Recently, a novel encephalopathy characterized by a combination of abnormal sleep behaviors, sleep apnea, gait instability, bulbar symptoms, gaze abnormalities, and dysautonomia has been reported in 8 patients1 and independently confirmed in another 3.2, 3, 4 The cardinal immunological hallmark of this new syndrome is the demonstration of IgLON5 antibodies in the serum and cerebrospinal fluid (CSF).1
Tako‐Tsubo cardiomyopathy (TCM), also known as transient left ventricular apical ballooning or stress cardiomyopathy, is a transient, focal left ventricular dysfunction with normal coronography, thus mimicking myocardial infarction. The underlying pathophysiology remains unclear, but excessive sympathetic stimulation has been proposed to play a triggering role.4, 5 We report on the first case of TCM in a patient with IgLON5 antibodies.
Case Report
A 70‐year‐old woman from Azerbaijan on a visit in Luxembourg was urgently admitted to the pulmonary department in June 2014, because of abrupt dyspnea attributed to laryngeal stridor. An emergency laryngoscopy showed a bilateral paralysis of the vocal cords in adduction, which required urgent tracheostomy. Neurological consultation was requested because the patient carried an external diagnosis of PSP. Medical history reported by the family revealed a progressive syndrome since 2006, first characterized by nonspecific gait disorder, followed by horizontal gaze restriction and a first episode of acute suffocation in 2012. In 2013, the patient developed an inability of sneezing and coughing, as well as various dysautonomic symptoms, including urinary frequency, orthostatic hypotension, and constipation. At the same time, she demonstrated nocturnal vocalizations (murmuring, groaning, and shouting) and elaborated nocturnal movements (opening of the window). At the beginning of 2014, she suffered from occasional episodes of nocturnal stridor, one of them complicated by TCM. Concordantly with established TCM diagnostic criteria,5 she presented an acute coronary syndrome with suggestive electrocardiogram changes and an elevation of T‐troponin levels; the echocardiography showed segmental contraction impairment of the midanterior and anteroseptal heart walls; angiography revealed normal coronary circulation, but midventricular regional motion abnormalities (Fig. 1). Cardiac MRI performed 5 days later confirmed these findings; there was no evidence of ischemic scar or myocarditis.
Figure 1.
Left ventricular angiography in diastole (left) and systole (right), showing akinesia of the mild ventricular segments (arrows) with normal contraction of the basal apical regions which is typically observed in Tako‐Tsubo syndrome.
The neurological exam showed mild dysarthria and dysphagia, bilateral horizontal gaze restriction with, in particular, irregular, hyometric, and slowly initiated horizontal saccades (see Video 1), only mild vertical gaze restriction, mild bradykinesia, and postural gait instability as well as bilateral Babinski sign. Of note, there was no hypomimia and no dysmetria.
Routine blood tests were normal, including blood count, ions, ferritin, vitamin B12, thyroid, kidney and liver function, plasma and urinary copper studies, and screening for nuclear autoantibodies. The Schellong test showed orthostatic hypotension. A levodopa challenge (375 mg) was negative.
Cerebral MRI showed mesencephalic atrophy with subtle hummingbird sign (Fig. 2). DaTscan showed reduced asymmetric striatal uptake. Myocardial metaiodobenzylguanidine scintigraphy (MIBG‐SPECT [single‐photon emission computed tomography]) performed 5 months after the TCM syndrome evidenced moderately reduced global uptake. IgLON5 antibodies (titer, 1:200) were found in serum and later confirmed by the IDIBAPS Laboratory in Barcelona. The patient refused lumbar puncture, human leukocyte antigen HLA genotype, polysomnography, and experimental treatment with immunoglobulins. She returned to her country. After 17 months of stabilized condition, she died because of aspiration pneumonia in her country. An autopsy was not performed.
Figure 2.
Mesencephalic atrophy with subtle hummingbird sign.
Discussion
We report on the first case of TCM associated with serum IgLON5 antibodies. The slowly evolving syndrome over several years with gait disorder, gaze palsy, bulbar and respiratory symptoms, and reported sleep abnormalities is suggestive of an IgLON5 encephalopathy,1, 2, 3, 4 although CSF analysis with demonstration of CSF antibodies as in the originally reported patients has not been performed. We consider this as a limitation of the present observation. Cardiac abnormalities (bradyarrhythmia or ventricular tachycardia) have been reported before, however, to the best of our knowledge, TCM has not been reported before. The acute stress induced by dyspnea attributed to laryngeal stridor may primarily trigger TCM, but there are also several arguments suggestive of a direct link between TCM and IgLON5 antibodies. First, the dysfunctional cardiac sympathetic stimulation demonstrated by globally reduced postsynaptic noradrenergic uptake cannot be explained by a late‐term TCM sign, given that the typical TCM‐related SPECT finding is a regional, transitory pattern uptake of the 123I‐MIBG. In contrast, a global and permanent heart involvement, as described here, can be observed in myocardial dysautonomia related to a synucleinopathy.6, 7, 8 Second, neurological cause of TCM has been reported, linked to inappropriate brainstem regulation of the coronary microcirculation related with myocardial stunning in TCM.8, 9 In analogy, IgLON5 encephalopathy also primarily involves the brainstem, as shown by neuropathological findings.1, 3 Third, the IgLON5 protein is a cell adhesion molecule, which is also expressed on myocardiocytes.10, 11 Finally,intermittent ventricular tachycardia has been reported,4 and, in the initial report, sudden death occurred in 6 patients1; so, could previously unnoticed TCM have triggered consecutive (fatal) arrhythmias in these patients? Though such a relationship is purely speculative at this point, we suggest adding careful cardiologic evaluation to the diagnostic panel in patients with IgLON5 antibodies, given that the puzzle of this complex new syndrome remains incomplete.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; D. Supervision; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
T.M.S.: 1A, 1C, 2A
V.P.: 1B, 1C, 2B
F.B.: 1C, 2B
A.C.: 1C, 2B
N.J.D.: 1A, 1B, 1D, 2B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: The authors declare that there are no disclosures to report.
Supporting information
A video accompanying this article is available in the supporting information here.
Video 1. This video clip illustrates the most prominent clinical findings of the neurological exam of our patient: (1) Horizontal gaze restriction with saccadic abnormalities. (2) Bimanual bradykinesia. (3) Patient's tracheostoma. Tracheostomy had been performed because of acute respiratory insufficiency attributed to laryngeal stridor in relation to bilateral paralysis of the vocal cords in adduction.
Acknowledgments
We thank Prof. Dalmau and Prof. Graus from IDIBAPS Laboratory in Barcelona for laboratory diagnostic confirmation and Dr. G. Wirtz, MD, and Dr. P. Kerschen, MD, Centre Hospitalier de Luxembourg, for assistance in clinical care.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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Associated Data
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Supplementary Materials
A video accompanying this article is available in the supporting information here.
Video 1. This video clip illustrates the most prominent clinical findings of the neurological exam of our patient: (1) Horizontal gaze restriction with saccadic abnormalities. (2) Bimanual bradykinesia. (3) Patient's tracheostoma. Tracheostomy had been performed because of acute respiratory insufficiency attributed to laryngeal stridor in relation to bilateral paralysis of the vocal cords in adduction.