Defining Features of Patients who Develop Takotsubo Cardiomyopathy during Myasthenic Crisis: A Systematic Review of Case Studies

Background. Myasthenic crisis can induce Takotsubo cardiomyopathy leading to transient systolic and diastolic left ventricular dysfunction and wall-motion abnormalities, including the characteristic apical ballooning. We aimed to define the clinical features of this disease entity. Methods. A systematic review was conducted to examine the characteristics of Takotsubo cardiomyopathy presenting in myasthenia gravis patients. Case reports were accessed by searching MEDLINE/PubMed, Google Scholar, CINAHL, and Web of Science databases. 523 articles were identified and 14 were selected for review. Results. Takotsubo cardiomyopathy presenting in myasthenia gravis’ patients tends to affect women between the ages of 40 to 77. History of atrial fibrillation or hypertension was found in a minority of cases. Generalized weakness, fatigue, dysphagia and respiratory distress were common at presentation. Vital signs demonstrated normal blood pressure without tachycardia or bradycardia. Elevated values of troponins, creatine kinase (CK), and CK-MB isoenzymes were recorded. ST-segment elevation followed by T-wave inversion were predominantly found on electrocardiograms. Apical abnormalities in the form of ballooning, hypokinesia, or sparing and reduced left ventricular ejection fraction (≤45%) were observed using transthoracic echocardiogram or left ventriculography. Coronary angiography demonstrated no obstructive lesions. Ventilatory support, cholinesterase inhibitors and glucocorticoids resulted in the recovery or improvement of the left ventricular ejection fraction and hemodynamic stability. Only a minority of patients died of refractory heart failure. Treatment with inotropes and/or vasopressors led to poorer outcomes, including death or intractable heart failure. Conclusion. The management of Takotsubo cardiomyopathy developing in myasthenia gravis patients should focus on addressing the myasthenic crisis, while proving supportive care in and intensive care setting.


Introduction
Takotsubo cardiomyopathy is characterized by transient systolic and diastolic left ventricular dysfunction with a variety of wall-motion abnormalities, most commonly the ballooning of the left ventricular apex [1]. This syndrome has been given the name of "Takotsubo," or Japanese octopus trap [2]. Patients with Takotsubo cardiomyopathy present with substernal chest pain and dyspnea that resembles acute coronary syndrome. There can be associated electrocardiographic abnormalities such as ST-segment elevation, T-wave inversion, QTprolongation, or abnormal Q-waves. There can also be elevated cardiac troponin, ft is a diagnosis of exclusion, after pheochromocytoma or myocarditis have been ruled out.
Although previous studies have suggested that Takotsubo cardiomyopathy is predominantly preceded by emotional triggers, subsequent reports indicate that this syndrome may also occur with physical triggers. A recent study concluded that the prevalence of physical triggers exceeds that of emotional triggers [1]. For patients with myasthenia gravis, this physical trigger is a cholinergic crisis.
Myasthenia gravis is an autoimmune neuromuscular disorder in which antibodies bind to acetylcholine receptors or to functionally related molecules in the post-synaptic membrane at the neuromuscular junction causing muscle weakness and fatigue [3]. Typically, there is fluctuating and fatigable extraocular (e.g. diplopia, ptosis) and bulbar (dysarthria, dysphagia) muscle weakness. Symmetrical proximal weakness involving the neck (e.g. difficulty holding up the head) and upper extremities (e.g. difficulty combing hair) is also seen. Sensation, reflexes, muscle bulk/tone, and autonomic function are usually intact.
Precipitating stress caused by infection (e.g. pneumonia), surgery, or various medication (e.g. azithromycin) may lead to high levels of circulating catecholamines leading to myasthenic crisis, characterized by acute deterioration in bulbar and respiratory muscles, which can lead to respiratory failure requiring mechanical ventilation [3] and possibly stressinduced cardiomyopathy. patients with myasthenia gravis exhibit several types of cardiac involvement, ranging from asymptomatic electrocardiogram changes to myocarditis, heart failure, and sudden death [5]. Currently, there is scanty research on the topic of patients with Takotsubo cardiomyopathy induced by myasthenic crisis [6]. This systematic review aimed to determine the characteristics of patients with takotsubo cardiomyopathy and myasthenia gravis based on existing case reports, as well as recovery and outcomes following treatment.

Protocol and Registration
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, found in Supplementary Table 1, was utilized to for this systematic review. The protocol was not registered.

Eligibility Criteria
Inclusion Criteria.-Only articles that reported the association of myasthenia gravis and Takotsubo cardiomyopathy were included.
Exclusion Criteria.-Studies were excluded if: (1) they were not case reports or case series, (2) they were not peer-reviewed, or (3) they were not in English.

Information Sources and Search Strategies
A comprehensive literature search using MEDLINE/PubMed, Google Scholar, CINAHL, and Web of Science databases up to and including 30 October 2018. The terms "Takotsubo," "Tako-Tsubo," "stress cardiomyopathy(ies)," "stress induced cardiomyopathy(ies)," or "apical ballooning" were selected in combination with the words "myasthenia," "myasthenic," "gravis," or "crisis" for the complete search strategy, which is found in Supplementary Material.

