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A Case That Is Not for the Faint of Heart
A Case That Is Not for the Faint of Heart Amy McGregor A 5-year-old was admitted after an episode of loss of consciousness and an episode of convulsive activity. Information that aids in differentiating seizures and syncope is discussed. Semin Pediatr Neurol 15:167–173 © 2008 Elsevier Inc. All rights reserved.
A
5-year-old male with a family history of seizure-related deaths was evaluated in the epilepsy monitoring unit (EMU) for possible seizures. His first event occurred at 4 years of age. He was outdoors and suddenly felt as if he was going to fall. He tried to hold onto his father’s truck but was not able to catch himself. His mother saw him trying to get up from the ground. When she approached him, he fell backwards, his eyes rolled back, and he lost consciousness. He was unconscious for 2 to 3 minutes. He had no convulsive activity but did have urinary incontinence. He was briefly confused. At the time of the event, he was taking no medications. He was seen at an outside emergency room where a computed tomography scan and electrocardiogram (EKG) were reportedly normal. The patient underwent routine and sleep-deprived electroencephalograms (EEGs) that were normal. A Holter monitor showed 1 ventricular couplet and 45 beats in ventricular bigeminy primarily in 2 runs but no ventricular tachycardia. He had recently been placed on methylphenidate for attention-deficit hyperactivity disorder. He was referred to the cardiology department, and methylphenidate was discontinued. He underwent an echocardiogram and a cardiac catheterization with a comprehensive electrophysiology study, which were normal. The patient had a second event at 5 years of age. He was on a ride at the fair, and his mother believes he became scared. The patient slumped over and his eyes rolled up. He became blue around his mouth and lost consciousness. He had convulsive activity for 3 to 4 minutes and then was confused for 1 to 2 minutes. He also had urinary incontinence associated with this event. A repeat EEG was unremarkable. Birth history was unremarkable. The mother said that the patient’s development was normal, but she had difficulty remembering specific milestones. In addition to attention-
From the University of Tennessee Health Science Center, LeBonheur Comprehensive Epilepsy Program, Neuroscience Institute, LeBonheur Children’s Medical Center, Memphis, TN. Address reprint requests to Amy McGregor, 777 Washington Avenue Suite 335, Memphis, TN 38105. E-mail: [email protected]
1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2008.10.003
deficit hyperactivity disorder, the patient also had a history of learning problems. He had no previous hospitalizations. The patient’s mother was giving him methylphenidate intermittently at the time of admission to the EMU. (She did not think that she had given it on the day of the second event.) The patient’s family history was remarkable for seizure activity in his sister, maternal grandmother, and maternal uncle. The patient’s sister and maternal grandmother died after seizure activity. His sister was 4 years old at the time of her death. During her first seizure, she fell into a pool and died. The patient’s grandmother knew she was going to have a seizure while driving and pulled over to the side of the road. She had profuse secretions during the seizure. The mother said that the patient’s grandmother “swallowed her tongue and died.” At the time of admission to the EMU, the patient’s general and neurologic examinations were normal. Methylphenidate was discontinued. Magnetic resonance imaging of the brain with epilepsy protocol was unremarkable. Continuous video-EEG monitoring for 72 hours showed no epileptiform discharges. A 24-hour Holter monitor was normal. Because of the family history of sudden deaths and the negative video-EEG monitoring, the cardiology department performed an epinephrine challenge test. During the test, he had QTc (QT interval corrected for heart rate) prolongation associated with torsade de pointes requiring defibrillation (Fig 1). He was diagnosed with long QT syndrome, transferred to the cardiac floor, and metoprolol was started. An EKG performed the next day showed a QTc of 465 milliseconds. While on metoprolol, he had one syncopal episode after playing outside. His mother stated that he came in to sit on the couch, his eyes rolled back in his head, and he was unresponsive. She shook him, and he returned to his normal state. Because of continued syncope despite medication, he underwent implantable cardioverter defibrillator (ICD) placement. Genetic testing has not yet been completed. 167
A. Mcgregor
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Figure 1 Sustained torsade de pointes. Infusion of epinephrine resulted in a marked increase in the QT interval. The baseline heart rate was 88 bpm (beats per minute) with a QTc (QT interval corrected for heart rate) of 448 ms. During epinephrine infusion, the rate increased to 97 bpm with a QTc of 490 ms. Then, his rhythm degenerated to torsade de pointes.
Discussion Differentiating Syncope From Seizures Given the patient’s diagnosis, he most likely has had episodes of syncope and an episode of convulsive syncope rather than seizures. The signs and symptoms of seizures and syncope, particularly convulsive syncope, overlap. One study showed that myoclonic activity, head turning, oral automatisms, auditory and visual hallucinations, and eye opening occurred in the majority of cases of syncope.1 Pupil dilation and incontinence can also occur.2 To make matters more confusing, seizures can result in syncope. Specifically, seizure activity can cause asystole, resulting in collapse.3-5 Clues that help to differentiate syncope from seizures include pallor, diaphoresis, lightheadedness or other presyncopal symptoms, and relatively brief unconsciousness.3,6 If the episodes are affected by position, level of activity, or environmental temperature, then syncope is more likely.6 If syncope is suspected, an EKG is indicated according to American Heart Association practice guidelines.7 If the history, physical examination, and EKG are not diagnostic for orthostatic hypotension or neurocardiogenic syncope, then further evaluation, such as an echocardiogram and exercise test, is recommended to investigate for more dangerous conditions. Indications of a serious etiology include syncope
without a trigger or prodrome, syncope during exertion or swimming, syncope associated with palpitations or chest pain, convulsive activity, and a family history of cardiac death at an early age.8 In these cases, evaluation by a cardiologist is particularly important. A cardiology evaluation is also indicated if syncope is recurrent, if there is a family history of recurrent syncope, or if syncope occurs in response to noxious stimuli.9 A cardiology evaluation is recommended before starting psychotherapeutic agents, including stimulants, if a patient has palpitations, presyncope, syncope, or a family history of long QT syndrome (LQTS) or sudden, unexplained death.10 A seizure is more likely than syncope if the patient has an aura, prodromal mood changes, cyanosis, tongue biting, urinary incontinence, postictal confusion, or focal neurologic signs.6,11 Video-EEG monitoring may aid in differentiating seizure activity and convulsive syncope.11 If a patient falls suddenly during a partial seizure, EEG-EKG monitoring is recommended because this may indicate ictal asystole.4,12 Although some patients with ictal asystole have an obvious complex partial seizure before losing tone, other patients with ictal asystole fall at the onset of the seizure.5 There is concern that ictal asystole contributes to sudden unexplained death in epilepsy, but this has not been proven.5,12,13 Regardless, ictal asystole is an indication for a cardiologic evaluation.12
