Advertisement
Mayo Clinic Proceedings Home

Electrical Storm in the Brain and in the Heart: Epilepsy and Brugada Syndrome

      Abstract

      We describe a patient with the coincidence of 2 ion channel disorders with autosomal dominant inheritance: Brugada syndrome, a potentially fatal cardiac condition, and cryptogenic focal epilepsy, likely due to a neurologic channelopathy. Although Brugada syndrome was discovered incidentally, most of the clinical features of epilepsy in this patient shared the risk factor characteristics of sudden unexplained death in epilepsy syndrome. This case provides additional information on the potential interaction between ion channel abnormalities in the heart and in the brain. Furthermore, it may suggest that patients with epilepsy at increased risk for sudden unexplained death in epilepsy syndrome should undergo a careful cardiac evaluation.

      Abbreviations and Acronyms:

      BS (Brugada syndrome), ECG (electrocardiogram), EEG (electroencephalogram), ICD (implantable cardioverter-defibrillator), LQT (long QT), STE (ST elevation), SUDEP (sudden unexplained death in epilepsy), VT (ventricular tachycardia)
      Brugada syndrome (BS) is a rare autosomal dominant genetic disorder hallmarked by the “Brugada electrocardiogram (ECG),” which displays a “pseudo–right bundle branch block” appearance with an ST elevation (STE) in leads V1 to V3, and sudden cardiac death due to ventricular arrhythmias in patients with apparently normal hearts.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      The ECG abnormality and the susceptibility to ventricular arrhythmias are due to a loss-of-function mutation in the HCN5A gene encoding the α subunit of the sodium channel current of the cell membrane. Brugada syndrome is estimated to be responsible for at least 4% of all sudden deaths and at least 20% of deaths in patients with structurally normal hearts.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      Sudden cardiac death occurs at a mean age of 41 years, typically at rest and at night. Presumed precipitating factors of the ventricular arrhythmias include an increase in vagal tone and a febrile state.
      The prevalence of epilepsy is 0.5% to 1%. It is known to carry an up to 24-fold risk of sudden death compared with the general population,
      • Ficker D.M.
      • So E.L.
      • Shen W.K.
      • et al.
      Population-based study of the incidence of sudden unexplained death in epilepsy.
      an entity called sudden unexplained death in epilepsy (SUDEP) syndrome.
      • Leestma J.E.
      • Kalelkar M.B.
      • Teas S.S.
      • et al.
      Sudden unexpected death associated with seizures: analysis of 66 cases.
      The role of ventricular arrhythmias is assumed in at least some of these incidents, and the coincidence of epilepsy and some potentially lethal primary cardiac ion channel disorders has recently been reported.
      • Nashef L.
      • Hindocha N.
      • Makoff A.
      Risk factors in sudden death in epilepsy (SUDEP): the quest for mechanisms.
      • Aurlien D.
      • Leren T.P.
      • Tauboll E.
      • et al.
      New SCN5A mutation in a SUDEP victim with idiopathic epilepsy.
      • Goldman A.M.
      • Glasscock E.
      • Yoo J.
      • et al.
      Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death.
      We describe a patient with asymptomatic BS and concomitant focal epilepsy likely related to abnormal ion channel function with an autosomal dominant inheritance.