Study Selection
Initial triage of articles was based on whether titles or abstracts met the inclusion criteria. Full-text articles were then read, and those that did not satisfy the inclusion/exclusion criteria were excluded.

Data Collection Process and Data Items
Data extracted from articles included the name of first author, year of publication, country, and study design. Variables for which data were sought included the age and sex of the patient, past medical history, past surgical history, chief complaints, intubation, medications, electrocardiography results, transthoracic electrocardiogram results including ejection fraction, pertinent radiology results, peak troponin values, peak creatine kinase values, peak creatine kinase-muscle/brain values, peak acetylcholine receptor antibodies, outcome, and follow-up.

Synthesis of Results and Summary of Measures
Data were tabulated, evaluated, and summarized.

Risk of Bias across Studies
Potential bias across studies were analyzed within study characteristics.

Results of Individual Studies
A summary of findings is given in Table 2.

Synthesis of Results
Patient profile.-The patients' age ranged between 40 to 77-years. The average age for all studies was 60.9 years. Adjusting for location, the average age for American studies was 62.4 years, while Asian studies averaged 53.8 years. The average age for European studies was 73.7 years. 4 articles described male patients with an average age of 64.1 years [8,12,14,17], while the remaining 10 studies of female patients had an average age of 60.5 years [7,9,10,11,13,15,16,18,19,20]. Common medical history aside from myasthenia gravis and change in thyroid function included atrial fibrillation [13,15,19] and hypertension [9,13,14]. Grave's disease [9] and polymyalgia rheumatica [14] were reported affecting 1 patient each.

Risk of Bias across Studies
Due to the nature of descriptive studies, the results being presented are liable to investigator, procedure, and selection bias. The small sample size limits the feasibility of statistical calculations.

Discussion
Although this is not the first review to attribute Takotsubo cardiomyopathy to myasthenic crisis [6], it is the first systematic review to provide a comprehensive picture of patients concurrently afflicted by the two disorders. This systematic review revealed that those affected were mostly women between the ages of 40 and 77 years. A minority of patients had a history of atrial fibrillation or hypertension. The patients presented with respiratory distress, generalized weakness and fatigue, and dysphagia. Blood pressure was within normal range and neither tachycardia or bradycardia were observed. Laboratory tests revealed elevated troponin, CK, and CK-MB values. EKG changes consisted of ST-segment elevation followed by T-wave inversion. Apical abnormalities in the form of ballooning, hypokinesia, or sparing and reduced left ventricular ejection fraction were observed during the transthoracic echocardiogram or left ventriculography. Coronary angiography demonstrated no obstructive lesions. Patients were intubated and treated with cholinesterase inhibitors and glucocorticoids, which resulted in the recovery or improvement of ejection fraction and hemodynamic stability. Only a very small minority died of refractory heart failure. Over a third of the patients were treated with inotropes and/or vasopressors, leading to high mortality or intractable heart failure.
Myasthenia gravis-related clinical heart disease and heart dysfunction are very rare even though functional imaging studies have shown minor and sub-clinical dysfunction [21]. In population-based studies, myasthenia gravis has not been associated with an increase in mortality related to heart disease [22]. For example, although myocarditis is found in increased frequency in patients with myasthenia gravis, it is still a rare finding [4]. Acute myocarditis can mimic Takotsubo due to their similar clinical presentation. In some cases, acute myocarditis presents with similar regional left ventricular wall motion abnormalities [21]. It is unknown whether there are similar mechanisms attributed to both myocarditis and Takotsubo cardiomyopathy. striking differences. Chest pain was not a prominent feature in the systematic review, but respiratory distress was. Neurologic or psychiatric disorders afflicted nearly half of patients in the Templin et al. study [1], whereas a single patient had a past medical history of depression [19]. Ventilation was required by 17.3% of patients in the Templin et al. study [1], whereas all patients in the systematic review required intubation and mechanical ventilation due to respiratory collapse from myasthenic crisis.
It is questionable whether medical treatment influences the outcome after the acute phase of takotsubo cardiomyopathy. Our data suggest that the management of myasthenic crisis contributed to the recovery of the clear majority of patients, whereas the use of inotropes and/or vasopressors resulted in poorer outcome. The mortality rate of patients in myasthenic crisis (4.47%) [23] or major adverse cardiac and cerebrovascular events within 30 days after hospital admission of patients with takotsubo cardiomyopathy (7.1%) [1] are similar to the mortality rate of heart-related causes as determined by this systematic review (7.1%).
A characteristic feature of Takotsubo cardiomyopathy is the spontaneous resolution of left ventricular wall motion within hours to weeks [24]. The management in the acute stage during myasthenic crisis should be no different. Therefore, treatment should be supportive and focus on resolving complications of the myasthenic crisis. Patients with worsening weakness who require intubation should receive fast-acting immunosuppressive agents and admission to an intensive care unit. Intravenous immunoglobulin and plasmapheresis are regarded equally effective in treating severe myasthenia gravis [25].
There are multiple limitations to this systematic review including small sample size of available cases and the lack of long term follow-up and outcomes.
In conclusion, this systematic review unveiled the pertinent clinical characteristics of Takotsubo cardiopathy occurring during myasthenic crisis. The therapies employed in the cases reinforces the need to focus on addressing the myasthenic crisis, in order to allow for a full recovery for this complex patients.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.