Not for the faint of heart
LQTS LQTS is a group of genetic disorders that cause slowed ventricular repolarization and prolongation of the QT interval usually as a result of changes in cardiac ion channels.14 The QT interval is the EKG manifestation of ventricular repolarization; prolongation of the QT interval may be caused by decreased repolarizing currents or increased late depolarizing currents.15 Torsade de pointes, a polymorphic ventricular tachycardia, is the classic dysrhythmia associated with LQTS. Self-limited torsade de pointes results in syncope.16 However, torsade de pointes can result in ventricular fibrillation, cardiac arrest, and death.17 Therefore, LQTS may cause presyncope, syncope, palpitations, cardiac arrest, or sudden death.18,19 There may be a family history of drowning, sudden infant death syndrome, or death while driving, as described in the case.19 As alluded to previously, LQTS may present with seizures/ epilepsy.20-24 Studies of these patients have resulted in a list of characteristics that help to differentiate patients with LQTS from those with seizures. Loss of consciousness before seizure activity is suggestive of LQTS.24 Presyncopal symptoms; a family history of sudden death, deafness, or arrhythmias; and palpitations are also clues that these patients have LQTS rather than seizures.22 There may be a precipitating factor such as a loud noise or surge of adrenaline.21 The neurologic examination, EEG, and imaging are typically normal.22 It has been stated that the EKG lead during an EEG can aid in this diagnosis; however, it may be normal.20 Since many of the genes that cause LQTS are expressed in the brain, and ion channel mutations can cause idiopathic epilepsy, there has been speculation that there is a link between LQTS, epilepsy, and SUDEP (sudden unexplained death in epilepsy); however, data is lacking at this time.25,26 Diagnosis As noted earlier, LQTS is associated with QT interval prolongation. The QT interval is measured from the beginning of the QRS complex to the end of the T-wave in leads II and V5 or V6.27 A U-wave should not be included unless it is fused with the T-wave.28 Inappropriate inclusion of the U-wave can lead to overdiagnosis, which can result in unnecessary treatment.29 The mean QT interval value of 3 to 5 heartbeats is calculated, and the longest value is determined.27 Typically, the QT interval corrected for heart rate (the QTc) is used for diagnosis of LQTS. Bazett’s formula is used to calculate this; the QTc is equal to the QT interval divided by the square root of the RR interval (QTc ⫽ QT/公RR). However, this is not accurate at slow and fast heart rates. Normal values for the QTc vary with age and sex; it is normally less than 460 milliseconds in women and 440 milliseconds in men.19 In children 1 to 15 years of age, Goldenberg recommended defining a normal QTc as ⬍440 milliseconds and a prolonged QTc as ⬎ 460 milliseconds.27 There are multiple problems with using the QTc alone to diagnose LQTS. An individual’s QTc value can vary from EKG to EKG.30 Also, studies have shown that most physicians are unable to calculate the QTc, including many cardiologists.31 In addition, there are multiple acquired causes of a prolonged
169 QT interval include hypocalcemia, hypokalemia, hypomagnesemia, hypothyroidism, myocardial ischemia, cardiomyopathies, hypothermia, and certain medications.18,19,21 Furthermore, carriers of LQTS mutations may have QTc values that overlap with normal individuals.29,32 Approximately 25% to 50% of patients with the most common LQTS genotypes have a nondiagnostic QTc.33 Before genetic testing, a scoring system was created to assist in identifying patients with LQTS; it is sometimes referred to as the Schwartz score.34 This score used EKG findings (QTc, torsade de pointes, T-wave alternans, a notched T-wave in 3 leads, or low heart rate), clinical history (syncope or congenital deafness), and family history (definite LQTS or unexplained sudden cardiac death in an immediate family member who is younger than 30) to determine the probability that a patient has LQTS. The scoring was revised slightly in 2006.30 Other testing may be helpful in diagnosing LQTS. Ambulatory monitoring or checking EKGs in family members may aid in diagnosis.28 Exercise testing and epinephrine QT stress testing may also reveal the diagnosis in certain types of LQTS.28,33 The epinephrine test has been found to be safe, and, unlike the patient discussed earlier, usually patients do not require defibrillation.33 Of note, beta-blockers, which are often used to treat LQTS, interfere with this test. Genetics Before molecular genetic testing, LQTS was divided into Romano-Ward and Jervell and Lange-Nielson syndromes. Romano-Ward syndrome is autosomal dominant, and Jervell and Lange-Nielson syndrome is autosomal recessive and associated with deafness. Currently, there are 11 LQT subtypes.35 However, some authors believe that not all of the subtypes should be considered part of LQTS.30,36 The most prevalent forms of LQTS are LQT1, LQT2, and LQT3.36 LQT1, which is the most common type of LQTS, is caused by mutations in the KCNQ1 gene. LQT2 is caused by a mutation in the KCNH2 gene, which is also known as HERG. LQT1 and LQT2, respectively, affect slowly and rapidly acting repolarizing cardiac potassium currents.15 LQT3 results from the gain of function of cardiac sodium channels rather than a loss of potassium channel function.14 Specifically, a mutation in the SCN5A gene causes LQT3. LQT4, LQT5, and LQT6 are, respectively, because of mutations in the ANK2, KCNE1, and KCNE2 genes.36 LQT7, which is caused by mutations in the KCNJ2 gene, is associated with periodic paralysis.35 LQT8, or Timothy syndrome, is the most malignant form of LQTS.28 It is caused by a mutation in the CACNA1C gene, affects multiple organ systems, and is associated with autism.36 LQT9, LQT10, and LQT11 are caused by mutations in the CAV3, SCN4B, and AKAP9 genes, respectively.35 Therefore, LQT1, LQT2, LQT5, LQT6, LQT7, and LQT11 affect potassium currents; LQT3 and LQT10 affect sodium currents; and LQT8 affects calcium currents.15,35,37 Ackerman recommended genetic testing for LQTS in the following situations: a significantly prolonged QT of unknown etiology (eg, QTc ⬎500 milliseconds), if LQTS is suspected on clinical grounds, patients with medication-in-
