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Misdiagnosis of Long QT Syndrome as Epilepsy at First Presentation
CARDIOLOGY/ORIGINAL RESEARCH
Misdiagnosis of Long QT Syndrome as Epilepsy at First Presentation Judith M. MacCormick, MBChB Hugh McAlister, FCSANZ Jackie Crawford, NZCS John K. French, PhD Ian Crozier, MD Andrew N. Shelling, PhD Carey-Anne Eddy, MSc (Med) Mark I. Rees, PhD Jonathan R. Skinner, MD
From the Green Lane Paediatric and Congenital Cardiac Service, Starship Children’s Hospital, Auckland, New Zealand (MacCormick, Crawford, Skinner); Cardiac Inherited Diseases Group, New Zealand (MacCormick, McAlister, Crawford, French, Crozier, Shelling, Eddy, Rees, Skinner); Department of Cardiology, Waikato Hospital, Hamilton, New Zealand (McAlister); Department of Cardiology, Liverpool Hospital, Sydney, New South Wales, Australia (French); Department of Cardiology, Christchurch Hospital, New Zealand (Crozier); Department of Obstetrics and Gynaecology (Shelling, Eddy) and Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand (Rees); and the School of Medicine, University of Wales Swansea, Swansea, Wales, United Kingdom (Rees).
Study objective: Long QT syndrome has significant mortality, which is reduced with appropriate management. It is known that long QT syndrome masquerades as other conditions, including seizure disorders. We aim to evaluate a series of patients with genetically confirmed long QT syndrome to establish the frequency of delayed recognition. We also examine causes and potential consequences of diagnostic delay. Methods: A consecutive case series of patients with long QT syndrome was identified through the Cardiac Inherited Disease Registry in New Zealand between 2000 and 2005. Detailed retrospective review of 31 cases was undertaken. The primary outcome was the time from first presentation with sudden loss of consciousness to a diagnosis of long QT syndrome. If the diagnosis was not made at the initial presentation, it was considered delayed. For the patients with a delayed diagnosis, the median duration of delay was compared between the subgroup of patients initially misdiagnosed with epilepsy and the others. Results: Genetic mutations in 31 probands were consistent with long QT type 1 in 18 (58%) patients, long QT type 2 in 10 (32%) and long QT type 3 in 3 (10%). Median age at diagnosis was 21 years (1 day to 54 years). Thirteen patients (39%) experienced diagnostic delay after presentation with syncope or seizure: median delay 2.4 years (2 months to 23 years). Electroencephalograms were obtained in 10 patients; 5 were diagnosed with epilepsy. For those labeled epileptic, diagnostic delay was significantly longer than with other misdiagnoses: estimated median difference 9.75 years (95% confidence interval 7.6 to 20.7 years). During the delay period, 4 sudden unexplained deaths reportedly occurred in young relatives. Ten of the 13 had an ECG before diagnosis, with unrecognized pulse rate– corrected QT interval prolongation in 8 cases (range 0.47 to 0.65 seconds). Conclusion: Delayed diagnosis of long QT syndrome is frequent. Symptoms are often attributed to alternative diagnoses, most commonly seizure disorder. Patients labeled as epileptic experience a particularly long diagnostic delay. ECGs were frequently requested, but interpretation errors were common. Given the potentially preventable mortality of long QT syndrome, emergency physicians investigating syncope and seizure should maintain a high index of suspicion. [Ann Emerg Med. 2009;54:26-32.] Provide feedback on this article at the journal’s Web site, www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2008 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2009.01.031
INTRODUCTION Background It has been 25 years since the first case report of long QT syndrome being misdiagnosed as epilepsy was published.1 Several other cases have since appeared in the literature.2-4 We recently reported the history of a 12-year-old boy diagnosed with and treated for epilepsy who was subsequently a victim of sudden death. Although his death was 26 Annals of Emergency Medicine
initially ascribed to sudden unexplained death in epilepsy, posthumous genetic screening identified long QT syndrome type 1.5 Importance The natural history of long QT syndrome suggests mortality greater than 20% in the year after the first syncopal event, with nearly 50% mortality at 5 years.6 Appropriate intervention can Volume , . : July
MacCormick et al
Misdiagnosis of Long QT Syndrome as Epilepsy
Editor’s Capsule Summary
What is already known on this topic Long QT syndrome is an uncommon but potentially lethal condition. What question this study addressed This retrospective case series of patients shown to have long QT syndrome after initially presenting with loss of consciousness examined how often diagnosis was delayed and what diagnoses were made instead. What this study adds to our knowledge The diagnosis of long QT syndrome may be particularly delayed when an initial diagnosis of epilepsy is made. This may increase the mortality risk of the patient and their affected family members. How this might change clinical practice Emergency physicians should be cognizant that patients with sudden loss of consciousness could have a long QT syndrome.
significantly reduce mortality and morbidity, making prompt diagnosis essential.7-10 Goals of This Investigation Concerned by the ongoing delayed recognition of a condition with preventable mortality, we aimed to establish the frequency of this problem in a series of patients with genetically confirmed long QT syndrome. We also explored the factors contributing to, and the consequences of, diagnostic delay of long QT syndrome.
MATERIALS AND METHODS Between 2000 and 2005, 84 families underwent molecular diagnostic screening through the Cardiac Inherited Disease Registry in New Zealand. A team of physicians interested in inherited causes of arrhythmia and sudden death has formed across the country, with members in all the major centers. These physicians are involved in the majority of cases of long QT syndrome nationwide and arrange genetic testing, although they would not see all case patients. Physicians in the Cardiac Inherited Disease Group routinely refer their patients to the registry, but this is at the discretion of the physician and the patient. A member of each family underwent genetic screening of 5 long QT syndrome genes: KCNQ1, HERG, SCN5A, KCNE1, and KCNE2. The registry is ethically approved to record confidential clinical and genetic information for management of and research into inherited cardiac disease. Volume , . : July
Ethical approval for this registry has been obtained from the national ethics committee. We recently described the genetic abnormalities in 40 consecutive probands with long QT syndrome (the proband being the first member of the family to be diagnosed).11 The current article is a case series of the 31 New Zealand probands who had consented for the collection and storage of detailed clinical information when joining the registry. The other 9 subjects either lived outside New Zealand (6 cases) or had not provided consent for detailed clinical audit. New Zealand provides every user of the health system with a National Health Index number, a unique personal identifier used consistently throughout the country. This enabled a thorough review of previous hospital records in the New Zealand patients who had consented for detailed clinical information collection. Our intention was to identify those patients who had presented with significant cardiac events before recognition of long QT syndrome. Therefore we defined a “previous presentation” as a previous assessment in a hospital emergency department (ED) or specialist outpatient clinic, at which the primary complaint involved sudden loss of consciousness without obvious precipitating factors. Earlier medical assessments for other symptoms, such as palpitations, were reviewed but not included as previous presentations because it was less certain that these events were related to the eventual diagnosis of long QT syndrome. Information was abstracted from the clinical records by the first author, who was not blinded to the final diagnosis. Data were collated with a standard abstraction form about history, investigations, diagnosis, and management. ECGs from previous presentations were reviewed when available. QT intervals corrected for pulse rate (QTc) were retrospectively remeasured and calculated with the Bazett formula12 by the first author and checked independently by the senior author. The QTc was measured in leads II and V5, which have been shown to correlate best to genotype status in families with long QT syndrome13 and avoids leads V2 to V4, which often have complex repolarization patterns. The QT interval was measured from the onset of the QRS to the intersection of the end of the T wave with baseline or to the end of the U wave if this was greater than 50% of the height of the T wave. The Bazett formula is a method of correcting the absolute QT interval for pulse rate and involves dividing the measured absolute QT by the square root of the preceding RR interval. The QTc interval was considered prolonged if one of the measurements was greater than or equal to 0.48 and borderline from 0.44 to 0.48. The authors’ ECG findings were subsequently compared with the interpretation documented by the treating physician in the clinical record at presentation. The majority of ECGs reviewed had no automated measurement of QTc. For those patients with a delayed diagnosis of long QT syndrome, the median duration of delay was compared between the subgroup of patients initially misdiagnosed with epilepsy Annals of Emergency Medicine 27
Misdiagnosis of Long QT Syndrome as Epilepsy
MacCormick et al
Table. Long QT syndrome probands with delayed diagnosis.
