Systematic review Takotsubo syndrome in the paediatric population: a case report and a systematic review Alessia Urbinati, Pierpaolo Pellicori, Federico Guerra, Alessandro Capucci and Andrew L. Clark We describe the case of a takotsubo syndrome in a 12-year-old male patient following an acute intracranial haemorrhage, which had a favourable outcome. We also performed a systematic review of published case reports in patients younger than 18 years. Although takotsubo syndrome is common in postmenopausal women, in the paediatric population it equally affects both sexes. Compared with adults, paediatric patients more commonly present with heart failure symptoms or loss of consciousness. A higher proportion of paediatric patients have ST segment depression on ECG. Moreover, in younger patients, a high proportion has nonapical anatomical variants and more severe left ventricular impairment. The increase in troponin and the decrease in left ventricular ejection fraction, the Introduction Takotsubo syndrome (TTS) has been reported with increasing frequency in the past 25 years. It is characterized by transient left ventricular (LV) dysfunction in patients with no significant obstructive coronary artery disease and it most commonly affects postmenopausal women.1 In its typical form, LV wall motion abnormalities are localized to the apex, which expands like a ‘balloon’ to give an appearance similar to a Japanese octopus fishing pot (whence the origin of the name for the syndrome), usually followed by complete recovery within days or weeks.2 So far, only isolated cases of TTS have been reported in patients younger than 18 years. We present the case of an atypical basal form of TTS in a 12-year-old boy following an acute intracranial haemorrhage. Because of the rarity of the anatomical variant, and the young age and the sex of the patient, we performed a systematic review to clarify the relation between TTS, sex, triggers, and LV involvement in the paediatric population, and we compared these findings with those reported in a large contemporary registry in an adult population.1 prevalence of neurological or psychological disorders, and in-hospital outcome are similar between adults and children. J Cardiovasc Med 2017, 18:262–267 Keywords: paediatric population, reverse, takotsubo, takotsubo syndrome a Castle Hill Hospital, Cottingham, United Kingdom and bOspedali Riuniti di Ancona, Ancona, Italy Correspondence to Alessia Urbinati, MD, Castle Hill Hospital, Cottingham, United Kingdom E-mail: alessiaurbinati@hotmail.it Received 17 June 2016 Revised 12 August 2016 Accepted 25 August 2016 showed a right supratentorial intracerebral haemorrhage (Fig. 1). On admission to the ICU, an ECG showed sinus tachycardia at a rate of 105 bpm, ST depression in leads V3–V6 with concomitant T wave inversion, and prolonged QT (500 ms) (Fig. 2). His first high sensitivity troponin-I was 1.00 ng/ml (normal value <0.055 ng/ml). An echocardiogram showed an LV ejection fraction (LVEF) of 25% with akinesia of the basal and mid-LV segments and a hyperkinetic LV apex (Fig. 3). After 2 h, BP dropped to 98/60 mmHg, and the patient required haemodynamic support with fluids, intravenous dopamine (10 mg/kg/min increasing to 15 mg/kg/min), and adrenaline (0.05 mg/kg/min). After 6 h, troponin-I was 5.42 ng/ml. His ECG the following day had returned to normal (QTc 430 ms) (Fig. 4), and a new echocardiogram showed partial LV recovery, with an LVEF of 45%. Adrenaline infusion was stopped and dopamine was gradually down-titrated. Subsequent CT angiography showed a right internal carotid artery aneurysm, which was treated by endovascular embolization. Coronary angiography was not performed. The patient was discharged on day 12 with an LVEF of 60% and no wall motion abnormalities. Case presentation A 12-year-old boy was admitted to the emergency department with headache and altered consciousness. On arrival, his arterial blood pressure (BP) was 105/60 mmHg, heart rate 110 bpm, and arterial oxygen saturation 98% on supplemental oxygen at a flow rate of 7 l/min. Because of a Glasgow Coma Scale score of 8, the patient was intubated. Urgent brain computed tomography (CT) scan 1558-2027 ß 2017 Italian Federation of Cardiology. All rights reserved. Methodology We searched PubMed using the terms ‘takotsubo’, ‘apical ballooning’,‘stress-inducedcardiomyopathy’,‘brokenheart’ AND ‘children’, ‘paediatric’, ‘young age’, and ‘child’. The articles obtained3–36 were filtered on the basis of relevance of abstract and title. When suitable cases were found, the full texts were obtained and the reference lists scanned for other DOI:10.2459/JCM.0000000000000446 © 2017 Italian Federation of Cardiology. All rights reserved. Takotsubo syndrome in the paediatric population Urbinati et al. 263 total of 34 articles were found3–36 with acceptable clinical details for the purpose of the review (Supplementary Fig. 1, http://links.lww.com/JCM/A92). Fig. 1 Results Clinical presentation A total of 37 cases of TTS in patients younger than 18 