170 duced torsade de pointes or aborted cardiac arrest, and firstdegree relatives of patients who are genotype positive.16 Because of false-negatives, he also recommended retesting patients with strongly suspected LQTS if testing had not been performed recently or if the patients had limited genetic testing. Schwartz advised genotyping each proband followed by molecular screening of all family members.30 Because carriers have a risk of life-threatening arrhythmias if exposed to specific medications, he stated “. . . it is no longer possible to state that a first-degree relative of an LQTS patient is ‘not affected’ on the basis of a normal ECG. It has now become a medical duty to do everything possible to identify ‘silent mutation carriers’.” In Napolitano’s genotyping study, 40% of family members who were carriers did not have an abnormal QTc.32 Also, only 12% of probands had a de novo mutation; 88% inherited the mutation. However, a mutation may not be identified in all LQTS patients; many families have a specific mutation unique to the family.28 A number of genotype-phenotype correlations have been found. LQT1, LQT2, and LQT3 are each associated with specific T-wave repolarization patterns.38 Symptoms usually occur earlier in patients with LQT1 than in patients with LQT2 or LQT3.28 Cardiac events are more common in LQT1 and LQT2 but are more likely to be lethal in LQT3.39 Sympathetic activation results in life-threatening events for patients with LQT1.30 In fact, each genotype is associated with specific triggers of arrhythmia.40 Exercise, especially swimming, is a trigger for patients with LQT1, auditory stimuli are triggers for patients with LQT2, and sleep and rest are triggers for patients with LQT3.30,40,41 Exercise testing and epinephrine QT stress testing are helpful for the diagnosis of patients with LQT1.28,33 In these patients, epinephrine infusion causes prolongation of the QT interval rather than the normal decrease.33 Prognosis In addition to genotype, different mutations and variable penetrance affect the clinical presentation.15 A parent who is an asymptomatic carrier can have a child who is symptomatic, and a symptomatic parent can have an asymptomatic child.42 It has been proposed that modifier genes or polymorphisms help to account for phenotypic variation.30 Aside from genotype, a number of factors help to predict risk. The duration of the QT interval is a major risk factor.43 Specifically, a QTc of ⱖ500 milliseconds is associated with a higher risk for cardiac events such as syncope, aborted cardiac arrest, and sudden cardiac death.18 Also, a history of syncope is a strong predictor of future life-threatening cardiac events.18 A QTc ⱖ500 milliseconds and a history of syncope predict risk in preadolescent children as well.44 In addition, male sex is associated with a significantly higher risk of lethal or near-lethal events in this age group. Sudden death of a sibling is associated with an increased risk of syncope but not with an increased risk of aborted cardiac arrest or LQTS-related death.45 Treatment According to American College of Cardiology/American Heart Association/European Society of Cardiology practice
A. Mcgregor guidelines, lifestyle changes are a class I recommendation.43 Specifically, patients with LQTS should not participate in competitive sports. Patients with LQT1 should be cautious about swimming. LQT2 patients, who are sensitive to auditory stimuli, should avoid placing telephones and alarms next to the bed. They may also need to muffle telephones and doorbells.28 It has been recommended that patients with LQT2 (who can have events during sleep) and patients with LQT3 (who classically have events during sleep) have a monitor/intercom next to their bed in case they give a gasp because of torsade de pointes.36 Patients with LQTS should avoid medications that prolong the QT interval or deplete potassium or magnesium.43 A list of medications that can affect the QT interval is published by the Arizona Center for Education and Research on Therapeutics and is available online at www. qtdrugs.org/medical-pros/drug-lists/drug-lists.cfm.36 Stimulants do not affect the QT interval, but they have sympathomimetic characteristics and can increase heart rate.46 The use of beta-blockers in patients with a clinical diagnosis of LQTS is a class I recommendation.43 The effectiveness of beta-blockers in preventing fatal cardiac events has been shown in children as well as adults.18,44 There is evidence showing that beta-blockers may reduce sudden cardiac death in patients with a LQTS gene mutation and a normal QT interval; this is a class IIa recommendation.43 Beta-blockers have been shown to be more effective in treating patients with LQT1 than LQT2 and LQT3.47 It is thought that the antiadrenergic properties of beta-blockers help to prevent the sympathetic activation that triggers events in LQT1 patients.30 It has been suggested that beta-blockers should be avoided in patients with LQT3 syndrome in whom arrhythmia is more likely during rest.14 The concern is that beta-blockers, which inhibit sympathetic activity, may in fact increase the risk of arrhythmia. It has been shown that the QT prolongs at low heart rates and at night in LQT3 patients.48,49 However, other authors state that beta-blockers do not harm LQT3 patients but concede that they may not be fully protective.30 Mexiletine, which is a sodium channel blocker, has also been used with some success in LQT3 patients (who have sodium channel mutations resulting in gain of function).36 Implantable cardioverter defibrillator (ICD) implantation is a class I recommendation for patients on beta-blockers who have suffered cardiac arrest if they are functional and expected to survive more than 1 year.43 It is a class IIa recommendation for patients on beta-blockers who experience syncope or ventricular tachycardia. It may be considered in patients with a higher risk of cardiac arrest, such as patients with LQT2 or LTQ3, to prevent sudden cardiac death; this is a class IIb recommendation. However, there are potential disadvantages of ICD implantation in young patients such as the need for battery replacements and the stress of receiving a discharge while conscious.36 According to American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines, permanent pacing is “reasonable for high-risk patients with congenital long-QT syndrome”; it is a class IIa recommendation.50 Crotti et al stated that implantation of an ICD with pacing
Not for the faint of heart modes is probably more reasonable than a pacemaker, and pacemakers should not be used alone in the treatment of LQTS.36 Pacing has also been used for infants in whom ICD implantation is difficult; it allows the dose of beta-blockers to be maximized in these patients.30 Left cardiac sympathetic denervation is a class IIb recommendation for patients having syncope, torsade de pointes, or cardiac arrest despite beta-blocker therapy.43 It has also been recommended for patients with an ICD receiving multiple shocks.30 However, cardiac events including sudden death may continue to occur despite the procedure.51
Case Discussion Given the patient’s response to the ride at the fair and during epinephrine testing, the author suspects that he has LQT1. She is thankful that the patient did not have a similar episode during placement of the EEG leads or intravenous line. It has been recommended that tact be used when describing upsetting diagnoses or procedures to patients with QT prolongation because adrenergic surges may cause torsade de pointes.21 Genetic testing of the mother will probably show that she carries the same mutation as her son. The maternal uncle may also carry this mutation, as he has been diagnosed with “seizures.” The patient’s sister and maternal grandmother in all probability had sudden death caused by LQTS. Kaufman’s study indicates that the patient is not at higher risk for death because of his sister’s death; however, his sex and history of syncope suggest that he is at increased risk according to Goldenberg’s study.44,45 According to American College of Cardiology/American Heart Association/European Society of Cardiology practice guidelines, it was reasonable to place an ICD because he had syncope while taking a betablocker.43
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Conclusion This case shows the need for neurologists to be aware of cardiac causes of neurologic presentations because some etiologies may be lethal. Neurologists need to be aware of indications for cardiology referral. It should also be kept in mind that a normal EKG does not rule out a cardiac etiology. Epilepsy monitoring units need to be prepared in case of cardiac arrest in “seizure” patients with malignant cardiac arrhythmias and patients with ictal asystole.
