cardiac involvementfied as equivocal. doppler studies were per-formed to exclude obstructions...

Br Heart,J 1994;72:584-590

Cardiac involvement in tuberous sclerosis

Eberhard G Miihler, Vlatka Tumiski-Harder, Wolfgang Engelhardt, Goetz von Bernuth

AbstractObjective-To assess the incidence,importance, and history of cardiacinvolvement in infants and children withtuberous sclerosis.Design-Prospective study; clinicalexamination, sector and Dopplerechocardiography, standard and ambula-tory electrocardiography.Setting-A tertiary referral centre.Patients-21 patients with tuberous scle-rosis aged 1 day to 16 years (mean 6-3years); follow up investigations wereavailable in 14 cases (10 retrospective, 4prospective; mean follow up 4-3 years).Results-Multiple cardiac rhabdomy-omas in the right ventricle (11) and leftventricle (14) as well as in the rightatrium (1) were present in 14/21 patients.Two of them had obstruction of the leftventricular inflow and outflow tractrelated to a tumour. In the remaining 7patients, echocardiography was normalin 4 and equivocal in 3 cases. The stan-dard electrocardiogram (n = 20) showedventricular hypertrophy (2), ventricularpre-excitation (1), arrhythmias (2), andrepolarisation disturbances (4) in 7/13patients with rhabdomyomas but wasnormal in all patients with a normal orequivocal echocardiogram. The ambula-tory electrocardiogram (n = 19) showedfrequent premature atrial (2) and poly-morphous ventricular (2) contractions.The polymorphous ventricular contrac-tions coexisted with rhabdomyomas. Noarrhythmias that needed medical treat-ment were found. Follow up investiga-tions showed return to a normal standardelectrocardiogram in 3 patients. Definiteregression or complete disappearance ofthe tumour occurred in 6 infants.Conclusions-Cardiac rhabdomyomas,although often present in these patientswith tuberous sclerosis, caused neithermajor arrhythmias nor haemodynamicobstruction except in the neonatalperiod. The indication for operation islimited to cases with life threateningobstruction or arrhythmias refractory tomedical treatment.

(Br Heart J 1994;72:584-590)

Tuberous sclerosis is one of the neurocuta-neous syndromes with autosomal dominantinheritance and has a reported incidence of1:10 000. Mental retardation, cerebral con-vulsions, and adenoma sebaceum are thecharacteristic signs of the disease and were

described in 1908 by Vogt.' Besides the neu-rocutaneous abnormalities many other organsystems may be involved.2A Primary and sec-ondary criteria for the diagnosis of tuberoussclerosis were defined by Gomez.5

In 1862 von Recklinghausen first describedthe coincidence of cardiac tumours andintracerebral sclerotic areas in a newbornbaby.6 Recent echocardiographic studiesreported a 50%-64% incidence of cardiacrhabdomyomas detected by ultrasound inpatients with tuberous sclerosis.79Our prospective study was performed to

examine the occurrence and the haemody-namic or arrhythmic relevance of cardiacrhabdomyomas in infants and children withtuberous sclerosis.

Patients and methodsPATIENTSTwenty one patients, 15 male and six femaleaged 1 day to 16 years (mean 6-3 years), werestudied. The diagnosis of tuberous sclerosiswas based on the criteria described byGomez,5 every patient had typical white spotsand characteristic subependymal hamartomasin the cranial computed tomogram. Allpatients had a history of cerebral convulsions.At the time of the study, three patients whowere not on medication had no seizures. Theremaining 18 patients were treated with anti-convulsive drugs, nine of them successfully.The age at the time of diagnosis varied

between 1 day and 8 years (mean 1-7 years).The most frequent condition leading to thediagnosis of tuberous sclerosis was cerebralconvulsions (14 patients). In two patients, aknown family history caused the patients to beexamined. Five patients presented first withcardiac symptoms leading to the diagnosis oftuberous sclerosis: a heart murmur was theindication for an echocardiographic examina-tion in four infants. In the other patient, thediagnosis of rhabdomyomatosis was alreadyknown before birth due to fetal arrhythmiasand consecutive echocardiographic examina-tions.