have been reported (median age 8 years; range 0–18 years), of whom almost half (n ¼ 17) were men, 46% [median age 12 (IQR: 5–15) years] vs 20 women, 54% [median age 7 (IQR: 1–12) years]. The majority of patients presented to hospital with loss of consciousness (n ¼ 14, 38%) or symptoms related to heart failure (n ¼ 15, 41%), often accompanied or preceded by nausea or vomiting (n ¼ 19, 51%). Brain computed tomography showing right putaminal haematoma that extends directly into the ventricle (arrow). relevant cases. Because the case reports are increasingly published on open access journals not indexed on PubMed, we performed a second search in the first 30 pages of returns from a Google search using the same associations of keywords. One author (A.U.) screened relevant articles, case reports, and case series. A senior author (P.P.) judged the relevance of the articles and confirmed or refuted cases. A Twenty patients had a classical form of the TTS, with apical LV wall motion abnormalities. In 17 cases, the pattern of myocardial involvement was atypical (basal wall motion abnormalities). In two cases, mainly the midLV segments were involved; in four cases, the basal LV segments as in our cases; and in three cases, there was focal LV involvement. In the remaining cases (n ¼ 8), the LV was globally impaired. The ECG at admission was reported in 33 patients. There were abnormalities of the ST segment in 21 cases, of which 15 were ST elevation (five having additional reciprocal ST depression). ST elevation and T wave inversion were more common in typical rather than atypical TTS (53 vs 36% and 68 vs 14%, respectively), Fig. 2 First ECG at admission showing sinus tachycardia and ST depression with T wave inversion in V3–V6. © 2017 Italian Federation of Cardiology. All rights reserved. 264 Journal of Cardiovascular Medicine 2017, Vol 18 No 4 Fig. 3 LV apex Mid LV Basal LV LV apex Mid LV Basal LV ECG performed 24 h after admission, with normal appearance. whereas the opposite was true for ST depression (26 vs 43%). Other ECG abnormalities included prolonged QT segment. A normal ECG (n ¼ 3) was seldom reported. LVEF was measured by echocardiography in 31 patients at presentation and ranged between 9 and 56% (median: 30%, IQR: 25–35%). Troponin, when measured (n ¼ 31), was rarely normal (n ¼ 4) with most of the patients having a mild troponin-I or troponin-T increase. Natriuretic peptides were also substantially elevated when measured (n ¼ 6). Other diagnostic tests were not routinely requested. When a coronary angiogram was performed (n ¼ 11), it revealed no stenosis in the main epicardial coronary arteries. Cardiac MRI (n ¼ 7) showed diffuse subendocardial hyperenhancement in one patient, global oedema in another, and normal perfusion in the rest. Trigger and predisposing conditions Fifty-nine percent of patients had underlying neurological or psychiatric disorders. Neurological conditions (n ¼ 15) included either intracerebral arterial or venous malformations (n ¼ 6) and brain cancers (n ¼ 6); other disorders (n ¼ 3) were rarer. Neurological triggers were also common (n ¼ 19) and were often related to surgical procedures or acute haemorrhages, or secondary to brain trauma or hypoxia. In three patients, TTS was associated with a phaeochromocytoma. Other trigger factors included drugs (atomoxetine) or drug withdrawal, emotional or physical stress (n ¼ 3), infections (n ¼ 4), or other rarer causes, including urolithiasis, a scorpion sting, or recent pericardiocentesis. Management and clinical course The majority of patients (n ¼ 20) required inotropic support. Milrinone and dobutamine were most commonly used during the acute phase. Loop diuretics were used in 12 cases. Some patients were prescribed angiotensin-converting enzyme inhibitors (ACE-I) (n ¼ 6) or beta-blockers (n ¼ 6). The three patients affected by Fig. 4 Parasternal long axis echocardiogram showing akinesia of basal and midventricular segments of the left ventricle and hyperkinesia of the apex. © 2017 Italian Federation of Cardiology. All rights reserved. Takotsubo syndrome in the paediatric population Urbinati et al. 265 phaeochromocytoma were treated by surgical excision. In patients who survived TTS (n ¼ 35, 95%), improvement in LVEF was almost complete (median LVEF 60%, IQR: 56–62%) after a median follow-up of 7 days (IQR: 4–14), and only three patients still had LVEF less than 50% at discharge. Two patients died – one of central brain herniation after 10 days and the other of cardiac arrest 36 h after presentation. Differences from an adult population A contemporary international registry with 1750 cases1 confirms that adult women represent around 90% of cases of TTS. In contrast, we found that TTS was almost equally distributed between men and women in the paediatric population. Compared with adults, who usually present with chest pain, paediatric patients more commonly present with symptoms suspicious of heart failure or following an episode of loss of consciousness (Table 1). A higher proportion of