19. 20.
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Acknowledgment I would like to thank Dr. Glenn Wetzel for his clinical assistance and for providing the figure.
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References 1. Lempert T, Bauer M, Schmidt D: Syncope: A videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 36:233-237, 2004 2. Rocamora R, Kurthen M, Lickfett L, et al: Cardiac asystole in epilepsy: Clinical and neurophysiologic features. Epilepsia 44:179-185, 2003 3. Krumholz A, Hopp J: Falls give another reason for taking seizures to heart. Neurology 70:1874-1875, 2008 4. Rubboli G, Bisulli F, Michelucci R, et al: Sudden falls due to seizure-
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induced cardiac asystole in drug-resistant focal epilepsy. Neurology 70:1933-1935, 2008 Schuele SU, Bermeo AC, Alexopoulos AV, et al: Video-electrographic and clinical features in patients with ictal asystole. Neurology 69:434441, 2007 Sheldon R, Rose S, Ritchie D, et al: Historical criteria that distinguish syncope and seizures. J Am Coll Cardiol 40:142-148, 2002 Strickberger SA, Benson DW, Biaggioni I, et al: AHA/ACCF Scientific Statement on the evaluation of syncope: From the American Heart Association Councils on Clinical Cardiology. Cardiovascular Nursing, Cardiovascular Disease in the Young, and Stroke, and the Quality of Care and Outcomes Research Interdisciplinary Working Group; and the American College of Cardiology Foundation: in collaboration with the Heart Rhythm Society: Endorsed by the American Autonomic Society. Circulation 113:316-327, 2006 Fish FA: Screening for sudden death in young patients. Semin Pediatr Neurol 12:39-51, 2005 Strieper MJ: Distinguishing benign syncope from life-threatening cardiac causes of syncope. Semin Pediatr Neurol 12:32-38, 2005 Gutgesell H, Atkins D, Barst R, et al: Cardiovascular monitoring of children and adolescents receiving psychotropic drugs: A statement for healthcare professionals from the Committee on Congenital Cardiac Defects. Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 99:979-982, 1999 McKeon A, Vaughn C, Delanty N: Seizure versus syncope. Lancet Neurol 5:171-180, 2006 So NK, Sperling MR: Ictal asystole and SUDEP. Neurology 69:423-424, 2007 Leung H, Kwan P, Elger CE: Finding the missing link between ictal bradyarrhythmia, ictal asystole, and sudden unexplained death in epilepsy. Epilepsy Behav 9:19-30, 2006 Boussy T, Paparella G, de Asmundis C, et al: Genetic basis of ventricular arrhythmias. Cardiol Clin 26:335-353, 2008 Moss AJ, Kass RS: Long QT syndrome: From channels to cardiac arrhythmias. J Clin Invest 115:2018-2024, 2005 Ackerman MJ: Cardiac causes of sudden unexpected death in children and their relationship to seizures and syncope: Genetic testing for cardiac electropathies. Semin Pediatr Neurol 12:52-58, 2005 Vincent GM: The long QT and Brugada syndromes: causes of syncope and sudden cardiac death in children and young adults. Semin Pediatr Neurol 12:15-24, 2005 Goldenberg I, Moss AJ: Long QT syndrome. J Am Coll Cardiol 51: 2291-2300, 2008 Roden DM: Long-QT syndrome. N Engl J Med 358:169-176, 2008 Allan WC, Gospe SM: Seizures, syncope, or breath-holding presenting to the pediatric neurologist—When is the etiology a life-threatening arrhythmia? Semin Pediatr Neurol 12:2-9, 2005 Hunt DPJ, Tang K: Long QT: Syndrome presenting as epileptic seizures in an adult. Emerg Med J 22:600-601, 2005 Pacia SV, Devinsky O, Luciano DJ, et al: The prolonged QT syndrome presenting as epilepsy. Neurology 44:1408-1410, 1994 Rossenbacker T, Nuyens D, Paesschen WV, et al: Epilepsy-video monitoring of long QT syndrome-related aborted sudden death. Heart Rhythm 4:1366-1367, 2007 Singh B, al Shahwan SA, Habbab MA, et al: Idiopathic long QT syndrome: Asking the right question. Lancet 341:741-742, 1993 Hindocha N, Nashef L, Elmslie F, et al: Two cases of sudden unexplained death in epilepsy in a GEFS⫹ family with an SCN1A mutation. Epilepsia 49:360-364, 2008 Nashef L, Hindocha N, Makoff A: Risk factors in sudden death in epilepsy (SUDEP): The quest for mechanisms. Epilepsia 48:859-871, 2007 Goldenberg I, Moss AJ, Zareba W: QT interval: How to measure it and what is “normal.” J Cardiovasc Electrophysiol 17:333-336, 2006 Vohra J: The long QT syndrome. Heart Lung Circ 16:S5-S12, 2007 Taggart NW, Haglund CM, Tester DJ, et al: Diagnostic miscues in congenital long-QT syndrome. Circulation 115:2613-2620, 2007 Schwartz PJ: The congenital long QT syndromes from genotype to phenotype: Clinical implications. J Intern Med 259:39-47, 2006
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172 31. 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 2:569-574, 2005 32. Napolitano C, Priori SG, Schwartz PJ: Genetic testing in the long QT syndrome: Development and validation of an efficient approach to genotyping in clinical practice. JAMA 294:2975-2980, 2005 33. Vyas H, Hejlik J, Ackerman MJ: Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: Diagnostic accuracy of the paradoxical QT response. Circulation 113:1385-1392, 2006 34. Schwartz PJ, Moss AJ, Vincent GM, et al: Diagnostic criteria for the long QT syndrome: An update. Circulation 88:782-784, 1993 35. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: {192500}: {2/26/2008}. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed July 28, 2008 36. Crotti L, Celano G, Dagradi F, et al: Congenital long QT syndrome. Orphanet J Rare Dis 3:18, 2008 37. Chen L, Marquardt ML, Tester DJ, et al: Mutation of an A-kinaseanchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A 104:20990-20995, 2007 38. Moss AJ, Zareba W, Benhorin J, et al: ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 92:2929-2934, 1995 39. Zareba W, Moss AJ, Schwartz PJ, et al: Influence of the genotype on the clinical course of the long-QT syndrome. N Engl J Med 339:960-965, 1998 40. Schwartz PJ, Priori SG, Spazzolini C, et al: Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation 103:89-95, 2001 41. Moss AJ, Robinson JL, Gessman L, et al: Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol 84:876-879, 1999 42. Priori SG, Napolitano C, Schwarz PJ: Low penetrance in the Long-QT syndrome: Clinical impact. Circulation 99:529-533, 1999 43. Zipes DP, Camm AJ, Borggrefe M, et al: ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the
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Prevention of Sudden Cardiac Death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114:e385-e484, 2006 Goldenberg I, Moss AJ, Peterson DR, et al: Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 117:2184-2191, 2008 Kaufman ES, McNitt S, Moss AJ, et al: Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm 5:831-836, 2008 Wilens TE, Prince JB, Spencer TJ, et al: Stimulants and sudden death: What is a physician to do? Pediatrics 118:1215-1219, 2006 Priori SG, Napolitano C, Schwartz P, et al: Association of long QT syndrome loci and cardiac events among patients treated with ß-blockers. JAMA 292:1341-1344, 2004 Schwartz PJ, Priori SG, Locati EH, et al: Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na⫹ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 92:3381-3386, 1995 Stramba-Badiale M, Priori SG, Napolitano C, et al: Gene-specific differences in the circadian variation of ventricular repolarization in the long QT syndrome: A key to sudden death during sleep? Ital Heart J 1:323328, 2000 Epstein AE, DiMarco JP, Ellenbogen KA, et al: ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): Developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. Circulation 117:e350-e408, 2008 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 109:1826-33, 2004