Follow up investigations were available in14 cases, including 10 with retrospective stud-ies (follow up 0-5-8-3 (mean 5-3) years) andfour neonates with prospective control exami-nations (follow up 0'6-3 5 (mean 1 9) years).

METHODSBesides a physical examination, the investiga-tive programme included a complete echocar-diographic study and a standard and a 24hour ambulatory electrocardiogram.The echocardiographic studies, docu-

mented on video tape, were assessed by two

Departnent ofPediatric Cardiology,RWTH Aachen,GermanyE G MihierV Turniski-HarderW EngelhardtG von BernuthCorrespondence to:Dr Eberhard G Miihler,Department of PediatricCardiology, Pauwelsstr 30,RWTH Aachen, D-52057Aachen, Germany.Accepted for publication20 June 1994

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Figure 1 Multipleintramural andintracavitaryrhabdomyomas in a 4week old baby withtuberous sclerosis. LV, leftventricle; LA, left atrium;Ao, ascending aorta;arrows, rhabdomyomas.

independent observers. High resolution sectorechocardiographic images were obtained by3 5, 5 0, or 7T5 MHz transducers with amechanical sector scanner from the paraster-nal, apical, and subcostal position.Rhabdomyomas were diagnosed if discreteareas of increased acoustic density were visi-ble within a cardiac cavity or wall in at leasttwo imaging planes. In cases where only verysmall echogenic regions were noticed withinthe interventricular septum or the right or theleft ventricular free wall, the patient was classi-fied as equivocal. Doppler studies were per-formed to exclude obstructions related to atumour.

Twelve lead standard electrocardiogramswere available in all but one patient, who hadechocardiographic evidence of rhabdomy-omas.

Ambulatory electrocardiographic studieswere performed with a continuous recordingsystem (Oxford Medilog 4500).Interpretation of the data were based on auto-mated reports with manual interaction duringprocessing and a careful review of the com-plete 24 hour electrocardiogram plotted onpaper. Ambulatory electrocardiograms werelacking in one patient with and in another onewithout echocardiographic evidence of hearttumours.

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Figure 2(A) Echocardiogram ofa S week old baby (subcostal view). A large tumour is adjacent to the mitral valve and obstructs the inflow tract. LA,left atrium; RA, right atrium; Tu, tumour. (B) Electrocardiogram of the same patient shows ventricular pre-excitation with negative delta waves in leadsIII and avF, and R > S in lead V, consistent with a left posterior accessory pathway.

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Figure 3(A) Six weekold baby with tuberoussclerosis. Echocardiographyshows an echogenic tumourarisingfrom theinterventricular septumwith obstruction of the leftventricular outflow tract(Doppler gradient 33 mmHg). (B) Echocardiogramof the same patient twoyears later: tumour isalmost completely regressedexceptfor small echogenicareas in the subaortalportion of theinterventricular septum.LV, left ventricle; RV,right ventricle; LA, leftatrium; Ao, ascendingaorta; arrow, tumour.

ResultsPHYSICAL EXAMINATIONSixteen patients had a normal cardiac exami-nation. An organic systolic heart murmur waspresent in four patients and an arrhythmia inthe other.