paediatric patients have ST segment depression on ECG. The increase in troponin and the decrease in LVEF, the prevalence of neurological or psychological disorders, and in-hospital outcome are similar between adults and children. The LV apex is the main site of LV involvement in TTS; however, in younger patients, a high proportion has nonapical anatomic variants and more severe LV impairment (Table 1). Discussion The current literature suggests that TTS can affect patients of any age. Neurological or psychiatric disorders are common triggers or precipitating factors in both adults and children.1–37 As in adults, natriuretic peptides and troponin are often raised in the younger population, and ECG abnormalities are common, predominantly involving cardiac repolarization as a whole.38,39 TTS could be related to high circulating levels of catecholamines, as seen in phaeochromocytoma or following an acute neurological event. The cardiomyopathy may then be triggered by several different possible mechanisms,40 including transient myocardial stunning secondary to vasoconstriction at the level of the coronary microcirculation.41 The typical anatomical distribution of LV dysfunction might be related to differential distribution or sensitivity of beta-adrenoreceptors throughout the LV, as shown in rat models.42 Whether individuals have different patterns of beta-adrenoreceptors distribution, whether their distribution changes from childhood to adulthood, and whether their sensitivity to catecholamine varies with age are currently unknown. A higher proportion of paediatric patients with TTS are men compared with adults; TTS is not exclusively a disease of postmenopausal women. It is possible that there is a protective feature of being woman that is lost at the menopause, such as circulating oestrogens, which is supported by animal models of induced TTS.43,44 In Differences and similarities between adults (adapted from Ref.1) and children affected by takotsubo syndrome Table 1 Variable Age (years) Woman (%) Presenting symptoms Chest pain (%) Dyspnoea/HF symptoms (%) Syncope (%) ECG changes ST elevation (%) ST depression (%) Isolated ST depression (%) SR on ECG (%) Comorbidities CAD (%) Neurological or psychiatric disorders (%) Echocardiography LVEF at admission (%) Reduced LVEF (%) Apical wall motion abnormalities (%) Midventricular wall motion abnormalities (%) Basal wall motion abnormalities (%) Focal wall motion abnormalities (%) Global wall motion abnormalities (%) Outcomes In-hospital death (%) Adults, Paediatric population, N ¼ 1750 N ¼ 37 66 (13) 90 8 (6) 54 76 47 8 11 41 38 43 7 NA 90 45 33 18 100 15 47 0 59 41 (12) 87 82 15 2 1 NA 30 (11) 84 54 5 11 8 22 4 5 CAD, coronary artery disease; HF, heart failure; LVEF, left ventricular ejection fraction; SR, sinus rhythm. animal models, oestrogen supplementation attenuates stress-induced cardiovascular responses,45 because of their possible direct effect on the heart and indirect effect on the brain.46 The published case reports of TTS in girls were almost exclusively of patients we assume to be prepubertal (median age 7 years), which might speculatively support a hormonal hypothesis. However, the numbers are small, and there may be considerable bias leading to younger patients being more likely to be reported. Much still remains to be addressed regarding epidemiology, pathophysiology, and clinical history of TTS in either adults or children. In particular, there are no data regarding longterm outcomes in paediatric patients with TTS. In the cases we found, only a few patients were discharged with betablockers and ACE-Is, but it is not clear if there is a potential benefit of this treatment, and whether this treatment might be discontinued once symptoms and LV have fully recovered. The creation of an international registry for the paediatric population would be helpful to allow description of the nature and clinical course of the disease. Limitations The patient reported did not undergo coronary angiography to rule out the presence of anomalous coronary anatomy as his ECG changes and LV function rapidly completely resolved. However, in more than 50% of the reported cases, invasive or noninvasive diagnostic tests were not performed to investigate the coronary circulation. The increasing availability and use of novel and © 2017 Italian Federation of Cardiology. All rights reserved. 266 Journal of Cardiovascular Medicine 2017, Vol 18 No 4 noninvasive imaging modalities might better clarify the cause of TTS in the paediatric population. Although some guidelines have been proposed,47 there is no universal consensus on the diagnosis and treatment of TTS. In our analysis, we chose to include three patients with phaeochromocytoma, which for many would have excluded a diagnosis of TTS. 16 17 18 19 Conclusion TTS affects not only adults, but people of any age, which should make clinicians aware of TTS in patients with a clinical history of neurological or psychiatric disorders. 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