EDITORIAL COMMENT
D
r McGregor’s case report presents a boy with episodes of loss of consciousness who had both a negative neurologic and cardiologic evaluation before her involvement. These evaluations as well as the evaluation in Dr McGregor’s epilepsy monitoring unit were apparently prompted by a family history of death in the patient’s sister and maternal grandmother after seizures. After negative video electroencephalographic monitoring for 72 hours, the patient underwent an epinephrine challenge test in the pediatric cardiology unit. This provoked prolongation of the corrected QT interval and the ventricular tachycardia, torsades de pointes, which required defibrillation. These events suggest that the patient’s episodes of loss of consciousness were caused by long QT syndrome (LQTS). Dr McGregor reviews the multiple channelopathies that constitute long QT syndrome and presents a view from the literature concerning when to evaluate the patient with loss of consciousness for LQTS. No matter how it is approached, the evaluation of these conditions is daunting and far from straightforward. At the risk of oversimplifying this difficult problem, the following points should be made. 1. First, LQTS is a needle in a haystack, a serious but relatively rare condition in comparison to other causes of lapse of consciousness. Estimates of the prevalence of all forms of
LQTS combined are on the order of 1 in 3,000 (see Gene Reviews: Romano-Ward Syndrome, www.ncbi.nlm.nih.gov/ bookshelf/br.fcgi?book⫽gene&part⫽rws). Syncope occurs in 1 in 10 to 15 children. This point is emphasized by the authors in a series of reviews of the problem of sudden death after syncope or seizures in the March 2005 issue of Seminars in Pediatric Neurology. In that issue, Dr Fish (Fish FA: Screening for sudden death in young patients. Semin Pediatr Neurol 12:39-51, 2005) suggests the following red flags should be heeded when deciding who to evaluate (Table 1).
Table 1 Syncope: Red Flags The absence of an identifiable trigger (not associated with upright posture or noxious stimulus) Absence of an identifiable prodrome Syncope during exertion Syncope while swimming Associated with palpitations or chest pain Associated with, or resulting in, a brief “seizure-like” event Syncope in a patient with known family history of early cardiac death
A
5-year-old male with a family history of seizure-related deaths was evaluated in the epilepsy monitoring unit (EMU) for possible seizures. His first event occurred at 4 years of age. He was outdoors and suddenly felt as if he was going to fall. He tried to hold onto his father’s truck but was not able to catch himself. His mother saw him trying to get up from the ground. When she approached him, he fell backwards, his eyes rolled back, and he lost consciousness. He was unconscious for 2 to 3 minutes. He had no convulsive activity but did have urinary incontinence. He was briefly confused. At the time of the event, he was taking no medications. He was seen at an outside emergency room where a computed tomography scan and electrocardiogram (EKG) were reportedly normal. The patient underwent routine and sleep-deprived electroencephalograms (EEGs) that were normal. A Holter monitor showed 1 ventricular couplet and 45 beats in ventricular bigeminy primarily in 2 runs but no ventricular tachycardia. He had recently been placed on methylphenidate for attention-deficit hyperactivity disorder. He was referred to the cardiology department, and methylphenidate was discontinued. He underwent an echocardiogram and a cardiac catheterization with a comprehensive electrophysiology study, which were normal. The patient had a second event at 5 years of age. He was on a ride at the fair, and his mother believes he became scared. The patient slumped over and his eyes rolled up. He became blue around his mouth and lost consciousness. He had convulsive activity for 3 to 4 minutes and then was confused for 1 to 2 minutes. He also had urinary incontinence associated with this event. A repeat EEG was unremarkable. Birth history was unremarkable. The mother said that the patient’s development was normal, but she had difficulty remembering specific milestones. In addition to attention-
From the University of Tennessee Health Science Center, LeBonheur Comprehensive Epilepsy Program, Neuroscience Institute, LeBonheur Children’s Medical Center, Memphis, TN. Address reprint requests to Amy McGregor, 777 Washington Avenue Suite 335, Memphis, TN 38105. E-mail: [email protected]
1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2008.10.003
deficit hyperactivity disorder, the patient also had a history of learning problems. He had no previous hospitalizations. The patient’s mother was giving him methylphenidate intermittently at the time of admission to the EMU. (She did not think that she had given it on the day of the second event.) The patient’s family history was remarkable for seizure activity in his sister, maternal grandmother, and maternal uncle. The patient’s sister and maternal grandmother died after seizure activity. His sister was 4 years old at the time of her death. During her first seizure, she fell into a pool and died. The patient’s grandmother knew she was going to have a seizure while driving and pulled over to the side of the road. She had profuse secretions during the seizure. The mother said that the patient’s grandmother “swallowed her tongue and died.” At the time of admission to the EMU, the patient’s general and neurologic examinations were normal. Methylphenidate was discontinued. Magnetic resonance imaging of the brain with epilepsy protocol was unremarkable. Continuous video-EEG monitoring for 72 hours showed no epileptiform discharges. A 24-hour Holter monitor was normal. Because of the family history of sudden deaths and the negative video-EEG monitoring, the cardiology department performed an epinephrine challenge test. During the test, he had QTc (QT interval corrected for heart rate) prolongation associated with torsade de pointes requiring defibrillation (Fig 1). He was diagnosed with long QT syndrome, transferred to the cardiac floor, and metoprolol was started. An EKG performed the next day showed a QTc of 465 milliseconds. While on metoprolol, he had one syncopal episode after playing outside. His mother stated that he came in to sit on the couch, his eyes rolled back in his head, and he was unresponsive. She shook him, and he returned to his normal state. Because of continued syncope despite medication, he underwent implantable cardioverter defibrillator (ICD) placement. Genetic testing has not yet been completed. 167
A. Mcgregor
168
Figure 1 Sustained torsade de pointes. Infusion of epinephrine resulted in a marked increase in the QT interval. The baseline heart rate was 88 bpm (beats per minute) with a QTc (QT interval corrected for heart rate) of 448 ms. During epinephrine infusion, the rate increased to 97 bpm with a QTc of 490 ms. Then, his rhythm degenerated to torsade de pointes.
