EP Research

Cardiology and Electrophysiology Considerations of Ehlers-Danlos Syndrome and Variants, Including Hypermobile Syndromes

Todd J. Cohen, MD,1 Bernadette Riley, DO,1 Diane Choi, BA,1 Adam Bitterman, DO,2 Hallie Zwibel, DO,1 Nancy A. Bono, DO1

1New York Institute of Technology College of Osteopathic Medicine, Long Island, New York;

2Department of Orthopaedic Surgery, Northwell Orthopaedic Institute, Huntington, New York

Todd J. Cohen, MD,1 Bernadette Riley, DO,1 Diane Choi, BA,1 Adam Bitterman, DO,2 Hallie Zwibel, DO,1 Nancy A. Bono, DO1

1New York Institute of Technology College of Osteopathic Medicine, Long Island, New York;

2Department of Orthopaedic Surgery, Northwell Orthopaedic Institute, Huntington, New York

Patients with Ehlers-Danlos Syndrome (EDS) and hypermobile conditions are rare and complex, and require a multidisciplinary approach in order to diagnose and treat their many ailments. Specifically, the cardiology and electrophysiology issues need to be addressed by an experienced specialist who can help to diagnose and treat their symptoms of palpitations and presyncope. This article introduces the reader to this complex and diverse group of patients, and provides our approach to the cardiac and electrophysiologic management of these patients.

Introduction

People with EDS and related hypermobile conditions are a complex group from a cardiology standpoint. Patients often complain of lightheadedness and dizziness, and sometimes true syncope. In addition, many patients complain of palpitations.1 It is important to perform a complete history and physical examination as well as an electrocardiogram (ECG) in these patients. Table 1 illustrates the signs and symptoms that have been clinically observed in patients with EDS. The echocardiogram is also an important evaluation, and specifically, one should look for the presence of mitral valve prolapse (MVP) and aortic root dilatation/aneurysms. More recently, the importance of this modality has come into question2; however, it is important to remember that this methodology is noninvasive, and the identification of cardiac pathology may be helpful in the management of patient’s symptoms. Cardiac monitoring and additional electrophysiology tests may be useful in the management and treatment of these patients.

General Overview of Hypermobility

General joint hypermobility refers to the ability of the joint in question to move beyond its physiological barrier.3 The degree to which hypermobility is seen could be classified as Hypermobility Spectrum Disorder (HSD). HSD refers to a group of disorders where patients present with hypermobility of differing types as well as cardiac and orthopedic symptoms. The 2017 International Classification of the Ehlers-Danlos Syndromes classified EDS into 13 specific subtypes.4 EDS are a group of heritable connective tissue disorders that present with a wide variety of symptoms. One subtype, hypermobile EDS (hEDS), is currently classified via clinical guidelines only.4 Some patients do not meet criteria for hEDS, but can be classified as HDS.5

Hypermobility Spectrum Disorder is currently divided into 4 types:

  1. Generalized Joint HSD (G-HSD): Generalized joint hypermobility;
  2. Peripheral Joint HSD (P-HSD): Hypermobility is in hands or feet “plus one of more secondary musculoskeletal manifestation”;3
  3. Localized Joint HSD (L-HSD): Limited to a single or group of joints “plus one of more secondary musculoskeletal manifestation”;
  4. Historical Joint HSD (H-HSD): Patient reports a history of hypermobility.

Various EDS Subtypes

Many EDS subtypes and similar hypermobile conditions have been described. This includes classical EDS (cEDS) and hEDS, as well as hypermobility spectrum disorder (HSD). More recently, a bi-allelic alteration in the AEBP1 gene that encodes the aortic carboxypeptidase-like protein (ACLP) associated with the extracellular matrix has been described.6 Certain cEDS patients have mutations in COL5A1 (~75-80%) and COL5A2 (~14%) genes and a small percentage of these present clinically with arterial dissections and ruptures.7 There is no identified genetic etiology for hEDS, but MVP and aortic root dilatation with Z-score > +2 are two key cardiac manifestations.4 hEDS falls under symptomatic joint hypermobility along with HSD, which has fewer requirements for diagnosis than hEDS. Because of overlapping clinical features of hEDS and HSD, it is important to perform basic cardiac workup for patients suspected of either disorders. Vascular EDS (vEDS) has a high risk for vascular complications (vascular dissection and rupture), and invasive cardiac procedures should not be performed.