ECHOCARDIOGRAPHIC STUDIESThe echocardiographic examination was nor-mal in four and equivocal in three patients. Inthe remaining 14 cases echocardiographyshowed multiple rhabdomyomas in the rightventricle (1 1) and left ventricle (14) (fig 1) as

well as in the right atrium (one). Twopatients, both neonates, had obstructionsrelated to a tumour. In the first case, a largetumour adjacent to the mitral valve led toobstruction of the left ventricular inflow (fig2). Recurrent episodes of puhlmonary oedemathat needed assisted ventilation were the indi-cation for surgical resection of the tumour atthe age of five weeks. The outcome wasunfavourable and the infant died from pro-gressive mitral valve insufficiency one monthafter the operation. In the second case,Doppler echocardiography confirmed that a

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Figure 4 Apicalfourchamber view (above) andparasternal short axis view(below) in a 3 day oldbaby shows multiplerhabdomyomas at theintraventricular septumand a very large tumour onthe lateral and apicalaspect of the left ventricle.Regression of tumour wasobvious seven months later.LV, left ventricle; LA, leftatrium; RV, rightventricle; RA, rightatrium; Tu, tumour; MV,mitral valve.

tumour that arose from the subaortic intra-ventricular septum caused an obstruction tothe left ventricular outflow tract (fig 3A). Thepatient was asymptomatic and thereforesurgery was not considered necessary. Followup investigations showed spontaneous regres-sion of the tumour within two years (fig 3B).

Besides these two infants with obstructivelesions, haemodynamic relevance could beexcluded by Doppler sonography in two fur-ther neonates: one with a large tumour withinthe right ventricle close to the tricuspid valve,the other with an extended tumour on the lat-eral and apical aspect of the left ventricle(fig 4).

STANDARD ELECTROCARDIOGRAMStandard electrocardiograms were available in

20 patients (table 1). Pre-excitation withoutepisodes of supraventricular tachycardia wasfound in the patient with a large tumour adja-cent to the mitral valve (fig 2). The standardelectrocardiogram was normal in all patientswith normal or equivocal echocardiographicinvestigation, but the electrocardiogram wasabnormal in seven of 13 patients withechocardiographic evidence of rhabdomy-omas.

24 HOUR AMBULATORY ELECTROCARDIOGRAMTable 2 shows the results of the 24 hourambulatory electrocardiographic studies,available in 19 patients. There was a predomi-nant sinus rhythm in all patients. Occasionaljunctional escape rhythms and a few shortepisodes of second degree atrioventricular

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Table 1 Standard electrocardiogram in 20 patients withtuberous sclerosis

Result No

Normal 13Abnormal: 6

Ventricular pre-excitation 1Premature atrial contractions 1Premature ventricular contractions IVentricular hypertrophy 2Repolarisation disturbances 4

block occurred each in one patient. Two of sixpatients without confirmed cardiac tumourshad a few (<100/24 hours) premature ventric-ular contractions but 10 of 13 patients withheart tumours had at least a few prematureventricular contractions. Frequent prematureatrial contractions were found in one patientwith and one without rhabdomyomas. Noneof the 19 patients had episodes of supraven-tricular or ventricular tachycardia, or arrhyth-mias that needed medical treatment.

FOLLOW UP INVESTIGATIONSRepeated echocardiographic studies wereavailable in 14 patients. Ten children had 22previous echocardiographic studies and fourinfants 21 prospective follow up studies (table3). Definite spontaneous regression of a

Table 2 24 h Ambulatoty electrocardiogram in 19patients with tuberous sclerosis

Sinus rhythm 19Junctional escape rhythm (intermittent) 1Second degree AV block (intermittent) 1

Premature atrial contractions:Frequent 2Blocked 1Consecutive I

Premature ventricular contractions:None 7< 100/24 h 10Frequent 2

Supraventricular or ventricular tachycardia 0

AV, Atrioventricular.

tumour or complete disappearance was foundin six patients (Nos 1-6) with first investiga-tion in infancy, whereas four patients (No7-11) showed no change in their tumoursduring childhood. Spontaneous relief of theobstruction was documented in one infant(fig 3).

Repeated standard electrocardiograms werepresent in 12 patients with a total number of45 electrocardiograms. Four patients pre-sented with repolarisation disturbances at thefirst investigation, in two of them the electro-cardiogram became normal before the lastinvestigation (fig 5). Arrhythmias disappearedin three of five patients during follow up.Overall, the standard electrocardiogram wasnormal in four patients at the first and inseven patients at the last investigation.

