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Cochlear implantation in Jervell and Lange-Nielsen syndrome
International Journal of Pediatric Otorhinolaryngology 66 (2002) 213 /221 www.elsevier.com/locate/ijporl
Cochlear implantation in Jervell and Lange-Nielsen syndrome R. Chorbachi a, J.M. Graham a,*, J. Ford a, C.H. Raine b a
Royal National Throat, Nose and Ear Hospital, Gray’s Inn Road, London WC1X 8DA, UK b Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK Received 21 May 1999; received in revised form 9 May 2002; accepted 11 May 2002
Abstract A case of familial prolonged QT interval and congenital sensorineural hearing loss is described emphasising the diagnostic and management implications. Jervell and Lange-Nielsen syndrome is important because of its potential association with sudden death in children with congenital sensorineural deafness. It is known to be associated with mutations of the genes KCNQ1 (KVQTI) and KCNE1 (Isk). The underlying molecular abnormality leads to cardiac and cochlear dysfunction through a potassium channel defect. All children with congenital sensorineural hearing loss who have suffered unexplained syncopal attacks or convulsions should be screened for this syndrome. There is also a strong case for including a 12 lead ECG as part of the investigative work up of all children with congenital sensorineural deafness in whom a firm aetiology has not been established. # 2002 Published by Elsevier Science Ireland Ltd. Keywords: Cochlear implantation; Jervell and Lange-Nielsen syndrome; Congenital sensorineural hearing loss
1. Introduction In 1957, Jervell and Lange-Nielsen [1] reported a sibship of four children with profound congenital sensorineural hearing loss, syncopal attacks, sudden death and a prolonged corrected QT interval (QTc) shown on electrocardiography. A century prior to the above report, Meissner documented a family with two children who died suddenly after emotional and physical stress, one of whom was profoundly deaf. Fraser [2], in 1976, published a
* Corresponding author E-mail address: [email protected] Graham).
(J.M.
large series describing clinical features and genetic implications. The syndrome’s possible association with severe anaemia, geographical distribution and its prevalence in adults has been noted firstly by Langslet and Sorland in 1975 and subsequently by others [3 /5]. Genetic markers as a diagnostic tool were proposed by Vincent in 1992 [6]. The syndrome is rare but has potentially grave implications if undiagnosed. It has a prevalence of 1:100 000, with the deafness usually being profound; vestibular dysfunction has not been documented. Cardiogenic syncope is common. Sudden death occurs in 70% of untreated cases due to ventricular arrhythmias consisting of abnormal ventricular repolarisation and ventricular multifocal ectopic
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beats, an abnormal T wave, sinus bradycardia and multi-axis ventricular tachycardia (Torsade des Pointes) in which the peaks (Pointes) of the ventricular activity on ECG show rotation (Torsade) about the electrical axis. The arrhythmias are usually precipitated by a sudden increase in autonomic activity. Secondary focal seizures may also occur. The syndrome is autosomal recessive and has a similar cardiac presentation to the autosomal dominant Romano-Ward syndrome (RWS) of prolonged QTc, without deafness [7 /9]. The underlying pathophysiology is due to an abnormality in the function of the potassium channel complex. In this report we describe three brothers with Jervell and Lange-Nielsen syndrome (JLNS), emphasising diagnostic and management implications, with particular reference to cochlear implantation.
2. Case report 2.1. Patients and methods This is a case study of a sibship of three brothers, born to consanguineous parents. The audiological and cardiac investigation results of the youngest brother (the index case) are reported first, as these findings were the first indicators to suggest JLNS being present in this sibship. 2.2. Case 1 The youngest of the brothers, aged 11 years, who is congenitally profoundly deaf (Table 1) had a Nucleus cochlear implant surgically inserted at the age of 3/12 years. During cochlear implantation assessment the only consistent aided response was observed at 100 dB SPL at 500 Hz with binaural hearing aids. He
Fig. 1. Post-implantation stimulation thresholds of the youngest brother (Case 1).
received a Nucleus Mini System 22 with the SPEAK speech processing strategy. After an initial period of inconsistent supra-threshold responses he has since made excellent use of his implant (Fig. 1). Aged 6, he had two attacks of loss of consciousness within a period of 1 month, whilst at school. The initial attack was described as being more like syncope following exertion, with the second episode being reported as a grand mal seizure. The episodes were initially thought to be neurogenic. However, because of the presence of the cochlear implant an MRI scan of his brain was contraindicated. While an in-patient after the second seizure, bradycardia and hypotension were noted. Cardiac investigations confirmed a prolonged corrected QT interval. Electrocardiography revealed a QTc of 0.613 s (upper limit of normal 0.44 s), (Fig. 2) with a heart rate of 65 beats per minute. Abnormal T waves were found in standard lead II and pre-cordial leads V4 to V6. He later developed bronchial
Table 1 Aided soundfield audiometric threshold levels of the youngest brother (Case 1) before implantation Frequency in Hz Intensity in db SPL
250 ?85
500 100
1000 NR at 100
2000 NR at 100
4000 NR at 90
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Fig. 2. Electrocardiogram of the youngest brother (index case) showing a prolonged QTc of 0.613 s in lead II and abnormal T waves.
asthma. The combination of congenital deafness and long QTc prompted the clinical diagnosis of JLNS.
