosis, Mean ± S.D Age of onset of symptoms, Mean ± S.D Lag period b/w symptom onset and diagnosis, Mean ± S.D Sex, M/F Symptoms • Seizures • Palpitations • Syncope Congenital sensorineural deafness Precipitating factors • Exercise • Noise • Rest Positive family history Schwartz score, Mean ± S.D QTc ms
10.3±2.8 y 5.6±2.9 y 5.6±3.14 y 6/0 6 2 1 2 4 0 2 2 6.66±1.16 556±41.31 ms
LQTS patients present with syncope, near syncope, seizures, palpitations or cardiac arrest due to its hallmark arrhythmia i.e., Torsades de pointes. Syncopal episodes associated with seizure like activity may be misdiagnosed as primary seizure disorder leading to delay in the proper management of this life threatening entity [2, 3, 23]. Ventricular arrhythmia can be initiated by triggers like exercise, loud noise, emotional stress, drugs causing QT prolongation but can occur at rest also . In the present study symptoms were preceded by physical activity in four patients while two patients had seizures at rest. All the patients in the index study presented with seizures, which is much higher than that reported in other studies (10 %) . This may be attributed to hemodynamically unstable arrhythmia persisting for a longer duration in pediatric patients leading to seizures as major manifestation. Two of the patients had preceding palpitations before the seizures giving an important clue to the diagnosis. ECG is a simple and non invasive tool to diagnose this life threatening entity. QT prolongation is commonly seen at rest, but can occasionally be seen only on provocative drug testing. In the present study QTc was significantly high at resting ECG in all patients as compared to other studies  and may suggest their higher risk of arrhythmia and hence presentation as seizures. The ECG patterns showed predominant broad based T wave (4 patients) with other two patterns included deep inverted T waves with T wave alternans. Based on the T wave morphology, most common diagnosis was of LQT1, which also is the most common LQTS seen in literature. Genetic testing, which could not be done, would have validated the diagnosis further. Functional AV block (2:1) was seen in one patient in the present study due to significant QT prolongation which has also been reported in previous studies . Holter monitoring is valuable in understanding the diurnal repolarisation dynamics in LQTS and is especially useful in LQTS2 and LQTS3, due to the more pronounced QT prolongation at slow heart rates in these patients [24, 25]. Studies have reported the diagnostic and prognostic utility of Holter monitoring in evaluating LQTS , though the present study did not reveal any arrhythmias during Holter. Polymorphic
Indian J Pediatr Table 5 Treatment and follow up of LQTS patients
VT was documented in 4 patients. In one patient it was spontaneous while in three patients it was induced on provocative drug testing. The remaining two patients had characteristic ECG findings and had symptoms at rest, so provocative drug testing was not done. Provocative drug testing with epinephrine can bring out QT prolongation in patients with normal resting QTc, or sometimes induce classical torsades de pointes. Schwartz diagnostic criteria for congenital LQTS were first proposed in 1985  and were subsequently updated in 1993  and then again in 2006 . The new diagnostic criteria have relative points assigned to various electrocardiographic, clinical, and familial findings. In the present study the Schwartz score was 6.66±1.16, which was much higher, as compared to other studies . This is attributable to significant prolonged QTc and symptomatic patients in the index study. Patients were treated with oral beta blockers as the first line of therapy. Though most of the studies have used propranolol in LQTS, the authors used metoprolol due to better compliance and dosing schedule. One patient suspected to be LQT2, was started on oral nicorandil and an aldosterone receptor antagonist, while, the patient with 2:1 AV block underwent dual chamber pacemaker implantation. Prior anti-seizure medications were discontinued in all the patients. Over a mean follow up period of 17 mo none of the patients had any recurrence of symptoms. This finding confirms high efficacy of beta blockers in LQTS, even though previous studies have shown effectiveness of only 70 % in preventing symptom recurrence. This may suggest the class effect of beta blockers in the management of LQTS. Similarly, strategies to increase potassium level in patients with suspected LQTS2 can be effective in the amelioration of symptoms. In all patients, implantation of automated implantable cardiac defibrillator (AICD) was discussed. However in view of young age and good response to medications, AICD implantation was not done in any of the patients. Limitations of the study are small number of patients (though not small for LQTS patients presenting as seizures),
a relatively short term follow up and non-availability of genetic testing to diagnose LQTS type.
Conclusions LQTS is a genetic channelopathy, which can cause prolonged ventricular arrhythmias causing syncope and seizures, especially on exertion, and often is misdiagnosed as a seizure disorder. An ECG, hence, should be done in every pediatric patient presenting with drug refractory seizures, history of familial seizures or with a history of seizures induced on physical exertion to look for this condition. Treatment with betablockers, nicorandil, spironolactone or pacemaker is effective in preventing recurrences of ventricular arrhythmia related seizures, in patients with LQTS, over a short term follow up.
Contributions BT, TS and SS: Drafted the manuscript; AS: Reviewed and verified the pre and post procedure clinical data; SB: Analysis and interpretation of data and critical review of manuscript; JS: Collection of data and its analysis; TM: Revised the manuscript critically for important intellectual content. BT will act as guarantor for this paper. Conflict of Interest None. Role of Funding Source None.
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The QT interval is a risk marker for cardiac events such as torsades de pointes. However, QT measurements obtained from a 12-lead ECG during clinic hours may not capture the full extent of a patient's daily QT range.
Specific T-wave patterns on the resting electrocardiogram (ECG) aid in diagnosing long QT syndrome (LQTS) and identifying the specific genotype. However, provocation tests often are required to establish a diagnosis when the QT interval is borderline
Long QT syndrome (LQTS) is a potentially life-threatening cardiac arrhythmia characterized by delayed myocardial repolarization that produces QT prolongation and increased risk for torsades des pointes (TdP)-triggered syncope, seizures, and sudden ca
Solitary seizure is one of the controversies in neurology. This study was taken up to study the clinical profile of solitary seizure and the factors related to seizure recurrence with a view to evolve guidelines for management.
During the last decade, the understanding of the long QT-syndrome (LQTS) as an inherited arrhythmogenic disease has dramatically increased. The LQTS has been recognized to be a heterogeneous family of ion-channel disorders caused by numerous mutation