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We sought to examine the frequency of abnormal echocardiographic findings in patients with tuberous sclerosis complex.
In a retrospective cohort study, we included all patients with known tuberous sclerosis complex who had been sent to our cardiology department for echocardiographic screening from 1995 through August 2003 (n=56). Two research scientists independently reviewed the reports of the echocardiographic screening examinations for abnormal findings. We used descriptive statistics, the Mann-Whitney U test, and the χ2 test.
The mean age of patients included in the study was 35 years (range, 12–73 yr); 23 patients were male. Abnormal findings were seen in 22 patients (39%). The most common abnormal findings were focal areas of increased intramyocardial echogenicity, which were seen in 16 patients (29%). The clinical consequence of this finding is still unknown.
We conclude that echocardiographic abnormalities are common in patients with tuberous sclerosis complex.
Tuberous sclerosis complex (TSC) is an inheritable multiorgan disease. It is an autosomal dominant neurocutaneous disorder characterized by tumor-like malformations that involve many organ systems, including the brain, heart, kidneys, and skin.1 The birth incidence of TSC is approximately 1 per 5,000 to 10,000 live births.2 The diagnosis of TSC is made clinically. However, the expression and the severity of the disease show substantial variation within, as well as between, families.3 The classical diagnostic triad of seizures, mental retardation, and facial angiofibromas occurs in fewer than half of the patients. Therefore, a clinical scoring system was developed4 that divides the diagnostic criteria for TSC into major and minor features.
Single or multiple cardiac rhabdomyomas are considered a major feature.4 More than half of all infants with TSC show evidence of cardiac rhabdomyomas on echocardiography.5–7 However, rhabdomyomas tend to regress over time.6,8–11
Since 1995, our institution has been a national referral center for patients with TSC. A multidisciplinary approach is used in accordance with Dutch national TSC guidelines,12,13 which recommend at least 1 echocardiogram to screen for cardiac rhabdomyomas in patients with TSC. However, the recommendations for diagnostic evaluation in cases of TSC as defined at the Tuberous Sclerosis Consensus Conference in 1998 specify that echocardiography be performed during initial testing only if cardiac symptoms are present or if confirmation of a suspected cardiac lesion is needed; and that echocardiography be performed during repeat testing if cardiac dysfunction has occurred.14
The purpose of this study was to determine the frequency of abnormal findings seen upon screening echocardiography in a relatively large cohort of patients with TSC.
Study Design. We performed a retrospective cohort study that included all patients with TSC who were referred by our TSC outpatient clinic to our cardiology department for echocardiographic screening from the start of our outpatient TSC clinic in 1995 through August 2003. Our institutional review board approved this retrospective study and waived informed consent. Echocardiographic screening reports were available for all 56 patients included in the study.
Echocardiographic Data Acquisition. All patients underwent a standard screening echocardiographic examination at our cardiology department at some time during the study period. Transthoracic echocardiography was performed with an S3 transducer, range 1–3 MHz (Philips HP SONOS 5500® imaging system, Koninklijke Philips Electronics N.V.; Eindhoven, The Netherlands) in multiple planes, according to standard clinical practice. Parasternal long- and short-axis and apical 4-chamber views were obtained. All echocardiographic studies were performed by 1 of 2 sonographers, each of whom had more than 10 years of echocardiographic experience.
Echocardiographic Data Review. Two research scientists (MA and MB) independently studied the written reports on the screening echocardiographic examinations in search of abnormal findings. Abnormal findings for each patient were recorded on a case-record form. The research scientists were blinded to each other's forms. Cases in which the findings of the 2 reviewers disagreed were re-evaluated, and a final decision was made.
Data Analysis. Descriptive statistics were used to describe patients' characteristics and the number of findings that were abnormal upon screening echocardiography. We calculated an unweighted κ statistic to evaluate interobserver agreement between the 2 research scientists. We used the Mann-Whitney U test to compare means between groups and the χ2 test to compare proportions. Analyses were performed with Excel for Windows and SPSS version 15 (SPSS, Inc.; Chicago, Ill).
All 56 patients had TSC according to the criteria set forth by the consensus conference in 1998.4 The mean patient age was 35 years (range, 12–73 yr). Thirty-three of the 56 patients were female (59%). Abnormal findings on screening echocardiographic examinations were seen in 22 out of 56 patients (39%). Interobserver agreement for detection of abnormal findings in screening echocardiography reports was excellent (κ=1).