2.3. Case 2
Fig. 4. Post-implantation stimulation levels of Case 2.
The middle brother, aged 13 years, is also profoundly deaf (Fig. 3). He received a Nucleus 22 multi-channel cochlear implant at the age of 3 years. Figs. 4 and 5 show his stimulation thresholds and dynamic range using his implant. He has had no syncopal attacks, but is asthmatic. This brother was also found to have a prolonged QTc of 0.62 s, although he has so far remained asymptomatic. A 24 h ambulatory electrocardiograph (Fig. 6) showed a minimum heart rate of 60 beats per minute (with beta-blockade). His exercise ECG revealed grossly prolonged QTc.
2.4. Case 3 The eldest of the siblings, a boy, now aged 16, was diagnosed profoundly deaf (Fig. 7). Hearing aids were provided from the age of 23 months. An initial request for cochlear implantation was deferred, as at that time prelingually congenitally deaf children were not being considered for such a procedure. He developed attacks of syncope and experienced seizures following exertion which were treated with Carbamazepine. At the age of 4 he
Fig. 3. Unaided Pure Tone Audiogram thresholds of Case 2 before implantation.
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Fig. 5. Threshold and comfort levels (lower and upper ends of blocks) of Case 2.
Fig. 6. Electrocardiogram of Case 2 showing a prolonged QTc 0.62 s.
was referred for cochlear implantation, but was thought to be unsuitable because of the syncopal attacks and seizures and possible learning difficulties. He was re-assessed at the age of 8 years but again found to be unsuitable due to his chronological age. Meanwhile, he had no further
seizures and his electroencephalogram remained normal. Carbamazepine was discontinued. After the youngest brother had been found to suffer from JLNS. The eldest brother was then assessed because of his previous history of syncope. He was found to have a resting heart rate of 60 bpm, with an electrocardiogram revealing a QTc of 0.586 s (Fig. 8). During 24 h electrocardiography, no abnormal cardiac symptoms were experienced despite bradycardia of 43 beats per minute. His pure tone audiogram (Fig. 7) shows a profound deafness. He has little or no gain from amplification and he communicates by signing. More recently he developed Insulin dependent Diabetes Mellitus and Asthma. All three brothers were treated with the betablocking agent, Metoprolol and were then changed to Bisoprolol, successfully preventing arrhythmias. They are continually monitored, with no further episodes of syncope.
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Fig. 7. Pure Tone Audiogram of the eldest brother (Case 3).
Fig. 8. Electrocardiogram lead II of Case 3 showing a prolonged QTc of 0.5486 s.
Mutational analysis confirmed the clinical diagnosis of JLNS showing a mutation in KCNQ1, c.1686-1 G/A, a G to A transition in the invariant AG of the splice acceptor site of exon 14. The affected boys are homozygous for this mutation, both parents are carriers.
3. Discussion
3.1. Clinical aspects Since Jervell and Lange-Nielsen described this syndrome of syncopal attacks, cardiac arrhythmias, sudden death and congenital sensorineural deafness in 1957 several further reports have appeared in the literature. Many aspects of the syndrome’s diagnostic and management issues
continue to evolve. This case report will highlight some of these. The eldest brother in this sibship suffered from syncopal attacks and seizures on exertion, and was initially treated with anti-convulsant therapy for a period of 3 years. However, the seizures are now thought to have represented the cerebral effect of transient ischaemia occurring during episodes of ventricular tachycardia. This would explain the normal electroencephalogram; a similar case was reported by Cusimano et al. in 1991 [11]. The youngest of the three brothers had identical attacks to those of his eldest brother, with one of the attacks being clearly witnessed and described as a seizure. The middle brother has had no reported syncopal attacks, and has been asymptomatic despite an abnormal QTc. The severity of the arrhythmias and their clinical presentation is known to vary in JLNS. Although hypochromic anaemia can occur as part of this syndrome, none of the members of this sibship has haematological abnormalities. 3.2. ECG features A QTc interval equal to or greater than 0.44 s is diagnostic in males, as is an interval of equal to or greater than 0.46 s in females. Borderline cases
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been suggested by Glikson et al. and Wilson et al. [17,18].