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Figure 5(A) Electrocardiogram of a 23 month old boy with an echogenic tumour in the apex of the left ventricle shows repolarisation disturbancesincluding ST segment elevation in lead I and avL. (B) Electrocardiogram of the same patient 3 5 years later: completely normal.

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Table 3 Echocardiographic findings in 14 patients with follow up

First study Actual studyFollow up

Patient No Age Tumour Tumour Development (mo.)

1 intrauterine + + Regression 22*2 6 days + + Regression 42*3 3 days + + Regression 7*4 1 month + + Regression 23*5 4 months + + Regression 786 6 months + + Regression 827 46 months + + No change 738 59 months + + No change 829 103 months + + No change 7310 123 months + + No change 7111 68 months ? ? 512 3 months ? 2913 44 months - 10014 25 months - 48

*Prospective follow up; ?, equivocal.

DiscussionThe incidence of rhabdomyomas in patientswith tuberous sclerosis had been underesti-mated until sector echocardiography allowednon-invasive detection of tumours by screen-

ing.'0 Image quality with high frequency trans-ducers is usually good enough in infants andchildren to detect even small intramuraltumours. Magnetic resonance imaging hasproved to be of additional value especially inolder patients and in patients with poor imagequality due to bone and lung interference."' 12

Sixty five per cent of our patients withtuberous sclerosis had echocardiographic evi-dence of rhabdomyomas which correspondsto a reported incidence of 50%-64% in previ-ous studies.7-9 There is a wide range of symp-toms of tumours from total absence ofsymptoms to intrauterine or sudden postpar-tum death."3 14 Fetal hydrops, intrauterinearrhythmia, or multiple tumours detected byfetal ultrasound screening may be the firstsymptoms that lead to the diagnosis of tuber-ous sclerosis before delivery.'5-"7 Furthermore,tuberous sclerosis has been diagnosed byultrasound screening already in early fetal lifein patients with a known family history of thedisease.'8 19 In our study, cardiac manifesta-tion led to the diagnosis in five patientswhereas nine patients with rhabdomyomaswere completely asymptomatic and thetumours were only detected by screening ofpatients with tuberous sclerosis.

Syncopes in patients with tuberous sclerosisare likely to be attributed to cerebral causes:over 90% of children with tuberous sclerosishave epilepsy.20 Nevertheless, cardiac involve-ment includes the possibility of syncopes dueto severe arrhythmias or embolisation oftumours. Until now, there is little informationon the incidence and importance of arrhyth-mias in infants and children with tuberoussclerosis. To our knowledge, there are onlytwo previous reports that prospectively lookedfor arrhythmias in 11 and seven patients withtuberous sclerosis82: in summary, two of the18 patients showed important arrhythmias inthe ambulatory electrocardiogram-that is,supraventricular tachycardia. One of themhad rhabdomyomas. Our study gives furthersupport to the assumption that an arrhythmicorigin of syncope is unlikely. The ambulatoryelectrocardiogram disclosed no important

arrhythmias in patients with or without rhab-domyomas, although ventricular extrasystolesoccurred more often with rhabdomyomas. Alarge tumour adjacent to the mitral valve wasthe underlying cause of ventricular pre-excita-tion in one patient, but acute deteriorationwas related to obstruction of the left ventricu-lar inflow tract and not to supraventriculartachycardia.

Apart from arrhythmias, cerebral embolisa-tion is considered to be a potential cause of

22syncopes. None of our patients with intra-cavitary rhabdomyomas showed a peduncu-lated origin or an extended tumour mobilitylikely to cause embolisation. Although ahigher incidence of strokes has been reportedin patients with tuberous sclerosis, there is noconfirmation that cerebral embolisation byfragments of cardiac rhabdomyomas plays apart.23

Spontaneous regression and even completedisappearance of rhabdomyomas has becomeapparent since serial echocardiographic stud-ies are available. 10 2425 Our study confirmsthese findings; all four infants prospectivelyfollowed up showed spontaneous regressionof their tumours. This became even moreapparent when compared with the growingheart chambers. Obstruction related totumours was found only in early infancy.The indication for surgical treatment of

cardiac rhabdomyomas have changed duringthe past years. Recommendations of radicalexcision of the tumour in symptomatic oreven asymptomatic patients are now obso-lete.26 27 The benign natural history restrictsthe indication for an operation to patientswith life threatening obstruction or arrhyth-mias refractory to medical treatment.

