Imaging

Your patient has had an ischemic stroke, and so far you have found no obvious cause such as atrial fibrillation or carotid disease. Should you look for a patent foramen ovale (PFO)? And if you find it, what should you do?

See related commentary

This scenario continues to challenge primary care physicians and subspecialists and requires an understanding of the relationship between PFO and cryptogenic stroke, as well as familiarity with current data on the safety and effectiveness of the management options. PFO is known to be associated with cryptogenic stroke, but many questions remain, including:

• How can we tell if PFO is a culprit (“pathologic”) or an innocent bystander (“incidental”) in a patient who has had a cryptogenic stroke?
• Should stroke patients receive different medical therapy if they have a PFO? In particular, should they receive warfarin in addition to aspirin? And what about the novel oral anticoagulants?
• Which patients should undergo percutaneous closure of the PFO?
• Should we even be looking for PFO in stroke patients at this point, if we cannot say with certainty what we should do if we find it?

WHY IS THIS IMPORTANT?

Cerebrovascular disease is common and costly. The estimated yearly incidence of stroke in the United States is 795,000 events, at a cost of nearly $30 billion.¹ The incidence of stroke in Europe is more than 1 million annually.²

During the diagnostic evaluation of stroke or transient ischemic attack (TIA), PFO is occasionally discovered incidentally by echocardiography. The management decisions that follow often fall to the primary care physician, who must decipher the conflicting data currently available and explain the options to the patient.

Although reviews have been published on this subject,³ several newer key trials and data on risk stratification warrant consideration.

DEFINITIONS

PFO is the failure of the septum primum to fuse with the septum secundum, so that a communication remains between the atria (Figure 1). The diagnosis is commonly made by echocardiography, when agitated saline is injected into the venous system and bubbles can be seen in the left atrium within three to five cardiac cycles (see video).

Atrial septal aneurysm is loosely defined as a septal excursion or bulging of at least 10 to 15 mm into the left and right atria during the cardiac cycle (Figure 2). The combination of PFO and atrial septal aneurysm may be more of a risk factor for stroke than PFO alone (see discussion below).

Cryptogenic stroke. The diagnostic workup of stroke fails to elucidate a clear cause in up to 40% of cases, which are thus called cryptogenic.⁴ The workup varies, but typically includes a search for a cardioembolic source and for atherosclerotic disease. Embolic sources are evaluated for by electrocardiography, transthoracic echocardiography, and possibly imaging of the aortic arch. Evaluation for atherosclerotic disease of the intracranial and extracranial arteries includes magnetic resonance angiography or, if that is unavailable, computed tomographic angiography or carotid Doppler ultrasonography. If no source is found, long-term cardiac monitoring may be used to detect paroxysmal atrial fibrillation, which may be more common than previously thought.

PFO AND CRYPTOGENIC STROKE ARE COMMON

As noted, there are approximately 800,000 strokes every year in the United States. If 25% to 40% of them are cryptogenic (the true prevalence warrants more evaluation),^4,5 then 200,000 to 320,000 strokes are cryptogenic.

Autopsy studies indicate that 25% of the general population have a PFO, and if the prevalence is the same in people with cryptogenic stroke, that would equal 80,000 people with both cryptogenic stroke and PFO every year. However, the prevalence of PFO in patients with cryptogenic stroke appears to be significantly higher than in the general population.⁶ Although these numbers are crude estimates, they provide some insight into the prevalence of this clinical presentation.

HOW ARE CRYPTOGENIC STROKE AND PFO RELATED?

The exact relationship between PFO and cryptogenic stroke is unknown, although cases have been reported of thrombus in transit through a PFO, supporting paradoxical embolism as the plausible cause in stroke patients with PFO.^7–9

There is clear evidence that the two conditions are associated by more than chance. Homma and Sacco⁶ reported that, in several studies, 93 (46%) of 202 patients under age 55 with cryptogenic stroke had PFOs, compared with 29 (11%) of 271 controls (P < .05 in all studies).⁶

In their evaluation of 23 case-control studies, Alsheikh-Ali et al¹⁰ found that the summary odds ratio (OR) for PFO in cryptogenic stroke vs PFO in control patients was 2.9 (95% confidence interval [CI] 2.1–4), largely driven by an OR of 5.1 (3.3–7.8) in those under age 55. Through Bayesian probability theory, this correlated with only a 33% probability that PFO in a patient with cryptogenic stroke was an innocent bystander rather than the culprit.¹⁰

IS PFO A RISK FACTOR FOR STROKE?

One of the more puzzling aspects of the relationship of PFO to cryptogenic stroke is that despite a clear association, there is little evidence that the relationship is causal.

Di Tullio et al¹¹ followed 1,100 people who had no history of stroke and found that the risk of a first stroke in those with a PFO was not significantly higher than in those without a PFO, regardless of age, sex, or ethnic or racial group. At 80 months, the hazard ratio of stroke in people who had a PFO was 1.64 (95% CI 0.87–3.09).¹¹ The findings were similar at 11 years, with a hazard ratio of 1.10 (95% CI 0.64–1.91).¹²

A prospective study of 585 patients found a similar risk of stroke in those with and without a PFO, with a hazard ratio of 1.46 (95% CI 0.74–2.88; P = .28).¹³

These prospective trials suggest that although previous studies have found a higher prevalence of PFOs in patients with cryptogenic stroke than in patients without stroke, there appears to be very little if any increased risk from baseline for a first stroke or TIA.

The lack of statistical significance in these trials should be interpreted with some caution, as a small increased risk is difficult to show if the event rate is low (approximately 10% of patients had events over 11 years in the study by Di Tullio et al¹²).

HOW DO WE KNOW IF A PFO IS A CULPRIT OR BYSTANDER?

Unfortunately, this is largely unanswered, though experts have suggested that echocardiographic features of the PFO, radiographic characteristics of the stroke, and clinical features of the patient may provide useful information.

‘High-risk’ features on echocardiography

Certain features of PFO may portend a high risk of cerebrovascular events. Both right-to-left shunting at rest and septal hypermobility were found in one study¹⁴ to be more common in patients with a PFO who had a stroke or TIA than in patients with a PFO but no cerebrovascular events. Also, patients who had these features and had a stroke had a higher risk of recurrence than stroke patients without these features (12.5% vs 4.3%, P = .05).¹⁴

Septal hypermobility and shunting at rest are easily diagnosed by echocardiography, and detecting these “high-risk” features would be useful if they could identify patients who would benefit from special therapy, such as percutaneous closure of the PFO.

Unfortunately, when investigators looked at these features in subgroup analysis of the major randomized controlled trials of percutaneous closure vs medical therapy, the results were mixed.

CLOSURE 1 (the Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale)¹⁵ found percutaneous closure to be no better than medical therapy, regardless of shunt size or the presence of atrial septal aneurysm.

Similarly, the PC trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism)¹⁶ found no statistically significant benefit of closure in those with atrial septal aneurysm.

In contrast, the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)¹⁷ showed percutaneous closure to be beneficial in patients with atrial septal aneurysm or large shunt.

Radiographic characteristics of the stroke

Another area of interest in trying to identify culprit PFOs is the radiographic characteristics of the stroke.

In a study comparing patients with stroke related to atrial fibrillation vs patients with cryptogenic stroke and a known PFO, those in the latter group were more likely to have a single cortical infarction (34.2% vs 3.1%; P < .001) or multiple small scattered lesions (23.1% vs 5.9%; P < .01).¹⁸ Similarly, in a large database of patients with cryptogenic stroke and known PFO status, a superficially located stroke was associated with the presence of PFO (OR 1.54; P < .0001).¹⁹

Although these findings do not tell us with certainty that a patient’s PFO was the cause of his or her stroke, they provide guidance when dealing with the uncertainty of how to manage a patient with PFO. They may be useful in clinical practice, for example, when discussing treatment options with a young patient with cryptogenic stroke who has no risk factors and a superficial single infarct and who is found to have a PFO with a right-to-left shunting at rest.

Patient characteristics

Kent et al²⁰ developed a 10-point index (the RoPE score) in an attempt to assign a probability to whether a stroke was PFO-related. Points were assigned for patients who were younger, who had a cortical stroke on neuroimaging, and who did not have diabetes, hypertension, smoking, or prior stroke or TIA. Patients with cryptogenic stroke with a higher RoPE score were more likely to have a PFO and thus had a higher likelihood that the index event was related to PFO. Of note, the patients with the highest likelihood of PFO-related stroke were the least likely to have a recurrence (RoPE score of 9 to 10; PFO-attributable fraction 88%; estimated 2-year recurrence rate 2%; 95% CI 0%–4%), whereas those with a low RoPE score have more traditional risk factors for stroke and thus are more likely to have a recurrence (RoPE 0 to 3; estimated 2-year recurrence rate 20%; 95% CI 12%–28%).²⁰

Again, this sheds light on a difficulty faced by randomized controlled trials: the patients who may benefit from closure of a PFO may very well be those with the lowest recurrence rates without intervention.

The RoPE index was examined in an attempt to validate previously described morphologic criteria of “high-risk” PFO,²¹ though none of the previously described “high-risk” echocardiographic features (large physiologic size, hypermobile septum, shunt at rest) were more common in the group with presumed PFO-attributable stroke (RoPE score > 6). This underscores the difficulty of distinguishing pathologic PFO from incidental PFO.

KEY TREATMENT CONSIDERATIONS FOR SECONDARY PREVENTION

Given the complicated relationship between PFO and cryptogenic stroke, there has been much debate over management strategies. The three options are surgical closure, percutaneous closure with a device, and medical therapy. The goal of all three is to prevent the recurrence of stroke or TIA.

Surgical closure has largely been supplanted by percutaneous closure, but is still done in specific situations such as when a PFO is found incidentally on transesophageal echocardiography during surgery for another cardiac condition. The data on such cases²² tend to support the argument that asymptomatic PFOs in the general population have a relatively benign natural history.

Thus, the two key questions about management that warrant discussion are: is anticoagulation superior to antiplatelet therapy? And is percutaneous closure superior to medical management?

Anticoagulant vs antiplatelet therapy

Whether to treat with aspirin or with a vitamin K antagonist has been a subject of debate, although there is no strong evidence to suggest that anticoagulation is superior to antiplatelet therapy.

The concern that aspirin alone is insufficient in some patients stems from a study by Mas et al,²³ who followed 581 patients with cryptogenic stroke who had a PFO alone, a PFO with an atrial septal aneurysm, or neither. The rate of stroke recurrence at 4 years on aspirin therapy was 2.3% in those with a PFO alone, 15.2% in those with a PFO with an atrial septal aneurysm, and 4.2% in those with neither.

Many have concluded that aspirin therapy does not sufficiently protect those with both PFO and atrial septal aneurysm, given the high recurrence rate in this group. This might lead to the suggestion that anticoagulation could be of benefit in these patients.

However, the Patent Foramen Ovale in Cryptogenic Stroke Study (PiCSS)²⁴ and the Spanish Multicenter Study Into Right-to-Left Shunt in Cryptogenic Stroke (CODICIA)²⁵ found similar recurrence rates in patients with PFO and atrial septal aneurysm compared with those with only PFO. In these two studies, recurrence rates were similar regardless of whether patients were taking aspirin or warfarin.

In a study that followed 140 consecutive patients with both stroke and PFO, those treated in a nonrandomized fashion with antiplatelet agents had no difference in the recurrence rate compared with those treated with anticoagulation.²⁶

Although uncertainty remains because no head-to-head randomized controlled trial has been done, some patients with PFO have other indications for anticoagulation, most commonly atrial fibrillation and venous thromboembolic disease.

There are currently no data on the use of novel oral anticoagulants in this setting.

Is percutaneous closure better than medical therapy?

When cryptogenic stroke is treated with antiplatelet therapy or anticoagulation therapy, the recurrence rate is the same whether or not the patient has a PFO.^23–25 The belief that medical therapy offers adequate secondary protection is supported by a meta-analysis of 15 studies that found no increased risk of recurrent ischemic events in those with a PFO on medical therapy (antiplatelet or anticoagulant) vs those without a PFO (relative risk 1.1, 95% CI 0.8–1.5).²⁷

Despite the conflicting evidence, percutaneous closure of PFO is still performed, mostly on a case-by-case basis. This has been supported by an apparent benefit in observational studies.

A systematic review of 52 single-arm studies and 7 comparative nonrandomized studies of patients with PFO and cryptogenic stroke found the rate of recurrent stroke to be 0.36 per 100 person-years with percutaneous closure vs 2.53 per 100 person-years with medical therapy.²⁸ However, three long-awaited randomized controlled trials (CLOSURE 1, the PC trial, and RESPECT) failed to show a significant reduction in primary end points with percutaneous closure vs standard medical therapy.^15–17

These trials had several limitations: event rates were low, medical therapy varied by provider, and enrollment was slowed by out-of-study percutaneous closure in patients perceived to be at high risk (though, as discussed above, high risk is difficult to determine).

Intention-to-treat analysis in RESPECT showed no benefit from percutaneous closure, but a favorable outcome was noted with closure in as-treated analysis (HR 0.27; 95% CI 0.1–0.75; P = .007) and per-protocol analysis (HR 0.37; 95% CI 0.14–0.96; P = .03) of the 980 randomized patients.¹⁷ This suggests some benefit, as does the CLOSURE 1 trial, in which 3 of the 12 recurrent strokes in the percutaneous closure group occurred before the device was implanted.¹⁵

The low event rates in these studies prompted several meta-analyses.^29–35 However, only two suggested a benefit of percutaneous closure over medical therapy. In one recent meta-analysis,²⁹ observational study data suggested benefit from percutaneous closure, whereas three randomized controlled trials failed to show a statistically significant benefit.

The conclusions of the meta-analyses must be interpreted with caution because of inherent differences in the randomized controlled trials, including the closure device used, inclusion criteria, study end points, and variations in medical therapy.

Devices differ

A meta-analysis by Khan et al³⁵ showed a benefit of percutaneous closure when evaluating only studies using the Amplatzer PFO occluder (AGA Medical), as in RESPECT and the PC trial.³⁵ As data accumulate, it is important to remember that there are differences between devices. Ongoing trials continue to investigate the Amplatzer device (NCT01550588) and the GORE HELEX Septal Occluder/GORE Septal Occluder (Gore Medical) (NCT00738894).

In another meta-analysis, Pineda et al³¹ found a benefit with closure in the as-treated analysis using data from all three randomized controlled trials (OR 0.62; 95% CI 0.41–0.94; P = .02).³¹ Although paradoxical embolism through the PFO as the mechanism of stroke has been questioned, this finding suggests that actual closure of a PFO may protect against further events, presumably by preventing paradoxical embolism.

Different closure devices have different side effects. The incidence of atrial fibrillation with the CardioSEAL STARFlex device (NMT Medical) is higher than with medical therapy (used in the CLOSURE trial¹⁵), whereas this risk was not statistically significantly increased in the PC trial¹⁶ and RESPECT,¹⁷ which used the Amplatzer device.

Benefit in those with atrial septal aneurysm?

Percutaneous closure has been shown to be safe and effective in patients with PFO and atrial septal aneurysm.³⁶ There was some benefit of closure over medical therapy in a subgroup analysis from RESPECT in these patients, with a HR of 0.19 (95% CI 0.04–0.87, P = .02),¹⁷ although this was not seen in either CLOSURE 1 or the PC trial.

WHAT ARE THE RISKS OF PERCUTANEOUS CLOSURE?

Minor complications of percutaneous closure include bleeding, atrial arrhythmias, device embolization and fracture, and complications related to vascular access. Major complications include hemorrhage requiring transfusion, need for surgery, cardiac tamponade, pulmonary embolism, and death.

The cumulative rate of major complications in 10 observational studies was 1.5%, and the rate of minor complications was 7.9%.³⁷ The RESPECT investigators reported a serious adverse event in 4.2% of patients (ranging in severity from chest tightness to cardiac tamponade).¹⁷

Another possible consequence of percutaneous closure is the need for chronic anticoagulation because of the increased risk of postprocedural atrial fibrillation seen in meta-analyses,^29,31,32 though this may be device-specific.³²

Percutaneous closure was considered successful—ie, to have nearly or completely eliminated shunting of blood through the defect—at 6 months of follow-up in 95.9% of patients in the PC trial, 93.5% in RESPECT, and 86.1% in CLOSURE 1.^15–17

WHAT SHOULD WE BE DOING IN DAILY PRACTICE?

Give aspirin. Aspirin is effective in secondary stroke prevention, and data suggest that patients with PFO and cryptogenic stroke who receive aspirin therapy alone have a similar risk of recurrent events as patients without PFO.

Give warfarin if indicated. Evidence is insufficient to recommend vitamin K antagonist therapy in all patients with PFO and cryptogenic stroke. However, coexisting conditions that warrant anticoagulation must be taken into account.

Individualize. Given the lack of evidence to definitively guide management of patients with cryptogenic stroke and PFO, we need to individualize our approach, taking into account patient preferences, bleeding risk, ability to tolerate procedures, and the likelihood that the PFO is at fault.

No definitive answer on PFO closure. The most recent data suggest that closure may be beneficial, but key questions remain: Who will benefit? And what is the ideal medical therapy? Optimal management will only be established by the continued enrollment of appropriate patients into ongoing clinical trials.

Another question is whether it is possible to perform a randomized controlled trial with enough patients to definitively prove whether percutaneous closure is superior to medical therapy. Recent experience would suggest not.

In the meantime, we have some guidance from the American Heart Association and the American Stroke Association Council on Stroke³⁸ based on the limited evidence available.

Consider patient preference. The physician should present the options to the patient in a balanced manner to enable him or her to make an informed decision. Patients can also be encouraged to seek additional information at websites such as www.stroke.org and www.nlm.nih.gov.

Referral to an interventional cardiologist for evaluation for closure is reasonable in patients with recurrent stroke, medication failure, complicated atrial septal anatomy such as PFO with aneurysm or large shunt, concurrent thromboembolic disease, or contraindications to anticoagulation.

MORE WORK NEEDED

Areas for further study include further identifying the characteristics of patients with PFO and cryptogenic stroke that might indicate who would benefit from percutaneous closure, elucidating the mechanism of stroke in these patients, and determining whether routine stroke evaluation should include echocardiography with a bubble study if there is no change in management based on the finding of PFO.³⁹

Your patient has had an ischemic stroke, and so far you have found no obvious cause such as atrial fibrillation or carotid disease. Should you look for a patent foramen ovale (PFO)? And if you find it, what should you do?

See related commentary

This scenario continues to challenge primary care physicians and subspecialists and requires an understanding of the relationship between PFO and cryptogenic stroke, as well as familiarity with current data on the safety and effectiveness of the management options. PFO is known to be associated with cryptogenic stroke, but many questions remain, including:

• How can we tell if PFO is a culprit (“pathologic”) or an innocent bystander (“incidental”) in a patient who has had a cryptogenic stroke?
• Should stroke patients receive different medical therapy if they have a PFO? In particular, should they receive warfarin in addition to aspirin? And what about the novel oral anticoagulants?
• Which patients should undergo percutaneous closure of the PFO?
• Should we even be looking for PFO in stroke patients at this point, if we cannot say with certainty what we should do if we find it?

WHY IS THIS IMPORTANT?

Cerebrovascular disease is common and costly. The estimated yearly incidence of stroke in the United States is 795,000 events, at a cost of nearly $30 billion.¹ The incidence of stroke in Europe is more than 1 million annually.²

During the diagnostic evaluation of stroke or transient ischemic attack (TIA), PFO is occasionally discovered incidentally by echocardiography. The management decisions that follow often fall to the primary care physician, who must decipher the conflicting data currently available and explain the options to the patient.

Although reviews have been published on this subject,³ several newer key trials and data on risk stratification warrant consideration.

DEFINITIONS

PFO is the failure of the septum primum to fuse with the septum secundum, so that a communication remains between the atria (Figure 1). The diagnosis is commonly made by echocardiography, when agitated saline is injected into the venous system and bubbles can be seen in the left atrium within three to five cardiac cycles (see video).

Atrial septal aneurysm is loosely defined as a septal excursion or bulging of at least 10 to 15 mm into the left and right atria during the cardiac cycle (Figure 2). The combination of PFO and atrial septal aneurysm may be more of a risk factor for stroke than PFO alone (see discussion below).

Cryptogenic stroke. The diagnostic workup of stroke fails to elucidate a clear cause in up to 40% of cases, which are thus called cryptogenic.⁴ The workup varies, but typically includes a search for a cardioembolic source and for atherosclerotic disease. Embolic sources are evaluated for by electrocardiography, transthoracic echocardiography, and possibly imaging of the aortic arch. Evaluation for atherosclerotic disease of the intracranial and extracranial arteries includes magnetic resonance angiography or, if that is unavailable, computed tomographic angiography or carotid Doppler ultrasonography. If no source is found, long-term cardiac monitoring may be used to detect paroxysmal atrial fibrillation, which may be more common than previously thought.

PFO AND CRYPTOGENIC STROKE ARE COMMON

As noted, there are approximately 800,000 strokes every year in the United States. If 25% to 40% of them are cryptogenic (the true prevalence warrants more evaluation),^4,5 then 200,000 to 320,000 strokes are cryptogenic.

Autopsy studies indicate that 25% of the general population have a PFO, and if the prevalence is the same in people with cryptogenic stroke, that would equal 80,000 people with both cryptogenic stroke and PFO every year. However, the prevalence of PFO in patients with cryptogenic stroke appears to be significantly higher than in the general population.⁶ Although these numbers are crude estimates, they provide some insight into the prevalence of this clinical presentation.

HOW ARE CRYPTOGENIC STROKE AND PFO RELATED?

The exact relationship between PFO and cryptogenic stroke is unknown, although cases have been reported of thrombus in transit through a PFO, supporting paradoxical embolism as the plausible cause in stroke patients with PFO.^7–9

There is clear evidence that the two conditions are associated by more than chance. Homma and Sacco⁶ reported that, in several studies, 93 (46%) of 202 patients under age 55 with cryptogenic stroke had PFOs, compared with 29 (11%) of 271 controls (P < .05 in all studies).⁶

In their evaluation of 23 case-control studies, Alsheikh-Ali et al¹⁰ found that the summary odds ratio (OR) for PFO in cryptogenic stroke vs PFO in control patients was 2.9 (95% confidence interval [CI] 2.1–4), largely driven by an OR of 5.1 (3.3–7.8) in those under age 55. Through Bayesian probability theory, this correlated with only a 33% probability that PFO in a patient with cryptogenic stroke was an innocent bystander rather than the culprit.¹⁰

IS PFO A RISK FACTOR FOR STROKE?

One of the more puzzling aspects of the relationship of PFO to cryptogenic stroke is that despite a clear association, there is little evidence that the relationship is causal.

Di Tullio et al¹¹ followed 1,100 people who had no history of stroke and found that the risk of a first stroke in those with a PFO was not significantly higher than in those without a PFO, regardless of age, sex, or ethnic or racial group. At 80 months, the hazard ratio of stroke in people who had a PFO was 1.64 (95% CI 0.87–3.09).¹¹ The findings were similar at 11 years, with a hazard ratio of 1.10 (95% CI 0.64–1.91).¹²

A prospective study of 585 patients found a similar risk of stroke in those with and without a PFO, with a hazard ratio of 1.46 (95% CI 0.74–2.88; P = .28).¹³

These prospective trials suggest that although previous studies have found a higher prevalence of PFOs in patients with cryptogenic stroke than in patients without stroke, there appears to be very little if any increased risk from baseline for a first stroke or TIA.

The lack of statistical significance in these trials should be interpreted with some caution, as a small increased risk is difficult to show if the event rate is low (approximately 10% of patients had events over 11 years in the study by Di Tullio et al¹²).

HOW DO WE KNOW IF A PFO IS A CULPRIT OR BYSTANDER?

Unfortunately, this is largely unanswered, though experts have suggested that echocardiographic features of the PFO, radiographic characteristics of the stroke, and clinical features of the patient may provide useful information.

‘High-risk’ features on echocardiography

Certain features of PFO may portend a high risk of cerebrovascular events. Both right-to-left shunting at rest and septal hypermobility were found in one study¹⁴ to be more common in patients with a PFO who had a stroke or TIA than in patients with a PFO but no cerebrovascular events. Also, patients who had these features and had a stroke had a higher risk of recurrence than stroke patients without these features (12.5% vs 4.3%, P = .05).¹⁴

Septal hypermobility and shunting at rest are easily diagnosed by echocardiography, and detecting these “high-risk” features would be useful if they could identify patients who would benefit from special therapy, such as percutaneous closure of the PFO.

Unfortunately, when investigators looked at these features in subgroup analysis of the major randomized controlled trials of percutaneous closure vs medical therapy, the results were mixed.

CLOSURE 1 (the Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale)¹⁵ found percutaneous closure to be no better than medical therapy, regardless of shunt size or the presence of atrial septal aneurysm.

Similarly, the PC trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism)¹⁶ found no statistically significant benefit of closure in those with atrial septal aneurysm.

In contrast, the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)¹⁷ showed percutaneous closure to be beneficial in patients with atrial septal aneurysm or large shunt.

Radiographic characteristics of the stroke

Another area of interest in trying to identify culprit PFOs is the radiographic characteristics of the stroke.

In a study comparing patients with stroke related to atrial fibrillation vs patients with cryptogenic stroke and a known PFO, those in the latter group were more likely to have a single cortical infarction (34.2% vs 3.1%; P < .001) or multiple small scattered lesions (23.1% vs 5.9%; P < .01).¹⁸ Similarly, in a large database of patients with cryptogenic stroke and known PFO status, a superficially located stroke was associated with the presence of PFO (OR 1.54; P < .0001).¹⁹

Although these findings do not tell us with certainty that a patient’s PFO was the cause of his or her stroke, they provide guidance when dealing with the uncertainty of how to manage a patient with PFO. They may be useful in clinical practice, for example, when discussing treatment options with a young patient with cryptogenic stroke who has no risk factors and a superficial single infarct and who is found to have a PFO with a right-to-left shunting at rest.

Patient characteristics

Kent et al²⁰ developed a 10-point index (the RoPE score) in an attempt to assign a probability to whether a stroke was PFO-related. Points were assigned for patients who were younger, who had a cortical stroke on neuroimaging, and who did not have diabetes, hypertension, smoking, or prior stroke or TIA. Patients with cryptogenic stroke with a higher RoPE score were more likely to have a PFO and thus had a higher likelihood that the index event was related to PFO. Of note, the patients with the highest likelihood of PFO-related stroke were the least likely to have a recurrence (RoPE score of 9 to 10; PFO-attributable fraction 88%; estimated 2-year recurrence rate 2%; 95% CI 0%–4%), whereas those with a low RoPE score have more traditional risk factors for stroke and thus are more likely to have a recurrence (RoPE 0 to 3; estimated 2-year recurrence rate 20%; 95% CI 12%–28%).²⁰

Again, this sheds light on a difficulty faced by randomized controlled trials: the patients who may benefit from closure of a PFO may very well be those with the lowest recurrence rates without intervention.

The RoPE index was examined in an attempt to validate previously described morphologic criteria of “high-risk” PFO,²¹ though none of the previously described “high-risk” echocardiographic features (large physiologic size, hypermobile septum, shunt at rest) were more common in the group with presumed PFO-attributable stroke (RoPE score > 6). This underscores the difficulty of distinguishing pathologic PFO from incidental PFO.

KEY TREATMENT CONSIDERATIONS FOR SECONDARY PREVENTION

Given the complicated relationship between PFO and cryptogenic stroke, there has been much debate over management strategies. The three options are surgical closure, percutaneous closure with a device, and medical therapy. The goal of all three is to prevent the recurrence of stroke or TIA.

Surgical closure has largely been supplanted by percutaneous closure, but is still done in specific situations such as when a PFO is found incidentally on transesophageal echocardiography during surgery for another cardiac condition. The data on such cases²² tend to support the argument that asymptomatic PFOs in the general population have a relatively benign natural history.

Thus, the two key questions about management that warrant discussion are: is anticoagulation superior to antiplatelet therapy? And is percutaneous closure superior to medical management?

Anticoagulant vs antiplatelet therapy

Whether to treat with aspirin or with a vitamin K antagonist has been a subject of debate, although there is no strong evidence to suggest that anticoagulation is superior to antiplatelet therapy.

The concern that aspirin alone is insufficient in some patients stems from a study by Mas et al,²³ who followed 581 patients with cryptogenic stroke who had a PFO alone, a PFO with an atrial septal aneurysm, or neither. The rate of stroke recurrence at 4 years on aspirin therapy was 2.3% in those with a PFO alone, 15.2% in those with a PFO with an atrial septal aneurysm, and 4.2% in those with neither.

Many have concluded that aspirin therapy does not sufficiently protect those with both PFO and atrial septal aneurysm, given the high recurrence rate in this group. This might lead to the suggestion that anticoagulation could be of benefit in these patients.

However, the Patent Foramen Ovale in Cryptogenic Stroke Study (PiCSS)²⁴ and the Spanish Multicenter Study Into Right-to-Left Shunt in Cryptogenic Stroke (CODICIA)²⁵ found similar recurrence rates in patients with PFO and atrial septal aneurysm compared with those with only PFO. In these two studies, recurrence rates were similar regardless of whether patients were taking aspirin or warfarin.

In a study that followed 140 consecutive patients with both stroke and PFO, those treated in a nonrandomized fashion with antiplatelet agents had no difference in the recurrence rate compared with those treated with anticoagulation.²⁶

Although uncertainty remains because no head-to-head randomized controlled trial has been done, some patients with PFO have other indications for anticoagulation, most commonly atrial fibrillation and venous thromboembolic disease.

There are currently no data on the use of novel oral anticoagulants in this setting.

Is percutaneous closure better than medical therapy?

When cryptogenic stroke is treated with antiplatelet therapy or anticoagulation therapy, the recurrence rate is the same whether or not the patient has a PFO.^23–25 The belief that medical therapy offers adequate secondary protection is supported by a meta-analysis of 15 studies that found no increased risk of recurrent ischemic events in those with a PFO on medical therapy (antiplatelet or anticoagulant) vs those without a PFO (relative risk 1.1, 95% CI 0.8–1.5).²⁷

Despite the conflicting evidence, percutaneous closure of PFO is still performed, mostly on a case-by-case basis. This has been supported by an apparent benefit in observational studies.

A systematic review of 52 single-arm studies and 7 comparative nonrandomized studies of patients with PFO and cryptogenic stroke found the rate of recurrent stroke to be 0.36 per 100 person-years with percutaneous closure vs 2.53 per 100 person-years with medical therapy.²⁸ However, three long-awaited randomized controlled trials (CLOSURE 1, the PC trial, and RESPECT) failed to show a significant reduction in primary end points with percutaneous closure vs standard medical therapy.^15–17

These trials had several limitations: event rates were low, medical therapy varied by provider, and enrollment was slowed by out-of-study percutaneous closure in patients perceived to be at high risk (though, as discussed above, high risk is difficult to determine).

Intention-to-treat analysis in RESPECT showed no benefit from percutaneous closure, but a favorable outcome was noted with closure in as-treated analysis (HR 0.27; 95% CI 0.1–0.75; P = .007) and per-protocol analysis (HR 0.37; 95% CI 0.14–0.96; P = .03) of the 980 randomized patients.¹⁷ This suggests some benefit, as does the CLOSURE 1 trial, in which 3 of the 12 recurrent strokes in the percutaneous closure group occurred before the device was implanted.¹⁵

The low event rates in these studies prompted several meta-analyses.^29–35 However, only two suggested a benefit of percutaneous closure over medical therapy. In one recent meta-analysis,²⁹ observational study data suggested benefit from percutaneous closure, whereas three randomized controlled trials failed to show a statistically significant benefit.

The conclusions of the meta-analyses must be interpreted with caution because of inherent differences in the randomized controlled trials, including the closure device used, inclusion criteria, study end points, and variations in medical therapy.

Devices differ

A meta-analysis by Khan et al³⁵ showed a benefit of percutaneous closure when evaluating only studies using the Amplatzer PFO occluder (AGA Medical), as in RESPECT and the PC trial.³⁵ As data accumulate, it is important to remember that there are differences between devices. Ongoing trials continue to investigate the Amplatzer device (NCT01550588) and the GORE HELEX Septal Occluder/GORE Septal Occluder (Gore Medical) (NCT00738894).

In another meta-analysis, Pineda et al³¹ found a benefit with closure in the as-treated analysis using data from all three randomized controlled trials (OR 0.62; 95% CI 0.41–0.94; P = .02).³¹ Although paradoxical embolism through the PFO as the mechanism of stroke has been questioned, this finding suggests that actual closure of a PFO may protect against further events, presumably by preventing paradoxical embolism.

Different closure devices have different side effects. The incidence of atrial fibrillation with the CardioSEAL STARFlex device (NMT Medical) is higher than with medical therapy (used in the CLOSURE trial¹⁵), whereas this risk was not statistically significantly increased in the PC trial¹⁶ and RESPECT,¹⁷ which used the Amplatzer device.

Benefit in those with atrial septal aneurysm?

Percutaneous closure has been shown to be safe and effective in patients with PFO and atrial septal aneurysm.³⁶ There was some benefit of closure over medical therapy in a subgroup analysis from RESPECT in these patients, with a HR of 0.19 (95% CI 0.04–0.87, P = .02),¹⁷ although this was not seen in either CLOSURE 1 or the PC trial.

WHAT ARE THE RISKS OF PERCUTANEOUS CLOSURE?

Minor complications of percutaneous closure include bleeding, atrial arrhythmias, device embolization and fracture, and complications related to vascular access. Major complications include hemorrhage requiring transfusion, need for surgery, cardiac tamponade, pulmonary embolism, and death.

The cumulative rate of major complications in 10 observational studies was 1.5%, and the rate of minor complications was 7.9%.³⁷ The RESPECT investigators reported a serious adverse event in 4.2% of patients (ranging in severity from chest tightness to cardiac tamponade).¹⁷

Another possible consequence of percutaneous closure is the need for chronic anticoagulation because of the increased risk of postprocedural atrial fibrillation seen in meta-analyses,^29,31,32 though this may be device-specific.³²

Percutaneous closure was considered successful—ie, to have nearly or completely eliminated shunting of blood through the defect—at 6 months of follow-up in 95.9% of patients in the PC trial, 93.5% in RESPECT, and 86.1% in CLOSURE 1.^15–17

WHAT SHOULD WE BE DOING IN DAILY PRACTICE?

Give aspirin. Aspirin is effective in secondary stroke prevention, and data suggest that patients with PFO and cryptogenic stroke who receive aspirin therapy alone have a similar risk of recurrent events as patients without PFO.

Give warfarin if indicated. Evidence is insufficient to recommend vitamin K antagonist therapy in all patients with PFO and cryptogenic stroke. However, coexisting conditions that warrant anticoagulation must be taken into account.

Individualize. Given the lack of evidence to definitively guide management of patients with cryptogenic stroke and PFO, we need to individualize our approach, taking into account patient preferences, bleeding risk, ability to tolerate procedures, and the likelihood that the PFO is at fault.

No definitive answer on PFO closure. The most recent data suggest that closure may be beneficial, but key questions remain: Who will benefit? And what is the ideal medical therapy? Optimal management will only be established by the continued enrollment of appropriate patients into ongoing clinical trials.

Another question is whether it is possible to perform a randomized controlled trial with enough patients to definitively prove whether percutaneous closure is superior to medical therapy. Recent experience would suggest not.

In the meantime, we have some guidance from the American Heart Association and the American Stroke Association Council on Stroke³⁸ based on the limited evidence available.

Consider patient preference. The physician should present the options to the patient in a balanced manner to enable him or her to make an informed decision. Patients can also be encouraged to seek additional information at websites such as www.stroke.org and www.nlm.nih.gov.

Referral to an interventional cardiologist for evaluation for closure is reasonable in patients with recurrent stroke, medication failure, complicated atrial septal anatomy such as PFO with aneurysm or large shunt, concurrent thromboembolic disease, or contraindications to anticoagulation.

MORE WORK NEEDED

Areas for further study include further identifying the characteristics of patients with PFO and cryptogenic stroke that might indicate who would benefit from percutaneous closure, elucidating the mechanism of stroke in these patients, and determining whether routine stroke evaluation should include echocardiography with a bubble study if there is no change in management based on the finding of PFO.³⁹

Your patient has had an ischemic stroke, and so far you have found no obvious cause such as atrial fibrillation or carotid disease. Should you look for a patent foramen ovale (PFO)? And if you find it, what should you do?

See related commentary

This scenario continues to challenge primary care physicians and subspecialists and requires an understanding of the relationship between PFO and cryptogenic stroke, as well as familiarity with current data on the safety and effectiveness of the management options. PFO is known to be associated with cryptogenic stroke, but many questions remain, including:

• How can we tell if PFO is a culprit (“pathologic”) or an innocent bystander (“incidental”) in a patient who has had a cryptogenic stroke?
• Should stroke patients receive different medical therapy if they have a PFO? In particular, should they receive warfarin in addition to aspirin? And what about the novel oral anticoagulants?
• Which patients should undergo percutaneous closure of the PFO?
• Should we even be looking for PFO in stroke patients at this point, if we cannot say with certainty what we should do if we find it?

WHY IS THIS IMPORTANT?

Cerebrovascular disease is common and costly. The estimated yearly incidence of stroke in the United States is 795,000 events, at a cost of nearly $30 billion.¹ The incidence of stroke in Europe is more than 1 million annually.²

During the diagnostic evaluation of stroke or transient ischemic attack (TIA), PFO is occasionally discovered incidentally by echocardiography. The management decisions that follow often fall to the primary care physician, who must decipher the conflicting data currently available and explain the options to the patient.

Although reviews have been published on this subject,³ several newer key trials and data on risk stratification warrant consideration.

DEFINITIONS

PFO is the failure of the septum primum to fuse with the septum secundum, so that a communication remains between the atria (Figure 1). The diagnosis is commonly made by echocardiography, when agitated saline is injected into the venous system and bubbles can be seen in the left atrium within three to five cardiac cycles (see video).

Atrial septal aneurysm is loosely defined as a septal excursion or bulging of at least 10 to 15 mm into the left and right atria during the cardiac cycle (Figure 2). The combination of PFO and atrial septal aneurysm may be more of a risk factor for stroke than PFO alone (see discussion below).

Cryptogenic stroke. The diagnostic workup of stroke fails to elucidate a clear cause in up to 40% of cases, which are thus called cryptogenic.⁴ The workup varies, but typically includes a search for a cardioembolic source and for atherosclerotic disease. Embolic sources are evaluated for by electrocardiography, transthoracic echocardiography, and possibly imaging of the aortic arch. Evaluation for atherosclerotic disease of the intracranial and extracranial arteries includes magnetic resonance angiography or, if that is unavailable, computed tomographic angiography or carotid Doppler ultrasonography. If no source is found, long-term cardiac monitoring may be used to detect paroxysmal atrial fibrillation, which may be more common than previously thought.

PFO AND CRYPTOGENIC STROKE ARE COMMON

As noted, there are approximately 800,000 strokes every year in the United States. If 25% to 40% of them are cryptogenic (the true prevalence warrants more evaluation),^4,5 then 200,000 to 320,000 strokes are cryptogenic.

Autopsy studies indicate that 25% of the general population have a PFO, and if the prevalence is the same in people with cryptogenic stroke, that would equal 80,000 people with both cryptogenic stroke and PFO every year. However, the prevalence of PFO in patients with cryptogenic stroke appears to be significantly higher than in the general population.⁶ Although these numbers are crude estimates, they provide some insight into the prevalence of this clinical presentation.

HOW ARE CRYPTOGENIC STROKE AND PFO RELATED?

The exact relationship between PFO and cryptogenic stroke is unknown, although cases have been reported of thrombus in transit through a PFO, supporting paradoxical embolism as the plausible cause in stroke patients with PFO.^7–9

There is clear evidence that the two conditions are associated by more than chance. Homma and Sacco⁶ reported that, in several studies, 93 (46%) of 202 patients under age 55 with cryptogenic stroke had PFOs, compared with 29 (11%) of 271 controls (P < .05 in all studies).⁶

In their evaluation of 23 case-control studies, Alsheikh-Ali et al¹⁰ found that the summary odds ratio (OR) for PFO in cryptogenic stroke vs PFO in control patients was 2.9 (95% confidence interval [CI] 2.1–4), largely driven by an OR of 5.1 (3.3–7.8) in those under age 55. Through Bayesian probability theory, this correlated with only a 33% probability that PFO in a patient with cryptogenic stroke was an innocent bystander rather than the culprit.¹⁰

IS PFO A RISK FACTOR FOR STROKE?

One of the more puzzling aspects of the relationship of PFO to cryptogenic stroke is that despite a clear association, there is little evidence that the relationship is causal.

Di Tullio et al¹¹ followed 1,100 people who had no history of stroke and found that the risk of a first stroke in those with a PFO was not significantly higher than in those without a PFO, regardless of age, sex, or ethnic or racial group. At 80 months, the hazard ratio of stroke in people who had a PFO was 1.64 (95% CI 0.87–3.09).¹¹ The findings were similar at 11 years, with a hazard ratio of 1.10 (95% CI 0.64–1.91).¹²

A prospective study of 585 patients found a similar risk of stroke in those with and without a PFO, with a hazard ratio of 1.46 (95% CI 0.74–2.88; P = .28).¹³

These prospective trials suggest that although previous studies have found a higher prevalence of PFOs in patients with cryptogenic stroke than in patients without stroke, there appears to be very little if any increased risk from baseline for a first stroke or TIA.

The lack of statistical significance in these trials should be interpreted with some caution, as a small increased risk is difficult to show if the event rate is low (approximately 10% of patients had events over 11 years in the study by Di Tullio et al¹²).

HOW DO WE KNOW IF A PFO IS A CULPRIT OR BYSTANDER?

Unfortunately, this is largely unanswered, though experts have suggested that echocardiographic features of the PFO, radiographic characteristics of the stroke, and clinical features of the patient may provide useful information.

‘High-risk’ features on echocardiography

Certain features of PFO may portend a high risk of cerebrovascular events. Both right-to-left shunting at rest and septal hypermobility were found in one study¹⁴ to be more common in patients with a PFO who had a stroke or TIA than in patients with a PFO but no cerebrovascular events. Also, patients who had these features and had a stroke had a higher risk of recurrence than stroke patients without these features (12.5% vs 4.3%, P = .05).¹⁴

Septal hypermobility and shunting at rest are easily diagnosed by echocardiography, and detecting these “high-risk” features would be useful if they could identify patients who would benefit from special therapy, such as percutaneous closure of the PFO.

Unfortunately, when investigators looked at these features in subgroup analysis of the major randomized controlled trials of percutaneous closure vs medical therapy, the results were mixed.

CLOSURE 1 (the Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale)¹⁵ found percutaneous closure to be no better than medical therapy, regardless of shunt size or the presence of atrial septal aneurysm.

Similarly, the PC trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism)¹⁶ found no statistically significant benefit of closure in those with atrial septal aneurysm.

In contrast, the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment)¹⁷ showed percutaneous closure to be beneficial in patients with atrial septal aneurysm or large shunt.

Radiographic characteristics of the stroke

Another area of interest in trying to identify culprit PFOs is the radiographic characteristics of the stroke.

In a study comparing patients with stroke related to atrial fibrillation vs patients with cryptogenic stroke and a known PFO, those in the latter group were more likely to have a single cortical infarction (34.2% vs 3.1%; P < .001) or multiple small scattered lesions (23.1% vs 5.9%; P < .01).¹⁸ Similarly, in a large database of patients with cryptogenic stroke and known PFO status, a superficially located stroke was associated with the presence of PFO (OR 1.54; P < .0001).¹⁹

Although these findings do not tell us with certainty that a patient’s PFO was the cause of his or her stroke, they provide guidance when dealing with the uncertainty of how to manage a patient with PFO. They may be useful in clinical practice, for example, when discussing treatment options with a young patient with cryptogenic stroke who has no risk factors and a superficial single infarct and who is found to have a PFO with a right-to-left shunting at rest.

Patient characteristics

Kent et al²⁰ developed a 10-point index (the RoPE score) in an attempt to assign a probability to whether a stroke was PFO-related. Points were assigned for patients who were younger, who had a cortical stroke on neuroimaging, and who did not have diabetes, hypertension, smoking, or prior stroke or TIA. Patients with cryptogenic stroke with a higher RoPE score were more likely to have a PFO and thus had a higher likelihood that the index event was related to PFO. Of note, the patients with the highest likelihood of PFO-related stroke were the least likely to have a recurrence (RoPE score of 9 to 10; PFO-attributable fraction 88%; estimated 2-year recurrence rate 2%; 95% CI 0%–4%), whereas those with a low RoPE score have more traditional risk factors for stroke and thus are more likely to have a recurrence (RoPE 0 to 3; estimated 2-year recurrence rate 20%; 95% CI 12%–28%).²⁰

Again, this sheds light on a difficulty faced by randomized controlled trials: the patients who may benefit from closure of a PFO may very well be those with the lowest recurrence rates without intervention.

The RoPE index was examined in an attempt to validate previously described morphologic criteria of “high-risk” PFO,²¹ though none of the previously described “high-risk” echocardiographic features (large physiologic size, hypermobile septum, shunt at rest) were more common in the group with presumed PFO-attributable stroke (RoPE score > 6). This underscores the difficulty of distinguishing pathologic PFO from incidental PFO.

KEY TREATMENT CONSIDERATIONS FOR SECONDARY PREVENTION

Given the complicated relationship between PFO and cryptogenic stroke, there has been much debate over management strategies. The three options are surgical closure, percutaneous closure with a device, and medical therapy. The goal of all three is to prevent the recurrence of stroke or TIA.

Surgical closure has largely been supplanted by percutaneous closure, but is still done in specific situations such as when a PFO is found incidentally on transesophageal echocardiography during surgery for another cardiac condition. The data on such cases²² tend to support the argument that asymptomatic PFOs in the general population have a relatively benign natural history.

Thus, the two key questions about management that warrant discussion are: is anticoagulation superior to antiplatelet therapy? And is percutaneous closure superior to medical management?

Anticoagulant vs antiplatelet therapy

Whether to treat with aspirin or with a vitamin K antagonist has been a subject of debate, although there is no strong evidence to suggest that anticoagulation is superior to antiplatelet therapy.

The concern that aspirin alone is insufficient in some patients stems from a study by Mas et al,²³ who followed 581 patients with cryptogenic stroke who had a PFO alone, a PFO with an atrial septal aneurysm, or neither. The rate of stroke recurrence at 4 years on aspirin therapy was 2.3% in those with a PFO alone, 15.2% in those with a PFO with an atrial septal aneurysm, and 4.2% in those with neither.

Many have concluded that aspirin therapy does not sufficiently protect those with both PFO and atrial septal aneurysm, given the high recurrence rate in this group. This might lead to the suggestion that anticoagulation could be of benefit in these patients.

However, the Patent Foramen Ovale in Cryptogenic Stroke Study (PiCSS)²⁴ and the Spanish Multicenter Study Into Right-to-Left Shunt in Cryptogenic Stroke (CODICIA)²⁵ found similar recurrence rates in patients with PFO and atrial septal aneurysm compared with those with only PFO. In these two studies, recurrence rates were similar regardless of whether patients were taking aspirin or warfarin.

In a study that followed 140 consecutive patients with both stroke and PFO, those treated in a nonrandomized fashion with antiplatelet agents had no difference in the recurrence rate compared with those treated with anticoagulation.²⁶

Although uncertainty remains because no head-to-head randomized controlled trial has been done, some patients with PFO have other indications for anticoagulation, most commonly atrial fibrillation and venous thromboembolic disease.

There are currently no data on the use of novel oral anticoagulants in this setting.

Is percutaneous closure better than medical therapy?

When cryptogenic stroke is treated with antiplatelet therapy or anticoagulation therapy, the recurrence rate is the same whether or not the patient has a PFO.^23–25 The belief that medical therapy offers adequate secondary protection is supported by a meta-analysis of 15 studies that found no increased risk of recurrent ischemic events in those with a PFO on medical therapy (antiplatelet or anticoagulant) vs those without a PFO (relative risk 1.1, 95% CI 0.8–1.5).²⁷

Despite the conflicting evidence, percutaneous closure of PFO is still performed, mostly on a case-by-case basis. This has been supported by an apparent benefit in observational studies.

A systematic review of 52 single-arm studies and 7 comparative nonrandomized studies of patients with PFO and cryptogenic stroke found the rate of recurrent stroke to be 0.36 per 100 person-years with percutaneous closure vs 2.53 per 100 person-years with medical therapy.²⁸ However, three long-awaited randomized controlled trials (CLOSURE 1, the PC trial, and RESPECT) failed to show a significant reduction in primary end points with percutaneous closure vs standard medical therapy.^15–17

These trials had several limitations: event rates were low, medical therapy varied by provider, and enrollment was slowed by out-of-study percutaneous closure in patients perceived to be at high risk (though, as discussed above, high risk is difficult to determine).

Intention-to-treat analysis in RESPECT showed no benefit from percutaneous closure, but a favorable outcome was noted with closure in as-treated analysis (HR 0.27; 95% CI 0.1–0.75; P = .007) and per-protocol analysis (HR 0.37; 95% CI 0.14–0.96; P = .03) of the 980 randomized patients.¹⁷ This suggests some benefit, as does the CLOSURE 1 trial, in which 3 of the 12 recurrent strokes in the percutaneous closure group occurred before the device was implanted.¹⁵

The low event rates in these studies prompted several meta-analyses.^29–35 However, only two suggested a benefit of percutaneous closure over medical therapy. In one recent meta-analysis,²⁹ observational study data suggested benefit from percutaneous closure, whereas three randomized controlled trials failed to show a statistically significant benefit.

The conclusions of the meta-analyses must be interpreted with caution because of inherent differences in the randomized controlled trials, including the closure device used, inclusion criteria, study end points, and variations in medical therapy.

Devices differ

A meta-analysis by Khan et al³⁵ showed a benefit of percutaneous closure when evaluating only studies using the Amplatzer PFO occluder (AGA Medical), as in RESPECT and the PC trial.³⁵ As data accumulate, it is important to remember that there are differences between devices. Ongoing trials continue to investigate the Amplatzer device (NCT01550588) and the GORE HELEX Septal Occluder/GORE Septal Occluder (Gore Medical) (NCT00738894).

In another meta-analysis, Pineda et al³¹ found a benefit with closure in the as-treated analysis using data from all three randomized controlled trials (OR 0.62; 95% CI 0.41–0.94; P = .02).³¹ Although paradoxical embolism through the PFO as the mechanism of stroke has been questioned, this finding suggests that actual closure of a PFO may protect against further events, presumably by preventing paradoxical embolism.

Different closure devices have different side effects. The incidence of atrial fibrillation with the CardioSEAL STARFlex device (NMT Medical) is higher than with medical therapy (used in the CLOSURE trial¹⁵), whereas this risk was not statistically significantly increased in the PC trial¹⁶ and RESPECT,¹⁷ which used the Amplatzer device.

Benefit in those with atrial septal aneurysm?

Percutaneous closure has been shown to be safe and effective in patients with PFO and atrial septal aneurysm.³⁶ There was some benefit of closure over medical therapy in a subgroup analysis from RESPECT in these patients, with a HR of 0.19 (95% CI 0.04–0.87, P = .02),¹⁷ although this was not seen in either CLOSURE 1 or the PC trial.

WHAT ARE THE RISKS OF PERCUTANEOUS CLOSURE?

Minor complications of percutaneous closure include bleeding, atrial arrhythmias, device embolization and fracture, and complications related to vascular access. Major complications include hemorrhage requiring transfusion, need for surgery, cardiac tamponade, pulmonary embolism, and death.

The cumulative rate of major complications in 10 observational studies was 1.5%, and the rate of minor complications was 7.9%.³⁷ The RESPECT investigators reported a serious adverse event in 4.2% of patients (ranging in severity from chest tightness to cardiac tamponade).¹⁷

Another possible consequence of percutaneous closure is the need for chronic anticoagulation because of the increased risk of postprocedural atrial fibrillation seen in meta-analyses,^29,31,32 though this may be device-specific.³²

Percutaneous closure was considered successful—ie, to have nearly or completely eliminated shunting of blood through the defect—at 6 months of follow-up in 95.9% of patients in the PC trial, 93.5% in RESPECT, and 86.1% in CLOSURE 1.^15–17

WHAT SHOULD WE BE DOING IN DAILY PRACTICE?

Give aspirin. Aspirin is effective in secondary stroke prevention, and data suggest that patients with PFO and cryptogenic stroke who receive aspirin therapy alone have a similar risk of recurrent events as patients without PFO.

Give warfarin if indicated. Evidence is insufficient to recommend vitamin K antagonist therapy in all patients with PFO and cryptogenic stroke. However, coexisting conditions that warrant anticoagulation must be taken into account.

Individualize. Given the lack of evidence to definitively guide management of patients with cryptogenic stroke and PFO, we need to individualize our approach, taking into account patient preferences, bleeding risk, ability to tolerate procedures, and the likelihood that the PFO is at fault.

No definitive answer on PFO closure. The most recent data suggest that closure may be beneficial, but key questions remain: Who will benefit? And what is the ideal medical therapy? Optimal management will only be established by the continued enrollment of appropriate patients into ongoing clinical trials.

Another question is whether it is possible to perform a randomized controlled trial with enough patients to definitively prove whether percutaneous closure is superior to medical therapy. Recent experience would suggest not.

In the meantime, we have some guidance from the American Heart Association and the American Stroke Association Council on Stroke³⁸ based on the limited evidence available.

Consider patient preference. The physician should present the options to the patient in a balanced manner to enable him or her to make an informed decision. Patients can also be encouraged to seek additional information at websites such as www.stroke.org and www.nlm.nih.gov.

Referral to an interventional cardiologist for evaluation for closure is reasonable in patients with recurrent stroke, medication failure, complicated atrial septal anatomy such as PFO with aneurysm or large shunt, concurrent thromboembolic disease, or contraindications to anticoagulation.

MORE WORK NEEDED

Areas for further study include further identifying the characteristics of patients with PFO and cryptogenic stroke that might indicate who would benefit from percutaneous closure, elucidating the mechanism of stroke in these patients, and determining whether routine stroke evaluation should include echocardiography with a bubble study if there is no change in management based on the finding of PFO.³⁹

The article by Roth and Alli in this issue describes in depth more than 10 years of research that addresses the question, Should we close a patent foramen ovale (PFO) to prevent recurrent cryptogenic stroke?

See related article

There is no longer any doubt that PFO can be the pathway for thrombus from the venous circulation to go from the right atrium to the left atrium, bypassing the pulmonary capillary filtration bed, and entering the arterial side to produce a stroke, myocardial infarction, or peripheral embolus. Two questions remain: What should we do to prevent another episode? And is percutaneous closure of a PFO with the current devices preferable to medical therapy?

How much do we know about the risks and benefits of closure of PFO? I maintain that we know a great deal about interatrial shunt and paradoxical embolism as a cause of cryptogenic stroke. Prospective randomized clinical trials now give us data with which we can provide appropriate direction to our patients. Percutaneous closure is no longer an “experimental procedure,” as insurance companies claim. The experiment has been done, and the only issue is how one interprets the data from the randomized clinical trials.

The review by Roth and Alli comprehensively describes the observational studies, as well as the three randomized clinical trials done to determine whether PFO closure is preferable to medical therapy to prevent recurrent stroke in patients who have already had one cryptogenic stroke. If we understand some of the subtleties and differences between the trials, we can reach an appropriate conclusion as to what to recommend to our patients.

A review of 10 reports of transcatheter closure of PFO vs six reports of medical therapy for cryptogenic stroke showed a range of rates of recurrent stroke at 1 year—between 0% and 4.9% for transcatheter closure, and between 3.8% and 12% for medical therapy.¹

These numbers are important because they were used to estimate the number of patients that would be necessary to study in a randomized clinical trial to demonstrate a benefit of PFO closure vs medical therapy. Unlike most studies of new devices, the PFO closure trials were done in an environment in which patients could get their PFO closed with other devices that were already approved by the US Food and Drug Administration (FDA) for closure of an atrial septal defect. This ability of patients to obtain PFO closure outside of the trial with an off-label device meant that the patients who agreed to be randomized tended to have lower risk for recurrence than patients studied in the observational populations. From a practical standpoint, this meant that the event rate in the patients who participated in the randomized clinical trials (1.7% per year) was lower than predicted from the observational studies.^2,3

Another way of saying this is that the randomized clinical trials were underpowered to answer the question. A common way of dealing with this problem is to combine the results of different studies in a meta-analysis. This makes sense if the studies are assessing the same thing. This is not the case with the PFO closure trials. Although the topic of percutaneous PFO closure vs medical therapy was the same, the devices used were different.

In the CLOSURE trial (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale),³ the device used was the STARFlex, which is no longer produced—and for good reasons. It is not as effective as the Amplatzer or Helex devices in completely closing the right-to-left shunt produced by a PFO. In addition, the CardioSEAL or STARFlex device increases the risk of atrial fibrillation, which was seen in 6% of the treated patients.³ This was the major cause of recurrent stroke in the CLOSURE trial. The CardioSEAL STARFlex device was also more thrombogenic.

In the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment),² which used the Amplatzer PFO closure device, there was no increased incidence of atrial fibrillation in the device group compared with the control group. Therefore, it is not appropriate to combine the results of the CLOSURE trial with the results of the RESPECT trial and PC trial,⁴ both of which used the Amplatzer device.

Our patients want to know what the potential risks and benefits will be if they get their PFO closed with a specific device. They don’t want to know the average risk between two different devices.

However, if you do a meta-analysis of the RESPECT and PC trials, which used the same Amplatzer PFO occluder device, and combine the number of patients studied to increase the statistical power, then the benefit of PFO closure is significant even with an intention-to-treat analysis. By combining the two studies that assessed the same device, you reach a completely different interpretation than if you do a meta-analysis including the CLOSURE trial, which showed no benefit.

The medical community should not uncritically accept meta-analysis methodology. It is a marvelous case example of how scientific methods can be inappropriately used and two diametrically opposed conclusions reached if the meta-analysis combines two different types of devices vs a meta-analysis of just the Amplatzer device.

If we combine the numbers from the RESPECT and PC trials, there were 23 strokes in 691 patients (3.3%) in the medical groups and 10 strokes in 703 patients (1.4%) who underwent PFO closure. By chi square analysis of this intention-to-treat protocol, PFO closure provides a statistically significant reduction in preventing recurrent stroke (95% confidence interval 0.20–0.89, P = .02).

From the patient’s perspective, what is important is this: If I get my PFO closed with an Amplatzer PFO occluder device, what are the risks of the procedure, and what are the potential benefits compared with medical therapy? We can now answer that question definitively. I tell my patients, “The risks of the procedure are remarkably low (about 1%) in experienced hands, and the benefit is that your risk of recurrent stroke will be reduced 73%² compared with medical therapy.” In the RESPECT Trial, the as-treated cohort consisted of 958 patients with 21 primary end-point events (5 in the closure group and 16 in the medical-therapy group). The rate of the primary end point was 0.39 events per 100 patient-years in the closure group vs 1.45 events per 100 patient-years in the medical-therapy group (hazard ratio 0.27; 95% confidence interval 0.10–0.75; P = .007).

Not all cryptogenic strokes in people who have a PFO are caused by paradoxical embolism. PFO may be an innocent bystander. In addition, not all people who have a paradoxical embolism will have a recurrent stroke. For example, if a young woman presents with a PFO and stroke, is it possible that she can prevent another stroke just by stopping her birth-control pills and not have her PFO closed? What is the risk of recurrent stroke if she were to become pregnant? We do not know the answers to these questions.

Your patients do not want to wait to find out if they are going to have another stroke. The meta-analysis of the randomized clinical trials for paradoxical embolism demonstrates that the closure devices are safe and effective. The FDA should approve the Amplatzer PFO occluder with an indication to prevent recurrent stroke in patients with PFO and an initial cryptogenic event.

The article by Roth and Alli in this issue describes in depth more than 10 years of research that addresses the question, Should we close a patent foramen ovale (PFO) to prevent recurrent cryptogenic stroke?

See related article

There is no longer any doubt that PFO can be the pathway for thrombus from the venous circulation to go from the right atrium to the left atrium, bypassing the pulmonary capillary filtration bed, and entering the arterial side to produce a stroke, myocardial infarction, or peripheral embolus. Two questions remain: What should we do to prevent another episode? And is percutaneous closure of a PFO with the current devices preferable to medical therapy?

How much do we know about the risks and benefits of closure of PFO? I maintain that we know a great deal about interatrial shunt and paradoxical embolism as a cause of cryptogenic stroke. Prospective randomized clinical trials now give us data with which we can provide appropriate direction to our patients. Percutaneous closure is no longer an “experimental procedure,” as insurance companies claim. The experiment has been done, and the only issue is how one interprets the data from the randomized clinical trials.

The review by Roth and Alli comprehensively describes the observational studies, as well as the three randomized clinical trials done to determine whether PFO closure is preferable to medical therapy to prevent recurrent stroke in patients who have already had one cryptogenic stroke. If we understand some of the subtleties and differences between the trials, we can reach an appropriate conclusion as to what to recommend to our patients.

A review of 10 reports of transcatheter closure of PFO vs six reports of medical therapy for cryptogenic stroke showed a range of rates of recurrent stroke at 1 year—between 0% and 4.9% for transcatheter closure, and between 3.8% and 12% for medical therapy.¹

These numbers are important because they were used to estimate the number of patients that would be necessary to study in a randomized clinical trial to demonstrate a benefit of PFO closure vs medical therapy. Unlike most studies of new devices, the PFO closure trials were done in an environment in which patients could get their PFO closed with other devices that were already approved by the US Food and Drug Administration (FDA) for closure of an atrial septal defect. This ability of patients to obtain PFO closure outside of the trial with an off-label device meant that the patients who agreed to be randomized tended to have lower risk for recurrence than patients studied in the observational populations. From a practical standpoint, this meant that the event rate in the patients who participated in the randomized clinical trials (1.7% per year) was lower than predicted from the observational studies.^2,3

Another way of saying this is that the randomized clinical trials were underpowered to answer the question. A common way of dealing with this problem is to combine the results of different studies in a meta-analysis. This makes sense if the studies are assessing the same thing. This is not the case with the PFO closure trials. Although the topic of percutaneous PFO closure vs medical therapy was the same, the devices used were different.

In the CLOSURE trial (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale),³ the device used was the STARFlex, which is no longer produced—and for good reasons. It is not as effective as the Amplatzer or Helex devices in completely closing the right-to-left shunt produced by a PFO. In addition, the CardioSEAL or STARFlex device increases the risk of atrial fibrillation, which was seen in 6% of the treated patients.³ This was the major cause of recurrent stroke in the CLOSURE trial. The CardioSEAL STARFlex device was also more thrombogenic.

In the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment),² which used the Amplatzer PFO closure device, there was no increased incidence of atrial fibrillation in the device group compared with the control group. Therefore, it is not appropriate to combine the results of the CLOSURE trial with the results of the RESPECT trial and PC trial,⁴ both of which used the Amplatzer device.

Our patients want to know what the potential risks and benefits will be if they get their PFO closed with a specific device. They don’t want to know the average risk between two different devices.

However, if you do a meta-analysis of the RESPECT and PC trials, which used the same Amplatzer PFO occluder device, and combine the number of patients studied to increase the statistical power, then the benefit of PFO closure is significant even with an intention-to-treat analysis. By combining the two studies that assessed the same device, you reach a completely different interpretation than if you do a meta-analysis including the CLOSURE trial, which showed no benefit.

The medical community should not uncritically accept meta-analysis methodology. It is a marvelous case example of how scientific methods can be inappropriately used and two diametrically opposed conclusions reached if the meta-analysis combines two different types of devices vs a meta-analysis of just the Amplatzer device.

If we combine the numbers from the RESPECT and PC trials, there were 23 strokes in 691 patients (3.3%) in the medical groups and 10 strokes in 703 patients (1.4%) who underwent PFO closure. By chi square analysis of this intention-to-treat protocol, PFO closure provides a statistically significant reduction in preventing recurrent stroke (95% confidence interval 0.20–0.89, P = .02).

From the patient’s perspective, what is important is this: If I get my PFO closed with an Amplatzer PFO occluder device, what are the risks of the procedure, and what are the potential benefits compared with medical therapy? We can now answer that question definitively. I tell my patients, “The risks of the procedure are remarkably low (about 1%) in experienced hands, and the benefit is that your risk of recurrent stroke will be reduced 73%² compared with medical therapy.” In the RESPECT Trial, the as-treated cohort consisted of 958 patients with 21 primary end-point events (5 in the closure group and 16 in the medical-therapy group). The rate of the primary end point was 0.39 events per 100 patient-years in the closure group vs 1.45 events per 100 patient-years in the medical-therapy group (hazard ratio 0.27; 95% confidence interval 0.10–0.75; P = .007).

Not all cryptogenic strokes in people who have a PFO are caused by paradoxical embolism. PFO may be an innocent bystander. In addition, not all people who have a paradoxical embolism will have a recurrent stroke. For example, if a young woman presents with a PFO and stroke, is it possible that she can prevent another stroke just by stopping her birth-control pills and not have her PFO closed? What is the risk of recurrent stroke if she were to become pregnant? We do not know the answers to these questions.

Your patients do not want to wait to find out if they are going to have another stroke. The meta-analysis of the randomized clinical trials for paradoxical embolism demonstrates that the closure devices are safe and effective. The FDA should approve the Amplatzer PFO occluder with an indication to prevent recurrent stroke in patients with PFO and an initial cryptogenic event.

The article by Roth and Alli in this issue describes in depth more than 10 years of research that addresses the question, Should we close a patent foramen ovale (PFO) to prevent recurrent cryptogenic stroke?

See related article

There is no longer any doubt that PFO can be the pathway for thrombus from the venous circulation to go from the right atrium to the left atrium, bypassing the pulmonary capillary filtration bed, and entering the arterial side to produce a stroke, myocardial infarction, or peripheral embolus. Two questions remain: What should we do to prevent another episode? And is percutaneous closure of a PFO with the current devices preferable to medical therapy?

How much do we know about the risks and benefits of closure of PFO? I maintain that we know a great deal about interatrial shunt and paradoxical embolism as a cause of cryptogenic stroke. Prospective randomized clinical trials now give us data with which we can provide appropriate direction to our patients. Percutaneous closure is no longer an “experimental procedure,” as insurance companies claim. The experiment has been done, and the only issue is how one interprets the data from the randomized clinical trials.

The review by Roth and Alli comprehensively describes the observational studies, as well as the three randomized clinical trials done to determine whether PFO closure is preferable to medical therapy to prevent recurrent stroke in patients who have already had one cryptogenic stroke. If we understand some of the subtleties and differences between the trials, we can reach an appropriate conclusion as to what to recommend to our patients.

A review of 10 reports of transcatheter closure of PFO vs six reports of medical therapy for cryptogenic stroke showed a range of rates of recurrent stroke at 1 year—between 0% and 4.9% for transcatheter closure, and between 3.8% and 12% for medical therapy.¹

These numbers are important because they were used to estimate the number of patients that would be necessary to study in a randomized clinical trial to demonstrate a benefit of PFO closure vs medical therapy. Unlike most studies of new devices, the PFO closure trials were done in an environment in which patients could get their PFO closed with other devices that were already approved by the US Food and Drug Administration (FDA) for closure of an atrial septal defect. This ability of patients to obtain PFO closure outside of the trial with an off-label device meant that the patients who agreed to be randomized tended to have lower risk for recurrence than patients studied in the observational populations. From a practical standpoint, this meant that the event rate in the patients who participated in the randomized clinical trials (1.7% per year) was lower than predicted from the observational studies.^2,3

Another way of saying this is that the randomized clinical trials were underpowered to answer the question. A common way of dealing with this problem is to combine the results of different studies in a meta-analysis. This makes sense if the studies are assessing the same thing. This is not the case with the PFO closure trials. Although the topic of percutaneous PFO closure vs medical therapy was the same, the devices used were different.

In the CLOSURE trial (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale),³ the device used was the STARFlex, which is no longer produced—and for good reasons. It is not as effective as the Amplatzer or Helex devices in completely closing the right-to-left shunt produced by a PFO. In addition, the CardioSEAL or STARFlex device increases the risk of atrial fibrillation, which was seen in 6% of the treated patients.³ This was the major cause of recurrent stroke in the CLOSURE trial. The CardioSEAL STARFlex device was also more thrombogenic.

In the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment),² which used the Amplatzer PFO closure device, there was no increased incidence of atrial fibrillation in the device group compared with the control group. Therefore, it is not appropriate to combine the results of the CLOSURE trial with the results of the RESPECT trial and PC trial,⁴ both of which used the Amplatzer device.

Our patients want to know what the potential risks and benefits will be if they get their PFO closed with a specific device. They don’t want to know the average risk between two different devices.

However, if you do a meta-analysis of the RESPECT and PC trials, which used the same Amplatzer PFO occluder device, and combine the number of patients studied to increase the statistical power, then the benefit of PFO closure is significant even with an intention-to-treat analysis. By combining the two studies that assessed the same device, you reach a completely different interpretation than if you do a meta-analysis including the CLOSURE trial, which showed no benefit.

The medical community should not uncritically accept meta-analysis methodology. It is a marvelous case example of how scientific methods can be inappropriately used and two diametrically opposed conclusions reached if the meta-analysis combines two different types of devices vs a meta-analysis of just the Amplatzer device.

If we combine the numbers from the RESPECT and PC trials, there were 23 strokes in 691 patients (3.3%) in the medical groups and 10 strokes in 703 patients (1.4%) who underwent PFO closure. By chi square analysis of this intention-to-treat protocol, PFO closure provides a statistically significant reduction in preventing recurrent stroke (95% confidence interval 0.20–0.89, P = .02).

From the patient’s perspective, what is important is this: If I get my PFO closed with an Amplatzer PFO occluder device, what are the risks of the procedure, and what are the potential benefits compared with medical therapy? We can now answer that question definitively. I tell my patients, “The risks of the procedure are remarkably low (about 1%) in experienced hands, and the benefit is that your risk of recurrent stroke will be reduced 73%² compared with medical therapy.” In the RESPECT Trial, the as-treated cohort consisted of 958 patients with 21 primary end-point events (5 in the closure group and 16 in the medical-therapy group). The rate of the primary end point was 0.39 events per 100 patient-years in the closure group vs 1.45 events per 100 patient-years in the medical-therapy group (hazard ratio 0.27; 95% confidence interval 0.10–0.75; P = .007).

Not all cryptogenic strokes in people who have a PFO are caused by paradoxical embolism. PFO may be an innocent bystander. In addition, not all people who have a paradoxical embolism will have a recurrent stroke. For example, if a young woman presents with a PFO and stroke, is it possible that she can prevent another stroke just by stopping her birth-control pills and not have her PFO closed? What is the risk of recurrent stroke if she were to become pregnant? We do not know the answers to these questions.

Your patients do not want to wait to find out if they are going to have another stroke. The meta-analysis of the randomized clinical trials for paradoxical embolism demonstrates that the closure devices are safe and effective. The FDA should approve the Amplatzer PFO occluder with an indication to prevent recurrent stroke in patients with PFO and an initial cryptogenic event.

A 51-year-old man with end-stage liver disease from alcohol abuse presented with worsening dyspnea on exertion. He had a history of ascites requiring diuretic therapy and intermittent paracentesis, as well as symptomatic hepatic hydrothorax requiring thoracentesis. Chest radiography showed a large right hydrothorax (Figure 1).

See related commentary

The patient underwent high-volume thoracentesis, and 3.2 L of clear fluid was removed. Chest radiography after the procedure revealed a right-sided pneumothorax (Figure 2, arrow). The patient was mildly short of breath and was treated with high-flow oxygen. Later the same day, his shortness of breath worsened, and repeat chest radiography showed an unchanged pneumothorax that was now complicated by reexpansion pulmonary edema after thoracentesis (Figure 3, star). The reexpansion pulmonary edema resolved by the following day, and the pneumothorax resolved after placement of a pig-tail catheter into the pleural space (Figure 4).

Iatrogenic pneumothorax after thoracentesis occurs in 6% of cases.¹ Iatrogenic reexpansion pulmonary edema after thoracentesis occurs in fewer than 1% of cases.^2,3 Simultaneous pneumothorax and reexpansion pulmonary edema arising from the same procedure appears to be extremely rare.

A 51-year-old man with end-stage liver disease from alcohol abuse presented with worsening dyspnea on exertion. He had a history of ascites requiring diuretic therapy and intermittent paracentesis, as well as symptomatic hepatic hydrothorax requiring thoracentesis. Chest radiography showed a large right hydrothorax (Figure 1).

See related commentary

The patient underwent high-volume thoracentesis, and 3.2 L of clear fluid was removed. Chest radiography after the procedure revealed a right-sided pneumothorax (Figure 2, arrow). The patient was mildly short of breath and was treated with high-flow oxygen. Later the same day, his shortness of breath worsened, and repeat chest radiography showed an unchanged pneumothorax that was now complicated by reexpansion pulmonary edema after thoracentesis (Figure 3, star). The reexpansion pulmonary edema resolved by the following day, and the pneumothorax resolved after placement of a pig-tail catheter into the pleural space (Figure 4).

Iatrogenic pneumothorax after thoracentesis occurs in 6% of cases.¹ Iatrogenic reexpansion pulmonary edema after thoracentesis occurs in fewer than 1% of cases.^2,3 Simultaneous pneumothorax and reexpansion pulmonary edema arising from the same procedure appears to be extremely rare.

A 51-year-old man with end-stage liver disease from alcohol abuse presented with worsening dyspnea on exertion. He had a history of ascites requiring diuretic therapy and intermittent paracentesis, as well as symptomatic hepatic hydrothorax requiring thoracentesis. Chest radiography showed a large right hydrothorax (Figure 1).

See related commentary

The patient underwent high-volume thoracentesis, and 3.2 L of clear fluid was removed. Chest radiography after the procedure revealed a right-sided pneumothorax (Figure 2, arrow). The patient was mildly short of breath and was treated with high-flow oxygen. Later the same day, his shortness of breath worsened, and repeat chest radiography showed an unchanged pneumothorax that was now complicated by reexpansion pulmonary edema after thoracentesis (Figure 3, star). The reexpansion pulmonary edema resolved by the following day, and the pneumothorax resolved after placement of a pig-tail catheter into the pleural space (Figure 4).

Iatrogenic pneumothorax after thoracentesis occurs in 6% of cases.¹ Iatrogenic reexpansion pulmonary edema after thoracentesis occurs in fewer than 1% of cases.^2,3 Simultaneous pneumothorax and reexpansion pulmonary edema arising from the same procedure appears to be extremely rare.

A 32-year-old woman presents with a history of pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, with exacerbation of the symptoms during her menstrual cycles. Her menarche occurred at the age of 13 and her menses are regular. She has never undergone surgery and has no relevant pathologic processes. She also reports that for the past 18 months she has been unsuccessfully trying to conceive.

Two months ago, she went to the emergency department because of an acute episode of severe pelvic pain associated with abdominal cramps, vomiting, and dyschezia, occurring at the beginning of her menstrual cycle. At that time, her vital signs were within normal limits, but deep palpation of the right iliac fossa was painful. On that occasion, acute abdomen and bowel obstruction were excluded.

Now, vaginal examination reveals a bluish, painful, bulky induration in the posterior fornix. Digital rectal examination reveals a circular infiltrated area in the anterior rectal wall. Her cancer antigen 125 (CA 125) level is 230 U/mL (normal range 0–35 U/mL).

MENSES-RELATED SYMPTOMS AND THE DIAGNOSIS OF ENDOMETRIOSIS

The diagnosis of endometriosis should be considered in the patient described above. Many of her signs and symptoms can be associated with several diseases. However, the diagnostic hypothesis points strongly toward endometriosis, since her symptoms recur at the beginning of every menstrual cycle.¹

Endometriosis is the presence of endometrial tissue outside the uterine cavity. The affected organs usually include the ovaries, fallopian tubes,² peritoneal surface, vagina, cervix, abdominal wall,³ scar tissue, pouch of Douglas, urinary tract, and bowel. However, any organ can be involved.

So-called deeply infiltrating endometriosis is an endometriotic lesion penetrating into the retroperitoneal space (most often affecting the uterosacral ligaments and the rectovaginal septum) or the pelvic-organ wall to a depth of at least 5 mm and involving structures such as the rectum, vagina, ureters, and bladder.⁴ Its clinical presentation is highly variable, ranging from no symptoms to severe pain and dysfunction of pelvic organs.

Endometriosis can be diagnosed with certainty only when the endometriotic lesions are observed by laparoscopy or laparotomy and after the histologic examination of surgically resected lesions (Figure 1).¹ However, a presumptive diagnosis can be made on the basis of imaging findings, which can be useful in the differential diagnostic process (Table 1).

EXAMINATION AND BLOOD MARKERS PROVIDE LIMITED INFORMATION

Knowing the history of the patient, along with a physical examination that includes speculum and bimanual vaginal and rectal examination, can be helpful in the diagnostic process even if nothing abnormal is found.

Pelvic examination has a poor predictive value, as demonstrated in a study conducted by Nezhat et al⁵ in 91 patients with surgically confirmed endometriosis, 47% of whom had a normal bimanual examination.

CA 125 is the serologic marker most often used for diagnosing endometriosis. Levels are usually high in the sera of patients with endometriosis, especially in the advanced stages.⁶ However, levels increase both in the physiologic menstrual cycle and in epithelial ovarian cancers.⁷ Thus, the diagnostic value of CA 125 is limited in terms of both sensitivity and specificity.

INCLUDE IMAGING IN THE DIAGNOSTIC WORKUP

Surgical treatment is frequently offered to patients who have severe pelvic pain that does not respond to medical treatment, or in cases of infertility. Imaging investigations are mandatory both to ascertain the diagnosis and to assess involvement of internal organs before surgery. Moreover, imaging helps minimize the surgical risks.

The primary aim of the radiologic examination is to describe the precise location, the depth, and the number of pelvic endometriotic lesions. Furthermore, imaging is useful to check for endometriotic foci in pelvic organs such as the bowel, ureters, and bladder, which are often involved in the pathologic process.

Transvaginal ultrasonography and magnetic resonance imaging (MRI) can accurately delineate deeply infiltrating lesions of endometriosis that are not easily accessible laparoscopically.

Transvaginal ultrasonography

Transvaginal ultrasonography is the first-line imaging study when endometriosis is suspected: it is powerful, simple, widely available, and cost-effective. In particular, it is recommended for diagnosing endometriotic ovarian cysts (endometriomas)^8,9 and endometriosis of the bladder.¹⁰ However, its value for the assessment of superficial peritoneal lesions, ovarian foci, and deeply infiltrating endometriosis is questionable.

Although uncomfortable for the patient, transvaginal ultrasonography should be performed during menses, or when the pain reaches its highest level. In fact, during menstrual bleeding the endometrial implants grow and become easier to detect.

Mais et al⁸ reported that transvaginal ultrasonography has a sensitivity of 88% in differentiating endometriomas from other ovarian masses, and a specificity of 90% (Figure 2). Furthermore, its specificity is as high as that of MRI.^8,9

Endometriotic nodules detected in the uterosacral ligaments, rectovaginal septum, vagina, vesicouterine pouch, bladder (Figure 3), and ureters can be signs of deeply infiltrating endometriosis. Pelvic adhesions can be suspected when pelvic organs appear fixed to each other, when hyperechogenic plaques are found between the serosal surfaces of the different organs, and when the pouch of Douglas is partially or completely obliterated.

The accuracy of transvaginal ultrasonography strongly depends on the operator’s skill. Furthermore, lesions of the sigmoid colon are impossible to visualize by transvaginal ultrasonography; hence, further diagnostic procedures are required. Transvaginal ultrasonography is the most accurate technique in detecting endometriotic nodules of the bladder wall in patients with urinary symptoms.

Transvaginal ultrasonography combined with color Doppler can also demonstrate the flow of urine through the ureters to the bladder, thereby ascertaining the patency of the ureters and clarifying the anatomic relationship between the ureters and any endometriotic lesions in the detrusors.¹⁰ Hydronephrosis can arise from ureteral restriction caused by endometriotic nodules. Thus, transabdominal ultrasonography of the kidneys is always recommended when deeply infiltrating endometriosis is suspected.

Some centers use a bowel-preparation protocol consisting of a laxative taken 24 hours before the procedure, combined with a low-residue diet and an enema 1 hour before the examination to cleanse the rectosigmoid colon of fecal content and gas, which can interfere with the visual examination of the pelvic structures.¹¹

Transabdominal ultrasonography

Transabdominal ultrasonography can be used instead of transvaginal ultrasonography, eg, in young girls and women who have never been sexually active. When transabdominal ultrasonography is selected, the patient should have a full bladder to maximize the visualization of the pelvic structures. However, transvaginal ultrasonography is generally more sensitive than transabdominal in detecting adnexal masses and pelvic nodules.¹²

Magnetic resonance imaging

MRI has been recently introduced in the diagnosis of endometriosis. MRI is less operator-dependent than transvaginal ultrasonography and is more sensitive for detecting foci of deeply infiltrating endometriosis, because of its ability to completely survey the anterior and posterior compartments of the pelvis. However, its diagnostic value in cases of bladder endometriosis, superficial peritoneal lesions, and ovarian foci is still controversial.^13–16

On MRI, lesions of deeply infiltrating endometriosis mainly appear as areas or nodules with regular, irregular, indistinct, or stellate margins. A distortion of the normal pelvic anatomy or the detection of a loculated fluid collection can indirectly signal the presence of adhesions.

MRI has high specificity for the diagnosis of endometriomas as a result of its ability to detect aged hemorrhagic content (Figure 4).¹⁷ Despite the many studies that point to the limits of MRI in detecting small endometriotic lesions, recent studies demonstrated that MRI also has good sensitivity for small peritoneal implants and adhesions.^18,19 The injection of gadolinium contrast is still a debatable measure, because contrast-enhanced imaging cannot differentiate infiltrating lesions from other normal fibromuscular pelvic anatomic structures.^15,20

Bowel preparation can be done with an oral laxative the day before imaging, complemented by a low-residue diet. A single dose of a ready-to-use enema is given 30 minutes before the examination to cleanse the terminal section of the intestinal tract. To avoid motion artifacts caused by bowel peristalsis, images are obtained after intramuscular injections of a myorelaxant are given, if there is no contraindication. Bowel preparation is useful to eliminate fecal residue and gas, thereby allowing proper visualization of lesions of deeply infiltrating endometriosis, but it is not routinely prescribed in all centers.¹¹

In most cases, endometriotic lesions have an MRI signal intensity that comes very close to that of the surrounding fibromuscular structures. In this regard, vaginal and rectal distention and opacification using ultrasonographic gel clearly help to delineate the cervix, vaginal fornices, and vaginal wall, as well as the rectum and wall of the rectosigmoid junction (Figure  5).²⁰

PRESURGICAL IMAGING

Rectal endoscopic ultrasonography

Even though it should not be included in the routine diagnostic workup, rectal endoscopic ultrasonography, using a flexible echoendoscope, is suitable in certain presurgical cases. The aim of this imaging technique is to assess the depth of bowel wall infiltration thanks to the visualization of the different layers.²¹

Double-contrast barium enema and multislice computed tomography

Double-contrast barium enema is extensively used for the diagnosis of bowel endometriosis, once the decision to perform surgery has been made. It allows evaluation of the degree and length of the bowel occlusion at the level of the sigmoid or high rectosigmoid tract, but it does not permit differentiation of bowel endometriosis from other pathologies.

Multislice computed tomography offers the opportunity to evaluate the depth of the lesions with excellent precision. ²²

The most relevant disadvantage of both procedures is the exposure of women of reproductive age to ionizing radiation. In addition, multislice computed tomography requires the administration of an intravenous iodinated contrast medium and a retrograde colonic distention with about 2 L of water.

A 32-year-old woman presents with a history of pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, with exacerbation of the symptoms during her menstrual cycles. Her menarche occurred at the age of 13 and her menses are regular. She has never undergone surgery and has no relevant pathologic processes. She also reports that for the past 18 months she has been unsuccessfully trying to conceive.

Two months ago, she went to the emergency department because of an acute episode of severe pelvic pain associated with abdominal cramps, vomiting, and dyschezia, occurring at the beginning of her menstrual cycle. At that time, her vital signs were within normal limits, but deep palpation of the right iliac fossa was painful. On that occasion, acute abdomen and bowel obstruction were excluded.

Now, vaginal examination reveals a bluish, painful, bulky induration in the posterior fornix. Digital rectal examination reveals a circular infiltrated area in the anterior rectal wall. Her cancer antigen 125 (CA 125) level is 230 U/mL (normal range 0–35 U/mL).

MENSES-RELATED SYMPTOMS AND THE DIAGNOSIS OF ENDOMETRIOSIS

The diagnosis of endometriosis should be considered in the patient described above. Many of her signs and symptoms can be associated with several diseases. However, the diagnostic hypothesis points strongly toward endometriosis, since her symptoms recur at the beginning of every menstrual cycle.¹

Endometriosis is the presence of endometrial tissue outside the uterine cavity. The affected organs usually include the ovaries, fallopian tubes,² peritoneal surface, vagina, cervix, abdominal wall,³ scar tissue, pouch of Douglas, urinary tract, and bowel. However, any organ can be involved.

So-called deeply infiltrating endometriosis is an endometriotic lesion penetrating into the retroperitoneal space (most often affecting the uterosacral ligaments and the rectovaginal septum) or the pelvic-organ wall to a depth of at least 5 mm and involving structures such as the rectum, vagina, ureters, and bladder.⁴ Its clinical presentation is highly variable, ranging from no symptoms to severe pain and dysfunction of pelvic organs.

Endometriosis can be diagnosed with certainty only when the endometriotic lesions are observed by laparoscopy or laparotomy and after the histologic examination of surgically resected lesions (Figure 1).¹ However, a presumptive diagnosis can be made on the basis of imaging findings, which can be useful in the differential diagnostic process (Table 1).

EXAMINATION AND BLOOD MARKERS PROVIDE LIMITED INFORMATION

Knowing the history of the patient, along with a physical examination that includes speculum and bimanual vaginal and rectal examination, can be helpful in the diagnostic process even if nothing abnormal is found.

Pelvic examination has a poor predictive value, as demonstrated in a study conducted by Nezhat et al⁵ in 91 patients with surgically confirmed endometriosis, 47% of whom had a normal bimanual examination.

CA 125 is the serologic marker most often used for diagnosing endometriosis. Levels are usually high in the sera of patients with endometriosis, especially in the advanced stages.⁶ However, levels increase both in the physiologic menstrual cycle and in epithelial ovarian cancers.⁷ Thus, the diagnostic value of CA 125 is limited in terms of both sensitivity and specificity.

INCLUDE IMAGING IN THE DIAGNOSTIC WORKUP

Surgical treatment is frequently offered to patients who have severe pelvic pain that does not respond to medical treatment, or in cases of infertility. Imaging investigations are mandatory both to ascertain the diagnosis and to assess involvement of internal organs before surgery. Moreover, imaging helps minimize the surgical risks.

The primary aim of the radiologic examination is to describe the precise location, the depth, and the number of pelvic endometriotic lesions. Furthermore, imaging is useful to check for endometriotic foci in pelvic organs such as the bowel, ureters, and bladder, which are often involved in the pathologic process.

Transvaginal ultrasonography and magnetic resonance imaging (MRI) can accurately delineate deeply infiltrating lesions of endometriosis that are not easily accessible laparoscopically.

Transvaginal ultrasonography

Transvaginal ultrasonography is the first-line imaging study when endometriosis is suspected: it is powerful, simple, widely available, and cost-effective. In particular, it is recommended for diagnosing endometriotic ovarian cysts (endometriomas)^8,9 and endometriosis of the bladder.¹⁰ However, its value for the assessment of superficial peritoneal lesions, ovarian foci, and deeply infiltrating endometriosis is questionable.

Although uncomfortable for the patient, transvaginal ultrasonography should be performed during menses, or when the pain reaches its highest level. In fact, during menstrual bleeding the endometrial implants grow and become easier to detect.

Mais et al⁸ reported that transvaginal ultrasonography has a sensitivity of 88% in differentiating endometriomas from other ovarian masses, and a specificity of 90% (Figure 2). Furthermore, its specificity is as high as that of MRI.^8,9

Endometriotic nodules detected in the uterosacral ligaments, rectovaginal septum, vagina, vesicouterine pouch, bladder (Figure 3), and ureters can be signs of deeply infiltrating endometriosis. Pelvic adhesions can be suspected when pelvic organs appear fixed to each other, when hyperechogenic plaques are found between the serosal surfaces of the different organs, and when the pouch of Douglas is partially or completely obliterated.

The accuracy of transvaginal ultrasonography strongly depends on the operator’s skill. Furthermore, lesions of the sigmoid colon are impossible to visualize by transvaginal ultrasonography; hence, further diagnostic procedures are required. Transvaginal ultrasonography is the most accurate technique in detecting endometriotic nodules of the bladder wall in patients with urinary symptoms.

Transvaginal ultrasonography combined with color Doppler can also demonstrate the flow of urine through the ureters to the bladder, thereby ascertaining the patency of the ureters and clarifying the anatomic relationship between the ureters and any endometriotic lesions in the detrusors.¹⁰ Hydronephrosis can arise from ureteral restriction caused by endometriotic nodules. Thus, transabdominal ultrasonography of the kidneys is always recommended when deeply infiltrating endometriosis is suspected.

Some centers use a bowel-preparation protocol consisting of a laxative taken 24 hours before the procedure, combined with a low-residue diet and an enema 1 hour before the examination to cleanse the rectosigmoid colon of fecal content and gas, which can interfere with the visual examination of the pelvic structures.¹¹

Transabdominal ultrasonography

Transabdominal ultrasonography can be used instead of transvaginal ultrasonography, eg, in young girls and women who have never been sexually active. When transabdominal ultrasonography is selected, the patient should have a full bladder to maximize the visualization of the pelvic structures. However, transvaginal ultrasonography is generally more sensitive than transabdominal in detecting adnexal masses and pelvic nodules.¹²

Magnetic resonance imaging

MRI has been recently introduced in the diagnosis of endometriosis. MRI is less operator-dependent than transvaginal ultrasonography and is more sensitive for detecting foci of deeply infiltrating endometriosis, because of its ability to completely survey the anterior and posterior compartments of the pelvis. However, its diagnostic value in cases of bladder endometriosis, superficial peritoneal lesions, and ovarian foci is still controversial.^13–16

On MRI, lesions of deeply infiltrating endometriosis mainly appear as areas or nodules with regular, irregular, indistinct, or stellate margins. A distortion of the normal pelvic anatomy or the detection of a loculated fluid collection can indirectly signal the presence of adhesions.

MRI has high specificity for the diagnosis of endometriomas as a result of its ability to detect aged hemorrhagic content (Figure 4).¹⁷ Despite the many studies that point to the limits of MRI in detecting small endometriotic lesions, recent studies demonstrated that MRI also has good sensitivity for small peritoneal implants and adhesions.^18,19 The injection of gadolinium contrast is still a debatable measure, because contrast-enhanced imaging cannot differentiate infiltrating lesions from other normal fibromuscular pelvic anatomic structures.^15,20

Bowel preparation can be done with an oral laxative the day before imaging, complemented by a low-residue diet. A single dose of a ready-to-use enema is given 30 minutes before the examination to cleanse the terminal section of the intestinal tract. To avoid motion artifacts caused by bowel peristalsis, images are obtained after intramuscular injections of a myorelaxant are given, if there is no contraindication. Bowel preparation is useful to eliminate fecal residue and gas, thereby allowing proper visualization of lesions of deeply infiltrating endometriosis, but it is not routinely prescribed in all centers.¹¹

In most cases, endometriotic lesions have an MRI signal intensity that comes very close to that of the surrounding fibromuscular structures. In this regard, vaginal and rectal distention and opacification using ultrasonographic gel clearly help to delineate the cervix, vaginal fornices, and vaginal wall, as well as the rectum and wall of the rectosigmoid junction (Figure  5).²⁰

PRESURGICAL IMAGING

Rectal endoscopic ultrasonography

Even though it should not be included in the routine diagnostic workup, rectal endoscopic ultrasonography, using a flexible echoendoscope, is suitable in certain presurgical cases. The aim of this imaging technique is to assess the depth of bowel wall infiltration thanks to the visualization of the different layers.²¹

Double-contrast barium enema and multislice computed tomography

Double-contrast barium enema is extensively used for the diagnosis of bowel endometriosis, once the decision to perform surgery has been made. It allows evaluation of the degree and length of the bowel occlusion at the level of the sigmoid or high rectosigmoid tract, but it does not permit differentiation of bowel endometriosis from other pathologies.

Multislice computed tomography offers the opportunity to evaluate the depth of the lesions with excellent precision. ²²

The most relevant disadvantage of both procedures is the exposure of women of reproductive age to ionizing radiation. In addition, multislice computed tomography requires the administration of an intravenous iodinated contrast medium and a retrograde colonic distention with about 2 L of water.

A 32-year-old woman presents with a history of pelvic pain, dysmenorrhea, dyspareunia, dyschezia, and dysuria, with exacerbation of the symptoms during her menstrual cycles. Her menarche occurred at the age of 13 and her menses are regular. She has never undergone surgery and has no relevant pathologic processes. She also reports that for the past 18 months she has been unsuccessfully trying to conceive.

Two months ago, she went to the emergency department because of an acute episode of severe pelvic pain associated with abdominal cramps, vomiting, and dyschezia, occurring at the beginning of her menstrual cycle. At that time, her vital signs were within normal limits, but deep palpation of the right iliac fossa was painful. On that occasion, acute abdomen and bowel obstruction were excluded.

Now, vaginal examination reveals a bluish, painful, bulky induration in the posterior fornix. Digital rectal examination reveals a circular infiltrated area in the anterior rectal wall. Her cancer antigen 125 (CA 125) level is 230 U/mL (normal range 0–35 U/mL).

MENSES-RELATED SYMPTOMS AND THE DIAGNOSIS OF ENDOMETRIOSIS

The diagnosis of endometriosis should be considered in the patient described above. Many of her signs and symptoms can be associated with several diseases. However, the diagnostic hypothesis points strongly toward endometriosis, since her symptoms recur at the beginning of every menstrual cycle.¹

Endometriosis is the presence of endometrial tissue outside the uterine cavity. The affected organs usually include the ovaries, fallopian tubes,² peritoneal surface, vagina, cervix, abdominal wall,³ scar tissue, pouch of Douglas, urinary tract, and bowel. However, any organ can be involved.

So-called deeply infiltrating endometriosis is an endometriotic lesion penetrating into the retroperitoneal space (most often affecting the uterosacral ligaments and the rectovaginal septum) or the pelvic-organ wall to a depth of at least 5 mm and involving structures such as the rectum, vagina, ureters, and bladder.⁴ Its clinical presentation is highly variable, ranging from no symptoms to severe pain and dysfunction of pelvic organs.

Endometriosis can be diagnosed with certainty only when the endometriotic lesions are observed by laparoscopy or laparotomy and after the histologic examination of surgically resected lesions (Figure 1).¹ However, a presumptive diagnosis can be made on the basis of imaging findings, which can be useful in the differential diagnostic process (Table 1).

EXAMINATION AND BLOOD MARKERS PROVIDE LIMITED INFORMATION

Knowing the history of the patient, along with a physical examination that includes speculum and bimanual vaginal and rectal examination, can be helpful in the diagnostic process even if nothing abnormal is found.

Pelvic examination has a poor predictive value, as demonstrated in a study conducted by Nezhat et al⁵ in 91 patients with surgically confirmed endometriosis, 47% of whom had a normal bimanual examination.

CA 125 is the serologic marker most often used for diagnosing endometriosis. Levels are usually high in the sera of patients with endometriosis, especially in the advanced stages.⁶ However, levels increase both in the physiologic menstrual cycle and in epithelial ovarian cancers.⁷ Thus, the diagnostic value of CA 125 is limited in terms of both sensitivity and specificity.

INCLUDE IMAGING IN THE DIAGNOSTIC WORKUP

Surgical treatment is frequently offered to patients who have severe pelvic pain that does not respond to medical treatment, or in cases of infertility. Imaging investigations are mandatory both to ascertain the diagnosis and to assess involvement of internal organs before surgery. Moreover, imaging helps minimize the surgical risks.

The primary aim of the radiologic examination is to describe the precise location, the depth, and the number of pelvic endometriotic lesions. Furthermore, imaging is useful to check for endometriotic foci in pelvic organs such as the bowel, ureters, and bladder, which are often involved in the pathologic process.

Transvaginal ultrasonography and magnetic resonance imaging (MRI) can accurately delineate deeply infiltrating lesions of endometriosis that are not easily accessible laparoscopically.

Transvaginal ultrasonography

Transvaginal ultrasonography is the first-line imaging study when endometriosis is suspected: it is powerful, simple, widely available, and cost-effective. In particular, it is recommended for diagnosing endometriotic ovarian cysts (endometriomas)^8,9 and endometriosis of the bladder.¹⁰ However, its value for the assessment of superficial peritoneal lesions, ovarian foci, and deeply infiltrating endometriosis is questionable.

Although uncomfortable for the patient, transvaginal ultrasonography should be performed during menses, or when the pain reaches its highest level. In fact, during menstrual bleeding the endometrial implants grow and become easier to detect.

Mais et al⁸ reported that transvaginal ultrasonography has a sensitivity of 88% in differentiating endometriomas from other ovarian masses, and a specificity of 90% (Figure 2). Furthermore, its specificity is as high as that of MRI.^8,9

Endometriotic nodules detected in the uterosacral ligaments, rectovaginal septum, vagina, vesicouterine pouch, bladder (Figure 3), and ureters can be signs of deeply infiltrating endometriosis. Pelvic adhesions can be suspected when pelvic organs appear fixed to each other, when hyperechogenic plaques are found between the serosal surfaces of the different organs, and when the pouch of Douglas is partially or completely obliterated.

The accuracy of transvaginal ultrasonography strongly depends on the operator’s skill. Furthermore, lesions of the sigmoid colon are impossible to visualize by transvaginal ultrasonography; hence, further diagnostic procedures are required. Transvaginal ultrasonography is the most accurate technique in detecting endometriotic nodules of the bladder wall in patients with urinary symptoms.

Transvaginal ultrasonography combined with color Doppler can also demonstrate the flow of urine through the ureters to the bladder, thereby ascertaining the patency of the ureters and clarifying the anatomic relationship between the ureters and any endometriotic lesions in the detrusors.¹⁰ Hydronephrosis can arise from ureteral restriction caused by endometriotic nodules. Thus, transabdominal ultrasonography of the kidneys is always recommended when deeply infiltrating endometriosis is suspected.

Some centers use a bowel-preparation protocol consisting of a laxative taken 24 hours before the procedure, combined with a low-residue diet and an enema 1 hour before the examination to cleanse the rectosigmoid colon of fecal content and gas, which can interfere with the visual examination of the pelvic structures.¹¹

Transabdominal ultrasonography

Transabdominal ultrasonography can be used instead of transvaginal ultrasonography, eg, in young girls and women who have never been sexually active. When transabdominal ultrasonography is selected, the patient should have a full bladder to maximize the visualization of the pelvic structures. However, transvaginal ultrasonography is generally more sensitive than transabdominal in detecting adnexal masses and pelvic nodules.¹²

Magnetic resonance imaging

MRI has been recently introduced in the diagnosis of endometriosis. MRI is less operator-dependent than transvaginal ultrasonography and is more sensitive for detecting foci of deeply infiltrating endometriosis, because of its ability to completely survey the anterior and posterior compartments of the pelvis. However, its diagnostic value in cases of bladder endometriosis, superficial peritoneal lesions, and ovarian foci is still controversial.^13–16

On MRI, lesions of deeply infiltrating endometriosis mainly appear as areas or nodules with regular, irregular, indistinct, or stellate margins. A distortion of the normal pelvic anatomy or the detection of a loculated fluid collection can indirectly signal the presence of adhesions.

MRI has high specificity for the diagnosis of endometriomas as a result of its ability to detect aged hemorrhagic content (Figure 4).¹⁷ Despite the many studies that point to the limits of MRI in detecting small endometriotic lesions, recent studies demonstrated that MRI also has good sensitivity for small peritoneal implants and adhesions.^18,19 The injection of gadolinium contrast is still a debatable measure, because contrast-enhanced imaging cannot differentiate infiltrating lesions from other normal fibromuscular pelvic anatomic structures.^15,20

Bowel preparation can be done with an oral laxative the day before imaging, complemented by a low-residue diet. A single dose of a ready-to-use enema is given 30 minutes before the examination to cleanse the terminal section of the intestinal tract. To avoid motion artifacts caused by bowel peristalsis, images are obtained after intramuscular injections of a myorelaxant are given, if there is no contraindication. Bowel preparation is useful to eliminate fecal residue and gas, thereby allowing proper visualization of lesions of deeply infiltrating endometriosis, but it is not routinely prescribed in all centers.¹¹

In most cases, endometriotic lesions have an MRI signal intensity that comes very close to that of the surrounding fibromuscular structures. In this regard, vaginal and rectal distention and opacification using ultrasonographic gel clearly help to delineate the cervix, vaginal fornices, and vaginal wall, as well as the rectum and wall of the rectosigmoid junction (Figure  5).²⁰

PRESURGICAL IMAGING

Rectal endoscopic ultrasonography

Even though it should not be included in the routine diagnostic workup, rectal endoscopic ultrasonography, using a flexible echoendoscope, is suitable in certain presurgical cases. The aim of this imaging technique is to assess the depth of bowel wall infiltration thanks to the visualization of the different layers.²¹

Double-contrast barium enema and multislice computed tomography

Double-contrast barium enema is extensively used for the diagnosis of bowel endometriosis, once the decision to perform surgery has been made. It allows evaluation of the degree and length of the bowel occlusion at the level of the sigmoid or high rectosigmoid tract, but it does not permit differentiation of bowel endometriosis from other pathologies.

Multislice computed tomography offers the opportunity to evaluate the depth of the lesions with excellent precision. ²²

The most relevant disadvantage of both procedures is the exposure of women of reproductive age to ionizing radiation. In addition, multislice computed tomography requires the administration of an intravenous iodinated contrast medium and a retrograde colonic distention with about 2 L of water.