Takotsubo syndrome in bipolar affective disorder with alcohol withdrawal syndrome
- 1 Liaison Psychiatry, Mater Misericordiae University Hospital, Dublin, Ireland
- 2 Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK
- 3 Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland
- 4 Department of Psychiatry, Mater Misericordiae University Hospital, Dublin, Ireland
- Correspondence to Dr Deshwinder Singh Sidhu; deshwinder_sidhu@hotmail.com
Abstract
A 40-year-old woman presented to the emergency department with epigastric pain and agitation. She recently separated from her husband and was consuming 30 units of alcohol daily for 5 days. She had a history of bipolar affective disorder, borderline personality disorder and alcohol dependence syndrome. Investigations revealed the following: elevated troponin I levels, ST elevation, early Q waves and prolonged QTc. Emergency angiogram confirmed Takotsubo’s appearance. Medications with QTc prolongation propensity were held. A multidisciplinary apporach was required. She was discharged 10 days later when medically stabilised. It was later discovered that she died unexpectedly the following month. Takotsubo syndrome is a rare but unique cause of cardiac failure. This case highlights the need to consider the differential of Takotsubo syndrome in people presenting with possible acute ischaemic events, particularly in those with a history of combined emotional and physical stressors and a background history of mood disorder.
Background
Takotsubo syndrome is a relatively rare occurrence; however, it is an increasingly recognised differential in ST elevation myocardial infarction (STEMI), with symptoms of Takotsubo syndrome often mimicking those of STEMI. Takotsubo syndrome is characterised by a reversible transient left ventricular dysfunction and a clinical presentation which is similar to that of acute coronary syndrome,1 without any angiographic display of obstructive coronary artery disease (CAD).2 The International Expert Consensus Document on Takotsubo Syndrome 2018 proposed new international diagnostic criteria, International Takotsubo Diagnostic Criteria.3 The criteria include transient left ventricular dysfunction with either apical, midventricular, basal or focal wall motion abnormalities causing moderately increased levels of cardiac biomarkers.3 It can be triggered by neurological disorders and pheochromocytoma which was excluded previously in some diagnostic criteria.3 It also makes the diagnosis of Takotsubo syndrome possible in the presence of significant CAD.3
Women over the age of 55 have a fivefold increased risk of Takotsubo syndrome compared to women younger than 55 and make up the majority of cases.4 Psychiatric disorders are associated with increased risk of Takotsubo syndrome.5 There are a few reports of Takotsubo syndrome occurring in people with bipolar affective disorder.2 A literature review suggested an association of Takotsubo syndrome with alcohol withdrawal.6
We present a case of Takotsubo syndrome developing in a woman with a history of bipolar affective disorder and alcohol-dependence syndrome. The complex psychopharmacology used, rationalising the use of QTc prolonging medication and the management of cardiogenic risk are important features in this case.
Case presentation
Ms A was a 40-year-old woman who presented to the emergency department with epigastric pain, vomiting, malaena and poor dietary intake. She was drinking 30 units of alcohol daily for the past 5 days. A recent separation from her husband was an acute psychosocial stressor. On physical examination, there was a soft and non-tender abdomen and findings on examination were unremarkable.
Ms A had a psychiatric history of bipolar affective disorder, borderline personality disorder and alcohol-dependence syndrome. Her medical history was significant for type 2 diabetes mellitus, hypertension, morbid obesity (weight 140 kg), and a history of unprovoked pulmonary embolisms. She also had polycystic ovarian syndrome, a history of upper gastrointestinal bleeding, and hiatus hernia with Cameron lesions.
Her regular medications were quetiapine 200 mg two times a day, asenapine 10 mg once daily, sodium valproate 1400 mg nocte, pregabalin 75 mg three times daily, metformin 500 mg two times a day, trazadone 300 mg nocte, olmesartan 20 mg nocte, gliclazide 240 mg nocte, esomeprazole 40 mg two times a day, carbocysteine and Gaviscon. She reported a drug allergy to olanzapine (anaphylaxis reaction), risperidone, haloperidol, prochlorperazine and ciprofloxacilin. These hypersensitivity reactions were confirmed and documented on her previous discharge summary by her treating consultant psychiatrist.