Discussion Differentiating Syncope From Seizures Given the patient’s diagnosis, he most likely has had episodes of syncope and an episode of convulsive syncope rather than seizures. The signs and symptoms of seizures and syncope, particularly convulsive syncope, overlap. One study showed that myoclonic activity, head turning, oral automatisms, auditory and visual hallucinations, and eye opening occurred in the majority of cases of syncope.1 Pupil dilation and incontinence can also occur.2 To make matters more confusing, seizures can result in syncope. Specifically, seizure activity can cause asystole, resulting in collapse.3-5 Clues that help to differentiate syncope from seizures include pallor, diaphoresis, lightheadedness or other presyncopal symptoms, and relatively brief unconsciousness.3,6 If the episodes are affected by position, level of activity, or environmental temperature, then syncope is more likely.6 If syncope is suspected, an EKG is indicated according to American Heart Association practice guidelines.7 If the history, physical examination, and EKG are not diagnostic for orthostatic hypotension or neurocardiogenic syncope, then further evaluation, such as an echocardiogram and exercise test, is recommended to investigate for more dangerous conditions. Indications of a serious etiology include syncope
without a trigger or prodrome, syncope during exertion or swimming, syncope associated with palpitations or chest pain, convulsive activity, and a family history of cardiac death at an early age.8 In these cases, evaluation by a cardiologist is particularly important. A cardiology evaluation is also indicated if syncope is recurrent, if there is a family history of recurrent syncope, or if syncope occurs in response to noxious stimuli.9 A cardiology evaluation is recommended before starting psychotherapeutic agents, including stimulants, if a patient has palpitations, presyncope, syncope, or a family history of long QT syndrome (LQTS) or sudden, unexplained death.10 A seizure is more likely than syncope if the patient has an aura, prodromal mood changes, cyanosis, tongue biting, urinary incontinence, postictal confusion, or focal neurologic signs.6,11 Video-EEG monitoring may aid in differentiating seizure activity and convulsive syncope.11 If a patient falls suddenly during a partial seizure, EEG-EKG monitoring is recommended because this may indicate ictal asystole.4,12 Although some patients with ictal asystole have an obvious complex partial seizure before losing tone, other patients with ictal asystole fall at the onset of the seizure.5 There is concern that ictal asystole contributes to sudden unexplained death in epilepsy, but this has not been proven.5,12,13 Regardless, ictal asystole is an indication for a cardiologic evaluation.12
Not for the faint of heart
LQTS LQTS is a group of genetic disorders that cause slowed ventricular repolarization and prolongation of the QT interval usually as a result of changes in cardiac ion channels.14 The QT interval is the EKG manifestation of ventricular repolarization; prolongation of the QT interval may be caused by decreased repolarizing currents or increased late depolarizing currents.15 Torsade de pointes, a polymorphic ventricular tachycardia, is the classic dysrhythmia associated with LQTS. Self-limited torsade de pointes results in syncope.16 However, torsade de pointes can result in ventricular fibrillation, cardiac arrest, and death.17 Therefore, LQTS may cause presyncope, syncope, palpitations, cardiac arrest, or sudden death.18,19 There may be a family history of drowning, sudden infant death syndrome, or death while driving, as described in the case.19 As alluded to previously, LQTS may present with seizures/ epilepsy.20-24 Studies of these patients have resulted in a list of characteristics that help to differentiate patients with LQTS from those with seizures. Loss of consciousness before seizure activity is suggestive of LQTS.24 Presyncopal symptoms; a family history of sudden death, deafness, or arrhythmias; and palpitations are also clues that these patients have LQTS rather than seizures.22 There may be a precipitating factor such as a loud noise or surge of adrenaline.21 The neurologic examination, EEG, and imaging are typically normal.22 It has been stated that the EKG lead during an EEG can aid in this diagnosis; however, it may be normal.20 Since many of the genes that cause LQTS are expressed in the brain, and ion channel mutations can cause idiopathic epilepsy, there has been speculation that there is a link between LQTS, epilepsy, and SUDEP (sudden unexplained death in epilepsy); however, data is lacking at this time.25,26 Diagnosis As noted earlier, LQTS is associated with QT interval prolongation. The QT interval is measured from the beginning of the QRS complex to the end of the T-wave in leads II and V5 or V6.27 A U-wave should not be included unless it is fused with the T-wave.28 Inappropriate inclusion of the U-wave can lead to overdiagnosis, which can result in unnecessary treatment.29 The mean QT interval value of 3 to 5 heartbeats is calculated, and the longest value is determined.27 Typically, the QT interval corrected for heart rate (the QTc) is used for diagnosis of LQTS. Bazett’s formula is used to calculate this; the QTc is equal to the QT interval divided by the square root of the RR interval (QTc ⫽ QT/公RR). However, this is not accurate at slow and fast heart rates. Normal values for the QTc vary with age and sex; it is normally less than 460 milliseconds in women and 440 milliseconds in men.19 In children 1 to 15 years of age, Goldenberg recommended defining a normal QTc as ⬍440 milliseconds and a prolonged QTc as ⬎ 460 milliseconds.27 There are multiple problems with using the QTc alone to diagnose LQTS. An individual’s QTc value can vary from EKG to EKG.30 Also, studies have shown that most physicians are unable to calculate the QTc, including many cardiologists.31 In addition, there are multiple acquired causes of a prolonged