LQT Type
Ethnicity (by SelfReport)
Sex
Age at Diagnosis, y
Diagnostic Delay, y
1 1
European European
F F
27 4
23 0.3
1 1
European Maori
M F
10 12
0.8 1.1
1 1 2 2 2 2 2 2
European European Samoan European Chinese Maori European European
F M F F F F F F
43 11 29 35 37 35 31 41
2.4 0.3 12 13 9.5 10 15 2.4
2
European
F
25
0.2
Previous Primary Diagnosis Epilepsy Breath-holding spells Fall Other arrhythmia Hyperventilation Unknown Epilepsy Epilepsy Epilepsy Epilepsy Vasovagal Sleep dissociation state Vasovagal
Previously Proposed Differential Diagnoses Seizure disorder
Previous EEG
Previously Recorded QTc, Seconds
Retrospective QTc,* Seconds
Y Y
NR
0.44–0.46
NR NR
0.48 0.5
NR ULN † 0.37 NR
0.51–0.52 0.45–0.46 0.47–0.51 0.64–0.65
Seizure disorder Vasovagal
Y
Seizure disorder
Y Y Y Y Y
‡
Seizure disorder
Y
Cardiac arrhythmia
0.48 † 0.33
0.58 0.49
0.44
0.46–0.50
LQT, Long QT; QTc, pulse rate not corrected QT interval; NR, QTc not recorded in notes; ULN, recorded as being “upper limit of normal.” *Ranges represent the shortest and longest QTc in leads II and V5. † Miscalculations using Bazett formula. ‡ Reviewed by a cardiologist who believed that QTc was normal if U wave not included.
and the others. Statistical analysis included the Mann-Whitney U test for the difference between 2 medians.
RESULTS Thirty-one gene-positive probands were identified. The presentation resulting in eventual diagnosis of long QT syndrome was syncope in 20 (64.5%), resuscitated cardiac death requiring defibrillation in 6 (19.5%), incidental ECG abnormality in 3 (10%), palpitations in 1 (3%), and prenatal bradycardia in 1 (3%). The molecular mutations in these patients were consistent with LQT1 in 18 (58%), LQT2 in 10 (32%), and LQT3 in 3 (10%). Seventy-one percent of probands were female patients. The median age at diagnosis of long QT syndrome was 21 years, with a range of 1 day to 54 years. Eighteen patients (61%) were diagnosed with long QT syndrome at their first presentation to a hospital or outpatient clinic. Thirteen patients (39%) had been assessed for significant presentations with syncope or seizure before the diagnosis of long QT syndrome was made. For these 13 patients, genetic mutations were consistent with LQT1 in 6 and LQT2 in 7. That is, those who were misdiagnosed constituted 33% of the LQT1 probands and 70% of the LQT2 probands. Five of these patients had presented on 2 or more occasions with loss of consciousness, including seizures, before diagnosis. For the 13 probands with delayed diagnosis, the median time from the first presentation with sudden loss of consciousness until recognition of long QT syndrome was 2.4 years, with a range of 2 months to 23 years. In 3 cases, the delay was relatively minor (less than 4 months) because, although long 28 Annals of Emergency Medicine
QT syndrome was not recognized immediately, the patient was referred for appropriate follow-up and the diagnosis was then made. Of the total 31 patients, 10 (32%) underwent at least 1 electroencephalogram for suspected primary seizures before diagnosis of long QT syndrome. All the electroencephalogram results were normal. Nine patients were from the group of 13 with diagnostic delay. The tenth patient underwent electroencephalogram acutely at initial presentation, before the diagnosis of long QT syndrome became apparent on ECG the following day. Of the 13 patients with delayed recognition of long QT syndrome, 5 were given a diagnosis of seizure disorder. The remainder received various alternative diagnoses, including breath-holding spells, hyperventilation, sleep dissociation state, and a simple fall (Table). Three of the 5 patients who were diagnosed with epilepsy had their initial events during the night. For those who were misdiagnosed as having epilepsy, the median time for diagnostic delay was 11.8 years, with a range of 9.5 to 23 years. This was a significantly longer delay than those who received other diagnoses, for whom the median delay was 1 year, with a range of 0.2 to 15 years. With the Mann-Whitney U test, the estimated median difference is 9.75 years (95% confidence interval 7.6 to 20.7 years). In some cases, it was just by good fortune that the true diagnosis came to light. A 37-year-old woman with a longstanding diagnosis of epilepsy presented to hospital after a seizure. She was treated with anticonvulsants and required cardiac monitoring during the infusion. The diagnosis of long QT syndrome was suspected only when she was observed to Volume , . : July
MacCormick et al have episodes of ventricular tachycardia on the monitor. A 12lead ECG then confirmed the presence of a prolonged QT interval. Another woman in this study had been diagnosed with and treated for epilepsy for many years before reading an article about long QT syndrome in a magazine. The description was so consistent with her own experience that she was prompted to seek a further medical opinion, at which time the diagnosis of long QT syndrome was established. Ten of the 13 patients with delayed diagnosis were found to have had an ECG recorded at a previous presentation (Table). Retrospective review revealed at least 1 previous ECG with a QTc interval that was prolonged in 8 patients (QTc 0.47 to 0.65) and borderline in 2 patients. The ECGs in all 8 patients with prolonged QTc intervals had been interpreted as normal by the treating physician. The QTc interval had not been specifically documented in the original medical notes in 4 cases and was incorrectly recorded in 4 cases. Two of the latter cases could be identified as miscalculations with the Bazett formula. Two further patients were observed to have had previously unrecognized QTc prolongation on ECGs requested for other indications. One of these was a child with Kearns-Sayre Syndrome14 (QTc 0.48 to 0.50), and the other was an adult who had been investigated for palpitations (QTc 0.45 to 0.48). Both of these patients also had ECGs with normal QTc intervals in the past. The total number of patients identified with previously unrecognized QTc interval prolongation was 10 of 31 (32%). We reviewed the recorded family histories of the 13 patients with diagnostic delay to establish whether there were any sudden unexpected deaths at younger than 40 years. We were able to identify that in 4 cases, there was a reported history from the family of the sudden unexpected and unexplained death of a relative younger than 40 years during the time between the initial presentation of the proband and eventual recognition of long QT syndrome. The deceased was a sibling of the proband in 3 cases and a first cousin in the fourth case. In one case, both the proband and her deceased sibling had congenital deafness, meaning the diagnosis of long QT syndrome in the deceased was almost beyond doubt.