Cardiology and Electrophysiology Evaluation

The initial evaluation for hypermobile patients with syncope and presyncope should include tilt table testing and electrocardiographic monitoring. It is the authors’ preference to perform passive tilt table testing for 45 minutes at 70 degrees, and to be physically present and available when symptoms develop. Table 2 lists common findings observed during tilt table testing for EDS patients. It is important to differentiate neurocardiogenic syncope from orthostatic hypotension (OH) and Postural Tachycardia Syndrome (POTS). The latter appears to be more common in this group of conditions.8 It should be noted that POTS alone, without EDS, may be associated with MVP.9 The decision on whether to monitor the patient’s heart by a wearable technology as opposed to implantable technology, such as an implantable loop recorder, is a clinical one based on symptom frequency and patient preference.

Depending on the patient’s symptoms and severity, as well as abnormal cardiac findings on either examination, ECG, and/or echocardiogram, an electrophysiology (EP) study may prove useful but may not be necessary in many patients with EDS and EDS-like symptoms. The risks, benefits, and alternatives should be discussed with the patient. Many of these patients will have had significant monitoring (either implantable or wearable) before undergoing an EP study. The study may be useful at distinguishing physiologic for pathologic tachycardia. For example, patients may have inappropriate sinus tachycardia, which is separate and distinct from reentrant supraventricular tachycardias such as AV node reentry, AV reentry, or an ectopic atrial tachycardia. The former is best treated with supportive measures and medications such as beta blockers and/or calcium channel blockers, whereas the latter group of reentrant tachycardias may benefit from cardiac catheter ablation. The approach to managing a patient’s palpitations is tailored to each particular patient. Table 3 displays abnormal findings on ECG and implantable loop recorder. Clinically, we have identified a variety of supraventricular arrhythmias and premature ventricular contractions as the cause of arrhythmia-like symptoms in many of these patients. 

Overall Electrophysiology Approach to EDS and Hypermobility

Overall, we recommend a “patient-centric approach” that involves the EDS/Hypermobile team. By combining cardiac monitoring, and if necessary, findings during the EP study, we will employ a series of medical, catheter-based, and/or device-based therapies to address the presyncope and/or syncope in these patients. Specifically, depending on whether their presyncope and/or syncope is caused by either neutrally mediated tachycardia, orthostatic hypotension, and/or POTS, we provide education including postural and leg compression training, and recommend electrolytic hydration, high compression support stockings, and other medications such as midodrine, beta blockers, and/or fludrocortisone.

Patients with EDS experience a wide range of cardiology manifestations with respect to their signs and symptoms. It is important to perform a thorough exam, and the echocardiogram, tilt table test, and ECG monitoring are important tools in the diagnosis and management of this condition. Symptoms and cardiac findings that drive the need for an EP study should most likely be avoided in patients with vEDS. With respect to a patient’s specific arrhythmia, the EP study together with monitoring can help guide pharmacotherapy and determine the need for cardiac catheter ablation. If the tachycardia is reentrant or focal in nature, ablation may be preferable; however, medications may provide a helpful alternative. Long-term monitoring can be useful at assessing the outcomes of the ablation, as well as the need for additional medications.

The Ehlers-Danlos/Hypermobility Treatment Center at NYITCOM

Dr. Bernadette Riley, Director of NYITCOM’s Ehlers-Danlos Syndrome/Hypermobility Treatment Center, works closely with Dr. Todd Cohen, Director and Founder of the Long Island Heart Rhythm Center (LIHRC), who provides cardiac and electrophysiology expertise to this patient population. From an electrophysiology perspective, these patients are highly symptomatic, and most experience palpitations and/or presyncope. Together, cardiac and electrophysiology related problems are addressed in a patient-specific manner. The center provides a multidisciplinary approach to the EDS and hypermobile patients, and Dr. Cohen provides cardiac expertise to help manage these patients.

