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EXPERIENCE & REASON |
a Greenlane Paediatric and Congenital Cardiac Services
f Department of Paediatrics, Starship Children's Hospital, Grafton, Auckland, New Zealand
b Cardiac Inherited Disease Group, Auckland City Hospital, Grafton, Auckland, New Zealand
c Departments of Molecular Medicine
d Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
e Department of Paediatrics, Christchurch Public Hospital, Christchurch, New Zealand
g Department of Cardiology, Liverpool Hospital, Liverpool, New South Wales, Australia
h Molecular Neuroscience Group, School of Medicine, University of Wales Swansea, Swansea, United Kingdom
ABSTRACT
Fever can precipitate ventricular tachycardia in adults with Brugada syndrome, but such a link has not been reported in children. A 21-month-old white girl presented repeatedly with decreased conscious level and seizures during fever. During a typical episode, rapid ventricular tachycardia was documented. The resting 12-lead electrocardiogram revealed a Brugada electrocardiogram signature. Resting electrocardiograms of the asymptomatic brother and mother were normal, but fever in the mother and pharmacologic stress with ajmaline in the brother revealed Brugada electrocardiogram features. Genetic testing revealed an SCN5A mutation in the affected family members.
Key Words: fever • seizures • ventricular tachycardia • cardiac channelopathies • Brugada syndrome
Abbreviations: ECG, electrocardiogram • SCN5A, gene encoding for sodium channel, voltage-gated, type V, alpha • SCN5A/Nav1.5, gene product/protein sodium channel, voltage-gated, type V, alpha • dHPLC, denaturing high-pressure liquid chromatography
Febrile seizures are a common, benign phenomenon that occur in children between the ages of 6 months and 6 years. Death from febrile seizures has not been described.1 The seizures are typically brief and triggered by a rapid rise in temperature, usually caused by a viral illness. The prognosis is good, although a minority of children develop epilepsy without fever in later life.2,3 However, death during and after "epileptic" seizures is not infrequent and has its own pseudonym of SUDEP (sudden unexpected death in epilepsy).4
Sudden death syndromes are attributed partly to cardiac arrhythmia syndromes, in particular long QT syndrome and cardiomyopathic disorders.5,6 In Brugada syndrome, sudden unexpected death can occur as a result of ventricular fibrillation or rapid ventricular tachycardia.7 The 12-lead electrocardiogram (ECG) typically reveals an elevated ST segment in the anterior precordial leads with a right bundle branch block-like appearance. Approximately 10% to 30% of affected Brugada syndrome cases have been linked to mutations within SCN5A, a gene that codes for the 
subunit of the voltage-gated sodium channel Nav1.5 and is also associated with long QT syndrome type 3.8–11
In this report we present a child with a series of seizures associated with fever. The presentation initially led to an erroneous diagnosis of benign febrile seizures. However, rapid ventricular tachycardia was found with a resting ECG compatible with Brugada syndrome. A mutation within SCN5A, inherited from the mother, was discovered in the child. Such a presentation has not been described in children; therefore, features of the investigation, diagnosis, and treatment are discussed here.
CASE REPORT
A 21-month-old previously healthy white girl presented to the emergency department during the night after a third episode of seizure with a high fever. The patient had been seen at the same hospital 3 months earlier (during the second attack) with a high fever (38.5°C) that was diagnosed as a febrile seizure. On all 3 occasions, occurring some months apart, she woke the parents with a cry of distress; they found her in her cot with the sheet covering her while she was jerking rhythmically. She was "either asleep or unconscious." She felt very hot, and after uncovering her, the jerking, which affected both arms, rapidly ceased. After this she was limp, very pale, and unresponsive, but she was breathing. With efforts to cool her, her conscious level increased over a few minutes. During a third episode, described by the parents as identical to the previous 2 but lasting longer despite cooling, she presented to the emergency department.
She was pale and unwell; her temperature was 38.0°C and pulse rate was 200 beats per minute, with a gallop rhythm and poor peripheral perfusion. She was limp, distressed, and whimpering, not vocalizing clearly, and did not recognize her parents as being distinct from nursing staff.