LIMITATIONS This study was subject to all the usual pitfalls of retrospective review. Data recorded at the time of presentation were not collected for the purposes of later study. The information was collected by the first author, who was not blinded to the final diagnosis of long QT syndrome in these patients. Patient numbers are small, not all patients in the registry consented for review of medical records, and the study was restricted to those who had positive genotype testing results. Previous presentations to a hospital or specialist outpatient clinic were reviewed, and thus we may have missed those who had previously presented with syncope to their family practitioner, a community emergency clinic or other health professional. Volume , . : July
Misdiagnosis of Long QT Syndrome as Epilepsy However, we would propose that on balance these exclusions are likely to have resulted in an underrepresentation of the frequency of delayed diagnosis. The period covered by this review is long, and there may well have been changes in practice since the earlier presentations.
DISCUSSION The first description of a long QT syndrome in 1957 was of a recessive form associated with deafness,15 followed in the 1960s by reports of a syndrome with autosomal dominant inheritance.16,17 The first study using linkage analysis to establish an underlying genetic basis was published in 1991.18 To date, we know of 11 genes associated with long QT syndrome. Within these genes, there are more than 600 mutations described thus far, highlighting the significant genetic heterogeneity of the condition.11,19-23 The different genetic subtypes of long QT syndrome result in individual clinical disorders, with their own characteristic patterns of presentation, ECG abnormalities, prognosis, and optimal management.24-27 Current estimates of the prevalence of long QT syndrome vary from 1 in 2000 to 1 in 7000. These may still be underestimates, given that long QT syndrome is frequently unrecognized and has variable penetrance.24,28 The propensity for long QT syndrome to imitate other conditions has been described in the literature. It is well established that cardiac syncope can result in secondary hypoxia and convulsions, thus mimicking a primary seizure disorder.29 Misdiagnosis of long QT syndrome as epilepsy was described as early as 1983, and there have been subsequent cases reported in the literature.1-5 Nevertheless, the diagnosis of long QT syndrome continues to be missed. Prompt recognition of long QT syndrome is essential because mortality can be significantly reduced with established interventions. -Blocker therapy has proven effectiveness in LQT1 and LQT2.6,10 Left-sided cardiac sympathetic denervation has been shown to be helpful in high-risk patients,8,9 and overdrive cardiac pacing is useful in some patients. The introduction of implantable cardioverter defibrillators for high-risk patients with long QT syndrome has further reduced mortality.7 Our findings show that delayed recognition of long QT syndrome is still common, with 39% of the patients experiencing delay between initial presentation and diagnosis. Although the results and conclusions of this review are based on a New Zealand cohort, they are likely to be applicable to a wider population, including the United States. New Zealand has a high-quality government-funded national health and welfare service. The health expenditure as a proportion of gross domestic product is comparable to that of Finland, Spain, and the United Kingdom.30 The most frequent misdiagnosis in this study was of a primary seizure disorder. The observation that 31% of the patients were investigated with electroencephalograms illustrates the considerable overlap in the clinical presentation of the long QT syndrome and seizure disorders. Other misdiagnoses noted Annals of Emergency Medicine 29
Misdiagnosis of Long QT Syndrome as Epilepsy in this study included breath-holding spells, hyperventilation, sleep dissociation state, and a simple fall. Misdiagnosis as breath-holding has also been previously reported in the literature.31 The authors acknowledge that more than 1 condition may exist in an individual; a patient with long QT syndrome may also have vasovagal syncope or even epilepsy. However, on review of our case series it seems likely that most, if not all, of the previous events in this study were a result of long QT syndrome. We observed that an individual might be labeled as epileptic for many years before the correct diagnosis is made. An initial diagnosis of seizure disorder was associated with a longer delay in recognition of long QT syndrome than other misdiagnoses. All 5 patients with a diagnosis of epilepsy had a delay of greater than 9 years before long QT syndrome was recognized. This highlights a need to maintain a high degree of suspicion, even in patients with a longstanding diagnosis of epilepsy, and particularly in those with atypical presentations, refractory seizures, nocturnal seizures, or a normal electroencephalogram result. Previous studies have examined cohorts of patients with “epilepsy” and found the diagnosis to be incorrect in 20% to 42%.32-34 Many of these patients were found to have “cardiogenic” causes, particularly convulsive vasovagal syncope. The numbers of patients with unrecognized long QT syndrome in the epilepsy population may well be small, given the relatively low prevalence of long QT syndrome. Nevertheless, identification of even a single case of long QT syndrome potentially enables a reduction in mortality and morbidity for both the individual and the extended family. Cardiac syncope is typically described as being of sudden onset, without warning symptoms and with rapid return to baseline level of alertness, as opposed to a postictal state. It is well recognized that collapse associated with exercise should be a cause for concern, prompting careful investigation. The majority of patients misdiagnosed with epilepsy in this series had experienced their events nocturnally. It may be that this form of presentation is less likely to raise suspicion of cardiac syncope and thus more prone to misdiagnosis. Patients with LQT1 typically have episodes triggered by exercise or swimming, whereas events during sleep or rest are more common in LQT2,24 which might explain the trend toward a preponderance of misdiagnosis in probands with LQT2 over LQT1. It has been suggested that screening ECGs for long QT syndrome are indicated in those presenting with their first afebrile seizure (unless the electroencephalogram result is diagnostic), those with unexplained syncope, and those with congenital deafness.35 The current American College of Emergency Physicians clinical policy for the evaluation and management of adult patients presenting to the ED with newonset seizures does not recommend an ECG,36 which is in contrast to the English and Scottish guidelines for investigation of first seizure, both of which recommend ECGs according to 30 Annals of Emergency Medicine
MacCormick et al the clinical experience of the guideline development group.37,38 The authors of this article would agree that an ECG should be considered in all first episodes of seizure and also suggest consideration in cases in which there is a longstanding diagnosis of epilepsy, resistant to treatment, without a diagnostic electroencephalogram. Our case series suggests that even when ECGs are undertaken as part of the assessment for syncope and seizure, interpretation is often suboptimal, which is consistent with a recent study that found that less than 40% of physicians (noncardiologists) and less than 50% of cardiologists were able to calculate a QTc interval correctly.39 Most current ECG machines provide an automated QTc interval, but the clinical experience of the authors would not recommend relying on this. The QTc should be calculated manually, preferably in leads II and V5.13 The end of the T wave can be measured at the point where it intersects with the baseline, although a method using the intersection of the tangent to the steepest downward slope with the baseline is also sometimes used. When there is a U wave present, it is generally recommended that this be included in the T wave measurement when it is greater than 50% of the height of the T wave. T wave morphology can provide additional information when assessing for long QT syndrome, with different repolarization patterns being associated with particular genotypes.25 The hereditary nature of long QT syndrome means that early recognition of the condition in the proband has implications for the wider family. Up to approximately 50% of family members will be gene carriers and potentially at risk. Clinical and genetic screening can identify carriers, enabling therapeutic intervention. In our series, 4 family members reportedly died suddenly at a young age during the time from initial presentation of the proband until the diagnosis of long QT syndrome. Although we cannot confirm that all of these deaths resulted from long QT syndrome, the sudden and unexplained nature of the events at a young age make it highly likely. We propose that recognition of long QT syndrome within a family, resulting in appropriate advice and intervention, may lead to reduced mortality. Population-based studies of young sudden cardiac death victims have shown that a third have a negative postmortem result, with death presumed to be a result of arrhythmia.40,41 Long QT syndrome may account for 20% of such postmortem negative-result cases.42 Further efforts are needed to identify individuals with long QT syndrome. Some researchers have even recommended newborn screening with ECGs.43 Additional studies investigating the prevalence of arrhythmic syncope among those diagnosed with seizure disorders would be useful. The preventable mortality and hereditary nature of long QT syndrome make early diagnosis a priority for the individual and the family. We would suggest that, as well as taking a family history for syncope and young sudden death, an ECG be considered after all first afebrile seizures, including nocturnal Volume , . : July
MacCormick et al seizures. In addition, ECGs should be considered in patients presenting with seizure who have a longstanding diagnosis of epilepsy and a negative electroencephalogram result. Accurate calculation of the QTc interval is essential. The overlap in the clinical presentation of long QT syndrome with other disorders, particularly epilepsy, requires the medical community to maintain a high index of suspicion. Supervising editor: Keith A. Marill, MD Author contributions: All authors participated in the concept, design, analysis, writing, and revision of the article. JS takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. The Cardiac Inherited Disease Group is supported by Cure Kids, the Green Lane Research and Education Fund and the Lion Foundation. Dr. MacCormick was supported by a research fellowship grant from the Southern Trust. Publication dates: Received for publication June 22, 2008. Revisions received November 16, 2008, and January 18, 2009. Accepted for publication January 26, 2009. Available online March 12, 2009. Reprints not available from the authors. Address for correspondence: J. R. Skinner, MD, Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Level 3, Building 32, Private Bag 92 029, Auckland, New Zealand; 64-9-307-4949, fax 64-9-631-0785; E-mail [email protected]. REFERENCES 1. Ballardie FW, Murphy RP, Davis J. Epilepsy: a presentation of the Romano-Ward syndrome. Br Med J (Clin Res Ed). 1983;287:896897. 2. O’Callaghan CA, Trump D. Prolonged QT syndrome presenting as epilepsy. Lancet. 1993;341:759-760. 3. Herman LL, Stoshak M, Rittenberry TJ. Long QT syndrome presenting as a seizure. Am J Emerg Med. 1992;10:435-438. 4. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991;84:1136-1144. 5. Skinner J, Chong B, Fawkner M, et al. Use of the newborn screening card to define cause of death in a 12-year-old diagnosed with epilepsy. J Paediatr Child Health. 2004;40:651-653. 6. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J. 1985;109:399-411. 7. Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003;14:337-341. 8. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004;109:1826-1833. 9. Schwartz PJ, Locati EH, Moss AJ, et al. Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report. Circulation. 1991;84:503-511.
