Takotsubo cardiomyopathy secondary to electroconvulsive therapy in a young adult with Down syndrome regression disorder
Abstract
We report the case of an 18-year-old woman with Down syndrome (DS) who developed Takotsubo cardiomyopathy (TSC) immediately after the administration of electroconvulsive therapy (ECT), a treatment prescribed for Down syndrome regression disorder resistant to oral psychotropic drugs. TSC is a nonischemic cardiomyopathy related to psychological or physical stress, which has been described as a rare complication of ECT (Kinoshita et al., 2023, Journal of Electroconvulsive Therapy, 39, 185–192). The clinical description of the case is accompanied by a discussion of the peculiarities of the autonomic nervous system in DS.
1 INTRODUCTION
Down syndrome regression disorder (DSRD) is a clinical entity that has aroused significant interest in the last two decades. It is characterized by a marked, acute, or subacute loss of previously acquired skills, often accompanied by neuropsychiatric symptoms such as catatonia. It typically occurs in adolescence or early youth, and a high percentage of cases do not recover from symptoms in a remarkable way (Santoro, Patel, et al., 2022). Though its pathogenesis is still unclear, the following hypotheses have currently been proposed (Flórez & del Carmen Ortega, 2020): (a) a reaction with emotional and behavioral changes in response to an adverse or stressful life event and and (b) the inherent vulnerability of people with DS to suffer autoimmune alterations and inflammatory response at a molecular level. Some of the therapeutic strategies tested in this condition include high-dose benzodiazepines, antipsychotics, antidepressants, electroconvulsive therapy (ECT), or immunomodulatory therapies, such as intravenous immunoglobulins, rituximab, and other immunosuppressants (Santoro, Baumer, et al., 2022).
We present the case of an 18-year-old woman with DS who developed a severe cardiac event, Takotsubo cardiomyopathy (TSC), after ECT administration. The case description is accompanied by a discussion centered in the potential influence that the peculiar conformation of the autonomic nervous system in individuals with DS may have exerted on the development of such complication.
2 CASE REPORT
2.1 Medical history
The patient had a premature delivery at 30 weeks of gestation requiring a 2-month stay in the neonatel intensive care unit. She underwent corrective surgery for an atrial septal defect at 14 months of age, with full resolution of the cardiac defect. Prior to the onset of DSRD symptoms at age 13, the patient was in good overall health. She was independent in all basic activities of daily living, had good communicative verbal language, and attended high school.
2.2 Psychiatric history
At that timepoint the patient developed over the course of 4 months a sad mood, social isolation, decreased verbal communication, insomnia, and stereotyped movements (waving her hands, swaying, and twirling on herself). Three months before the onset of this clinical picture, the patient suffered bullying at school, which was considered a possible predisposing factor for these behaviors.
One year later, the patient's condition worsened, developing generalized mutism, except for some unintelligible low-pitched soliloquy, marked psychomotor slowing, swaying, lack of initiative, decreased appetite, weight loss, and a loss of functional autonomy for basic skills, such as feeding, toileting, ambulation, and dressing.
At the age of 16, she was referred to our clinic for psychiatric assessment (October 2021), and was diagnosed with DSRD, based on the current diagnostic criteria for this entity (Santoro et al., 2020; Santoro, Patel, et al., 2022; Worley et al., 2020). During the initial diagnostic workup, the patient was also diagnosed with obstructive sleep apnea, for which she was prescribed continuous positive airway pressure. Treatment with lorazepam was initiated (see doses and concurrent treatments in Table 1). Two months later, a state of increased severity with associated catatonic symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (American Psychiatric Association, 2013) criteria was evidenced, characterized by oppositionism, negativism, waxy flexibility with maintained cephalic lateralization, mutism, stupor with absence of eye contact and disconnection from the environment.
| Treatments prior to ECT | ||
|---|---|---|
| Drug | Dose ( mg/day) | Observations |
| Lorazepam | 15 | Progressive ascending regime from 2 to 15 mg/day |
| Sertraline | 100 | No response and worsening catatonic symptoms |
| Fluoxetine | 40 | No response |
| Aripiprazole | 5 | Side effects: extrapyramidal symptoms, sweating, and hypersomnia |
- Abbreviation: ECT, electroconvulsive therapy.