The most common abnormal finding upon screening echocardiographic examination in these patients with known TSC was focal areas of abnormal intramyocardial hyperechogenicity (Figs. 1 and and2),2), which were seen in 16 of 56 patients (29%) (Table I). Significantly more foci were found in males (10/23 = 43%) than in females (6/33 = 18%) (P=0.045). Intramyocardial hyperechogenic foci were located in the interventricular septum, the left ventricular wall, and the papillary muscles. Multiple focal areas of abnormal intramyocardial hyperechogenicity were seen in 5 of these 16 patients. Patients with focal areas of abnormal intramyocardial hyperechogenicity (mean age, 27 yr; range, 16–45 yr) were on average younger than were patients without these abnormalities (mean age, 38 yr; range, 12–73 yr) (P=0.007).
In the group of patients who had focal areas of abnormal intramyocardial hyperechogenicity, 5 patients had additional echocardiographic abnormalities that were described in the reports as unrelated to the focal areas of abnormal intramyocardial hyperechogenicity. These additional findings (1 per patient) were moderately severe regurgitation of the mitral valve (grade 3), moderately severe stenosis of the aortic valve, absence of a papillary muscle of the anterior mitral valve leaflet, hypokinetic posterior wall of the left ventricle, and hypokinetic interventricular septum (Table I).
In the group of patients who did not have focal areas of abnormal intramyocardial hyperechogenicity, 6 patients had isolated echocardiographic abnormalities. These findings were moderately severe tricuspid valve regurgitation (grade 2), mild mitral valve regurgitation (grade 1), late systolic mitral valve regurgitation caused by mitral valve prolapse, decreased left ventricular function (ejection fraction, 0.40), hypokinetic and mildly dilated left ventricle, and hypertrophic cardiomyopathy of the left ventricle (Table I).
There is a discrepancy between the Dutch national TSC guidelines12,13 and the recommendations for diagnostic evaluation of TSC developed during the Tuberous Sclerosis Consensus Conference in 1998: the Dutch guidelines recommend at least 1 screening echocardiogram in all TSC patients who are screened for cardiac rhabdomyomas regardless of the presence or absence of cardiac clinical symptoms, while the international consensus guidelines recommend echocardiography during initial testing only if cardiac symptoms are present or if confirmation of a suspected cardiac lesion is needed.14 Therefore, the purpose of our retrospective study was to determine the frequency of abnormal echocardiographic findings in a relatively large cohort of patients with known TSC who were referred to our cardiology department for screening under the less restrictive Dutch guidelines.
Abnormal cardiac findings were seen in about one third of all patients who were screened. The most common abnormal findings were focal areas of increased intramyocardial echogenicity, which were seen in 16 of 56 patients (29%). The clinical consequence of this finding is not yet known. These focal areas of increased intramyocardial echogenicity might be remnants of rhabdomyomas (that is, hyperechogenic nodules embedded in the ventricles from childhood), because more than half of all infants with TSC show evidence of cardiac rhabdomyomas on echocardiography.5-7,15–17 According to the medical literature, rhabdomyomas tend to regress over time.5,6,8–11,15,18,19 Echocardiographic evidence of cardiac rhabdomyomas is reported in about 20% of adult patients who have TSC.6,7 In our study, the patients with focal areas of increased intramyocardial echogenicity were indeed significantly younger than were the patients without such focal abnormalities. Furthermore, there appears to be a male predominance among patients with TSC who develop rhabdomyomas.9,15 In our study, there was also a male predominance among patients who showed focal areas of increased intramyocardial echogenicity.
After childhood, patients with TSC who develop cardiac dysfunction suffer mostly from arrhythmias.14 Although the literature describes an association between cardiac rhabdomyomas and cardiac arrhythmias,15,19–29 arrhythmias have also been described in TSC patients who have no echocardiographic evidence of rhabdomyomas14,17,26 and in a patient who had only extensive microscopic rhabdomyomatous changes.30 Maybe there is an association between cardiac arrhythmias in TSC and the focal areas of increased intramyocardial echogenicity that we found. However, the current study design does not enable us to answer this question.
In conclusion, focal areas of increased intramyocardial echogenicity are commonly seen in patients with TSC. Should a physician, in daily practice, encounter a focal area of increased intramyocardial echogenicity as shown in this article, he or she should remember to look for other features of TSC.
Address for reprints: Miraude E.A.P.M. Adriaensen, MD, MSc, Department of Radiology, Atrium Medical Center; Henri Dunantstraat 5, 6419 PC Heerlen, The Netherlands