Six months prior to this presentation, Ms A was investigated for dyspnoea. At the time, she was treated with the same medication and psychotropic polypharmacy. An ECG and transthoracic echocardiogram (TTE) were performed. Her ECG showed normal sinus rhythm with no abnormalities and a QTc of 440 ms. Her left ventricular function was normal with an ejection fraction greater than 55%. There were no abnormal findings.
Past psychiatric history/family history
Ms A was regularly attending community psychiatric services and had a significant psychiatric history. She was diagnosed with bipolar affective disorder 15 years ago, and was trialled on multiple psychotropic medications, including lithium carbonate (discontinued due to intolerability). She had multiple prior psychiatric hospitalisations, including five admissions to a public psychiatry facility and approximately 12 admissions to a private psychiatric facility in the last 15 years. She had one previous involuntary admission under the Mental Health Act 1 year ago. She had comorbid diagnoses of borderline personality disorder and alcohol-dependence syndrome. There was also a history of previous hypnotic misuse additional to alcohol dependence. She had a history of erratic compliance to psychiatric medications. She reported a last manic episode approximately 1 year ago.
Her parents are deceased and it was reported that her mother had depression, with no other known psychiatric history reported in the family. She was married, however, she reported marital disharmony and recent separation. She had financial stressors and limited social contact.
Investigations
During this admission, initial blood investigations revealed normal Sodium 133 mmol/L (normal range 133–146), low potassium 2.9 mmol/L (normal range 3.3–5.0), low magnesium 0.59 mmol/L (normal range 0.70–1.00), low chloride 90 mmol/L (normal range 95–108). She had a normal creatinine, with a low urea 2.2 mmol/L (normal range 2.8–8.6). Ethanol levels were 15 mg/dL. She had an elevated high-sensitivity cardiac troponin I 3789 ng/L (normal range <16) and C reactive protein 27 mg/L (normal range <7). Other tests included: amylase 19 I.U./l (normal range 28–97), alanine aminotransferase (ALT) 165 IU/L (normal range 0–55), gamma-glutamyl transferase 121 IU/L (normal range 8–53)and white blood cells were mildly elevated at 12.00×109/L (normal range 3.50–11.00) . Her ECG showed sinus rhythm, rate of 100 beats/min with anterior ST elevation, early Q waves and a prolonged QTc of 644 ms.
She was referred for emergency TTE for the evaluation of anterior STEMI. She had a reduced ejection fraction of 40%–45% (normal range 55%–70%). TTE revealed mild concentric left ventricular hypertrophy, apical and anterior hypo kinesis of left ventricle, and a maximum pressure gradient across aortic valve of 60 mm Hg AVmaxPG consistent with left ventricular outlflow tract obstruction.
Emergency angiogram was carried out the following day, which showed a left ventricular area of Takotsubo appearance, with a left ventricular end-diastolic pressure of 15–18 mm Hg. There were no significant coronary artery lesions. A repeat ECG revealed QTc prolongation of 560 ms, anterior ST elevation and Q waves.
Differential diagnosis
This was a complex presentation of Takotsubo syndrome with multiple risk factors. In this case, Takotsubo syndrome may have been precipitated by a combination of physical and emotional stressors, namely alcohol withdrawal and excessive alcohol consumption, and psychosocial stressors with significant interpersonal conflict. The majority of cases of Takotsubo syndrome have comorbid psychiatric and neurological conditions.7
The pathophysiology of Takotsubo syndrome is not fully known, however, it is hypothesised to be triggered by stressful events and the subsequent release of catecholamines.7 Treatment and management of risk factors with a multidisciplinary team (MDT) approach was essential as it required integrative longitudinal medical and psychiatric assessment and treatment.
In this case, many of the mentioned precipitating factors co-exist and have occurred in the same time frame. It is interesting to note, her previous ECG and echocardiogram showed no significant abnormality. Her QTc was normal 6 months ago while she was maintained on the same medications, including psychotropic polypharmacy. There was no evidence of overt mood disturbances during her admission; however, emotional instability was apparent throughout. It is likely that the iatrogenic effect of abrupt discontinuation of her psychotropic medication was a factor contributing to her emotional lability and instability during this period.
Treatment
In the emergency department, she received diazepam 10 mg intravenously, intra-arterial verapamil 2.5 mg, glyceryl trinitrate 200 μg and heparin 5000 units.