      Case Report

      A 41-year-old man was referred for urgent coronary intervention because of a sharp pain in the right side of his chest that had started an hour earlier. The 12-lead ECG transmitted by the ambulance team from the patient’s home and that recorded on his arrival at the hospital are displayed in Figure 1. Transthoracic echocardiography indicated normal left ventricular function with no wall motion abnormality, and the levels of cardiac enzymes and electrolytes were repeatedly within the reference ranges. A computed tomographic angiogram revealed no evidence of aortic dissection or pulmonary embolism. His medical history included the diagnosis of epilepsy at age 16 years on the basis of recurrent seizure spells. His recent medications were levetiracetam and oxcarbazepine. His family history was negative for any cardiac or neurologic disease.
      Figure thumbnail gr1
      Figure 1A, Initial 12-lead electrocardiogram (ECG) transmitted from the patient’s home. B, The 12-lead ECG recorded on arrival at the hospital.
      The patient was admitted to the hospital for evaluation of the abnormalities observed on the initial ECG. Slow intravenous administration of procainamide (400 mg) with an entirely normal starting ECG pattern initiated ventricular tachycardia (VT) at 187 beats/min, which terminated spontaneously after 85 seconds, and a type I Brugada ECG pattern appeared shortly after the VT (Figure 2, A). The patient remained conscious during the VT. A cardiac electrophysiologic study was also performed, and polymorphic VT at 250 beats/min was induced using programmed electrical stimulation from the right ventricular apex with 2 extrastimuli. This VT changed to a regular monomorphic pattern before spontaneous termination after 35 seconds (Figure 2, B). The patient remained responsive at this time; his sensation was somewhat similar to that during the auras before his spontaneous spells. The patient was then referred to an epilepsy clinic for reevaluation of his seizure spells and neurologic status.
      Figure thumbnail gr2
      Figure 2A, Electrocardiograms showing ventricular tachycardia initiated during procainamide infusion and the type I Brugada electrocardiographic pattern after termination. B, Electrocardiograms showing initiation and spontaneous termination of ventricular tachycardia. Tachycardia was initiated with double extrastimuli. BPM = beats/min.
      The detailed neurologic history revealed no previous epileptogenic brain insult. He had lost consciousness for the first time at age 16 years; this was attributed to epilepsy, and carbamazepine was prescribed. Multiple changes in the medication owing to noncompliance with medium daily doses of the drugs through the subsequent years included valproate, oxcarbazepine, and levetiracetam. Despite the therapy, the episodes recurred with variable frequency, usually 5 to 10 times a year, throughout the past 25 years. Almost all the attacks had occurred during the nighttime, and most during the past 2 decades had been witnessed by the patient's spouse and son. They reported that the seizures began with irregular breathing, tonic, approximately symmetrical flexion of both upper extremities, tongue biting, and unresponsiveness. The tonic muscle activity resolved spontaneously within 1 or 2 minutes, but the patient remained confused for 20 to 30 minutes and amnestic regarding the event. No atonic components of the seizures were reported. The episodes were often precipitated by a missed dose of antiepileptic medication or by stress. Recent cerebral computed tomographic and magnetic resonance imaging examination findings at 1.5-T field strength, according to an epilepsy protocol including T1- and T2-weighted images, fluid-attenuated inversion recovery images, and diffusion-weighted sequences, were repeatedly normal. Interictal standard electroencephalograms (EEGs) recorded on several occasions did not show any abnormal slow or epileptiform activity.
      A dual-chamber implantable cardioverter-defibrillator (ICD) was implanted, and the patient was discharged with no change in his antiepileptic medication. At the 6-week follow-up visit he reported 2 recent “usual” episodes of seizure. No arrhythmia was recorded in the memory of the ICD. The patient was referred again to a neurologist, who performed a sleep deprivation test with continuous EEG monitoring. In the 21st hour of sleep deprivation, a habitual seizure was recorded. The EEG showed normal slow sleep activity. A few seconds after awakening, movement-related and electromyographic artifacts occurred, indicating the emergence of some arousing event in the brain. Seven seconds thereafter, a rapid rhythmic seizure discharge with a frequency of approximately 10 Hz appeared in the left frontal area, followed by ipsilateral and contralateral spread (Figure 3). The seizure activity in the remaining part was predominantly left hemispheric. Irregular postictal slowing was present bilaterally. Throughout the attack, the ECG demonstrated sinus tachycardia at 110 beats/min.
      Figure thumbnail gr3
      Figure 3Ictal electroencephalographic recording, longitudinal bipolar montage. The ictal activity begins as a rhythmic discharge in 2 left frontal derivations (time scale, 30:44). It quickly spreads to the parietal cortex bilaterally (time scale, 30:52). Later, slow activity is maximal over most of the left hemisphere, and less abnormal theta activity dominates over the remaining cortex (time scale, 31:01). Note that the amplification changes from the upper to the lower panel.