There were clinical signs of an upper respiratory tract infection. The precordium was noted to be hyperactive. The 12-lead ECG showed a rapid, broad-complex tachycardia (Fig 1). The patient received 3 bolus doses of adenosine (50, 100, and 250 µg/kg), to no effect. After a cough, her sinus rhythm returned (Fig 2A). Immediately her color improved and she sat up, talked to her parents, and started naming objects in the room. She was started on oral sotalol 2 mg/kg twice daily. The fever took some days to settle and was managed with paracetomol; no additional seizures or tachycardias recurred. Brugada syndrome was suspected from the resting ECG (Fig 2A), and she was transferred to a pediatric cardiology unit for additional investigation.
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The family history revealed no incidences of seizure, sudden death, or syncope, and resting ECGs on the brother and both parents were normal. An echocardiogram and cardiac MRI scan were normal. An intravenous challenge with ajmaline, a short-acting sodium-channel–blocking agent,12 was performed. The result was strongly positive, with very marked exaggeration of the precordial ST segment elevation at low doses (0.2 mg/kg) (Fig 2B). The family was provided with an automatic external defibrillator for home use, given open access to the local hospital, and advised to treat fevers aggressively with paracetomol and tepid sponging. The sotalol was continued because of its apparent early therapeutic benefit, with no recurrence of seizures or ventricular tachycardia with subsequent fevers over the first few days. Before planned ajmaline tests on the parents, both of whom had normal resting ECGs, the mother had some palpitations during an attack of influenza. At the time of high fever, her ECG revealed typical Brugada features (Fig 3). An invasive electrophysiology study did not induce ventricular arrhythmias. The brother also had a normal resting ECG, but his ajmaline test was also positive, although the ECG changes occurred at higher doses than those of his sister (0.8 mg/kg).
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GENETIC ANALYSIS OF SCN5A
After obtaining informed consent for genetic testing, blood samples were taken from the presenting child for mutation analysis of SCN5A. The genomic DNA was used for polymerase chain reaction–based assays covering the coding and flanking intronic regions of the gene, and the polymerase chain reaction products were screened for heterozygous profiles by using conventional denaturing high-pressure liquid chromatography (dHPLC) technology (Transgenomic, Omaha, NE). The output profiles from the dHPLC were scrutinized for abnormal profiles indicating the presence of heterogeneous DNA mismatching. Abnormal dHPLC profiles were sequenced in both directions (Applied Biosystems, Foster City, CA), and sequence changes were verified by restriction fragment length polymorphism (RFLP) analysis when available. RFLP studies of mutation frequencies were conducted on 2% molecular screening agarose gels (Roche, Indianapolis, IN) using 150 random normal-control cases to evaluate candidate pathogenic mutations within the general population.
RESULTS
Genetic Testing
The dHPLC screening revealed several abnormal profiles that required sequencing. Sequencing of SCN5A exon 24 demonstrated a novel, heterozygous 1-base pair (bp) insertion mutation (InsG) in position nt4392–4396 of the SCN5A coding sequence (Fig 4). This mutation was also found in the mother and brother but not in the father. In the absence of differentiating restriction-enzyme–digest profiles, the mutation was excluded from 300 normal-control chromosomes by dHPLC profiling (not shown). No other mutations were found.
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DISCUSSION
Brugada syndrome most commonly causes sudden unexpected death in young Asian men during sleep.11 It is inherited in an autosomal dominant manner with variable clinical expression, and females are significantly less likely to die suddenly.13 We have not been able to find a single case report of death after a febrile seizure, which suggests that Brugada syndrome, with a fever-triggered ventricular arrhythmia causing decreased conscious level during fever, must be a very rare mimic of this usually benign condition. Nevertheless, ECGs are not typically a routine part of clinical assessment after a seizure associated with fever, and the condition may be more frequent than suspected. Furthermore, there may be a reluctance by forensic pathologists to attribute deaths during or after seizures to febrile seizure because of their benign nature by definition. Deaths with seizures secondary to long QT syndrome have been erroneously ascribed to epilepsy in the past.14
The Brugada syndrome mutations in SCN5A cause a dominant negative effect or loss of function in the sodium current, which is a determinant of the phase 0 and phase 1 segments of the cardiac action potential.15 Carriers of Brugada syndrome can have a normal resting ECG, but recent observations in adults have demonstrated that classical Brugada ECG features, even ventricular tachycardia and death, can be precipitated by fever.16–20 No such link to fever has been shown in children, yet 3 independent cases of infants with ventricular fibrillation or ventricular tachycardia have been reported recently in association with mutations in SCN5A: 2 associated with long QT syndrome type 3 and one in association with Brugada syndrome.21–23
In our patient, the 1-bp insertion causes the reading frame of SCN5A to be disrupted; a premature stop codon (at position 1483 of SCN5A[1483X]) results in a truncated SCN5A polypeptide. Other such SCN5A mutations that generate a premature termination codon are associated with distinct clinical phenotypes; 4196delA(V1397X) is associated with Brugada syndrome, and 5280delG(1768X) is associated with conduction disease.24,25 Electrophysiological studies of both of these mutants failed to express any sodium currents; thus, it is likely that the SCN5A mutation in the present case will also fail to produce sodium currents. Although cellular electrophysiology has not been performed, the ECG changes in the family are so characteristic that the Brugada phenotype is not in doubt.