She was admitted to the coronary care unit and her electrolyte abnormalities were appropriately corrected. During this admission, she was treated with medications for presumed ischaemic heart disease and two neurohumoral antagonists (ACE Inhibitor and a beta-blocker) for heart failure.
Medications with increased QTc prolongation propensity, namely quetiapine, asenapine and trazadone were stopped. She was monitored with telemetry.
She was commenced on an alcohol detoxification protocol for 7 days. She received pabrinex I and II intravenous three times daily for 4 days, Chlordiazepoxide 40 mg four times a day for 2 days, chlordiazepoxide 30 mg four times a day for 3 days and was switched to clonazepam 1 mg two times a day on day 5. She also received chlordiazepoxide 10–30 mg up to four times daily until the day of discharge. She was started on regular thiamine 300 mg.
She remained haemodynamically stable. ECG changes including ST elevation normalised and cardiac functioning improved after metoprolol 50 mg three times daily was switched to bisoprolol 7.5 mg daily with ramipril 3.75 mg daily.
Psychiatric interventions during admission for cardiomyopathy
Ms A presented as reasonably stable and cooperative at her initial psychiatric assessment. Due to existing cardiac complications and a prolonged QTc, quetiapine, asenapine and trazadone were stopped. Extensive psychoeducation surrounding her diagnosis and treatment approach was provided.
Two days later, she presented as labile in mood, tearful and distressed. She reported being distressed due to psychosocial stressors and was requesting that her medications be reinstated and if not she would self-discharge. She responded well to reassurance and psychoeducation surrounding her diagnosis, medication use and the risk of QTc prolongation and she was provided a treatment plan.
The Maudsley guidelines provide clinical recommendations in the management of QTc prolongation.8 It is noted that quetiapine is reported to have medium risk for QTc prolongation, whereas, trazadone and asenapine are identified as low risk; aripiprazole has no risk associated with QTc prolongation.8 In view of this, initially aripiprazole was trialled in this case on discontinuing QTc prolonging psychotropics. Sodium valproate has no known effect on QTc prolongation and was continued.8 She was trialled on low-dose aripiprazole 2.5 mg once daily, however, this was stopped on the following day as she reported akathisia. At this time, she had a QTc of 560 ms, compared with a QTc of 644 ms on admission.
On the fourth day of admission, as the QTc interval was normalising, she was started on quetiapine 50 mg nocte. Hereafter she reported further agitation and suicidal ideation, and she was reviewed by the duty psychiatrist and chlordiazepoxide was switched to clonazepam 1 mg two times a day which further helped in managing acute distress. She was also commenced on 1:1 observations. The management of acute agitation was made more challenging, due to previous adverse reaction to olanzapine, an antipsychotic with a low risk of QTc prolongation that precluded its use. There were no signs of alcohol withdrawal besides irritability. On review, she reported her last drink to be approximately 2 weeks ago, however, on admission, she reported consuming 30 units of alcohol daily for 5 days prior to her presentation. As her QTc was normalising at levels 490 ms, quetiapine was slowly increased to 100 mg, in increments of 25–50 mg daily with ongoing telemetry.
Outcome and follow-up
Ms A became more settled and stable in her mental state in the latter period of her admission, and was discharged home on day 10. She received supportive psychotherapy to manage her emotional distress throughout her admission. Her QTc on discharge was 474 ms and she was prescribed quetiapine 150 mg nocte. Her ECG on discharge showed normal sinus rhythm and T wave inversion, but was otherwise unremarkable. Her ALT was 81 IU/L (normal range 0–55) and all other blood profiles, including serum electrolytes were normal. Ms A was more hopeful and had future plans; she was scheduled for further follow-up with her treating psychiatrist the following day. Cardiology rehabilitation was arranged the following month on discharge; however, it was later discovered that she had passed away unexpectedly.
