Takotsubo syndrome in patients with myasthenia gravis: a systematic review of previously reported cases
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Myasthenia gravis associated takotsubo syndrome is a rare condition. This study aimed to explore its typical presentation, investigations and treatment through a systematic review of previously reported cases.
Databases and reference lists of the selected articles were searched for case reports on Myasthenia gravis associated takotsubo syndrome. CARE guidelines were used for the quality assessment of the selected articles.
Sixteen cases were selected out of 580 search results. Western Pacific, American and European regions contributed to 88% of the cases. Females were most affected (81%). Features of both myasthenia gravis and takotsubo syndrome were the common clinical presentations. All cases had a myasthenic crisis. Half of the cases had no prior diagnosis of myasthenia gravis. Pyridostigmine and prednisolone were useful for myasthenia gravis while dobutamine was most commonly used for takotsubo syndrome. All cases survived except four (25%).
Myasthenia gravis associated takotsubo syndrome via a myasthenic crisis is rare but life-threatening. Therefore, predisposition due to emotional and physical triggers needs to be avoided for its prevention. The rare entity should be suspected even in patients without a prior diagnosis of Myasthenia gravis.
KeywordsBroken heart syndrome Stress cardiomyopathy Apical ballooning Transient left ventricular dysfunction Ampulla cardiomyopathy Gebrochenes-Herz syndrome Myasthenic crisis
Medical Subject Headings
Population, intervention, comparison and outcome
Preferred reporting items for systematic reviews and meta-analyses
Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies against the postsynaptic membrane at the neuromuscular junction, mostly against acetylcholine receptors (AChR)  and in some against muscle-specific receptor tyrosine kinase (MuSK) [2, 3]. Also, autoantibodies against low-density lipoprotein receptor-related protein (LRP4) were found in AChR and MuSK antibody-negative MG patients . MG means “grave, or serious, muscle weakness”  and it causes fatigable weakness of skeletal muscles (ocular, facial, oropharyngeal, limb and respiratory) . Classification of MG subgroups is as follows: early-onset MG (AChR), late-onset MG (AChR), thymoma MG (AChR), MuSK MG, LRP4 MG, seronegative MG (no autoantibodies detected) and ocular MG (AChR, MuSK, LRP4 or none). Myasthenic crisis is a life-threatening, often spontaneous event in MG which is associated with respiratory failure  and a hospital mortality rate of 4.5% . Patients may need intubation and mechanical ventilation depending on the clinical status . Rarely, myasthenic crisis is the initial presentation of MG. The crisis may be triggered by stressors like infection, surgery, pregnancy, childbirth or drugs [8, 9]. Plasma exchange and intravenous immunoglobulin are used in the management of myasthenic crisis . Incidence, prevalence and the mortality rate for MG were 1.7–21.3, 15–179 and 0.06–0.89 per million person-years . Incidence increased with age in both sexes. The highest incidence was observed between 60 and 80 years. Male predominance was observed among older age group while female sex showed a bimodal distribution . MG is a multisystem disorder with cardiac involvement estimated to occur in 16% of cases . Arrhythmia , pericarditis  and myocarditis  have been reported to occur in association with MG. Rarely MG could lead to Takotsubo syndrome (TTS).
TTS is “characterised by transient systolic dysfunction of the apical and/or mid-segments of the left ventricle that mimics acute myocardial infarction but with no obstructive coronary artery disease” [16, 17, 18, 19]. An echocardiogram or a left ventriculogram of the patient with TTS appears like a Japanese octopus fishing pot (Takotsubo) . The disease is also known as takotsubo cardiomyopathy, broken heart syndrome, stress cardiomyopathy, stress-induced cardiomyopathy, apical ballooning, apical ballooning cardiomyopathy, transient left ventricular dysfunction, reversible left ventricular dysfunction, ampulla cardiomyopathy and Gebrochenes-Herz-syndrome. The prevalence of TTS was 2% in all patients presenting with the acute coronary syndrome . The vast majority of the patients with TTS were found to be aged ≥50 years and were females . Emotional and physical stressors can lead to TTS .
Pathogenesis of the TTS is attributed to adrenergic overstimulation by systemic catecholamine surge which can cause acute coronary and peripheral vasospasm followed by peripheral vasodilation and left ventricular systolic dysfunction . Patients with MG could have a myasthenic crisis which could subsequently trigger a TTS. The objective was to synthesise knowledge related to the rare clinical condition of MG associated TTS. We aim to systematically review globally reported cases of MG associated TTS concerning its presentation, investigations and treatment. In 2018, 2016 and 2014 a total of five separate summarises on MG associated TTS patients were published as part of a case report [22, 23, 24, 25] and as a correspondence . However, the present systemic review includes additional cases and in-depth analysis.