The Multidisciplinary Team

At NYITCOM, Dr. Riley is the “quarterback” for the many issues that afflict this diverse group of patients. Dr. Riley methodically evaluates and treats every patient with care. Besides Dr. Cohen’s cardiology and electrophysiology component of the Ehlers-Danlos Syndrome/Hypermobility Treatment Center, Dr. Riley utilizes this multidisciplinary approach (Figure 1) to address patient-specific issues related to pain, mobility, psychosocial issues, neurologic issues, etc.  The multidisciplinary team (Figure 2) also includes an orthopedic surgeon, Dr. Adam Bitterman, and two members of the Sports Medicine program at NYITCOM, Dr. Hallie Zwibel and Dr. Matthew Heller.

Dr. Bitterman has elaborated on some cervical laxity issues in the EDS and hypermobile patient population. Specifically, the connection between the head and neck is a very vulnerable location among patients with EDS. Ligamentous tissue connects bone to bone and in patients with EDS can be stretched more than in unaffected individuals. The cranio-cervical articulation and those joints within the cervical spine are subject to loose ligaments, which may cause instability at these joints. Surrounding anatomy that rely on a stable head-neck junction may be at risk for injuries. These vital structures include the spinal cord, exiting nerve roots, and vertebral arteries. Damage to nervous system structures may lead to coordination problems, sensory changes, and abnormal motor skills.

Special care needs to be directed to cervical spine management and airway management in those with an unstable loose cervical spine in order to maintain safety throughout any electrophysiology procedure, but especially those that may require a jerk from electrical cardioversion and/or defibrillation. These issues are often discussed in concert with the provider of anesthesia during the electrophysiology case. We provide a team-based approach to treat the hypermobile patient and all of the comorbidities that are seen. This multidisciplinary approach to the EDS/hypermobile patient is what makes NYITCOM’s Ehlers-Danlos Syndrome/Hypermobility Treatment Center and LIHRC unique and cohesive.

Summary

The cardiac and electrophysiology workup for the EDS and hypermobile patient population should be tailored to the specific patient’s symptoms, but should always include an echocardiogram and ECG. The EP study, tilt table, and implantable loop may be useful in helping to diagnose the cause of palpitations, presyncope, and/or syncope in these patients. We specifically look for and have extensive experience in diagnosing conditions such as POTS, supraventricular tachycardia (SVT), and other manifestations of this diverse disease. LIHRC tailors its treatment to the patient, and these treatments may include medications, device implants, and cardiac catheter ablation when indicated. 

Disclosures: The authors have no conflicts of interest to report regarding the content herein.   

References
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  2. Rauser‐Foltz KK, Starr LJ, Yetman AT. Utilization of echocardiography in Ehlers‐Danlos Syndrome. Congenit Heart Dis. 2019;00:1-4. doi:10.1111/chd.12824.
  3. Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet Part C Semin Med Genet. 2017;175C:148-157. doi:10.1002/ajmg.c.31539.
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  6. Blackburn PR, Xu Z, Tumelty KE, et al. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos Syndrome. Am J Hum Genet. 2018;102(4):696-705. doi:10.1016/j.ajhg.2018.02.018.
  7. Malfait F. Vascular aspects of the Ehlers-Danlos Syndromes. Matrix Biol. 2018;71-72:380-395. doi: 10.1016/j.matbio.2018.04.013.
  8. Miglis MG, Schultz B, Muppidi S. Postural tachycardia in hypermobile Ehlers-Danlos Syndrome: a distinct subtype? Auton Neurosci. 2017;208:146-149. doi:10.1016/j.autneu.2017.10.001.
  9. Cutsforth-Gregory JK, Sandroni P. Clinical neurophysiology of postural tachycardia syndrome. Handb Clin Neurol. 2019;161:429-445. doi:10.1016/B978-0-444-64142-7.00066-7.
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