This case is the first reported incident in which the febrile-onset phenomenon has occurred in a young child and is made more remarkable by the fact that she is both female and white. Overheating is a known risk factor for sudden infant death syndrome and the SCN5A gene is the most common of any to be linked to sudden infant death.26 It is tempting to speculate that this correlation may be attributable in part to heat-triggered ventricular tachycardia or fibrillation in such genetically vulnerable infants.
Our patient and her mother have a fever-dependent expression of the phenotype. In the case of our patient, the ventricular tachycardia may have happened during a critical developmental window, as reflected by the absence of ventricular tachycardia or seizures during subsequent febrile illness. A family with young-age–specific sudden death was described recently with a Brugada SCN5A mutation.27 It is also possible that sotalol therapy or liberal use of antipyretics have stopped a recurrence. No medications (including sotalol), with the emerging possible exception of quinidine,28 have proven therapeutic benefit for Brugada syndrome. Although pure ß blockers, in large doses, can unmask Brugada ECG changes and may be arrhythmogenic,29 we have been reluctant to discontinue sotalol (which has both ß-blocking and repolarization-prolonging [Vaughan-Williams type III] properties) because of the apparent beneficial effect on arrhythmia prevention during our patient's many subsequent high fevers over >3 years.
Molecular defects in Nav1 channels have been reported in association with temperature-sensitive disorders such as generalized epilepsy with febrile seizures plus and heat-induced myotonia and cold-induced paralysis in congenital paramyotonia.30–32 Furthermore, a patient with a febrile illness and cardiac conduction disease who experienced a syncope was reported to be a carrier for a SCN5A G514C mutation.33 A 42-year-old man who presented with fever-induced ventricular fibrillation carried a missense SCN5A mutation (F1344S); cellular electrophysiological testing showed a temperature-sensitive sodium current.34 SCN9A (Nav1.7) mutations have also been reported in primary erythermalgia, a rare disorder that is characterized by intermittent burning pain with redness and heat in the extremities.35,36
CONCLUSIONS
Fever can trigger ventricular tachycardia in young children with previously unrecognized Brugada syndrome, and the low-output state can trigger a seizure, the presentation thus mimicking febrile seizures.
This case serves as a reminder that occult cardiac channelopathies should be borne in mind in the investigation of childhood seizures with or without fever. However, we would not yet advise that all children who have a seizure or reduced conscious level during fever should have an ECG. It would be prudent to order an ECG if there are clinical features suggesting a cardiac arrhythmia (tachycardia out of proportion to the fever, weak peripheral pulses, hyperactive precordium, and marked pallor) or a family history suggesting Brugada syndrome, such as young sudden death, particularly in males at night.
ACKNOWLEDGMENTS
The molecular genetics work was enabled by grants from Cure Kids, the Lion Foundation, the Greenlane Research and Education Fund, and the John Neutze Fund.
We thank Dr Iain Melton for providing information and ECGs on the parents, and we thank the parents of the child concerned, who enthusiastically supported the publication of this report.
FOOTNOTES
Accepted Nov 1, 2006.
Address correspondence to Jonathan Robert Skinner, MB, ChB, FRACP, FRCPCH, MD, Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Park Road, 1141 Auckland, New Zealand. E-mail: jskinner{at}adhb.govt.nz
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
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300 beats per minute. Notching on the ECG traces suggests dissociated p-wave activity consistent with rapid ventricular tachycardia.