3.4. Genetics Fig. 9. Ventricular tachycardia (Torsade des Pointes) which may occur in this syndrome.
with intervals of 0.44 /0.46 without symptoms have been documented by Bazzet [12], Cusimano et al. [11] and Keating et al. [13]. Electrophysiological cardiac abnormalities in this syndrome, in addition to a prolonged QTc, can include abnormal T wave morphology: biphasic, inverted or bifid [14,15]. Multifocal ventricular ectopics can occur, and are associated with a poor prognosis. Ventricular tachycardia, ventricular fibrillation and Torsade des Pointes (Fig. 9) arrhythmias cause syncopal attacks and may lead to sudden death if not treated. The attacks can be precipitated by a sudden increase in autonomic activity, for example during exercise, or following emotional stress and loud sounds. 3.3. Management of arrhythmias The youngest of the brothers had abnormal T wave morphology in standard lead II and precordial leads V4 to V6 of his ECG. Holter monitoring and stress ECG was normal in all three brothers. Beta-blockade has, to date, controlled the symptoms of the youngest and eldest brother. The asymptomatic middle brother has also been given beta-blockade therapy. The benefits of such treatment had to be weighed against the potential side-effects, as all three brothers are known asthmatics. Beta-blocker therapy is the first line of management in this syndrome[16]. Limited success has been reported with left stellate ganglionectomy. Recently, the benefits of permanent internal cardiac defibrillator-pacers have been evaluated, with definite advantages over cardiac pacemakers in the prevention of sudden death and neurological damage. In patients unresponsive to medical treatment alone a combination of internal cardiac defibrillator-pacers with beta-blockade has also
Good progress has been made in the last few years in understanding the genetic basis of JLNS. At the molecular level, it has now been shown that autosomal recessive JLNS and autosomal dominant RWS are allelic, and are caused by mutation in either of the genes KCNQ1 and KCNE1(reviewed in Towbin and Vatta [9], Shulze-Bar et al. [19] and Tyson et al. [10,20]). KCNQ1 and KCNE1 encode the potassium channel responsible for the slow component of the delayed rectifier potassium current, Isk, in the heart. Expression of both genes has also been demonstrated in the mouse in the marginal cells of the stria vascularis of the inner ear, the tissue responsible for maintaining the high concentration of potassium in the endolymphatic fluid bathing the hair cells of the organ of corti [21,22] The role of these genes in JLNS is supported by data from the mouse. In particular the Isk knockout mouse is deaf, has vestibular dysfunction and shows an inner ear pathology closely resembling that seen in human subjects who have died from JLNS [21,23,24]. If RWS and JLNS are allelic, why are symptoms rarer in carriers of JLNS mutations? A comparison of mutations described to date in RWS with those found in JLNS shows some differences. The types of KCNQ1 mutation that predominate in autosomal dominant RWS are missense and appear to have a localised effect on the predicted protein. In contrast, frameshift/truncating mutations appear to be responsible for the majority of JLNS (LQTS database). Yet despite this difference in mutation type, recent data indicates a spectrum of functional effects for JLNS disease-causing mutations [25]. From a clinical point of view, the parents of children with JLNS may occasionally have prolonged QTc and some gene carriers may even be symptomatic [26 /28] but a family history of syncope and sudden death is rare in individuals with JLNS and has not been reported in the
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literature until recently [21,26]. The parents of the family described here have normal QTc. The importance of highlighting the sub-clinical cases genetically should be stressed, as severe symptoms and even sudden death can be triggered by certain drugs such as Sotalol, Amiodarone, Quinidine, Procainamide, Erythromycin, Terfenadine and possibly Fexofendine [29], Haloperidol and some tricyclic anti-depressants and Fluoroquinolones, all of which may effect cardiac repolarisation [30,31]. 3.5. Implications for cochlear implantation: before implantation 3.5.1. Aetiological investigations Cardiac investigation should part of the diagnostic work up of all patients with congenital or early onset hearing loss. JLNS may present in a potentially fatal manner but can be treatable. Haematological and biochemical investigations are also mandatory as the syndrome may be associated with anaemia and in one of our cases we report the presence of Insulin dependent Diabetes mellitus, it is not clear whether this may be related to the syndrome or a sporadic occurrence. 3.5.2. Anaesthetic considerations There are numerous reports in the literature of undiagnosed cases of JLNS with unpredictable preventable cardiac arrhythmias during surgery causing serious complications. Adu-Gyamfi et al. [32] reported a case of a child with congenital profound deafness, who was misdiagnosed as having epilepsy. While undergoing a CT scan of the brain under general anaesthesia he experienced polymorphous ventricular tachycardia on induction with Halothane. In retrospect he was found to have JLNS. Wig reported a case of cardiac arrest perioperatively in a patient undergoing abdominal surgery who, retrospectively, was found to have a prolonged QTc interval [33]. The authors commented on the lack of awareness of the patient’s condition pre-operatively, with inadequate anaesthetic precautions.