      Discussion

      An ECG finding not related to the referring diagnosis initiated extensive investigations in this patient to confirm or exclude a potentially lethal condition. The abnormalities observed in the telephonically transmitted ECG (Figure 1, A) were compatible with the classic or type I Brugada ECG pattern, which is characterized by a “coved” shape STE in leads V1 and V2, followed by a negative T wave. Saddleback-type STE (types II and III Brugada ECG pattern) is more prevalent in the general population but is considered less specific for BS. Although the ECG recorded using conventional equipment on arrival at the hospital (Figure 1, B) revealed no abnormalities, it did not exclude the diagnosis because STE in BS is often transient, with spontaneous changes between different types and normal ECG findings. The typical pattern observed in the initial ECG of the patient might have been induced by vagotonia triggered by the sharp chest pain. Sodium channel blockers such as procainamide can be used to unmask the Brugada ECG whenever the disease is suspected.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Veltmann C.
      • Wolpert C.
      • Sacher F.
      • et al.
      Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges.
      The transformation of a normal ECG or the saddleback pattern to a coved STE in response to the drug, as observed in this case, is specific for BS.
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      An electrophysiologic study, which may be considered as a class IIB indication in asymptomatic patients with BS and spontaneous STE,
      • Zipes D.P.
      • Camm A.J.
      • Borggrefe M.
      • et al.
      ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
      was also performed, although its value as a risk stratifier is controversial. Inducible sustained ventricular arrhythmia was associated with an 8-fold increase in the risk of sudden cardiac death compared with noninducible patients in one report,
      • Brugada J.
      • Brugada R.
      • Brugada P.
      Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
      whereas no prognostic value was demonstrated in another study.
      • Priori S.G.
      • Gasparini M.
      • Napolitano C.
      • et al.
      Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry.
      Although possibly not related to any clinical symptom, it was important to diagnose BS because ICD implantation may save the patient’s life in the future.
      • Probst V.
      • Veltmann C.
      • Eckardt L.
      • et al.
      Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
      Of note, ICD is not indicated in all patients diagnosed as having BS. According to the North American guidelines,
      • Zipes D.P.
      • Camm A.J.
      • Borggrefe M.
      • et al.
      ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
      • Epstein A.E.
      • DiMarco J.P.
      • Ellenbogen K.A.
      • 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).
      ICD implantation is reasonable for patients with BS and spontaneous STE in V1 and V2 or V3 who have had syncope (class IIA). According to the second consensus conference on BS,
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      the spontaneous type I ECG pattern with inducible sustained ventricular arrhythmia is a class IIA indication for the device. Although not confirmed by genetic testing or a definite family history, several clinical, EEG, and neuroimaging characteristics observed in this patient were compatible with autosomal dominant nocturnal frontal lobe epilepsy. Important features of this entity include a lack of neurologic symptoms and EEG abnormalities interictally, no computed tomographic–or magnetic resonance imaging–detectable epileptogenic brain pathologic abnormalities, the persistence of seizures throughout adult life with no progressive course, and the occurrence almost exclusively during sleep, often provoked by previous stress and by drug holidays.
      • Scheffer I.E.
      • Bhatia K.P.
      • Lopes-Cendes I.
      • et al.
      Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder.
      Although seizure suggests a primary neurologic problem, it can also be triggered by cerebral hypoperfusion, referred to as syncopal seizure.
      • Petkar S.
      • Hamid T.
      • Iddon P.
      • et al.
      Prolonged implantable electrocardiographic monitoring indicates a high rate of misdiagnosis of epilepsy: REVISE study.
      Some inherited arrhythmia entities are likely to manifest with seizure. The long QT (LQT) syndrome is a classic example of a seizure phenotype (especially LQT2), and almost half of affected patients (mostly children) are misdiagnosed and treated for epilepsy for years before the correct diagnosis is made.
      • Vincent G.M.