In February 2022, an additional inpatient neurological workup was performed. Brain magnetic resonance imaging and electroencephalogram did not reveal any abnormalities. The analysis of the cerebrospinal fluid obtained by lumbar puncture showed no signs of infectious, inflammatory, or autoimmune processes.
In March 2022, psychiatric admission for ECT was indicated after lack of response to several consecutive attempts with oral psychopharmacological treatments, which are summarized in Table 1.
The duration of the initial admission was 1 month, during which the patient received 12 sessions of bifrontal ECT. An echocardiogram, performed as part of a cardiology consult before starting ECT, showed no relevant structural abnormalities and a left ventricular ejection fraction of 55%. During the ECT, anesthetic induction was achieved using propofol for sessions 1–9 and thiopental for 10–12. Succinylcholine was used as a muscle relaxant. The patient responded favorably to this course of treatment, with improvement in catatonic symptoms, partial recovery of initiative and spontaneity of movements, greater facial expressiveness, connection, and interaction with the environment. She was no longer mute, although she did not recover her previous verbal expressive fluency. She also recovered her independence in basic daily activities such as food intake, toileting, and dressing. Upon leaving the hospital, she was discharged on fluoxetine 20 mg and lorazepam 6 mg daily.
Three months later (July 2022), she presented a relapse. It was decided to discontinue fluoxetine due to poor response, and clomipramine up to 35 mg (25 + 10) a day was started, maintaining lorazepam 6 mg a day. As no remarkable improvement was perceived over the fall, in December 2022, a maintenance ECT regime was started, with an average frequency of approximately one treatment session per month, during which the patient continued with clomipramine 35 mg a day and lorazepam 1 mg a day.
During the eighth maintenance ECT session (May 2023), the patient developed cardiac bigeminism and bradycardia, which subsided after the administration of 0.5 mg atropine. Immediately after that, she presented sinus tachycardia at 170 bpm, a hypertensive crisis, and severe acute hypoxemic respiratory failure. Administration of 5 mg labetalol and intubation was required. An emergent echocardiogram showed severe left ventricular dysfunction with apical and lateral hypokinesia, severe hypokinesia of all mid-apical segments, and moderately depressed global systolic function, consistent with acute pulmonary edema of cardiac origin in the context of TSC. The echocardiogram did not show any compromise in the dimension or function of the right ventricle.
The patient was admitted to the intensive care unit, where adrenaline and dobutamine were administered. She achieved a progressive improvement over the following days, and was discharged after 5 days in a situation of complete clinical recovery. Normalization of segmental contractility and left ventricular function was demonstrated with a new echocardiogram. The patient did not subsequently resume ECT treatment.
3 DISCUSSION
TSC is a rare cause of acute heart failure characterized by apical ballooning or midventricular wall motion abnormalities due to transient left ventricular apical dysfunction (Gianni et al., 2006). The condition was first described in Japan in 1990 and currently represents around 1%–2% of all acute coronary syndromes. It occurs most frequently in postmenopausal women or after an intense acute emotional impact, and although it is usually reversible, it can be complicated by cardiogenic shock, as in the present case (Bairashevskaia et al., 2022; Ghadri et al., 2018). Although its physiopathology is not fully understood, it is thought that a catecholamine release, reactive to acute and severe physical or emotional stress, could induce coronary vasospasm and lead to direct myocyte damage. TSC does not appear to have a specific Mendelian inheritance pattern, but rather it seems more likely that a genetic predisposition (if present) may interact with environmental factors to cause the final clinical event. Functional variants of adrenergic receptor genes and estrogen levels have been associated with the magnitude of cardiac dysfunction in patients with TSC (Ghadri et al., 2018).
ECT has been previously described as an iatrogenic trigger of this event (Guiné et al., 2022; Narayanan et al., 2014; Sharp & Welch, 2011). It has been suggested that the induction of seizure activity and/or the postictal state could lead to this acute catecholamine release (Kido & Guglin, 2017). A literature review published in 2011 highlighted 12 previously documented cases of TSC associated with ECT (Sharp & Welch, 2011). Preexisting conditions that compromise catecholaminergic regulation, such as some psychiatric conditions, may further predispose to its development.