169 QT interval include hypocalcemia, hypokalemia, hypomagnesemia, hypothyroidism, myocardial ischemia, cardiomyopathies, hypothermia, and certain medications.18,19,21 Furthermore, carriers of LQTS mutations may have QTc values that overlap with normal individuals.29,32 Approximately 25% to 50% of patients with the most common LQTS genotypes have a nondiagnostic QTc.33 Before genetic testing, a scoring system was created to assist in identifying patients with LQTS; it is sometimes referred to as the Schwartz score.34 This score used EKG findings (QTc, torsade de pointes, T-wave alternans, a notched T-wave in 3 leads, or low heart rate), clinical history (syncope or congenital deafness), and family history (definite LQTS or unexplained sudden cardiac death in an immediate family member who is younger than 30) to determine the probability that a patient has LQTS. The scoring was revised slightly in 2006.30 Other testing may be helpful in diagnosing LQTS. Ambulatory monitoring or checking EKGs in family members may aid in diagnosis.28 Exercise testing and epinephrine QT stress testing may also reveal the diagnosis in certain types of LQTS.28,33 The epinephrine test has been found to be safe, and, unlike the patient discussed earlier, usually patients do not require defibrillation.33 Of note, beta-blockers, which are often used to treat LQTS, interfere with this test. Genetics Before molecular genetic testing, LQTS was divided into Romano-Ward and Jervell and Lange-Nielson syndromes. Romano-Ward syndrome is autosomal dominant, and Jervell and Lange-Nielson syndrome is autosomal recessive and associated with deafness. Currently, there are 11 LQT subtypes.35 However, some authors believe that not all of the subtypes should be considered part of LQTS.30,36 The most prevalent forms of LQTS are LQT1, LQT2, and LQT3.36 LQT1, which is the most common type of LQTS, is caused by mutations in the KCNQ1 gene. LQT2 is caused by a mutation in the KCNH2 gene, which is also known as HERG. LQT1 and LQT2, respectively, affect slowly and rapidly acting repolarizing cardiac potassium currents.15 LQT3 results from the gain of function of cardiac sodium channels rather than a loss of potassium channel function.14 Specifically, a mutation in the SCN5A gene causes LQT3. LQT4, LQT5, and LQT6 are, respectively, because of mutations in the ANK2, KCNE1, and KCNE2 genes.36 LQT7, which is caused by mutations in the KCNJ2 gene, is associated with periodic paralysis.35 LQT8, or Timothy syndrome, is the most malignant form of LQTS.28 It is caused by a mutation in the CACNA1C gene, affects multiple organ systems, and is associated with autism.36 LQT9, LQT10, and LQT11 are caused by mutations in the CAV3, SCN4B, and AKAP9 genes, respectively.35 Therefore, LQT1, LQT2, LQT5, LQT6, LQT7, and LQT11 affect potassium currents; LQT3 and LQT10 affect sodium currents; and LQT8 affects calcium currents.15,35,37 Ackerman recommended genetic testing for LQTS in the following situations: a significantly prolonged QT of unknown etiology (eg, QTc ⬎500 milliseconds), if LQTS is suspected on clinical grounds, patients with medication-in-
170 duced torsade de pointes or aborted cardiac arrest, and firstdegree relatives of patients who are genotype positive.16 Because of false-negatives, he also recommended retesting patients with strongly suspected LQTS if testing had not been performed recently or if the patients had limited genetic testing. Schwartz advised genotyping each proband followed by molecular screening of all family members.30 Because carriers have a risk of life-threatening arrhythmias if exposed to specific medications, he stated “. . . it is no longer possible to state that a first-degree relative of an LQTS patient is ‘not affected’ on the basis of a normal ECG. It has now become a medical duty to do everything possible to identify ‘silent mutation carriers’.” In Napolitano’s genotyping study, 40% of family members who were carriers did not have an abnormal QTc.32 Also, only 12% of probands had a de novo mutation; 88% inherited the mutation. However, a mutation may not be identified in all LQTS patients; many families have a specific mutation unique to the family.28 A number of genotype-phenotype correlations have been found. LQT1, LQT2, and LQT3 are each associated with specific T-wave repolarization patterns.38 Symptoms usually occur earlier in patients with LQT1 than in patients with LQT2 or LQT3.28 Cardiac events are more common in LQT1 and LQT2 but are more likely to be lethal in LQT3.39 Sympathetic activation results in life-threatening events for patients with LQT1.30 In fact, each genotype is associated with specific triggers of arrhythmia.40 Exercise, especially swimming, is a trigger for patients with LQT1, auditory stimuli are triggers for patients with LQT2, and sleep and rest are triggers for patients with LQT3.30,40,41 Exercise testing and epinephrine QT stress testing are helpful for the diagnosis of patients with LQT1.28,33 In these patients, epinephrine infusion causes prolongation of the QT interval rather than the normal decrease.33 Prognosis In addition to genotype, different mutations and variable penetrance affect the clinical presentation.15 A parent who is an asymptomatic carrier can have a child who is symptomatic, and a symptomatic parent can have an asymptomatic child.42 It has been proposed that modifier genes or polymorphisms help to account for phenotypic variation.30 Aside from genotype, a number of factors help to predict risk. The duration of the QT interval is a major risk factor.43 Specifically, a QTc of ⱖ500 milliseconds is associated with a higher risk for cardiac events such as syncope, aborted cardiac arrest, and sudden cardiac death.18 Also, a history of syncope is a strong predictor of future life-threatening cardiac events.18 A QTc ⱖ500 milliseconds and a history of syncope predict risk in preadolescent children as well.44 In addition, male sex is associated with a significantly higher risk of lethal or near-lethal events in this age group. Sudden death of a sibling is associated with an increased risk of syncope but not with an increased risk of aborted cardiac arrest or LQTS-related death.45 Treatment According to American College of Cardiology/American Heart Association/European Society of Cardiology practice
A. Mcgregor guidelines, lifestyle changes are a class I recommendation.43 Specifically, patients with LQTS should not participate in competitive sports. Patients with LQT1 should be cautious about swimming. LQT2 patients, who are sensitive to auditory stimuli, should avoid placing telephones and alarms next to the bed. They may also need to muffle telephones and doorbells.28 It has been recommended that patients with LQT2 (who can have events during sleep) and patients with LQT3 (who classically have events during sleep) have a monitor/intercom next to their bed in case they give a gasp because of torsade de pointes.36 Patients with LQTS should avoid medications that prolong the QT interval or deplete potassium or magnesium.43 A list of medications that can affect the QT interval is published by the Arizona Center for Education and Research on Therapeutics and is available online at www. qtdrugs.org/medical-pros/drug-lists/drug-lists.cfm.36 Stimulants do not affect the QT interval, but they have sympathomimetic characteristics and can increase heart rate.46 The use of beta-blockers in patients with a clinical diagnosis of LQTS is a class I recommendation.43 The effectiveness of beta-blockers in preventing fatal cardiac events has been shown in children as well as adults.18,44 There is evidence showing that beta-blockers