All published case reports on MG associated TTS were included. The diagnosis of MG and TTS for eligibility was done by using the reporting physician’s clinical diagnosis. Standard diagnostic criteria were not used to confirm the diagnosis because it was impossible to apply it retrospectively based purely on reported data. Reports in non-English language were excluded. Reports were not excluded based on the year of publication or patient population.
Information sources and search strategy
DR and MK were involved in study selection independently. DR performed a comprehensive literature search. MK independently screened the titles and abstracts of all identified studies for selection, according to the inclusion criteria. The selected study was independently reviewed by DR to confirm the eligibility. DR and MK independently extracted data and the datasheet was finalized by consensus.
Data collection process, data items and data analysis
Demographic data, clinical presentation, investigation findings and the management plan were extracted from the selected studies. The proposed diagnostic criteria for MG  and the international Takotsubo diagnostic criteria (InterTAK Diagnostic Criteria)  were used to summarize the findings. However, the above two criteria were not considered to determine the eligibility of case reports for selection. SI units were used to present the units of measurements. The data were analysed using Microsoft Excel (Additional file 1). Descriptive statistics were used to describe the data. The quality of the selected reports was assessed using the CARE guidelines . One point was given for each item of the CARE guidelines, i.e. a maximum score of 30 for a report. The review was reported according to the Preferred Reporting Items for Systematic survey and Meta-Analysis (PRISMA) statement  (Additional file 2).
Selected case reports
Additional file 1 contains data from each of the 16 reports selected for this review. Seven case reports were from the region of Americas (44%), four from Western Pacific (25%), three from Europe (19%) and two from South-East Asia (13%). There were no case reports from the African or Eastern Mediterranean regions. Country wise, United States of America topped the list with four reported cases followed by India and Japan having two cases each. All other countries (Austria, Australia, Brazil, Colombia, Italy, Mexico, Singapore and the United Kingdom) reported one case each. The mean age of the patients was 61.6 (SD 14.1) years, with an age range of 34–80 years. There were 13 (81%) female patients. According to this review, the first case reported on MG associated TTS was by Sousa JMA et al. in 2005 from Brazil . The latest report was from Austria by Finsterer J et al. in 2018 .
Presenting complaints of patients who presented with both Myasthenia gravis and Takotsubo syndrome
Cases reported out of 16 (%)
Shortness of breath
Difficulty in mastication
Difficulty in swallowing
Summary of results for myasthenia gravis
Summary of results for the diagnostic criteria on Myasthenia gravis 
Frequency out of 16 (%)
Eye movement disorder (Diplopia - 6, Opthalmoparesis - 2)
Facial muscle weakness (Facial diplegia - 4)
Cervical muscle weakness
Limb muscle weakness
B. Pathogenic autoantibodies
Positive antiacetylcholine receptor (AChR) antibody
C. Neuromuscular junction disorders
Positive on eyelid easy fatigability test
Positive on edrophonium chloride (Tensilon) test
Positive on repetitive stimulation test
Summary of results for Takotsubo syndrome
Summary of results for the diagnostic criteria on Takotsubo syndrome 
Frequency out of 16 (%)
1. Left ventricular dysfunction (hypokinesia - 8, akinesia - 7, dyskinesia - 1)
2. Presence of a trigger (emotional, physical, or combined)
3. Neurologic disorders (e.g. subarachnoid haemorrhage, stroke/transient ischaemic attack, seizures or pheochromocytoma)
4. New Electrocardiography abnormalities
5. Levels of cardiac biomarkers
Elevated troponin level
Elevated creatine kinase level (CK - 3, CKMB - 3, both - 1)
6. Coronary artery disease
Past medical history
Past medical history of patients who presented with both Myasthenia gravis and Takotsubo syndrome
Cases reported out of 16 (%)
Myasthenia gravis (General - 7, Ocular - 1)
Chronic obstructive pulmonary disease
Hoarseness of voice due to the injured recurrent laryngeal nerve
Myasthenia gravis related drug history
Cases reported out of 8a (%)
Anti-cholinesterase (Pyridostigmine - 5, Neostigmine - 2, Drug unidentified - 1)
Corticosteroids (Prednisolone - 2, Methylprednisolone - 1)
Additional investigation findings
Chest X-ray revealed hilar infiltrates in 3 cases while cardiac dilatation, enlargement of the mediastinal shadow and mild hyperinflation were observed in one case each. Further, blood gas analysis, computed tomography, coronary angiogram, left ventriculography, magnetic resonance imaging and transthoracic echocardiography were performed and the results of which are summarised in Additional file 1. Respiratory acidosis was found in 83% (5/6) and respiratory alkalosis in 17% (1/6) of the patients who had a blood gas analysis.