Kinoshita et al. (2023) identified 24 cases of ECT-induced TSC, with a predominance in middle-aged women with affective disorders or schizophrenia. In this review, approximately 70% of the cases presented this complication after successive ECT sessions, and 10% developed cardiogenic shock. All cases recovered without remarkable sequelae and returned to ECT sessions without repercussions. The use of β-blockers has been proposed as an identified strategy for restarting ECT (Medved et al., 2018).
To our knowledge, no case of TSC in individuals with DS associated with the use of ECT has been described. Likewise, there is no prior evidence to suggest that people with DS might be more susceptible to the development of TSC of any cause. Noteworthy, our patient did not have any relevant structural heart disease prior to the event. The existence of autonomic nervous system (ANS) and renin–angiotensin–aldosterone system dysfunctions in people with DS has been described (Medved et al., 2018). Clinically, this is manifested by a lower heart rate and blood pressure than in nontrisomic individuals, both at baseline and under stress (Fernhall & Otterstetter, 1985; Roy-Vallejo, Galván-Román, et al., 2020). An insufficient response to catecholamines during exercise in patients with DS has also been observed (Eberhard et al., 1991; Fernhall et al., 2009). This “chronotropic incompetence” has been linked to the hypogenesis of the ANS, which appears to be mediated by the hyposecretion of neural growth factor during the embryonic period. For this reason, individuals with DS may be compromised in situations where rapid adaptation of the cardiovascular system may be required, and are thus more predisposed to neuromediated syncopes (Roy-Vallejo, Alonso, et al., 2020). In this underlying context, the hemodynamic response of the patient in the present case is particularly surprising on the surface, since this structural dysfunction of the ANS in DS should have theoretically acted as a protective factor against the development of catecholaminergic complications. However, the administration of atropine prior to the event might have blunted the physiological parasympathetic predominance in our patient and thus have led to TSC as a final complication. The treatment that the patient was receiving prior to the ECT session has also been scrutinized, but none of the drugs have been related to a higher incidence of TSC. Finally, the appearance of TSC in the twentieth ECT session does not seem to be due to other potential unaccounted exogenous factors such as increased surrounding stress or substantive changes in the environment. As a final consideration, in other cases of post-ECT TSC this treatment has been reintroduced without further complications (Medved et al., 2018). However, the final decision on continuing or withdrawing this treatment should certainly include a weighted risk–benefit balance, as well as incorporate the preferences of the patient and her family. Therefore, it is complex to be able to offer any prognostic conclusions or prognostic assessments of the current case.
4 CONCLUSION
ECT is currently considered an accepted treatment with good results in the management of severe conditions such as DSRD (Ghaziuddin et al., 2015; Miles et al., 2019; Santoro, Baumer, et al., 2022). Despite the risk of severe complications, TSC should be considered a rare complication that can occur both in people with DS, as well as in the general population. The accumulation of knowledge through case descriptions may clarify over time whether this population group is more vulnerable to the appearance of certain types of cardiac events in relation to the application of ECT. Further research is needed to investigate possible predisposing factors that may increase the risk of developing TSC for someone with DS.
AUTHOR CONTRIBUTIONS
María del Carmen Ortega: Conceptualization, methodology, validation, formal analysis, data collection, writing original draft preparation, editing of intellectual content, and the major contributor in writing the article. José Pablo Bullard: Validation and data collection. María del Mar Unceta: Visualization and reviewed data. Felipe Ortuño Sánchez-Pedreño: Visualization and reviewed data. Patricio Molero: Writing original draft preparation. Diego Real de Asúa: Conceptualization, methodology, validation, writing original draft preparation, drafting of the manuscript, editing for intellectual content, and translation into English.
ACKNOWLEDGMENTS
The authors would like to thank the patient and her parents (legal representatives), who provided written informed consent, allowing us to share and publish clinically relevant information linked to her case.
CONFLICT OF INTEREST STATEMENT
The authors declare that the article was conducted in the absence of commercial or financial relationships that could be interpreted as a potential conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