      The long QT and Brugada syndromes: causes of unexpected syncope and sudden cardiac death in children and young adults.
      The coincidence of epilepsy and a cardiac channelopathy has also been reported. In a recent case report from Mayo Clinic, concealed LQT2 syndrome and partial temporal lobe epilepsy were diagnosed in a young girl with recurrent seizures and a family history of unexplained sudden death.
      • Anderson H.J.
      • Bos J.M.
      • Meyer F.B.
      • et al.
      Concealed long QT syndrome and intractable partial epilepsy: a case report.
      An incidental diagnosis of BS was also reported in a male patient with a long-standing history of epilepsy.
      • Fauchier L.
      • Babuty D.
      • Cosnay P.
      Epilepsy, Brugada syndrome and the risk of sudden unexpected death.
      In both of those cases and in the present patient alike, the clinical presentation suggested a neurologic background. Note that autosomal dominant nocturnal frontal lobe epilepsy, which was not proved but was suggested by the clinical presentation in this patient, is the only well-delineated human focal epilepsy that is known to result from an abnormal ion channel function in the brain; therefore, a cardiac and a neurologic channelopathy may have coincided in the present patient. Patients with epilepsy carry a 24-fold greater risk of SUDEP syndrome compared with the general population. Although the exact mechanism of death remains unknown, the role of arrhythmias is assumed in at least some of these incidents. Most of the known risk factors for the syndrome,
      • Petkar S.
      • Hamid T.
      • Iddon P.
      • et al.
      Prolonged implantable electrocardiographic monitoring indicates a high rate of misdiagnosis of epilepsy: REVISE study.
      including male sex, epilepsy diagnosed before age 16 years, a long history of seizures, multiple antiepileptic drug changes, failure to achieve remission, and compliance issues, were present in this patient. Brugada syndrome proved by postmortem genetic testing has been reported in a patient with SUDEP syndrome,
      • Aurlien D.
      • Leren T.P.
      • Tauboll E.
      • et al.
      New SCN5A mutation in a SUDEP victim with idiopathic epilepsy.
      and the present patient should also be regarded as a SUDEP syndrome “candidate.” Currently it is not possible to estimate the contribution of genetic cardiac ion channel disorders to SUDEP syndrome because of the often concealed clinical presentation and the rare performance of molecular autopsy. Epilepsies presenting later as SUDEP syndrome typically present clinically at a relatively early stage of life, similar to cardiac ion channel disorders.
      Although there is no convincing clinical evidence that any mutation of a cardiac ion channel gene may cause genuine epilepsy, the possibility of a dual arrhythmogenic potential of an ion channel abnormality coexpressed in the heart and the brain has recently been suggested.
      • Goldman A.M.
      • Glasscock E.
      • Yoo J.
      • et al.
      Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death.
      • Hartmann H.A.
      • Colom L.V.
      • Sutherland M.L.
      • et al.
      Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain.
      Ion channels thought to be specific to the heart, such as the KvLQT1 delayed rectifier channel, have been shown in the forebrain neuronal networks and in brainstem nuclei in mice.
      • Goldman A.M.
      • Glasscock E.
      • Yoo J.
      • et al.
      Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death.
      Mutations in the KCNQ1 gene encoding the KvLQT1 protein are responsible for the most common type of the LQT syndrome (LQT1). Mouse lines bearing dominant human LQT1 mutations exhibit spontaneous seizures, arrhythmias, and even sudden death, and the mouse version of SUDEP syndrome has been observed in one animal. Both BS and LQT3 are linked to a mutation in the SCN5A gene, which has been shown to be selectively expressed in the limbic regions of the rat brain,
      • Hartmann H.A.
      • Colom L.V.
      • Sutherland M.L.
      • et al.
      Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain.
      suggesting that arrhythmias of the heart and brain may be related in some cases. Until we have a better understanding of the real coincidence and the potential interactions between genuine electrical diseases of the heart and brain, it remains important for the clinician to enact a multidisciplinary approach and a wide-angle view while treating these patients. Epileptic patients presenting with clinical characteristics that suggest an increased risk of SUDEP syndrome should also undergo a careful cardiac evaluation, and fainting spells in patients with cardiac ion channel disease may require further neurologic workup if the clinical scenario is atypical for cardiac syncope.

