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Paradoxical embolisation in right-sided infective endocarditis and patent foramen ovale
  1. Tyler T Shimfessel1,
  2. Sami A El-Dalati1,
  3. Michael Sekela2 and
  4. Taha Ahmed1
  1. 1Internal Medicine, University of Kentucky Medical Center, Lexington, Kentucky, USA
  2. 2Cardiothoracic Surgery, University of Kentucky Medical Center, Lexington, Kentucky, USA
  1. Correspondence to Dr Taha Ahmed; tahaahmedfairview{at}gmail.com

Abstract

Intravenous drug use (IVDU) is a growing public health crisis worldwide. A known complication of IVDU is right-sided infective endocarditis (RSIE) involving the tricuspid valve. As the tricuspid valve is burdened with infectious vegetations, it becomes a potential source of pulmonary and, very rarely, paradoxical systemic emboli. We report two patients with RSIE involving the tricuspid valve presenting with acute change in mental status. Subsequent imaging demonstrated embolisation to the brain in the setting of elevated right atrial pressures and the presence of a patent foramen ovale (PFO) with right-to-left shunting. We employed a strategy of percutaneous closure of PFO, to prevent further embolisation, as a successful bridge to definitive surgical management of RSIE. We emphasise that clinicians should evaluate for intracardiac shunting and pursue transesophageal echocardiography when encountering systemic emboli of unknown origin, particularly in patients with RSIE.

  • Valvar diseases
  • Interventional cardiology
  • Cardiovascular system
  • Infections

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Background

Paradoxical embolisation occurs when an embolus of venous origin crosses an intracardiac defect into the systemic arterial circulation.1 Aetiologies of intracardiac defects include patent foramen ovale (PFO, most common), atrial septal defects and ventricular septal defects. Fetal circulation involves a physiological communication between the right and left atrium, deemed a foramen ovale. This passageway closes after birth, but remains open in approximately 25% of the population, leaving them with a PFO.2 PFO is often clinically inapparent but may be the source of paradoxical emboli or cryptogenic stroke. PFO is reportedly found in one-third of ischaemic cryptogenic strokes which may present with signs of cerebrovascular ischaemia.2 In fact, paradoxical embolism through PFO is probably the most common cause of cryptogenic stroke.3 Due to the diverse clinical presentation of paradoxical emboli and cryptogenic stroke, the initial workup should include neurovascular assessment with CT of the head, MRI of the brain, as well as cardiac assessment by ECG and echocardiography (transthoracic echocardiogram (TTE) and possibly transesophageal echocardiogram (TEE)).4 We present two rare cases of intravenous drug use (IVDU)-related right-sided infective endocarditis (RSIE) involving the tricuspid valve (TV) with cerebral paradoxical embolism due to right-to-left shunting through a PFO.

Case 1

Case presentation

Patient 1 is a young woman in her 20s who initially presented to a local hospital with fevers, shortness of breath and an acute change in mental status. She had a known history of IVDU, RSIE involving the TV complicated by multiple septic pulmonary emboli and hepatitis C. At the time of presentation, her vital signs included a temperature of 37.1°C, blood pressure of 96/62 mm Hg, heart rate of 92 beats per minute, respiratory rate of 28 breaths per minute. Physical examination was notable for an agitated female patient with track marks on upper limbs, raised jugular venous pulse, systolic murmur over the precordium and lower extremity oedema. The patient underwent emergent endotracheal intubation for worsening hypoxia and encephalopathy and was flown to our tertiary care facility.

Investigations

Laboratory examination revealed a normal white cell count of 8.12 (normal reference range: 3.70–10.30 × 109/L), low haemoglobin 100 (112–157 g/L), as well as normal platelets 240 (155–369 × 103/µL), sodium 143 (136–145 mmol/L), potassium 4.1 (3.7–4.8 mmol/L). Blood cultures at the local hospital grew methicillin-resistant Staphylococcus aureus. A CT scan of the brain revealed features of septic emboli followed by an MRI of the brain showing scattered punctate emboli in frontal lobes and acute infarcts involving the right parietal lobe and right insular cortex (figure 1).

Figure 1

MRI of the brain demonstrating acute infarcts in the (A) right insular cortex and (B) right parietal lobe (white arrows).

No mycotic cerebral aneurysms were identified by CT-angiography. A CT scan of the chest revealed multiple non-cavitary nodular opacities within bilateral lungs concerning for septic emboli. A TTE demonstrated an abnormal TV with severe wide open acute tricuspid regurgitation with flail appearing septal leaflet of the TV with a >1.0 cm vegetation (figure 2). There was evidence of severe right atrial dilation and significant bowing of the interatrial septum to the left. Additionally, colour Doppler and agitated saline contrast identified significant right-to-left shunt indicative of PFO. There were no significant valvular abnormalities on any of the other cardiac valves.

Figure 2

Transthoracic echocardiogram parasternal right ventricular inflow view showing (A) vegetation on tricuspid valve leaflet (yellow arrow), (B) severe tricuspid regurgitation, (C) bowing of the interatrial septum into the left atrium (red arrow), PFO with right-to-left shunt on colour Doppler.

Treatment

Our patient met modified Duke criteria for RSIE. She was initiated on intravenous vancomycin 1 g every 12 hours. Her blood cultures cleared after 48-hours on parenteral antibiotics. After a multidisciplinary meeting with surgeons, critical care clinicians, cardiology and infectious disease teams, it was recommended that patient undergo a percutaneous approach PFO closure to help reduce right-left shunting across the PFO and prevent further paradoxical embolisation as a bridge to definitive surgery. Within 48 hours of presentation, our patient underwent a successful percutaneous closure of PFO. During an intracardiac echocardiogram, the PFO was identified with colour Doppler with brisk right-to-left shunting and was closed percutaneously with a Gore Occluder Helix 25 mm device (figure 3). Postprocedure, the patient was started on dual antiplatelet therapy with aspirin and clopidogrel.

Figure 3

Intracardiac echocardiogram with colour Doppler showing PFO with brisk right-to-left shunting.

Our patient’s hypoxia continued to improve progressively after the percutaneous PFO closure, and she was liberated from the ventilator the next day. Due to the patient’s history of substance use disorder, the inpatient addiction medicine team was consulted. She was started on buprenorphine/naloxone injections while inpatient. After discussion with the patient and family, the patient underwent TV replacement using a 29 mm Saint Jude epic porcine prosthesis, removal of previously placed percutaneous PFO closure device, and operative closure of PFO on day 10 of hospital stay. An intraoperative TEE did not reveal any evidence of endocarditis involving the left-sided heart valves.

Outcome and follow-up

The patient tolerated the surgery well and postsurgically, she continued and completed intravenous vancomycin 1 g every 12 hours for 2 weeks after valve replacement.5 She was discharged in good clinical condition on aspirin 75 mg daily and metoprolol tartrate 25 mg two times per day, directly to an inpatient addiction treatment centre. On discharge, the patient continued with addiction medicine treatment as well as infectious diseases follow-up, successfully completing therapy for hepatitis C.

On a 3-month telemedicine follow-up, our patient is doing well with no relapsed substance use.

Case 2

Case presentation

Patient 2 is a young woman in her early 30s who presented to our hospital after being found unresponsive at her home. Her medical history was significant for a known history of methicillin-susceptible S. aureus TV endocarditis complicated by pulmonary septic emboli, substance use disorder complicated by IVDU and hepatitis C. The patient had two hospital admissions during the 6 months prior to the index hospitalisation, both due to infective endocarditis. In her most recent hospital admission 3 months prior, the patient had been diagnosed with septic pulmonary embolism secondary to infective endocarditis of the TV, for which she was discharged on an antibiotic course. TTE during that admission demonstrated a 1.4 × 0.7 cm multilobular vegetation on the TV with moderate TV regurgitation and an aneurysmal interatrial septum (figure 4). Once clinically stable, she was discharged home on a 6-week course of intravenous cefazolin 2 g every 8 hours under the auspices of a clinical trial assessing the safety of home intravenous antibiotic therapy in patients with opioid use disorder treated with buprenorphine.

Figure 4

Transthoracic echocardiogram apical four-chamber view demonstrating the tricuspid valve vegetation (blue arrow) and aneurysmal interatrial septum (yellow star).

At the time of the index presentation, her vital signs included a temperature of 36.9°C, blood pressure 105/65 mm Hg, regular heart rate of 108 beats per minute, respiratory rate of 24 breaths per minute. Physical examination was notable for a non-verbal woman with minimal voluntary function, a 2/6 holosystolic murmur heard throughout precordium, microvascular lesions on the left fifth finger and Glasgow Coma Scale score of 11. The patient was administered 4 mg intravenous naloxone with no response.

Investigations

Laboratory examination revealed an elevation in white cell count of 11.22 (normal reference range: 3.70–10.30 × 109/L), as well as low haemoglobin of 94 (112–157 g/L), platelets of 112 (155–369 × 103/µL), sodium of 130 (136–145 mmol/L) and potassium of 3.0 (3.7–4.8 mmol/L). Blood cultures were collected and grew Serratia marcescens. ECG showed non-specific ST-T wave changes and high sensitivity troponins were mildly elevated with insignificant delta. A CT scan of the brain revealed a right frontal lesion, which was followed up by an MRI/MRA of the head and neck that demonstrated areas of restricted diffusion in the paramedian anterior frontal lobes, posterior frontal lobes and cerebellar vermis suggestive of infarcts involving multiple vascular territories (figure 5). No evidence of carotid or vertebral stenosis was found. CT scan of the chest demonstrated cavitary lesions consistent with chronic septic pulmonary emboli and cortical erosions of the left sternoclavicular joint indicative of septic arthritis. Cardiovascular workup included a TTE, which revealed a 0.9 × 0.7 cm TV vegetation with severe TV regurgitation, an aneurysmal interatrial septum with bubble study showed an early appearance of agitated saline in the left heart at rest, with no lesions on left-sided heart valves. Notably, TEE was not performed.

Figure 5

MRI of the brain demonstrating areas of restricted diffusion in the (A) right lateral frontal cortex, (B) left paramedian posterior frontal lobe and (C) left paramedian anterior frontal lobes, suggestive of multiple infarcts involving multiple vascular territories.

During the index hospitalisation, our patient presented with fever and altered mental status, with an MRI of the brain suggestive of septic emboli. She met the modified Duke criteria for infective endocarditis (1 major: echocardiogram positive for infective endocarditis, 4 minor: IVDU, fever, septic pulmonary infarcts, positive blood culture). Due to the suspicion of paradoxical origin of the cerebral emboli from TV endocarditis, a bubble study was performedand it demonstrated an early appearance of agitated saline bubbles in the left heart at rest. At that time, the presumed diagnosis was TV endocarditis with paradoxical cerebral embolisation secondary to right-to-left shunting across the PFO.

Treatment

On index presentation, the patient was started on broad-spectrum antibiotics for treatment of severe sepsis, including parenteral vancomycin with intermittent renal dosing to achieve therapeutic levels, cefepime 2 g every 8 hours and metronidazole 500 mg every 8 hours. Once cultures were obtained, antibiotics were de-escalated to include parenteral cefepime 2 g every 8 hours and oral ciprofloxacin 750 mg two times per day for treatment of S. marcescens native TV endocarditis.

Our multidisciplinary endocarditis team recommended percutaneous PFO closure to prevent further embolisation. An intracardiac echocardiogram confirmed an aneurysmal interatrial aneurysm with a PFO and right-to-left shunt (figure 6). Postprocedure, the patient was started on dual antiplatelet therapy with aspirin and clopidogrel. Addiction medicine was consulted while she was inpatient, and the patient was treated with oral buprenorphine/naloxone which she tolerated.

Figure 6

Intracardiac echocardiogram showing an aneurysmal interatrial septum and a PFO (yellow arrow) with right-to-left shunt.

Outcome and follow-up

The patient’s neurological status improved on antibiotic therapy. However, 3 weeks after percutaneous closure of PFO, while the patient was continuing inpatient treatment RISE, she developed acute onset of sharp left upper quadrant abdominal pain radiating to the back. Physical examination revealed tenderness to palpation in the left upper quadrant and splenomegaly. CT of the abdomen demonstrated band-like splenic hypodensities suggestive of infarctions (figure 7).

Figure 7

CT of the abdomen demonstrating wedge-shaped splenic hypodensity (red arrow).

A TEE was performed which demonstrated mobile vegetation on the posterior leaflet of the mitral valve, with perforation of the posterior leaflet with associated moderate-to-severe mitral regurgitation (figure 8).

Figure 8

Transesophageal echocardiogram demonstrating (A) vegetation of the posterior mitral valve leaflet, (B) with leaflet perforation and mitral regurgitation and (C) intact PFO closure device.

The interatrial septal closure device was without evidence of residual shunt, thrombosis or adjacent vegetation. Cardiothoracic surgery was consulted and recommended valve surgery with removal of the PFO closure device. The patient required 5-day washout period of clopidogrel. The patient then underwent sternotomy, mitral valve repair with resection of commissural leaflets, placement of a 28 mm physio two annuloplasty ring, TV replacement using a 29 mm epic porcine prosthesis, removal of Amplatzer PFO closure device and surgical closure of the PFO.

The patient tolerated the surgery well. Postsurgically, she was continued on intravenous meropenem 2 g every 8 hours for 1 week given that she had already completed >6 weeks of antibiotic therapy. She was discharged with oral sulfamethoxazole/trimethoprim 800–160 mg two times per day and follow-up lab monitoring 1 week postdischarge. On discharge, she was counselled on needle exchanges, safe injection practices, harm reduction and given an intranasal naloxone kit.

On outpatient follow-up 3 months after the initial diagnosis, she noted mild shortness of breath and lower extremity oedema, after which she was prescribed a diuretic. She was without infectious symptoms off antibiotic therapy and continued to follow in the addiction medicine and infectious diseases clinics.

Discussion

RSIE constitutes 5%–10% of endocarditis cases with a substantial proportion of episodes secondary to IVDU.6 Multiple studies have demonstrated a significant increase in the incidence of IVDU related endocarditis in the USA from 15% in 2010 to 29% in 2015.6 Greater than 85% of IVDU-related endocarditis is right sided and almost 90% involve the TV.7

In cases of TV endocarditis, the valve is burdened with vegetations with progressive valvular damage and regurgitation into the right atrium. Septic emboli to the pulmonary vasculature from these may cause pulmonary hypertension, which may further increase right atrial pressure. This increase in pressure can promote right-to-left shunting in patients who have intracardiac septal defects, such as PFO. Based on autopsy studies, PFOs have an incidence of 27.3%, with a declining incidence with increasing age.8 In most patients, PFO is a haemodynamically and clinically insignificant interatrial communication with bidirectional flow. However, approximately 40%–50% of patients with cryptogenic stroke are subsequently found to have a PFO.9

In cases of RSIE complicated by PFO, septic emboli may travel from the right heart through an intracardiac defect to the systemic vasculature.10 Paradoxical cerebral embolisation from right-sided endocarditis is an uncommon complication of a common disease that should be suspected in patients with a fever, altered mental status and signs of RSIE. Atrial septal aneurysms are commonly associated with a PFO and portend a high risk of recurrent stroke after an index PFO-associated stroke.11 Although the Risk of Paradoxical Embolisation (ROPE) score is used in patients with cryptogenic stroke to determine the probability of PFO causing the stroke, it does not factor in critical elements like bacteraemia and the presence of endocarditis.12 13

Generally, the presence of systemic emboli is a rare occurrence in RSIE and should raise suspicion for concomitant left-sided infective endocarditis, particularly given the relative insensitivity of TTE for the diagnosis of left-sided vegetations relative to TV lesions.14 Patient 2 developed splenic infarcts while on parenteral antibiotic therapy. However, a TTE obtained prior to and after the splenic infarcts did not visualise a mitral valve vegetation. However, TEE performed shortly after the splenic infarcts clearly demonstrated a mitral valve vegetation and leaflet perforation. In this case, it can be postulated that she had mitral valve endocarditis on admission that was undetected by TTE rather than paradoxical cerebral emboli. Consequently, placement of the PFO closure device may not have offered her a significant clinical benefit.

A meta-analysis of five randomised clinical trials in patient with cryptogenic cerebrovascular events not secondary to endocarditis and originating through a confirmed PFO found that percutaneous PFO closure was superior to medical therapy in preventing secondary stroke (2.0% vs 4.5%).15 Percutaneous PFO closure is particularly beneficial in patients with hypermobility or septal aneurysms who have higher risk of recurrent embolic events.16 17 However, there is little data regarding the role of percutaneous PFO closure in patients with active infective endocarditis. While there is the potential benefit of preventing future episodes of paradoxical emboli, this must be counter-balanced by the potential for infection of the PFO closure device. Surgical valve replacement and PFO closure for TV endocarditis complicated by paradoxical septic emboli is the preferred treatment given the dual benefit of allowing for removal of the infection and closure of the conduit to the systemic circulation.

Many patients with RSIE, such as case 1, may present as too critically ill to initially undergo valve surgery. In that case, percutaneous PFO closure prevented future embolic events and resolved the large right-left shunt present across the PFO which allowed the patient to be successfully weaned from mechanical ventilation, thereby significantly reducing her operative risk with a valve replacement. She was then able to successfully undergo open TV replacement and PFO closure later in her index hospitalisation with removal of the PFO closure device at that time. In this example, percutaneous PFO closure provided a temporary bridge to definitive valve surgery.

Our case series also demonstrates the limitations of TTE and the importance of excluding left-sided endocarditis prior to proceeding with percutaneous PFO closure in this specific cohort. Patient 2 could very well have mitral valve endocarditis that went undetected by TTE rather than paradoxical embolisation from RSIE, and she continued to have systemic emboli despite the presence of the PFO closure device and a prolonged course of parenteral antibiotic therapy. However, she had evidence of elevated right atrial pressures, an aneurysmal interatrial septum with a PFO and right-to-left shunt.

Systemic paradoxical embolisation is a very rare occurrence in RSIE and literature on management is lacking. In patients with RSIE and PFO who are too critically to undergo valve surgery percutaneous PFO closure may be used as a bridge therapy to reduce right-left shunting and further systemic embolisation allowing for delayed surgical management. However, it is prudent for providers to more definitively rule out left-sided endocarditis with TEE prior to pursuing this approach. Further studies are required to further evaluate the safety of placement of a prosthetic PFO closure device in the setting of active infective endocarditis.

Learning points

  • Patent foramen ovales (PFOs) are thought to be present in over 20% of the population.

  • Right-sided infective endocarditis (RSIE) is predominantly related to intravenous drug use and involves the tricuspid valve.

  • RSIE can lead to pulmonary septic emboli and very rarely paradoxical systemic emboli via intracardiac shunts.

  • Patients with known RSIE and subsequent paradoxical emboli and/or cerebrovascular insult should be evaluated for PFO by echocardiography.

Ethics statements

Patient consent for publication

Acknowledgments

The authors would like to acknowledge the contributions of Dr John Gurley with this manuscript.

References

Footnotes

  • Twitter @TahaAhmedMD

  • Contributors TTS: performed the literature review, drafted the manuscript and reviewed the manuscript. SAE: contributed to the case presentation and discussion, revised the manuscript critically for important intellectual content and gave final approval for the version published. MS: contributed to the case presentation and discussion and performed critical review and supervision. TA: designed the study, performed the literature review, drafted the manuscript and reviewed the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.