Discussion
Psychiatric comorbidity
A high prevalence of comorbid mental disorders has been reported in Takotsubo syndrome.5 7 The association between mental disorder and Takotsubo syndrome has been mentioned in multiple case reports.7 Depression and anxiety disorders are most commonly reported, with both more commonly seen in patients with Takotsubo syndrome than controls.9 We present a relatively novel association between bipolar affective disorder and Takotsubo syndrome. There are much fewer cases reporting the development of Takotsubo syndrome in bipolar affective disorder. As discussed in a case series, underlying psychiatric conditions can lead to Takotsubo syndrome.10 One of four cases discussed in this case series was diagnosed with bipolar affective disorder.10 Similar to Ms A, the case aforementioned had presented to hospital “with chest pain, dyspnoea and precordial T-wave inversions with prolonged QTc interval. After cardiac catheterisation, she was diagnosed with Takotsubo syndrome (LVEF=30%).”10
Another case report describes one of the earliest reported clinical cases of Takotsubo syndrome triggered by acute mania,11 further providing case evidence of an association between Takotsubo syndrome and bipolar affective disorder. Psychiatric disorders, and in particular mood disorders are postulated to be associated with an increased risk of Takotsubo syndrome due to heightened adrenergic and sympathetic response to acute emotional stress,12 which increases the risk for stress-induced cardiac events.
The stress factor
A characteristic of Takotsubo syndrome is a preceding stressful event. Emotionally laden stressful events were initially thought to be primary triggers for Takotsubo syndrome, but evidence now supports the relationship with physical stressors also.13 A greater prevalence of emotional stressors is associated with Takotsubo syndrome in females, with a preponderance of physical stressors in males.5 Ms A had exposure to both physical and emotional stressors as triggers for Takotsubo syndrome. She was experiencing marital discord and a separation from her husband, an emotionally stressful event, which is a known typical trigger for Takotsubo syndrome.7 A literature review found no robust associations between the rate of onset or recurrence of Takotsubo syndrome secondary to emotional triggers in those with psychiatric illness compared with those with no psychiatric illness.1 2 A retrospective study of 306 cases with Takotsubo syndrome found 37% with pre-existing psychiatric illness.1 It further identified an increased risk of Takotsubo syndrome recurrence in patients with pre-existing psychiatric illness.1 However, there was no association between reduced survival rates and pre-existing psychiatric illness.1
Acute alcohol withdrawal and alcohol intoxication
It is important to note the significance of alcohol withdrawal as a precipitant to this presentation. As initially discussed, Ms A arrived to the emergency department with vomiting and agitation, features seen in alcohol withdrawal. It has been hypothesised that the hyperadrenergic state in alcohol withdrawal may be a trigger for the development of Takotsubo syndrome.6
Another case report has described the onset of Takotsubo syndrome in a woman in the context of acute alcohol withdrawal.14 A literature review identified 11 case reports which linked alcohol withdrawal and Takotsubo syndrome, of which six patients exhibited delirium tremens, one patient with possible delirium tremens, two patients with withdrawal seizures and two patients with mild withdrawal symptoms.6 Of these 11 case reports, six patients presented with QT prolongation, and one resulted in ventricular fibrillation.6 Ms A presented with both alcohol withdrawal symptoms and QT prolongation. Literature reviews suggest a high prevalence of QTc prolongation in Takotsubo syndrome.6 15
QTc prolongation
The cause of the QTc prolongation in this case presentation remains questionable. It may have been secondary to cardiomyopathy, or a consequence of excess alcohol intake, alcohol withdrawal, psychotropic polypharmacy or a combination of one or more factors. It is less likely, however, that it is due to psychotropic polypharmacy, as Ms A had a normal ECG and echocardiogram 6 months earlier while maintained on the same medications. QTc prolongation may have been contributed to by the electrolyte imbalances caused during alcohol withdrawal.6
Learning points
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Takotsubo syndrome is a rare but unique cause of cardiac failure.
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This case highlights the need to consider the differential of Takotsubo syndrome in people presenting with possible acute ischaemic events, particularly in those with a history of combined emotional and physical stressors and a background history of mood disorder.
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The implementation of multidisciplinary interventions can contribute to the successful resolution of clinical features due to Takotsubo syndrome.
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There remains a need to better clarify the relationship between mood disorders and Takotsubo syndrome, and to better understand if bipolar affective disorder is associated with an increased risk.
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Longer-term follow-up studies are required to better establish effective and safe longer term treatments to reduce the risk of recurrent cardiomyopathy in bipolar affective disorder and other mood disorders.
Footnotes
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Contributors All three authors have met the criteria for authorship. In addition to that, DSS was primary investigator and involved in drafting the manuscript. RF and JL provided critical revision of the material.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Next of kin consent obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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