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Holland, in 1993, reported multifocal ventricular extrasystoles and ventricular fibrillation during anaesthesia in a congenitally deaf child undergoing adenoidectomy [34]. The arrhythmias were converted to sinus rhythm by defibrillation and Lignocaine. The author stressed the importance of an adequate history and anaesthetic precautions in order to avoid cardiac events in JLNS, which was diagnosed retrospectively in this case. In cases when the diagnosis of JLNS and Romano-Ward has already been made, pre-operative beta-blockade, with optimisation of the dose, should be commenced prior to the induction of anaesthesia, as anaesthesia increases the risk of ventricular arrhythmias. Drugs such as Halothane, which sensitise the myocardium to the effect of catecholamines, should be avoided. Effective preoperative sedation, oximetry and avoidance of drugs which might further prolong the QT interval, ensuring a normal serum potassium and electrolytes and, above all, continuous ECG monitoring from the time the patient enters the anaesthetic room are all important aspects of management. O’Callaghan et al. reported difficulties in reverting arrhythmias to sinus rhythm during anaesthesia [35]. They described the anaesthetic implications of two cases with prolonged QTc, stressing the need to avoid bradycardia, increased sympathetic activity and drugs which may prolong the QTc interval, and advocating beta-blockade as the mainstay treatment of choice. Pre-operative awareness that a patient has JLNS is the best way of ensuring a safe anaesthetic. However, where the diagnosis of JLNS has not been suspected, routine ECG monitoring would not only allow peri- and per-operative arrhythmias to be detected and treated, but should also draw the attention of surgeon and anaesthetist to the fact that this syndrome is present. 3.6. Implications for cochlear implants: after implantation 3.6.1. Electrical interference The presence of a cochlear implant is unlikely to provoke cardiac arrhythmias, and did not do so in the case of the asymptomatic implanted middle
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brother in this sibship. No reports have yet been published on the effects of cardiovertor pacer devices on the cochlear implant, however because of the distance between the chest and the ear it is improbable that interaction between the two devices would occur. 3.6.2. Trauma to the cochlear implant in the event of syncope Should the cardiac arrhythmias not be fully controlled there is a risk of syncopal attacks causing head injury and trauma, potentially damaging the transducer component of the device. A light-weight helmet (usually modified from high quality sports head gear types and tailored to the individual) is advisable especially during strenuous physical activity. Contact sports should be avoided [36]. Vestibular function is currently being assessed in this sibship; if found to be abnormal it may contribute to imbalance and the risk of trauma. To our knowledge these are the first published clinical details of patients with JLNS with this novel mutation to receive cochlear implants. The diagnosis was made in retrospect as this condition is very often difficult to identify, unless a 12 lead ECG has been performed. All children with congenital sensorineural deafness should be screened for JLNS with a 12 lead ECG. Early diagnosis will lead to the effective management of syncopal attacks with Beta-blockers, cardiac pacemakers, or implanted pacer-defibrillators, and to the planning of safe general anaesthesia for these patients.
4. Summary We report the clinical presentation of three cases with JLNS, two of whom had cochlear implantation (the youngest and the middle brother). Early diagnosis of this syndrome will enable appropriate planning of medical, surgical and rehabilitative strategies. Control of his syncopal attacks may theoretically prevent damage to the implant device in the youngest brother. In the future it may be possible to identify the known mutations of the KCNQ1 and KCNE1
early enough to initiate medical preventative measures of the cardiac complications, and effective audiological habilitation. Further research is needed to establish practical criteria to investigate those children who have a borderline prolonged QTc interval (0.44 s in males; 0.46 s in females) on resting ECG and who are asymptomatic. Further cardiac rhythm investigations, including a stress ECG and Holter monitoring, seem not to be indicated and may cause unnecessary anxiety to the parents and child.
Acknowledgements We acknowledge the helpful technical advice of Michael Conway, Medical Physicist and member of the UCL Cochlear Implant Team, the UCL/ RNTNE cochlear implant team and Sarah Palser for her invaluable help and support. Dr Nick Archer, consultant paediatric cardiologist at the John Radcliffe Hospital, Oxford, England kindly supplied the ECG data. We are very grateful to Dr Jessica Tyson, at the Institute of Child Health for her comprehensive review of the genetics aspects of this paper.