      References

        • Antzelevitch C.
        • Brugada P.
        • Borggrefe M.
        • et al.
        Brugada syndrome: report of the second consensus conference.
        Circulation. 2005; 111: 659-670
        • Ficker D.M.
        • So E.L.
        • Shen W.K.
        • et al.
        Population-based study of the incidence of sudden unexplained death in epilepsy.
        Neurology. 1998; 51: 1270-1274
        • Leestma J.E.
        • Kalelkar M.B.
        • Teas S.S.
        • et al.
        Sudden unexpected death associated with seizures: analysis of 66 cases.
        Epilepsia. 1984; 25: 84-88
        • Nashef L.
        • Hindocha N.
        • Makoff A.
        Risk factors in sudden death in epilepsy (SUDEP): the quest for mechanisms.
        Epilepsia. 2007; 48: 859-871
        • Aurlien D.
        • Leren T.P.
        • Tauboll E.
        • et al.
        New SCN5A mutation in a SUDEP victim with idiopathic epilepsy.
        Seizure. 2009; 18: 158-160
        • Goldman A.M.
        • Glasscock E.
        • Yoo J.
        • et al.
        Arrhythmia in heart and brain: KCNQ1 mutations link epilepsy and sudden unexplained death.
        Sci Transl Med. 2009; 1: 2ra6
        • Veltmann C.
        • Wolpert C.
        • Sacher F.
        • et al.
        Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges.
        Europace. 2009; 11: 1345-1352
        • Brugada J.
        • Brugada R.
        • Brugada P.
        Determinants of sudden cardiac death in individuals with the electrocardiographic pattern of Brugada syndrome and no previous cardiac arrest.
        Circulation. 2003; 108: 3092-3096
        • Zipes D.P.
        • Camm A.J.
        • Borggrefe M.
        • et al.
        ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.
        Europace. 2006; 8: 746-837
        • Priori S.G.
        • Gasparini M.
        • Napolitano C.
        • et al.
        Risk stratification in Brugada syndrome: results of the PRELUDE (PRogrammed ELectrical stimUlation preDictive valuE) registry.
        J Am Coll Cardiol. 2012; 59: 37-45
        • Probst V.
        • Veltmann C.
        • Eckardt L.
        • et al.
        Long-term prognosis of patients diagnosed with Brugada syndrome: results from the FINGER Brugada Syndrome Registry.
        Circulation. 2010; 121: 635-643
        • Epstein A.E.
        • DiMarco J.P.
        • Ellenbogen K.A.
        • 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).
        J Am Coll Cardiol. 2008; 51: e1-e62
        • Scheffer I.E.
        • Bhatia K.P.
        • Lopes-Cendes I.
        • et al.
        Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder.
        Brain. 1995; 118: 61-73
        • Petkar S.
        • Hamid T.
        • Iddon P.
        • et al.
        Prolonged implantable electrocardiographic monitoring indicates a high rate of misdiagnosis of epilepsy: REVISE study.
        Europace. 2012; 14: 1653-1660
        • Vincent G.M.
        The long QT and Brugada syndromes: causes of unexpected syncope and sudden cardiac death in children and young adults.
        Semin Pediatr Neurol. 2005; 12: 15-24
        • Anderson H.J.
        • Bos J.M.
        • Meyer F.B.
        • et al.
        Concealed long QT syndrome and intractable partial epilepsy: a case report.
        Mayo Clin Proc. 2012; 87: 1128-1131
        • Fauchier L.
        • Babuty D.
        • Cosnay P.
        Epilepsy, Brugada syndrome and the risk of sudden unexpected death.
        J Neurol. 2000; 247: 643-644
        • Hartmann H.A.
        • Colom L.V.
        • Sutherland M.L.
        • et al.
        Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain.
        Nat Neurosci. 1999; 2: 593-595