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Misdiagnosis of Long QT Syndrome as Epilepsy 10. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101:616-623. 11. Chung S-K, MacCormick JM, McCulley CH, et al. Long QT and Brugada syndrome gene mutations in New Zealand. Heart Rhythm. 2007;4:1306-1314. 12. Bazett H. An analysis of the time relations of electrocardiograms. Heart. 1920;7:353-367. 13. Monnig G, Eckardt L, Wedekind H, et al. Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J. 2006;27:2074-2080. 14. Skinner JR, Yang T, Purvis D, et al. Coinheritance of long QT syndrome and Kearns-Sayre syndrome. Heart Rhythm. 2007;4: 1568-1572. 15. Jervell A, Lange-Neilson F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59-68. 16. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’eta pediatrica. II. Accessi sincopali per febrillazione ventricolare parossistica. Clin Pediatr (Bologna). 1963;45:656-683. 17. Ward O. New familial cardiac syndrome in children. J Irish Med Assoc. 1964;54:103-106. 18. Keating M, Atkinson D, Dunn C, et al. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252:704-706. 19. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long QT syndrome genes. Circulation. 2000;102:1178-1185. 20. Jongbloed R, Marcelis C, Velter C, et al. DHPLC analysis of potassium ion channel genes in congenital long QT syndrome. Hum Mutat. 2002;20:383-391. 21. Liu W, Yang J, Hu D, et al. KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. Hum Mutat. 2002;20:475-476. 22. Tester DJ, Will ML, Haglund CM, et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2:507517. 23. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294: 2975-2980. 24. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for lifethreatening arrhythmias. Circulation. 2001;103:89-95. 25. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000; 102:2849-2855. 26. Napolitano C, Bloise R, Priori SG. Gene-specific therapy for inherited arrhythmogenic diseases. Pharmacol Ther. 2006;110:1-13. 27. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998;339: 960-965. 28. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the LongQT syndrome: clinical impact. Circulation. 1999;99:529-533. 29. Schott GD, McLeod AA, Jewitt DE. Cardiac arrhythmias that masquerade as epilepsy. Br Med J. 1977;1:1454-1457. 30. New Zealand health and disability sector overview. Ministry of Health. Available at: http://www.moh.govt.nz. Accessed September 4, 2007. 31. Franklin WH, Hickey RW. Long-QT syndrome. N Engl J Med. 1995; 333:355.
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Misdiagnosis of Long QT Syndrome as Epilepsy 32. Zaidi A, Clough P, Cooper P, et al. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol. 2000;36:181-184. 33. McDade G, Brown SW. Non-epileptic seizures: management and predictive factors of outcome. Seizure. 1992;1:7-10. 34. Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM. 1999;92:15-23. 35. Davis AM, Wilkinson JL. The long QT syndrome and seizures in childhood. J Paediatr Child Health. 1998;34:410-411. 36. American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med. 2004;43:605-625. 37. The diagnosis and management of the epilepsies in adults and children in primary and secondary care. NHS National Institute for Clinical Excellence. Available at: http://www.nice.org.uk/nicemedia/ pdf/CG020fullguideline.pdf. Accessed September 20, 2008.
MacCormick et al 38. Diagnosis and management of epilepsies in children and young people. Scottish Intercollegiate Guidelines Network. Available at: http://www.sign.ac.uk/pdf/sign81.pdf. Accessed September 20, 2008. 39. Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm. 2005;2:569-574. 40. Puranik R, Chow CK, Duflou JA, et al. Sudden death in the young. Heart Rhythm. 2005;2:1277-1282. 41. Doolan A, Langlois N, Semsarian C. Causes of sudden cardiac death in young Australians. Med J Aust. 2004;180:110-112. 42. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49:240-246. 43. Quaglini S, Rognoni C, Spazzolini C, et al. Cost-effectiveness of neonatal ECG screening for the long QT syndrome. Eur Heart J. 2006;27:1824-1832.
Residents’ Perspective: Call for Submissions The Residents’ Perspective section of Annals of Emergency Medicine has been a fixture in the journal since 1993 and provides a peer-reviewed venue for the unique perspective of the resident physician. We publish brief articles authored or co-authored by residents, including data-based reviews of important topics that have not been well covered elsewhere, informative instructional pieces of particular interest to residents, and occasionally, well-referenced position papers. We also welcome small-scale original research articles, especially those that address educational innovations and are presented in the context of a broader discussion of the current literature. We do not publish individual opinion pieces. We are particularly, though not exclusively, interested in pieces co-authored by residents and expert faculty in the field. If you have a topic you would like to cover and are not able to find a co-author, please contact us, as we may be able to suggest one. To develop a manuscript for the Residents’ Perspective section, please complete a brief literature review on your chosen topic to ensure that it has not recently been covered elsewhere and then submit a 300-word structured abstract. The abstract should include the following information: the proposed title and authors (not included in the 300 words); a brief background of the topic, including its significance to emergency medicine practice; an outline of the proposed structure of the article; and any pertinent references. If you are interested in submitting a well-referenced original manuscript that is already completed, please contact us by e-mail. All submitted abstracts should be received by July 14th, 2009. Once abstracts have been approved, final manuscripts should be received within 2 months of approval date. Submit abstracts by email to Aaron Brown, MD and Suzanne Lippert, MD, MS, Resident Fellows, at [email protected].