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[22] N. Neyroud, F. Tesson, I. Denjoy, M. Leibovici, C. Donger, J. Barhanin, et al., A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome, Nat. Genet. 15 (1997) 186 /189. [23] I. Friedmann, G.R. Fraser, P. Froggatt, Pathology of the ear in the cardioauditory syndrome of Jervell and LangeNielsen recessive deafness with electrocardiographic abnormalities, J. Laryngol. 80 (1966) 451 /470. [24] I. Friedmann, G.R. Fraser, P. Froggatt, Pathology of the ear in the cardioauditory syndrome of Jervell and LangeNielsen (a report of a third case with an appendix on possible linkage with the Rh blood group locus), J. Laryngol. 82 (1968) 883 /896. [25] L. Huang, M. Bitner-Glindizicz, L. Tranebjaerg, A. Tinker, A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome, Cardiovasc. Res. 4 (51) (2001) 670 /680. [26] I. Splawski, K.W. Timothy, G.M. Vincent, D.L. Atkinson, M.T. Keating, Molecular basis of the long-QT syndrome associated with deafness, N. Engl. J. Med. 336 (22) (1997) 1562 /1567. [27] P. Duggal, M.R. Vesely, D. Wattanasirichaigoon, V. Villafanej, Kaushik, A.H. Beggs, Mutation of the gene for isk associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long-QT syndrome, Circulation 97 (1998) 142 /146. [28] W. Zareba, A. Moss, P. Schwartz, G.M. Vincent, J.L. Robinson, S.G. Priori, et al., Influence of the genotype on the clinical course of the long-QT syndrome, N. Engl. J. Med. 339 (1998) 960 /965. [29] Y.M. Pinto, I.C. van Gelder, M. Heeringa, H.J.G.M. Crijns, QT lengthening and life-threatening arrhythmias associated with fexofenadine, The Lancet 353 (1999) 980. [30] Y.G. Yap, J. Camm, Risk of torsades de pointes with noncardiac drugs, BMJ 320 (2000) 1158 /1159. [31] C. Donger, I. Denjoy, M. Berthet, N. Neyroud, C. Cruaud, M. Bennaceur, et al., KVLQT C-Terminal missense mutation causes a Forme Fruste Long QT syndrome, Circulation 96 (1997) 2778 /2781. [32] Y. Adu-Gyamfi, A. Said, U. Chowdhary, A. Abumelha, S. Sanyal, Anaesthetic-induced ventricular tachy-arrhythmia in Jervell and Lange Nielsen syndrome, Can. J. Anaesth. 38 (1991) 345 /346. [33] J. Wig, J. Bali, R. Singh, R.N. Kataria, H.N. Khattri, Prolonged QT interval syndrome, sudden cardiac arrest during anaesthesia, Anaesthesia 34 (1979) 37 /40. [34] J.J. Holland, Cardiac arrest under anaesthesia in a child with previously undiagnosed Jervell and Lange-Nielsen syndrome, Anaesthesia 48 (1993) 149 /151. [35] C. O’Callaghan, P. Normandale, M. Morgan, The prolonged Q-T syndrome. A review with anaesthetic implications and a report of two cases, Anaesth. Intens. Care 10 (1982) 50 /55. [36] British Cochlear Implant Group. Recommended Guidelines on Safety for Cochlear Implant Users. (2000) 1 /6.
Cochlear implantation in Jervell and Lange-Nielsen syndrome R. Chorbachi a, J.M. Graham a,*, J. Ford a, C.H. Raine b a
Royal National Throat, Nose and Ear Hospital, Gray’s Inn Road, London WC1X 8DA, UK b Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK Received 21 May 1999; received in revised form 9 May 2002; accepted 11 May 2002
Abstract A case of familial prolonged QT interval and congenital sensorineural hearing loss is described emphasising the diagnostic and management implications. Jervell and Lange-Nielsen syndrome is important because of its potential association with sudden death in children with congenital sensorineural deafness. It is known to be associated with mutations of the genes KCNQ1 (KVQTI) and KCNE1 (Isk). The underlying molecular abnormality leads to cardiac and cochlear dysfunction through a potassium channel defect. All children with congenital sensorineural hearing loss who have suffered unexplained syncopal attacks or convulsions should be screened for this syndrome. There is also a strong case for including a 12 lead ECG as part of the investigative work up of all children with congenital sensorineural deafness in whom a firm aetiology has not been established. # 2002 Published by Elsevier Science Ireland Ltd. Keywords: Cochlear implantation; Jervell and Lange-Nielsen syndrome; Congenital sensorineural hearing loss
1. Introduction In 1957, Jervell and Lange-Nielsen [1] reported a sibship of four children with profound congenital sensorineural hearing loss, syncopal attacks, sudden death and a prolonged corrected QT interval (QTc) shown on electrocardiography. A century prior to the above report, Meissner documented a family with two children who died suddenly after emotional and physical stress, one of whom was profoundly deaf. Fraser [2], in 1976, published a
* Corresponding author E-mail address: [email protected] Graham).
(J.M.
large series describing clinical features and genetic implications. The syndrome’s possible association with severe anaemia, geographical distribution and its prevalence in adults has been noted firstly by Langslet and Sorland in 1975 and subsequently by others [3 /5]. Genetic markers as a diagnostic tool were proposed by Vincent in 1992 [6]. The syndrome is rare but has potentially grave implications if undiagnosed. It has a prevalence of 1:100 000, with the deafness usually being profound; vestibular dysfunction has not been documented. Cardiogenic syncope is common. Sudden death occurs in 70% of untreated cases due to ventricular arrhythmias consisting of abnormal ventricular repolarisation and ventricular multifocal ectopic
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beats, an abnormal T wave, sinus bradycardia and multi-axis ventricular tachycardia (Torsade des Pointes) in which the peaks (Pointes) of the ventricular activity on ECG show rotation (Torsade) about the electrical axis. The arrhythmias are usually precipitated by a sudden increase in autonomic activity. Secondary focal seizures may also occur. The syndrome is autosomal recessive and has a similar cardiac presentation to the autosomal dominant Romano-Ward syndrome (RWS) of prolonged QTc, without deafness [7 /9]. The underlying pathophysiology is due to an abnormality in the function of the potassium channel complex. In this report we describe three brothers with Jervell and Lange-Nielsen syndrome (JLNS), emphasising diagnostic and management implications, with particular reference to cochlear implantation.