may reduce sudden cardiac death in patients with a LQTS gene mutation and a normal QT interval; this is a class IIa recommendation.43 Beta-blockers have been shown to be more effective in treating patients with LQT1 than LQT2 and LQT3.47 It is thought that the antiadrenergic properties of beta-blockers help to prevent the sympathetic activation that triggers events in LQT1 patients.30 It has been suggested that beta-blockers should be avoided in patients with LQT3 syndrome in whom arrhythmia is more likely during rest.14 The concern is that beta-blockers, which inhibit sympathetic activity, may in fact increase the risk of arrhythmia. It has been shown that the QT prolongs at low heart rates and at night in LQT3 patients.48,49 However, other authors state that beta-blockers do not harm LQT3 patients but concede that they may not be fully protective.30 Mexiletine, which is a sodium channel blocker, has also been used with some success in LQT3 patients (who have sodium channel mutations resulting in gain of function).36 Implantable cardioverter defibrillator (ICD) implantation is a class I recommendation for patients on beta-blockers who have suffered cardiac arrest if they are functional and expected to survive more than 1 year.43 It is a class IIa recommendation for patients on beta-blockers who experience syncope or ventricular tachycardia. It may be considered in patients with a higher risk of cardiac arrest, such as patients with LQT2 or LTQ3, to prevent sudden cardiac death; this is a class IIb recommendation. However, there are potential disadvantages of ICD implantation in young patients such as the need for battery replacements and the stress of receiving a discharge while conscious.36 According to American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines, permanent pacing is “reasonable for high-risk patients with congenital long-QT syndrome”; it is a class IIa recommendation.50 Crotti et al stated that implantation of an ICD with pacing
Not for the faint of heart modes is probably more reasonable than a pacemaker, and pacemakers should not be used alone in the treatment of LQTS.36 Pacing has also been used for infants in whom ICD implantation is difficult; it allows the dose of beta-blockers to be maximized in these patients.30 Left cardiac sympathetic denervation is a class IIb recommendation for patients having syncope, torsade de pointes, or cardiac arrest despite beta-blocker therapy.43 It has also been recommended for patients with an ICD receiving multiple shocks.30 However, cardiac events including sudden death may continue to occur despite the procedure.51
Case Discussion Given the patient’s response to the ride at the fair and during epinephrine testing, the author suspects that he has LQT1. She is thankful that the patient did not have a similar episode during placement of the EEG leads or intravenous line. It has been recommended that tact be used when describing upsetting diagnoses or procedures to patients with QT prolongation because adrenergic surges may cause torsade de pointes.21 Genetic testing of the mother will probably show that she carries the same mutation as her son. The maternal uncle may also carry this mutation, as he has been diagnosed with “seizures.” The patient’s sister and maternal grandmother in all probability had sudden death caused by LQTS. Kaufman’s study indicates that the patient is not at higher risk for death because of his sister’s death; however, his sex and history of syncope suggest that he is at increased risk according to Goldenberg’s study.44,45 According to American College of Cardiology/American Heart Association/European Society of Cardiology practice guidelines, it was reasonable to place an ICD because he had syncope while taking a betablocker.43
171
5.
6. 7.
8. 9. 10.
11. 12. 13.
14. 15. 16.
17.
18.
Conclusion This case shows the need for neurologists to be aware of cardiac causes of neurologic presentations because some etiologies may be lethal. Neurologists need to be aware of indications for cardiology referral. It should also be kept in mind that a normal EKG does not rule out a cardiac etiology. Epilepsy monitoring units need to be prepared in case of cardiac arrest in “seizure” patients with malignant cardiac arrhythmias and patients with ictal asystole.
19. 20.
21. 22. 23.
24.
Acknowledgment I would like to thank Dr. Glenn Wetzel for his clinical assistance and for providing the figure.
25.
26.
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EDITORIAL COMMENT
D
r McGregor’s case report presents a boy with episodes of loss of consciousness who had both a negative neurologic and cardiologic evaluation before her involvement. These evaluations as well as the evaluation in Dr McGregor’s epilepsy monitoring unit were apparently prompted by a family history of death in the patient’s sister and maternal grandmother after seizures. After negative video electroencephalographic monitoring for 72 hours, the patient underwent an epinephrine challenge test in the pediatric cardiology unit. This provoked prolongation of the corrected QT interval and the ventricular tachycardia, torsades de pointes, which required defibrillation. These events suggest that the patient’s episodes of loss of consciousness were caused by long QT syndrome (LQTS). Dr McGregor reviews the multiple channelopathies that constitute long QT syndrome and presents a view from the literature concerning when to evaluate the patient with loss of consciousness for LQTS. No matter how it is approached, the evaluation of these conditions is daunting and far from straightforward. At the risk of oversimplifying this difficult problem, the following points should be made. 1. First, LQTS is a needle in a haystack, a serious but relatively rare condition in comparison to other causes of lapse of consciousness. Estimates of the prevalence of all forms of
LQTS combined are on the order of 1 in 3,000 (see Gene Reviews: Romano-Ward Syndrome, www.ncbi.nlm.nih.gov/ bookshelf/br.fcgi?book⫽gene&part⫽rws). Syncope occurs in 1 in 10 to 15 children. This point is emphasized by the authors in a series of reviews of the problem of sudden death after syncope or seizures in the March 2005 issue of Seminars in Pediatric Neurology. In that issue, Dr Fish (Fish FA: Screening for sudden death in young patients. Semin Pediatr Neurol 12:39-51, 2005) suggests the following red flags should be heeded when deciding who to evaluate (Table 1).
Table 1 Syncope: Red Flags The absence of an identifiable trigger (not associated with upright posture or noxious stimulus) Absence of an identifiable prodrome Syncope during exertion Syncope while swimming Associated with palpitations or chest pain Associated with, or resulting in, a brief “seizure-like” event Syncope in a patient with known family history of early cardiac death