32 Annals of Emergency Medicine
Volume , . : July
Misdiagnosis of Long QT Syndrome as Epilepsy at First Presentation Judith M. MacCormick, MBChB Hugh McAlister, FCSANZ Jackie Crawford, NZCS John K. French, PhD Ian Crozier, MD Andrew N. Shelling, PhD Carey-Anne Eddy, MSc (Med) Mark I. Rees, PhD Jonathan R. Skinner, MD
From the Green Lane Paediatric and Congenital Cardiac Service, Starship Children’s Hospital, Auckland, New Zealand (MacCormick, Crawford, Skinner); Cardiac Inherited Diseases Group, New Zealand (MacCormick, McAlister, Crawford, French, Crozier, Shelling, Eddy, Rees, Skinner); Department of Cardiology, Waikato Hospital, Hamilton, New Zealand (McAlister); Department of Cardiology, Liverpool Hospital, Sydney, New South Wales, Australia (French); Department of Cardiology, Christchurch Hospital, New Zealand (Crozier); Department of Obstetrics and Gynaecology (Shelling, Eddy) and Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand (Rees); and the School of Medicine, University of Wales Swansea, Swansea, Wales, United Kingdom (Rees).
Study objective: Long QT syndrome has significant mortality, which is reduced with appropriate management. It is known that long QT syndrome masquerades as other conditions, including seizure disorders. We aim to evaluate a series of patients with genetically confirmed long QT syndrome to establish the frequency of delayed recognition. We also examine causes and potential consequences of diagnostic delay. Methods: A consecutive case series of patients with long QT syndrome was identified through the Cardiac Inherited Disease Registry in New Zealand between 2000 and 2005. Detailed retrospective review of 31 cases was undertaken. The primary outcome was the time from first presentation with sudden loss of consciousness to a diagnosis of long QT syndrome. If the diagnosis was not made at the initial presentation, it was considered delayed. For the patients with a delayed diagnosis, the median duration of delay was compared between the subgroup of patients initially misdiagnosed with epilepsy and the others. Results: Genetic mutations in 31 probands were consistent with long QT type 1 in 18 (58%) patients, long QT type 2 in 10 (32%) and long QT type 3 in 3 (10%). Median age at diagnosis was 21 years (1 day to 54 years). Thirteen patients (39%) experienced diagnostic delay after presentation with syncope or seizure: median delay 2.4 years (2 months to 23 years). Electroencephalograms were obtained in 10 patients; 5 were diagnosed with epilepsy. For those labeled epileptic, diagnostic delay was significantly longer than with other misdiagnoses: estimated median difference 9.75 years (95% confidence interval 7.6 to 20.7 years). During the delay period, 4 sudden unexplained deaths reportedly occurred in young relatives. Ten of the 13 had an ECG before diagnosis, with unrecognized pulse rate– corrected QT interval prolongation in 8 cases (range 0.47 to 0.65 seconds). Conclusion: Delayed diagnosis of long QT syndrome is frequent. Symptoms are often attributed to alternative diagnoses, most commonly seizure disorder. Patients labeled as epileptic experience a particularly long diagnostic delay. ECGs were frequently requested, but interpretation errors were common. Given the potentially preventable mortality of long QT syndrome, emergency physicians investigating syncope and seizure should maintain a high index of suspicion. [Ann Emerg Med. 2009;54:26-32.] Provide feedback on this article at the journal’s Web site, www.annemergmed.com. 0196-0644/$-see front matter Copyright © 2008 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2009.01.031
INTRODUCTION Background It has been 25 years since the first case report of long QT syndrome being misdiagnosed as epilepsy was published.1 Several other cases have since appeared in the literature.2-4 We recently reported the history of a 12-year-old boy diagnosed with and treated for epilepsy who was subsequently a victim of sudden death. Although his death was 26 Annals of Emergency Medicine
initially ascribed to sudden unexplained death in epilepsy, posthumous genetic screening identified long QT syndrome type 1.5 Importance The natural history of long QT syndrome suggests mortality greater than 20% in the year after the first syncopal event, with nearly 50% mortality at 5 years.6 Appropriate intervention can Volume , . : July
MacCormick et al
Misdiagnosis of Long QT Syndrome as Epilepsy
Editor’s Capsule Summary
What is already known on this topic Long QT syndrome is an uncommon but potentially lethal condition. What question this study addressed This retrospective case series of patients shown to have long QT syndrome after initially presenting with loss of consciousness examined how often diagnosis was delayed and what diagnoses were made instead. What this study adds to our knowledge The diagnosis of long QT syndrome may be particularly delayed when an initial diagnosis of epilepsy is made. This may increase the mortality risk of the patient and their affected family members. How this might change clinical practice Emergency physicians should be cognizant that patients with sudden loss of consciousness could have a long QT syndrome.
significantly reduce mortality and morbidity, making prompt diagnosis essential.7-10 Goals of This Investigation Concerned by the ongoing delayed recognition of a condition with preventable mortality, we aimed to establish the frequency of this problem in a series of patients with genetically confirmed long QT syndrome. We also explored the factors contributing to, and the consequences of, diagnostic delay of long QT syndrome.
MATERIALS AND METHODS Between 2000 and 2005, 84 families underwent molecular diagnostic screening through the Cardiac Inherited Disease Registry in New Zealand. A team of physicians interested in inherited causes of arrhythmia and sudden death has formed across the country, with members in all the major centers. These physicians are involved in the majority of cases of long QT syndrome nationwide and arrange genetic testing, although they would not see all case patients. Physicians in the Cardiac Inherited Disease Group routinely refer their patients to the registry, but this is at the discretion of the physician and the patient. A member of each family underwent genetic screening of 5 long QT syndrome genes: KCNQ1, HERG, SCN5A, KCNE1, and KCNE2. The registry is ethically approved to record confidential clinical and genetic information for management of and research into inherited cardiac disease. Volume , . : July
Ethical approval for this registry has been obtained from the national ethics committee. We recently described the genetic abnormalities in 40 consecutive probands with long QT syndrome (the proband being the first member of the family to be diagnosed).11 The current article is a case series of the 31 New Zealand probands who had consented for the collection and storage of detailed clinical information when joining the registry. The other 9 subjects either lived outside New Zealand (6 cases) or had not provided consent for detailed clinical audit. New Zealand provides every user of the health system with a National Health Index number, a unique personal identifier used consistently throughout the country. This enabled a thorough review of previous hospital records in the New Zealand patients who had consented for detailed clinical information collection. Our intention was to identify those patients who had presented with significant cardiac events before recognition of long QT syndrome. Therefore we defined a “previous presentation” as a previous assessment in a hospital emergency department (ED) or specialist outpatient clinic, at which the primary complaint involved sudden loss of consciousness without obvious precipitating factors. Earlier medical assessments for other symptoms, such as palpitations, were reviewed but not included as previous presentations because it was less certain that these events were related to the eventual diagnosis of long QT syndrome. Information was abstracted from the clinical records by the first author, who was not blinded to the final diagnosis. Data were collated with a standard abstraction form about history, investigations, diagnosis, and management. ECGs from previous presentations were reviewed when available. QT intervals corrected for pulse rate (QTc) were retrospectively remeasured and calculated with the Bazett formula12 by the first author and checked independently by the senior author. The QTc was measured in leads II and V5, which have been shown to correlate best to genotype status in families with long QT syndrome13 and avoids leads V2 to V4, which often have complex repolarization patterns. The QT interval was measured from the onset of the QRS to the intersection of the end of the T wave with baseline or to the end of the U wave if this was greater than 50% of the height of the T wave. The Bazett formula is a method of correcting the absolute QT interval for pulse rate and involves dividing the measured absolute QT by the square root of the preceding RR interval. The QTc interval was considered prolonged if one of the measurements was greater than or equal to 0.48 and borderline from 0.44 to 0.48. The authors’ ECG findings were subsequently compared with the interpretation documented by the treating physician in the clinical record at presentation. The majority of ECGs reviewed had no automated measurement of QTc. For those patients with a delayed diagnosis of long QT syndrome, the median duration of delay was compared between the subgroup of patients initially misdiagnosed with epilepsy Annals of Emergency Medicine 27
Misdiagnosis of Long QT Syndrome as Epilepsy
MacCormick et al
Table. Long QT syndrome probands with delayed diagnosis.