2. Case report 2.1. Patients and methods This is a case study of a sibship of three brothers, born to consanguineous parents. The audiological and cardiac investigation results of the youngest brother (the index case) are reported first, as these findings were the first indicators to suggest JLNS being present in this sibship. 2.2. Case 1 The youngest of the brothers, aged 11 years, who is congenitally profoundly deaf (Table 1) had a Nucleus cochlear implant surgically inserted at the age of 3/12 years. During cochlear implantation assessment the only consistent aided response was observed at 100 dB SPL at 500 Hz with binaural hearing aids. He
Fig. 1. Post-implantation stimulation thresholds of the youngest brother (Case 1).
received a Nucleus Mini System 22 with the SPEAK speech processing strategy. After an initial period of inconsistent supra-threshold responses he has since made excellent use of his implant (Fig. 1). Aged 6, he had two attacks of loss of consciousness within a period of 1 month, whilst at school. The initial attack was described as being more like syncope following exertion, with the second episode being reported as a grand mal seizure. The episodes were initially thought to be neurogenic. However, because of the presence of the cochlear implant an MRI scan of his brain was contraindicated. While an in-patient after the second seizure, bradycardia and hypotension were noted. Cardiac investigations confirmed a prolonged corrected QT interval. Electrocardiography revealed a QTc of 0.613 s (upper limit of normal 0.44 s), (Fig. 2) with a heart rate of 65 beats per minute. Abnormal T waves were found in standard lead II and pre-cordial leads V4 to V6. He later developed bronchial
Table 1 Aided soundfield audiometric threshold levels of the youngest brother (Case 1) before implantation Frequency in Hz Intensity in db SPL
250 ?85
500 100
1000 NR at 100
2000 NR at 100
4000 NR at 90
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Fig. 2. Electrocardiogram of the youngest brother (index case) showing a prolonged QTc of 0.613 s in lead II and abnormal T waves.
asthma. The combination of congenital deafness and long QTc prompted the clinical diagnosis of JLNS.
2.3. Case 2
Fig. 4. Post-implantation stimulation levels of Case 2.
The middle brother, aged 13 years, is also profoundly deaf (Fig. 3). He received a Nucleus 22 multi-channel cochlear implant at the age of 3 years. Figs. 4 and 5 show his stimulation thresholds and dynamic range using his implant. He has had no syncopal attacks, but is asthmatic. This brother was also found to have a prolonged QTc of 0.62 s, although he has so far remained asymptomatic. A 24 h ambulatory electrocardiograph (Fig. 6) showed a minimum heart rate of 60 beats per minute (with beta-blockade). His exercise ECG revealed grossly prolonged QTc.
2.4. Case 3 The eldest of the siblings, a boy, now aged 16, was diagnosed profoundly deaf (Fig. 7). Hearing aids were provided from the age of 23 months. An initial request for cochlear implantation was deferred, as at that time prelingually congenitally deaf children were not being considered for such a procedure. He developed attacks of syncope and experienced seizures following exertion which were treated with Carbamazepine. At the age of 4 he
Fig. 3. Unaided Pure Tone Audiogram thresholds of Case 2 before implantation.
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Fig. 5. Threshold and comfort levels (lower and upper ends of blocks) of Case 2.
Fig. 6. Electrocardiogram of Case 2 showing a prolonged QTc 0.62 s.
was referred for cochlear implantation, but was thought to be unsuitable because of the syncopal attacks and seizures and possible learning difficulties. He was re-assessed at the age of 8 years but again found to be unsuitable due to his chronological age. Meanwhile, he had no further
seizures and his electroencephalogram remained normal. Carbamazepine was discontinued. After the youngest brother had been found to suffer from JLNS. The eldest brother was then assessed because of his previous history of syncope. He was found to have a resting heart rate of 60 bpm, with an electrocardiogram revealing a QTc of 0.586 s (Fig. 8). During 24 h electrocardiography, no abnormal cardiac symptoms were experienced despite bradycardia of 43 beats per minute. His pure tone audiogram (Fig. 7) shows a profound deafness. He has little or no gain from amplification and he communicates by signing. More recently he developed Insulin dependent Diabetes Mellitus and Asthma. All three brothers were treated with the betablocking agent, Metoprolol and were then changed to Bisoprolol, successfully preventing arrhythmias. They are continually monitored, with no further episodes of syncope.
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Fig. 7. Pure Tone Audiogram of the eldest brother (Case 3).
Fig. 8. Electrocardiogram lead II of Case 3 showing a prolonged QTc of 0.5486 s.
Mutational analysis confirmed the clinical diagnosis of JLNS showing a mutation in KCNQ1, c.1686-1 G/A, a G to A transition in the invariant AG of the splice acceptor site of exon 14. The affected boys are homozygous for this mutation, both parents are carriers.