Treatment modalities and survival
Treatment during the present admission
Frequency out of 16 (%)
Drugs for Myasthenia gravis
Anti-cholinesterase (pyridostigmine - 8, neostigmine - 5, unidentified drug - 2)
Corticosteroids (prednisolone - 8, hydrocortisone - 1, methylprednisolone - 1)
Immunosuppressants (mycophenolate mofetil - 1, unidentified drug - 1)
Drugs for Takotsubo syndrome
Angiotensin-converting enzyme (drug unidentified)
Diuretics (drug unidentified)
Treatment on discharge
Among the selected cases following complications were noted: respiratory failure (4/16), pulmonary oedema (2/16), respiratory arrest (2/16), acute enteritis (1/16), acute kidney injury (1/16), anemia (1/16), aspiration pneumonia (1/16), asystole (1/16), disseminated intravascular coagulation (1/16), heart failure (1/16), hypercalcemia (1/16), hypertension (1/16), hypocalcemia (1/16), hypoparathyroidism (1/16), hypoproteinemia (1/16), hypotension (1/16), hypoxia (1/16), myocardial oedema (1/16), proteinuria (1/16), renal insufficiency (1/16), sepsis (1/16), streptococcal pneumonia (1/16), supraventricular bradyarrhythmia (1/16), tonic-clonic seizure (1/16), vitamin-D deficiency (1/16). Out of the selected cases, 75% (12/16) completely recovered from their illness. Four patients died out of which two cases had a multi-organ failure secondary to heart failure and sepsis, and the cause of death was not reported in the rest of the two deaths.
Western Pacific, American and European regions have contributed to the vast majority (88%) of cases on MG associated TTS. It was noted that there were no cases reported from African or Eastern Mediterranean regions. Females were most affected (81%), and this is predictable as TTS is common among females [11, 21]. MG associated TTS showied a wide age range from 34 to 80 years. However, 69% (11/16) of the participants were over 60 years of age. Clinical features of both MG and TTS were commonly observed. Both MG and TTS have similar emotional and physical triggers [8, 21]. Therefore, a common trigger could have resulted in triggering them together. However, myasthenic crisis was experienced by all patients making it a possible trigger for TTS in MG. Therefore, it is necessary to be vigilant for TTS in MG patients with myasthenic crisis. Further, optimum pharmacological management in patients with MG is proposed to prevent myasthenic crisis and a subsequent TTS. Also, past medical history of MG was found only in 50% of the patients. Hence, a rare presentation of MG associated TTS could be the first presentation of MG. Further, certain cardiac agents like beta-adrenergic antagonists, calcium channel antagonists, procainamide and quinidine have the potential to trigger a myasthenic crisis . Therefore, treatment of TTS using similar agents needs to be done with caution among patients with MG. The above facts highlight the importance of optimum vigilance on MG associated TTS.
The mean quality assessment score for the selected articles was 20.4 (SD ± 2.3) out of a total of 30 per article. Differences in reporting of clinical presentation, investigation findings and treatment options limited the review from producing a comprehensive summary. Also, a systematic review of case reports cannot establish a causal relationship between MG and TTS. Moreover, the lack of data on the control of other co-morbid diseases prevents us from pinpointing MG as the sole trigger of TTS. Nevertheless, the review has produced excellent information on MG associated TTS. Future prospective studies on MG associated TTS are methodologically challenging considering the unusual nature of the combined presentation. However, continuous reporting of similar cases will help improve the understanding of this rare entity.
MG associated TTS is rare but can be life-threatening. Predisposition especially due to emotional and physical triggers need to be addressed for the prevention of MG associated TTS. Identification of myasthenia crisis should alert the treating clinician to look for features of TTS. Hence, the early detection could help optimise pharmacological management.
DR conceived the idea and designed the review. DR and MK were involved in study selection independently. DR performed a comprehensive literature search. MK independently screened the titles and abstracts of all identified studies for selection, according to the inclusion criteria. The selected study was independently reviewed by DR to confirm the eligibility. DR and MK independently extracted data and the datasheet was finalized by consensus. Both DR and MK were involved in the writing of the manuscript. Both authors approved the final manuscript.
The study was self-funded.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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