LQT Type
Ethnicity (by SelfReport)
Sex
Age at Diagnosis, y
Diagnostic Delay, y
1 1
European European
F F
27 4
23 0.3
1 1
European Maori
M F
10 12
0.8 1.1
1 1 2 2 2 2 2 2
European European Samoan European Chinese Maori European European
F M F F F F F F
43 11 29 35 37 35 31 41
2.4 0.3 12 13 9.5 10 15 2.4
2
European
F
25
0.2
Previous Primary Diagnosis Epilepsy Breath-holding spells Fall Other arrhythmia Hyperventilation Unknown Epilepsy Epilepsy Epilepsy Epilepsy Vasovagal Sleep dissociation state Vasovagal
Previously Proposed Differential Diagnoses Seizure disorder
Previous EEG
Previously Recorded QTc, Seconds
Retrospective QTc,* Seconds
Y Y
NR
0.44–0.46
NR NR
0.48 0.5
NR ULN † 0.37 NR
0.51–0.52 0.45–0.46 0.47–0.51 0.64–0.65
Seizure disorder Vasovagal
Y
Seizure disorder
Y Y Y Y Y
‡
Seizure disorder
Y
Cardiac arrhythmia
0.48 † 0.33
0.58 0.49
0.44
0.46–0.50
LQT, Long QT; QTc, pulse rate not corrected QT interval; NR, QTc not recorded in notes; ULN, recorded as being “upper limit of normal.” *Ranges represent the shortest and longest QTc in leads II and V5. † Miscalculations using Bazett formula. ‡ Reviewed by a cardiologist who believed that QTc was normal if U wave not included.
and the others. Statistical analysis included the Mann-Whitney U test for the difference between 2 medians.
RESULTS Thirty-one gene-positive probands were identified. The presentation resulting in eventual diagnosis of long QT syndrome was syncope in 20 (64.5%), resuscitated cardiac death requiring defibrillation in 6 (19.5%), incidental ECG abnormality in 3 (10%), palpitations in 1 (3%), and prenatal bradycardia in 1 (3%). The molecular mutations in these patients were consistent with LQT1 in 18 (58%), LQT2 in 10 (32%), and LQT3 in 3 (10%). Seventy-one percent of probands were female patients. The median age at diagnosis of long QT syndrome was 21 years, with a range of 1 day to 54 years. Eighteen patients (61%) were diagnosed with long QT syndrome at their first presentation to a hospital or outpatient clinic. Thirteen patients (39%) had been assessed for significant presentations with syncope or seizure before the diagnosis of long QT syndrome was made. For these 13 patients, genetic mutations were consistent with LQT1 in 6 and LQT2 in 7. That is, those who were misdiagnosed constituted 33% of the LQT1 probands and 70% of the LQT2 probands. Five of these patients had presented on 2 or more occasions with loss of consciousness, including seizures, before diagnosis. For the 13 probands with delayed diagnosis, the median time from the first presentation with sudden loss of consciousness until recognition of long QT syndrome was 2.4 years, with a range of 2 months to 23 years. In 3 cases, the delay was relatively minor (less than 4 months) because, although long 28 Annals of Emergency Medicine
QT syndrome was not recognized immediately, the patient was referred for appropriate follow-up and the diagnosis was then made. Of the total 31 patients, 10 (32%) underwent at least 1 electroencephalogram for suspected primary seizures before diagnosis of long QT syndrome. All the electroencephalogram results were normal. Nine patients were from the group of 13 with diagnostic delay. The tenth patient underwent electroencephalogram acutely at initial presentation, before the diagnosis of long QT syndrome became apparent on ECG the following day. Of the 13 patients with delayed recognition of long QT syndrome, 5 were given a diagnosis of seizure disorder. The remainder received various alternative diagnoses, including breath-holding spells, hyperventilation, sleep dissociation state, and a simple fall (Table). Three of the 5 patients who were diagnosed with epilepsy had their initial events during the night. For those who were misdiagnosed as having epilepsy, the median time for diagnostic delay was 11.8 years, with a range of 9.5 to 23 years. This was a significantly longer delay than those who received other diagnoses, for whom the median delay was 1 year, with a range of 0.2 to 15 years. With the Mann-Whitney U test, the estimated median difference is 9.75 years (95% confidence interval 7.6 to 20.7 years). In some cases, it was just by good fortune that the true diagnosis came to light. A 37-year-old woman with a longstanding diagnosis of epilepsy presented to hospital after a seizure. She was treated with anticonvulsants and required cardiac monitoring during the infusion. The diagnosis of long QT syndrome was suspected only when she was observed to Volume , . : July
MacCormick et al have episodes of ventricular tachycardia on the monitor. A 12lead ECG then confirmed the presence of a prolonged QT interval. Another woman in this study had been diagnosed with and treated for epilepsy for many years before reading an article about long QT syndrome in a magazine. The description was so consistent with her own experience that she was prompted to seek a further medical opinion, at which time the diagnosis of long QT syndrome was established. Ten of the 13 patients with delayed diagnosis were found to have had an ECG recorded at a previous presentation (Table). Retrospective review revealed at least 1 previous ECG with a QTc interval that was prolonged in 8 patients (QTc 0.47 to 0.65) and borderline in 2 patients. The ECGs in all 8 patients with prolonged QTc intervals had been interpreted as normal by the treating physician. The QTc interval had not been specifically documented in the original medical notes in 4 cases and was incorrectly recorded in 4 cases. Two of the latter cases could be identified as miscalculations with the Bazett formula. Two further patients were observed to have had previously unrecognized QTc prolongation on ECGs requested for other indications. One of these was a child with Kearns-Sayre Syndrome14 (QTc 0.48 to 0.50), and the other was an adult who had been investigated for palpitations (QTc 0.45 to 0.48). Both of these patients also had ECGs with normal QTc intervals in the past. The total number of patients identified with previously unrecognized QTc interval prolongation was 10 of 31 (32%). We reviewed the recorded family histories of the 13 patients with diagnostic delay to establish whether there were any sudden unexpected deaths at younger than 40 years. We were able to identify that in 4 cases, there was a reported history from the family of the sudden unexpected and unexplained death of a relative younger than 40 years during the time between the initial presentation of the proband and eventual recognition of long QT syndrome. The deceased was a sibling of the proband in 3 cases and a first cousin in the fourth case. In one case, both the proband and her deceased sibling had congenital deafness, meaning the diagnosis of long QT syndrome in the deceased was almost beyond doubt.
LIMITATIONS This study was subject to all the usual pitfalls of retrospective review. Data recorded at the time of presentation were not collected for the purposes of later study. The information was collected by the first author, who was not blinded to the final diagnosis of long QT syndrome in these patients. Patient numbers are small, not all patients in the registry consented for review of medical records, and the study was restricted to those who had positive genotype testing results. Previous presentations to a hospital or specialist outpatient clinic were reviewed, and thus we may have missed those who had previously presented with syncope to their family practitioner, a community emergency clinic or other health professional. Volume , . : July
Misdiagnosis of Long QT Syndrome as Epilepsy However, we would propose that on balance these exclusions are likely to have resulted in an underrepresentation of the frequency of delayed diagnosis. The period covered by this review is long, and there may well have been changes in practice since the earlier presentations.
DISCUSSION The first description of a long QT syndrome in 1957 was of a recessive form associated with deafness,15 followed in the 1960s by reports of a syndrome with autosomal dominant inheritance.16,17 The first study using linkage analysis to establish an underlying genetic basis was published in 1991.18 To date, we know of 11 genes associated with long QT syndrome. Within these genes, there are more than 600 mutations described thus far, highlighting the significant genetic heterogeneity of the condition.11,19-23 The different genetic subtypes of long QT syndrome result in individual clinical disorders, with their own characteristic patterns of presentation, ECG abnormalities, prognosis, and optimal management.24-27 Current estimates of the prevalence of long QT syndrome vary from 1 in 2000 to 1 in 7000. These may still be underestimates, given that long QT syndrome is frequently unrecognized and has variable penetrance.24,28 The propensity for long QT syndrome to imitate other conditions has been described in the literature. It is well established that cardiac syncope can result in secondary hypoxia and convulsions, thus mimicking a primary seizure disorder.29 Misdiagnosis of long QT syndrome as epilepsy was described as early as 1983, and there have been subsequent cases reported in the literature.1-5 Nevertheless, the diagnosis of long QT syndrome continues to be missed. Prompt recognition of long QT syndrome is essential because mortality can be significantly reduced with established interventions. -Blocker therapy has proven effectiveness in LQT1 and LQT2.6,10 Left-sided cardiac sympathetic denervation has been shown to be helpful in high-risk patients,8,9 and overdrive cardiac pacing is useful in some patients. The introduction of implantable cardioverter defibrillators for high-risk patients with long QT syndrome has further reduced mortality.7 Our findings show that delayed recognition of long QT syndrome is still common, with 39% of the patients experiencing delay between initial presentation and diagnosis. Although the results and conclusions of this review are based on a New Zealand cohort, they are likely to be applicable to a wider population, including the United States. New Zealand has a high-quality government-funded national health and welfare service. The health expenditure as a proportion of gross domestic product is comparable to that of Finland, Spain, and the United Kingdom.30 The most frequent misdiagnosis in this study was of a primary seizure disorder. The observation that 31% of the patients were investigated with electroencephalograms illustrates the considerable overlap in the clinical presentation of the long QT syndrome and seizure disorders. Other misdiagnoses noted Annals of Emergency Medicine 29
Misdiagnosis of Long QT Syndrome as Epilepsy in this study included breath-holding spells, hyperventilation, sleep dissociation state, and a simple fall. Misdiagnosis as breath-holding has also been previously reported in the literature.31 The authors acknowledge that more than 1 condition may exist in an individual; a patient with long QT syndrome may also have vasovagal syncope or even epilepsy. However, on review of our case series it seems likely that most, if not all, of the previous events in this study were a result of long QT syndrome. We observed that an individual might be labeled as epileptic for many years before the correct diagnosis is made. An initial diagnosis of seizure disorder was associated with a longer delay in recognition of long QT syndrome than other misdiagnoses. All 5 patients with a diagnosis of epilepsy had a delay of greater than 9 years before long QT syndrome was recognized. This highlights a need to maintain a high degree of suspicion, even in patients with a longstanding diagnosis of epilepsy, and particularly in those with atypical presentations, refractory seizures, nocturnal seizures, or a normal electroencephalogram result. Previous studies have examined cohorts of patients with “epilepsy” and found the diagnosis to be incorrect in 20% to 42%.32-34 Many of these patients were found to have “cardiogenic” causes, particularly convulsive vasovagal syncope. The numbers of patients with unrecognized long QT syndrome in the epilepsy population may well be small, given the relatively low prevalence of long QT syndrome. Nevertheless, identification of even a single case of long QT syndrome potentially enables a reduction in mortality and morbidity for both the individual and the extended family. Cardiac syncope is typically described as being of sudden onset, without warning symptoms and with rapid return to baseline level of alertness, as opposed to a postictal state. It is well recognized that collapse associated with exercise should be a cause for concern, prompting careful investigation. The majority of patients misdiagnosed with epilepsy in this series had experienced their events nocturnally. It may be that this form of presentation is less likely to raise suspicion of cardiac syncope and thus more prone to misdiagnosis. Patients with LQT1 typically have episodes triggered by exercise or swimming, whereas events during sleep or rest are more common in LQT2,24 which might explain the trend toward a preponderance of misdiagnosis in probands with LQT2 over LQT1. It has been suggested that screening ECGs for long QT syndrome are indicated in those presenting with their first afebrile seizure (unless the electroencephalogram result is diagnostic), those with unexplained syncope, and those with congenital deafness.35 The current American College of Emergency Physicians clinical policy for the evaluation and management of adult patients presenting to the ED with newonset seizures does not recommend an ECG,36 which is in contrast to the English and Scottish guidelines for investigation of first seizure, both of which recommend ECGs according to 30 Annals of Emergency Medicine
MacCormick et al the clinical experience of the guideline development group.37,38 The authors of this article would agree that an ECG should be considered in all first episodes of seizure and also suggest consideration in cases in which there is a longstanding diagnosis of epilepsy, resistant to treatment, without a diagnostic electroencephalogram. Our case series suggests that even when ECGs are undertaken as part of the assessment for syncope and seizure, interpretation is often suboptimal, which is consistent with a recent study that found that less than 40% of physicians (noncardiologists) and less than 50% of cardiologists were able to calculate a QTc interval correctly.39 Most current ECG machines provide an automated QTc interval, but the clinical experience of the authors would not recommend relying on this. The QTc should be calculated manually, preferably in leads II and V5.13 The end of the T wave can be measured at the point where it intersects with the baseline, although a method using the intersection of the tangent to the steepest downward slope with the baseline is also sometimes used. When there is a U wave present, it is generally recommended that this be included in the T wave measurement when it is greater than 50% of the height of the T wave. T wave morphology can provide additional information when assessing for long QT syndrome, with different repolarization patterns being associated with particular genotypes.25 The hereditary nature of long QT syndrome means that early recognition of the condition in the proband has implications for the wider family. Up to approximately 50% of family members will be gene carriers and potentially at risk. Clinical and genetic screening can identify carriers, enabling therapeutic intervention. In our series, 4 family members reportedly died suddenly at a young age during the time from initial presentation of the proband until the diagnosis of long QT syndrome. Although we cannot confirm that all of these deaths resulted from long QT syndrome, the sudden and unexplained nature of the events at a young age make it highly likely. We propose that recognition of long QT syndrome within a family, resulting in appropriate advice and intervention, may lead to reduced mortality. Population-based studies of young sudden cardiac death victims have shown that a third have a negative postmortem result, with death presumed to be a result of arrhythmia.40,41 Long QT syndrome may account for 20% of such postmortem negative-result cases.42 Further efforts are needed to identify individuals with long QT syndrome. Some researchers have even recommended newborn screening with ECGs.43 Additional studies investigating the prevalence of arrhythmic syncope among those diagnosed with seizure disorders would be useful. The preventable mortality and hereditary nature of long QT syndrome make early diagnosis a priority for the individual and the family. We would suggest that, as well as taking a family history for syncope and young sudden death, an ECG be considered after all first afebrile seizures, including nocturnal Volume , . : July
MacCormick et al seizures. In addition, ECGs should be considered in patients presenting with seizure who have a longstanding diagnosis of epilepsy and a negative electroencephalogram result. Accurate calculation of the QTc interval is essential. The overlap in the clinical presentation of long QT syndrome with other disorders, particularly epilepsy, requires the medical community to maintain a high index of suspicion. Supervising editor: Keith A. Marill, MD Author contributions: All authors participated in the concept, design, analysis, writing, and revision of the article. JS takes responsibility for the paper as a whole. Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. The Cardiac Inherited Disease Group is supported by Cure Kids, the Green Lane Research and Education Fund and the Lion Foundation. Dr. MacCormick was supported by a research fellowship grant from the Southern Trust. Publication dates: Received for publication June 22, 2008. Revisions received November 16, 2008, and January 18, 2009. Accepted for publication January 26, 2009. Available online March 12, 2009. Reprints not available from the authors. Address for correspondence: J. R. Skinner, MD, Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Level 3, Building 32, Private Bag 92 029, Auckland, New Zealand; 64-9-307-4949, fax 64-9-631-0785; E-mail [email protected]. REFERENCES 1. Ballardie FW, Murphy RP, Davis J. Epilepsy: a presentation of the Romano-Ward syndrome. Br Med J (Clin Res Ed). 1983;287:896897. 2. O’Callaghan CA, Trump D. Prolonged QT syndrome presenting as epilepsy. Lancet. 1993;341:759-760. 3. Herman LL, Stoshak M, Rittenberry TJ. Long QT syndrome presenting as a seizure. Am J Emerg Med. 1992;10:435-438. 4. Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991;84:1136-1144. 5. Skinner J, Chong B, Fawkner M, et al. Use of the newborn screening card to define cause of death in a 12-year-old diagnosed with epilepsy. J Paediatr Child Health. 2004;40:651-653. 6. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J. 1985;109:399-411. 7. Zareba W, Moss AJ, Daubert JP, et al. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003;14:337-341. 8. Schwartz PJ, Priori SG, Cerrone M, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004;109:1826-1833. 9. Schwartz PJ, Locati EH, Moss AJ, et al. Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report. Circulation. 1991;84:503-511.
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Misdiagnosis of Long QT Syndrome as Epilepsy 10. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101:616-623. 11. Chung S-K, MacCormick JM, McCulley CH, et al. Long QT and Brugada syndrome gene mutations in New Zealand. Heart Rhythm. 2007;4:1306-1314. 12. Bazett H. An analysis of the time relations of electrocardiograms. Heart. 1920;7:353-367. 13. Monnig G, Eckardt L, Wedekind H, et al. Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J. 2006;27:2074-2080. 14. Skinner JR, Yang T, Purvis D, et al. Coinheritance of long QT syndrome and Kearns-Sayre syndrome. Heart Rhythm. 2007;4: 1568-1572. 15. Jervell A, Lange-Neilson F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59-68. 16. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’eta pediatrica. II. Accessi sincopali per febrillazione ventricolare parossistica. Clin Pediatr (Bologna). 1963;45:656-683. 17. Ward O. New familial cardiac syndrome in children. J Irish Med Assoc. 1964;54:103-106. 18. Keating M, Atkinson D, Dunn C, et al. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science. 1991;252:704-706. 19. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long QT syndrome genes. Circulation. 2000;102:1178-1185. 20. Jongbloed R, Marcelis C, Velter C, et al. DHPLC analysis of potassium ion channel genes in congenital long QT syndrome. Hum Mutat. 2002;20:383-391. 21. Liu W, Yang J, Hu D, et al. KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population. Hum Mutat. 2002;20:475-476. 22. Tester DJ, Will ML, Haglund CM, et al. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2:507517. 23. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294: 2975-2980. 24. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for lifethreatening arrhythmias. Circulation. 2001;103:89-95. 25. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000; 102:2849-2855. 26. Napolitano C, Bloise R, Priori SG. Gene-specific therapy for inherited arrhythmogenic diseases. Pharmacol Ther. 2006;110:1-13. 27. Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998;339: 960-965. 28. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the LongQT syndrome: clinical impact. Circulation. 1999;99:529-533. 29. Schott GD, McLeod AA, Jewitt DE. Cardiac arrhythmias that masquerade as epilepsy. Br Med J. 1977;1:1454-1457. 30. New Zealand health and disability sector overview. Ministry of Health. Available at: http://www.moh.govt.nz. Accessed September 4, 2007. 31. Franklin WH, Hickey RW. Long-QT syndrome. N Engl J Med. 1995; 333:355.
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Misdiagnosis of Long QT Syndrome as Epilepsy 32. Zaidi A, Clough P, Cooper P, et al. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol. 2000;36:181-184. 33. McDade G, Brown SW. Non-epileptic seizures: management and predictive factors of outcome. Seizure. 1992;1:7-10. 34. Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. QJM. 1999;92:15-23. 35. Davis AM, Wilkinson JL. The long QT syndrome and seizures in childhood. J Paediatr Child Health. 1998;34:410-411. 36. American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures. Ann Emerg Med. 2004;43:605-625. 37. The diagnosis and management of the epilepsies in adults and children in primary and secondary care. NHS National Institute for Clinical Excellence. Available at: http://www.nice.org.uk/nicemedia/ pdf/CG020fullguideline.pdf. Accessed September 20, 2008.
MacCormick et al 38. Diagnosis and management of epilepsies in children and young people. Scottish Intercollegiate Guidelines Network. Available at: http://www.sign.ac.uk/pdf/sign81.pdf. Accessed September 20, 2008. 39. Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm. 2005;2:569-574. 40. Puranik R, Chow CK, Duflou JA, et al. Sudden death in the young. Heart Rhythm. 2005;2:1277-1282. 41. Doolan A, Langlois N, Semsarian C. Causes of sudden cardiac death in young Australians. Med J Aust. 2004;180:110-112. 42. Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007;49:240-246. 43. Quaglini S, Rognoni C, Spazzolini C, et al. Cost-effectiveness of neonatal ECG screening for the long QT syndrome. Eur Heart J. 2006;27:1824-1832.
Residents’ Perspective: Call for Submissions The Residents’ Perspective section of Annals of Emergency Medicine has been a fixture in the journal since 1993 and provides a peer-reviewed venue for the unique perspective of the resident physician. We publish brief articles authored or co-authored by residents, including data-based reviews of important topics that have not been well covered elsewhere, informative instructional pieces of particular interest to residents, and occasionally, well-referenced position papers. We also welcome small-scale original research articles, especially those that address educational innovations and are presented in the context of a broader discussion of the current literature. We do not publish individual opinion pieces. We are particularly, though not exclusively, interested in pieces co-authored by residents and expert faculty in the field. If you have a topic you would like to cover and are not able to find a co-author, please contact us, as we may be able to suggest one. To develop a manuscript for the Residents’ Perspective section, please complete a brief literature review on your chosen topic to ensure that it has not recently been covered elsewhere and then submit a 300-word structured abstract. The abstract should include the following information: the proposed title and authors (not included in the 300 words); a brief background of the topic, including its significance to emergency medicine practice; an outline of the proposed structure of the article; and any pertinent references. If you are interested in submitting a well-referenced original manuscript that is already completed, please contact us by e-mail. All submitted abstracts should be received by July 14th, 2009. Once abstracts have been approved, final manuscripts should be received within 2 months of approval date. Submit abstracts by email to Aaron Brown, MD and Suzanne Lippert, MD, MS, Resident Fellows, at [email protected].
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