3. Discussion
3.1. Clinical aspects Since Jervell and Lange-Nielsen described this syndrome of syncopal attacks, cardiac arrhythmias, sudden death and congenital sensorineural deafness in 1957 several further reports have appeared in the literature. Many aspects of the syndrome’s diagnostic and management issues
continue to evolve. This case report will highlight some of these. The eldest brother in this sibship suffered from syncopal attacks and seizures on exertion, and was initially treated with anti-convulsant therapy for a period of 3 years. However, the seizures are now thought to have represented the cerebral effect of transient ischaemia occurring during episodes of ventricular tachycardia. This would explain the normal electroencephalogram; a similar case was reported by Cusimano et al. in 1991 [11]. The youngest of the three brothers had identical attacks to those of his eldest brother, with one of the attacks being clearly witnessed and described as a seizure. The middle brother has had no reported syncopal attacks, and has been asymptomatic despite an abnormal QTc. The severity of the arrhythmias and their clinical presentation is known to vary in JLNS. Although hypochromic anaemia can occur as part of this syndrome, none of the members of this sibship has haematological abnormalities. 3.2. ECG features A QTc interval equal to or greater than 0.44 s is diagnostic in males, as is an interval of equal to or greater than 0.46 s in females. Borderline cases
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been suggested by Glikson et al. and Wilson et al. [17,18].
3.4. Genetics Fig. 9. Ventricular tachycardia (Torsade des Pointes) which may occur in this syndrome.
with intervals of 0.44 /0.46 without symptoms have been documented by Bazzet [12], Cusimano et al. [11] and Keating et al. [13]. Electrophysiological cardiac abnormalities in this syndrome, in addition to a prolonged QTc, can include abnormal T wave morphology: biphasic, inverted or bifid [14,15]. Multifocal ventricular ectopics can occur, and are associated with a poor prognosis. Ventricular tachycardia, ventricular fibrillation and Torsade des Pointes (Fig. 9) arrhythmias cause syncopal attacks and may lead to sudden death if not treated. The attacks can be precipitated by a sudden increase in autonomic activity, for example during exercise, or following emotional stress and loud sounds. 3.3. Management of arrhythmias The youngest of the brothers had abnormal T wave morphology in standard lead II and precordial leads V4 to V6 of his ECG. Holter monitoring and stress ECG was normal in all three brothers. Beta-blockade has, to date, controlled the symptoms of the youngest and eldest brother. The asymptomatic middle brother has also been given beta-blockade therapy. The benefits of such treatment had to be weighed against the potential side-effects, as all three brothers are known asthmatics. Beta-blocker therapy is the first line of management in this syndrome[16]. Limited success has been reported with left stellate ganglionectomy. Recently, the benefits of permanent internal cardiac defibrillator-pacers have been evaluated, with definite advantages over cardiac pacemakers in the prevention of sudden death and neurological damage. In patients unresponsive to medical treatment alone a combination of internal cardiac defibrillator-pacers with beta-blockade has also
Good progress has been made in the last few years in understanding the genetic basis of JLNS. At the molecular level, it has now been shown that autosomal recessive JLNS and autosomal dominant RWS are allelic, and are caused by mutation in either of the genes KCNQ1 and KCNE1(reviewed in Towbin and Vatta [9], Shulze-Bar et al. [19] and Tyson et al. [10,20]). KCNQ1 and KCNE1 encode the potassium channel responsible for the slow component of the delayed rectifier potassium current, Isk, in the heart. Expression of both genes has also been demonstrated in the mouse in the marginal cells of the stria vascularis of the inner ear, the tissue responsible for maintaining the high concentration of potassium in the endolymphatic fluid bathing the hair cells of the organ of corti [21,22] The role of these genes in JLNS is supported by data from the mouse. In particular the Isk knockout mouse is deaf, has vestibular dysfunction and shows an inner ear pathology closely resembling that seen in human subjects who have died from JLNS [21,23,24]. If RWS and JLNS are allelic, why are symptoms rarer in carriers of JLNS mutations? A comparison of mutations described to date in RWS with those found in JLNS shows some differences. The types of KCNQ1 mutation that predominate in autosomal dominant RWS are missense and appear to have a localised effect on the predicted protein. In contrast, frameshift/truncating mutations appear to be responsible for the majority of JLNS (LQTS database). Yet despite this difference in mutation type, recent data indicates a spectrum of functional effects for JLNS disease-causing mutations [25]. From a clinical point of view, the parents of children with JLNS may occasionally have prolonged QTc and some gene carriers may even be symptomatic [26 /28] but a family history of syncope and sudden death is rare in individuals with JLNS and has not been reported in the
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literature until recently [21,26]. The parents of the family described here have normal QTc. The importance of highlighting the sub-clinical cases genetically should be stressed, as severe symptoms and even sudden death can be triggered by certain drugs such as Sotalol, Amiodarone, Quinidine, Procainamide, Erythromycin, Terfenadine and possibly Fexofendine [29], Haloperidol and some tricyclic anti-depressants and Fluoroquinolones, all of which may effect cardiac repolarisation [30,31]. 3.5. Implications for cochlear implantation: before implantation 3.5.1. Aetiological investigations Cardiac investigation should part of the diagnostic work up of all patients with congenital or early onset hearing loss. JLNS may present in a potentially fatal manner but can be treatable. Haematological and biochemical investigations are also mandatory as the syndrome may be associated with anaemia and in one of our cases we report the presence of Insulin dependent Diabetes mellitus, it is not clear whether this may be related to the syndrome or a sporadic occurrence. 3.5.2. Anaesthetic considerations There are numerous reports in the literature of undiagnosed cases of JLNS with unpredictable preventable cardiac arrhythmias during surgery causing serious complications. Adu-Gyamfi et al. [32] reported a case of a child with congenital profound deafness, who was misdiagnosed as having epilepsy. While undergoing a CT scan of the brain under general anaesthesia he experienced polymorphous ventricular tachycardia on induction with Halothane. In retrospect he was found to have JLNS. Wig reported a case of cardiac arrest perioperatively in a patient undergoing abdominal surgery who, retrospectively, was found to have a prolonged QTc interval [33]. The authors commented on the lack of awareness of the patient’s condition pre-operatively, with inadequate anaesthetic precautions.
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Holland, in 1993, reported multifocal ventricular extrasystoles and ventricular fibrillation during anaesthesia in a congenitally deaf child undergoing adenoidectomy [34]. The arrhythmias were converted to sinus rhythm by defibrillation and Lignocaine. The author stressed the importance of an adequate history and anaesthetic precautions in order to avoid cardiac events in JLNS, which was diagnosed retrospectively in this case. In cases when the diagnosis of JLNS and Romano-Ward has already been made, pre-operative beta-blockade, with optimisation of the dose, should be commenced prior to the induction of anaesthesia, as anaesthesia increases the risk of ventricular arrhythmias. Drugs such as Halothane, which sensitise the myocardium to the effect of catecholamines, should be avoided. Effective preoperative sedation, oximetry and avoidance of drugs which might further prolong the QT interval, ensuring a normal serum potassium and electrolytes and, above all, continuous ECG monitoring from the time the patient enters the anaesthetic room are all important aspects of management. O’Callaghan et al. reported difficulties in reverting arrhythmias to sinus rhythm during anaesthesia [35]. They described the anaesthetic implications of two cases with prolonged QTc, stressing the need to avoid bradycardia, increased sympathetic activity and drugs which may prolong the QTc interval, and advocating beta-blockade as the mainstay treatment of choice. Pre-operative awareness that a patient has JLNS is the best way of ensuring a safe anaesthetic. However, where the diagnosis of JLNS has not been suspected, routine ECG monitoring would not only allow peri- and per-operative arrhythmias to be detected and treated, but should also draw the attention of surgeon and anaesthetist to the fact that this syndrome is present. 3.6. Implications for cochlear implants: after implantation 3.6.1. Electrical interference The presence of a cochlear implant is unlikely to provoke cardiac arrhythmias, and did not do so in the case of the asymptomatic implanted middle
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brother in this sibship. No reports have yet been published on the effects of cardiovertor pacer devices on the cochlear implant, however because of the distance between the chest and the ear it is improbable that interaction between the two devices would occur. 3.6.2. Trauma to the cochlear implant in the event of syncope Should the cardiac arrhythmias not be fully controlled there is a risk of syncopal attacks causing head injury and trauma, potentially damaging the transducer component of the device. A light-weight helmet (usually modified from high quality sports head gear types and tailored to the individual) is advisable especially during strenuous physical activity. Contact sports should be avoided [36]. Vestibular function is currently being assessed in this sibship; if found to be abnormal it may contribute to imbalance and the risk of trauma. To our knowledge these are the first published clinical details of patients with JLNS with this novel mutation to receive cochlear implants. The diagnosis was made in retrospect as this condition is very often difficult to identify, unless a 12 lead ECG has been performed. All children with congenital sensorineural deafness should be screened for JLNS with a 12 lead ECG. Early diagnosis will lead to the effective management of syncopal attacks with Beta-blockers, cardiac pacemakers, or implanted pacer-defibrillators, and to the planning of safe general anaesthesia for these patients.
4. Summary We report the clinical presentation of three cases with JLNS, two of whom had cochlear implantation (the youngest and the middle brother). Early diagnosis of this syndrome will enable appropriate planning of medical, surgical and rehabilitative strategies. Control of his syncopal attacks may theoretically prevent damage to the implant device in the youngest brother. In the future it may be possible to identify the known mutations of the KCNQ1 and KCNE1
early enough to initiate medical preventative measures of the cardiac complications, and effective audiological habilitation. Further research is needed to establish practical criteria to investigate those children who have a borderline prolonged QTc interval (0.44 s in males; 0.46 s in females) on resting ECG and who are asymptomatic. Further cardiac rhythm investigations, including a stress ECG and Holter monitoring, seem not to be indicated and may cause unnecessary anxiety to the parents and child.
Acknowledgements We acknowledge the helpful technical advice of Michael Conway, Medical Physicist and member of the UCL Cochlear Implant Team, the UCL/ RNTNE cochlear implant team and Sarah Palser for her invaluable help and support. Dr Nick Archer, consultant paediatric cardiologist at the John Radcliffe Hospital, Oxford, England kindly supplied the ECG data. We are very grateful to Dr Jessica Tyson, at the Institute of Child Health for her comprehensive review of the genetics aspects of this paper.
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