1 Vogt H. Zur Diagnostik der tuberosen Sklerose. Zeitschriftfur Erforsch Behandljugendl Schwachsinns 1908;2: 1-16.

2 Fryer AE, Osborne JP. Tuberous sclerosis-a clinicalappraisal. Pediatric Rev Commun 1987;1:239-55.

3 Narla LD, Slovis TL, Watts FB, Nigro M. The renallesions of tuberosclerosis (cysts and angiomyolipoma)-screening with sonography and computerized tomogra-phy. PediatrRadiol 1988;18:205-9.

4 Slingerland JM, Grossman RF, Chamberlain D, TremblayCE. Pulmonary manifestations of tuberous sclerosis infirst degree relatives. Thorax 1989;44:212-4.

5 Gomez MR. Tuberous sclerosis. New York: Raven Press,1988.

6 von Recklinghausen FD. Verhandlungen der Gesellschaftfur Geburtshilfe. Ein Herz von einem Neugeborenen.Monatsschrnft fr Geburiskunde und Frauenkrankheiten1862;20: 1-3.

7 Blass JL, Breningstall GN, Swaiman KF. Echo-cardiographic incidence of cardiac rhabdomyoma intuberous sclerosis. Am J Cardiol 1985;55: 1379-82.

8 Gibbs JL. The heart and tuberous sclerosis. An echocar-diographic and electrocardiographic study. Br Heart Jf1985;54:596-9.

9 Smith HC, Watson GH, Patel RG, Super M. Cardiacrhabdomyomata in tuberous sclerosis: their course anddiagnostic value. Arch Dis Child 1989;64: 196-200.

10 Smythe JF, Dyck JD, Smallhom JF, Freedom RM.Natural history of cardiac rhabdomyoma in infancy andchildhood. Am Jf Cardiol 1990;66: 1247-9.

11 Freedberg RS, Kronzon I, Rumancik WM, Liebeskind D.The contribution of magnetic resonance imaging to theevaluation of intracardiac tumors diagnosed by echocar-diography. Circulation 1988;77:96-103.

12 Matsumura M, Nishioka K, Yamashita K, et al. Evaluationof cardiac tumors in tuberous sclerosis by magnetic reso-nance imaging. Am J Cardiol 1991;68:281-3.

13 Rigle DA, Dexter RD, McGee MB. Cardiac rhabdomy-oma presenting as sudden infant death syndrome. JForensic Sci 1989;34:694-8.

14 Groves AM, Fagg NL, Cook AC, Allan LD. Cardiactumours in intrauterine life. Arch Dis Child1992;67:1189-92.

15 Scurry J, Watkins A, Acton C, Drew J. Tachyarrhythmia,

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cardiac rhabdomyomata and fetal hydrops in a prema-ture infant with tuberous sclerosis. Y Paediatr ChildHealth 1992;28:260-2.

16 Sauter R, Hummler H, Klemm I. Neonatal heart tumor.Early symptom of tuberous sclerosis. MonatsschrKinderheilkd 1992;140:21-3.

17 Bimbaum SE, McGahan JP, Janos GG, Meyers M. Fetaltachycardia and intramyocardial tumors. Y Am CollCardiol 1985;6:1358-61.

18 Platt LD, Devore GR, Horenstein J, Pavlova Z, Kovacs B,Falk RE. Prenatal diagnosis of tuberous sclerosis: the useof fetal echocardiography. JI'renat Diagn 1987;7:407-1 1.

