Embolic Ischemic Cortical Stroke in a Young Flight Instructor with a Small Patent Foramen Ovale

CASE REPORT

The case refers to a 28-yr-old male Australian flight instructor who held a Commercial Pilot License with over 2000 h of flight experience and a valid Class 1 medical certificate issued by the Australian Civil Aviation Safety Authority (CASA). He instructs part-time in light sport aircraft regulated by Recreational Aviation Australia (RAAus) outside of his regular employment in information technology. Besides a previous lower back injury and hearing loss sustained during prior military service, he was in good health, a nonsmoker, social drinker, and with no significant family history of cardiovascular disease.

He presented to the hospital with sudden onset left-sided facial paresthesia, left hand weakness, and blurred vision, accompanied by gradual onset, moderate severity, bilateral headache. Prior to this presentation, he had no preceding illness, injury, or symptoms associated with deep vein thrombosis. While the cranial symptoms resolved within 30 min, he had persistent left-hand weakness and paresthesia. His cranial computerized tomography scan was negative and he was admitted for further workup. The left-hand symptoms resolved after 3 d. However, a magnetic resonance imaging scan revealed two hyperintense punctate foci on diffusion weighted imaging in the right precentral gyrus and superior parietal lobe suggestive of acute ischemic embolic stroke (Fig. 1). Vasculitis and thrombophilia screen, computerized tomography angiography, lower limb Doppler, 7-d Holter monitoring, and stress echocardiogram were normal. His lipid profile demonstrated dyslipidemia with a raised total cholesterol of 6.0 mmol · L⁻¹ (232.0 mg · dL⁻¹), triglycerides of 3.4 mmol · L⁻¹ (301.1 mg · dL⁻¹), low-density lipoprotein of 3.6 mmol · L⁻¹ (139.2 mg · dL⁻¹), and reduced high-density lipoprotein of 0.9 mmol · L⁻¹ (34.8 mg · dL⁻¹).

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While an initial transthoracic echocardiogram did not reveal a PFO on agitated saline flush, a later transesophageal echocardiogram demonstrated a PFO with a small bidirectional shunt. There was no ASA, intramural thrombus, or evidence of atheroma in the proximal aorta.

Despite his Risk of Paradoxical Embolism (RoPE) score being 10 due to the absence of a clear precipitating event and the small size of the shunt, both the cardiologist and neurologist opined that the PFO was unlikely to have caused his stroke. The neurologist stated that, using pooled recurrence data, the patient’s individual annualized risk due to the tiny size of the lesions was < 1.8%, with a negligible risk of seizures. The pilot was placed on life-long aspirin and atorvastatin for secondary stroke prevention and to treat his hyperlipidemia. PFO closure was offered; however, as the all-cause complication rate (including stroke) was considered to exceed his annualized stroke recurrence risk, he declined the procedure.

Under RAAus rules, private driving medical standards were met, and thus he was able to return to flying LSA without restriction. However, an “as or with copilot” restriction for general aviation activities was placed on his Class 1 and 2 medical certificates by CASA. Following the renewal of his Class 2 medical 2 yr later, despite no reoccurrence and remaining compliant with medical therapy, the copilot restriction was upheld. The pilot has since been successful in applying for a self-declared Class 5 medical certificate without restriction, which allows for limited solo private operations in a general aviation aircraft under day visual flight rules only.

DISCUSSION

This case highlights the difficulty in determining an individualized risk for pilots recovering from a stroke associated with a small PFO, as well as differences in certification depending on type of flying activity and the local aviation regulator. For pilots who have permanent neurological deficits and multiple significant risk factors for stroke, there is no argument for changing existing certification standards. However, it may be argued that in patients who have complete neurological recovery, with no or minimal risk factors and appropriate mitigation strategies, a return to normal flying duties could be considered with or without restriction.

There are multiple mechanisms by which a PFO may be involved with or cause a stroke. These include passage of a venous thromboembolism, cardiac arrhythmia, and in-situ clot formation.⁶ Where an ASA is present in addition to a PFO, this is associated with a 4-yr recurrence risk of 15.2% vs. 2.3% in patients without PFO closure.⁴ In addition, the size of the PFO and the presence of a significant right to left shunt has been associated with an increased risk.^2,5 Without the presence of a PFO and assuming there are no other identifiable risk factors, up to 38% of strokes are considered cryptogenic.² In a subset of these patients, it may be due to an occult atrial fibrillation (AF).²

Controversy exists regarding how to best risk-stratify this population and the appropriate mitigation strategy.^1,3,5 The development of percutaneous device closure, which offers lower risks compared to open surgical closure, was met with initial enthusiasm. However, a network meta-analysis of four randomized control trials demonstrated that while a trend toward superior stroke prevention was present in one device, overall, it did not demonstrate the superiority of closure over medical therapy.⁷ It is noted that there was significant heterogeneity in the patient characteristics and the echocardiographic features between the trials, and potentially, an improved risk prediction model could be used to determine which patients may most benefit from device closure.⁷

The RoPE score is a validated tool used to determine whether a cryptogenic stroke is associated with a PFO and provides a 2-yr recurrence risk.^6,8,9 It is a 10-point score that considers smoking, diabetes, hypertension, previous stroke/transient ischemic attack, presence of cortical lesions on imaging, and age.⁶ While a high RoPE score suggests a strong association between the PFO and the stroke, the risk of recurrence is less than stroke of all other causes.⁶ The score does not consider the size of the defect, the presence or volume of a right-to-left shunt or an atrial septal defect, nor does it determine optimal treatment. In particular, it does not account for the relative risk reduction that either medical or surgical treatment may provide. Scores > 7 have been validated in retrospective analysis of a percutaneous closure trial to show that PFOs in this group are likely to be pathological.⁸ While it has been suggested that a RoPE > 7 be an indication for closure, the analysis did not show a statistically significant result despite a 69% relative risk reduction.⁸

In a recent meta-analysis assessing treatment for patients who are on medical therapy and with no other associated risk factors, the annual stroke recurrence risk with a PFO is 1.2%.¹⁰ Percutaneous device closure has significantly reduced the likelihood of serious complications compared to surgical closure via thoracotomy, including stroke, perforation, and tamponade.¹⁰ However, up to 3.4% of patients will experience transient AF during the periprocedural period, and for those with a previous history of pulmonary embolism, there is an increased risk of recurrence.¹⁰ While successful closure combined with antiplatelet therapy is associated with a moderate decrease in stroke recurrence, the number needed to treat to prevent one stroke is 24.¹⁰ Noting that ASA and the presence of a large right to left shunt are associated with an increased stroke risk,⁴ and a number needed to treat with closure in these cases is 13 and 15, respectively,¹⁰ this shows that in these higher risk groups there is a greater benefit to closure over standard medical therapy.

To further improve risk stratification, the PFO-associated stroke causal likelihood (PASCAL) classification system was developed to consider the presence of a shunt or ASA along with a RoPE score > 7.² It classifies patients into three categories of unlikely (no factors present), possible (one factor present) and probable (both present) with an associated relative stroke risk reduction with closure of 67% and 90% in the later groups.² Of note, there was net harm to patients in the unlikely group who underwent closure, with a 4.7% risk of late onset AF (vs. 0.7% and 1.5%, respectively, in the other groups).² The pilot in our case report would be classified in the possible group using PASCAL and would be recommended as benefiting from closure.

Detecting the presence of a shunt can be difficult, due to daily physiological variation, patient compliance with a Valsalva and technical ability.¹¹ Recently, a novel technique has been described to detect the presence of right-to-left shunts using echocardiography during hypoxic stimulation testing.¹² By inducing pulmonary vasoconstriction, the increase in right-sided pressure can produce a dynamic shunt across the PFO that is clinically relevant.¹² It is well known that long-haul flying is conducive to the formation of deep vein thromboses. Thus, if hypoxia can produce a dynamic right-to-left shunt in patients with septal defects, this may create a favorable path for thromboembolisms to cross into systemic circulation. Consideration should be given to conditions such as obstructive sleep apnea or prolonged altitude exposure and whether they may pose additional risks in pilots with PFO. The presence of dynamic or hypoxia-induced shunting could be combined with PASCAL classification to further refine the risk stratification following further data and validation of this novel technique.

In terms of aeromedical certification, pilots who have made a full recovery may be granted a medical clearance, albeit often with an as or with copilot restriction. This is despite the degree of initial deficit, size of lesion, associated risk factors or the treatment that is undertaken. While such restrictions are placed due to the concern of sudden incapacitation in flight, in young patients on aspirin, the annual recurrence risk is approximately 1.2%.¹⁰ Many of these pilots will never have a recurrent event and, as they age, stroke is more likely to be due to other risk factors. It should be noted that there are numerous pilots flying without restriction over the age of 50 who may or may not have a PFO and whose annualized stroke risk would exceed this 1.2% risk.

While acknowledging the potentially serious outcome of a recurrent event in flight, it is noted that some regulators have recently considered revising the traditionally rigid 1% rule as the cut-off for unrestricted certification with private operations for certain conditions. This is in acknowledgment that many private pilots would be flying a limited number of hours per year and thus the likelihood of an incapacitating event occurring in flight is extremely remote. Not without controversy, but recently both CASA and the Federal Aviation Administration have introduced certification for limited LSA and private aircraft operations under specific restrictions for pilots who may not otherwise qualify under existing medical standards. With the literature showing that the stroke recurrence risk would be less than 2% for pilots who are appropriately managed either medically or with PFO closure, it could be within the appetite of a local regulator to consider granting waivers or clearance for these pilots for private operations.

Considering the contemporary evidence, it is suggested by the authors that a stratified approach with a combination of RoPE score, echocardiographic findings, and PASCAL classification be used to certify pilots’ fitness to fly following a stroke associated with PFO. For patients with multiple risk factors (i.e., low RoPE score) and who have significant or persistent deficits, certification restrictions should remain unless those risk factors can be sufficiently mitigated. For patients who make full recoveries without deficit, have high RoPE scores, and are on medical treatment, clearance should be granted. The decision for a copilot restriction should be on a case-by-case basis and duly considered as to whether this would be necessary for private operations only. For patients who have a demonstrated ASA and/or a significant right-to-left shunt, closure should be considered to minimize the stroke risk. