Introduction:

Sinus node dysfunction, commonly known as sick sinus syndrome (SSS) refers to the inability of the sinoatrial (SA) node to generate a heart rate required to meet the physiologic needs of an individual [1,2]. The diagnosis is made clinically, based upon history and electrocardiogram (ECG) monitoring. Presenting signs and symptoms typically include fatigue, lightheadedness, palpitations, presyncope and/or syncope. Given that standard routine ECG findings tend to be nonspecific, ambulatory ECG monitoring is often required for a definitive diagnosis. Sick sinus syndrome is an umbrella term, encompassing a wide range of SA node dysfunction, including inappropriate sinus bradycardia, sinus pauses and tachycardia-bradycardia syndrome [1,2].

Treatment is aimed at relieving symptoms, typically with implantation of a permanent pacemaker. Current recommendations indicate that the most effective treatment for patients with symptomatic sinus node dysfunction is permanent pacemaker implantation, with literature documenting a reversal of symptoms with appropriate insertion [3].

This is a unique case of ischemic stroke following permanent pacemaker implantation. While there have been other similar cases reported, this case explores a multifactorial analysis of the patient's ultimate stroke. Current literature has detailed very few cases of malpositioned leads and lead displacement through a patent foramen ovale, resulting in cerebrovascular accidents [4- 6]. This case report intends to illustrate further evidence of the thrombogenic potential of pacemaker leads, and highlight this underrepresented source of thrombus in PFO-associated strokes. Additionally, there is conflicting evidence regarding the appropriateness of medical therapy, in patients under these circumstances, to prevent recurrent strokes. Therefore, these disparities in literature will be an imperative aspect of the discussion as well.

Report of Case:

A 73-year-old Caucasian male with a history of well-controlled hypertension presented to the cardiology outpatient clinic reporting episodes of his heart racing with associated dyspnea, extreme fatigue, dizziness, and weakness. The patient denied a history of atrial fibrillation. He was a lifelong non-smoker and revealed no significant family history of cardiovascular disease. Routine ECG in clinic showed sinus rhythm. Given these symptoms, the patient was given a Holter monitor and was instructed to return to the clinic in five to six weeks. Upon return to the clinic in five weeks, the patient continued to describe episodes of weakness, palpitations and near syncope. The cardiac monitor displayed the following: transient third-degree atrioventricular block and a few episodes of non-sustained ventricular tachycardia. An echocardiogram showed a left ventricular ejection fraction of 60% with trivial mitral regurgitation. Based on these findings, a permanent pacemaker insertion was recommended.

Patient underwent a dual chamber permanent pacemaker insertion without any complications. Post-procedural chest x-ray revealed good lead placement. Following the procedure, the patient and family were educated on the importance of wearing an immobilizing sling for the next two to three weeks to prevent dislodgement of the new leads. On ten-day follow-up visit, the patient reported mild soreness to the site but no signs of infection. The patient endorsed compliance with his immobilizer sling and antibiotics with marked symptom improvement.

Several days later, the patient was admitted to the emergency department with left-sided weakness and blurry vision. A computed tomography of the head, without contrast, showed a subacute right occipital lobe infarct. On device interrogation, the patient was found to have a pacemaker lead dislodgement. Once stable and on appropriate medical management, the patient was transferred to another hospital for further evaluation and treatment. Upon admission to the new center of care, a 12-lead ECG obtained was abnormal, showing an atrial-paced rhythm with prolonged atrioventricular conduction, premature atrial complexes and a prolonged QTc interval. A transesophageal echocardiogram was performed. Images obtained from the esophageal and transgastric views revealed the right atrial pacemaker lead crossing a patent foramen ovale, and in the left atrium, a large 2.5x1.8cm mass was visualized, attached along the posterolateral left atrial wall, consistent with a thrombus. In some views, the mass appeared to be attached to the lead as well. A small thrombus was also seen at the patent foramen ovale on the left atrial side where the lead was crossing into the left atrium.

After six weeks of dual oral anticoagulation therapy, the lead was repositioned without complication. The device was interrogated and demonstrated new onset atrial fibrillation. The patient was placed on a loading dose of antithrombotic, Eliquis, to be transitioned to 5mg BID upon discharge. In the final follow-up visit with the outpatient cardiology clinic several weeks later, a repeat permanent pacemaker interrogation revealed that all parameters were within normal limits. The patient reported his neurological symptoms have improved, and his vision had returned to baseline normal.

Discussion:

There are four primary sources that can be identified as the potential cause of this patient's adverse event: (1) pacemaker lead dislodgement, (2) post-operative conversion to atrial fibrillation, (3) inappropriate immobilization, and (4) previously undiagnosed patent foramen ovale. The interrelation and combination of all four served to predispose this patient to the subsequent stroke. While it is impossible to discern which of these contributed most significantly to the patient's adverse outcome, all four will be explored in the following discussion.

Interestingly, pacemaker lead displacements are quite uncommon and, in general, are defined as any change in the position of the lead. However, current literature predominantly describes clinically relevant dislodgements; i.e., those that affect the functionality of the pacing system [7,8]. Dislodgements are divided into early displacements or late displacements, the former occurring within six weeks of implantation. Early displacements occur more frequently and in the context of atrial leads [8]. The incidence of such lead dislodgements is 1% in ventricle-only pacing (VVI) and 5.2% in dual-chamber pacing (DDD), with more cases affecting atrial leads (3.8%) than ventricular leads (1.4%) [8]. Early lead displacements involving atrial leads are the most common and are a well-studied cause of reintervention [8,9].

While the stroke risk following pacemaker insertion cannot be positively ascertained, studies have shown that 4.5-23% of paced sick sinus syndrome patients presented with a cerebrovascular accident two to three years following pacemaker insertion [10-12]. This finding suggests a thrombogenic potential of pacemaker leads. However, significant conclusions cannot be drawn concerning whether the pacemaker leads were an independent cause of stroke, or if there were other contributing factors. For instance, atrial fibrillation is a widely recognized risk factor for subsequent development of strokes, and the condition has been found to develop in 25-30% of paced sick sinus syndrome patients two to three years following pacemaker insertion [12]. Patients with sick sinus syndrome, who convert to atrial fibrillation after pacemaker insertion, may represent a high-risk subgroup for cardioembolic stroke who may require additional medical therapy. The role of anticoagulant therapy has been explored in patients with sick sinus syndrome and tachycardia-bradycardia syndrome [11], but current research contains significant paucities in external validity [13].

Patients are often required to immobilize their arm following pacemaker/implantable cardioverter-defibrillator (ICD) implantation to mitigate the risk of lead displacement. The American College of Sports Medicine guidelines recommend that patients avoid lifting their affected arm above shoulder height for 2 to 3 weeks [14]. However, following these guidelines prevents patients from performing daily activities, such as reaching overhead to wash their hair, opening cabinets, or in the case of this patient, sleeping in a comfortable position. While such activity restrictions are intended to protect the patient postoperatively, there may be unintended consequences, such as lack of compliance or excessive fear of self-injury. Naffe et al. demonstrated that patients can safely perform resistive range-of-motion exercises within 24 hours of implantable cardiac device insertion without lead displacement. Additionally, the study documented a concerningly wide variation in the use and application of sling immobilization following implantation across several hospitals and providers [15]

Patients with on other source or risk factors for stroke, who experience an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left shunt, are diagnosed with a PFO- associated stroke. There has been a long-standing debate among expert researchers on the recommendation of percutaneous PFO closure for the secondary prevention of cryptogenic stroke. While early trials, like the CLOSURE I have failed to demonstrate a significant benefit [16], newer long-term follow-up data from the RESPECT and CLOSE and REDUCE trials demonstrates that transcatheter PFO closure significantly reduces the risk of recurrent stroke compared with medical therapy in patients with cryptogenic stroke [17,18]. In the context of this case, it is important to discuss the indications and selection criteria for PFO closure in patients with PFO-associated stroke. The PFO-associated stroke causal likelihood (PASCAL) classification system incorporates the Risk of Paradoxical Embolism (RoPE) score to guide decision-making for PFO device closure [19,20]. In the setting of a patient <60 years old, with no other apparent source of stroke, PFO closure is sanctioned if the RoPE score is >6 and/or if there is a presence of a large shunt or atrial septal aneurysm [19]. In patients >60 years of age with a PASCAL classification of a possible, probable, or definite causal association, the safety and benefit of PFO closure is not well-defined [20]. These patients were often excluded in randomized trials, and patient-level meta-analysis displayed an increased risk for atrial fibrillation with increased age [21].

Conclusion:

Despite the lack of prior risk factors for stroke in this patient, and taking into account that initial permanent pacemaker lead positioning was appropriate, patient still experienced a sequela of adverse events and eventually developed a major and rare complication of his condition. According to evidence- based medicine, this patient's age disqualifies him for percutaneous PFO closure. While the role of medical therapy vs. PFO closure in this patient population is still unclear, patients without an indication for anticoagulation should be treated with antiplatelet therapy. Those with a high clinical suspicion for, or concurrent conditions associated with a hypercoagulable state, should be on oral anticoagulant therapy. All patients should be routinely monitored and re-evaluated for the continued benefit or unnecessary harm while on medical therapy. Furthermore, continued research in the safety and efficacy of early mobilization following pacemaker/ICD implantation is necessary to develop consistent guidelines which encourage safe range-of-motion exercises to promote healing and lead to a more rapid return to the patient's baseline quality of life. Little research has been conducted regarding the primary prevention of stroke in patients undergoing implantation of intracardiac devices. Future research should be dictated by the following questions: Should we view endocardial lead patients differently by introducing pre-operative PFO screenings? Should we consider PFO closure or epicardial leads in those with especially large PFOs or higher right atrial pressures? Until more research becomes available, decisions in such patients should be based upon individualized assessment of potential risks and benefits, as well as patient preferences.

Acknowledgement:

All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Informed Consent/Disclosures:

The patient in this study provided written informed consent prior to participation. All authors have declared that no financial support was received from any organization for the submitted work. All authors have declared that they have no financial relationships with any organizations that may have an interest in the submitted work. All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Figure 1: Thrombus on the dislodged lead in the left atrium.

Figure 2: Thrombus on the dislodged lead in the left atrium.

Figure 3: Thrombus on the dislodged lead in the left atrium.

Figure 4: Thrombus on the dislodged lead in the left atrium.

Figure 5: Thrombus on the dislodged lead in the left atrium.