19 Crawford DC, Garret C, Tynan M, Neville BG, Allan LD.Cardiac rhabdomyomata as a marker for the antenataldetection of tuberous sclerosis. Y Med Genet 1983;20:303-12.

20 Riikonen R, Simell 0. Tuberous sclerosis and infantilespasms. Dev Med Child Neurol 1990;32:203-9.

21 Manetti A, De Simone L, Favilli S, et al. Echo-

cardiographic study of heart rhabdomyoma in tuberoussclerosis. G Ital Cardiol 1989;19:319-23.

22 Konkol RJ, Walsh EP, Power T, Bresnan MJ. Cerebralembolization resulting from an intracardiac tumor intuberous sclerosis. Pediatr Neurol 1986;2: 108-10.

23 Gomez MR. Strokes in tuberous sclerosis: are rhabdomy-omas a cause? Brain Dev 1989; 11: 14-9.

24 Farooki ZQ, Ross RD, Paridon SM, Humes RA,Karpawich PP, Pinsky WW. Spontaneous regression ofcardiac rhabdomyoma. Am Cardiol 199 1;67:897-900.

25 Alkalay AL, Ferry DA, Lin B, Fink BW, Pomerance JJ.Spontaneous regression of cardiac rhabdomyoma intuberous sclerosis. Clin Pediatr 1987;26:532-5.

26 Houser S, Forbes N, Stewart S. Rhabdomyoma of theheart: a diagnostic and therapeutic challenge. AnnThorac Surg 1980;29:373-7.

27 Pesonen E, Leijala M, Jarvenpaa AL, Teramo K. Cardiacrhabdomyomas in a newborn baby. Acta Paediatr Scand1985;74:824-7.

CORRECTION

Table 2 Electrocardiographic responses during maximal (P value) and submaximalexercise and dobutamine stress testing

Maximal vsAll patients Maximal Submaximal submaximal

ExerciseSensitivity 43/56 (77%) 39/44 (89%) 4/12 (33%) 0-0003Specificity 13/30 (43%) 4/19 (21%) 9/11 (82%) 0-002Accuracy 56/86 (65%) 43/63 (68%) 13/23 (57%) NS

DobutamineSensitivity 18/56 (32%) 13/22 (59%) 5/34 (15%) <0.001Specificity 19/30 (63%) 7/13 (54%) 12/17 (71%) NSAccuracy 37/86 (43%) 20/35 (57%) 17/51 (33%) 0-02

Comparative ability of dobutamine and exercisestress in inducing myocardial ischaemia in activepatients. TH Marwick, A M D'Hondt, G H Mairesse,T Baudhuin, W Wijns, M Detry, A Melin.The authors of this article miscalculated some percent-ages in tables 2 and 6 (Br Heart 1994;72:31-8).Their corrected versions of these tables appear along-side.

Table 6 Perfusion abnormalities on scintigraphy during maximal and submaximal exer-cise and dobutamine stress testing

Maximal vsAll patients Maximal Submaximal submaximal

ExerciseSensitivity

Overall 41/56 (73%) 33/44 (75%) 8/12 (67%) NSSingle vessel disease 14/22 (64%) 12/18 (67%) 2/4 (50%) NSMultivessel disease 27/34 (79%) 21/26 (81%) 6/8 (75%) NS

Specificity 21/30 (70%) 13/19 (68%) 8/11 (73%) NSAccuracy 62/86 (72%) 46/63 (73%) 16/23 (70%) NS

DobutamineSensitivity

Overall 35/54 (65%) 16/21 (76%) 19/33 (58%) NSSingle vessel disease 15/22 (68%) 8/10 (80%) 7/12 (58%) NSMultivessel disease 20/32 (63%) 8/11 (73%) 12/21 (57%) NS

Specificity 19/28 (68%) 7/11 (64%) 12/17 (71%) NSAccuracy 54/82 (66%) 23/32 (72%) 31/50 (62%) NS

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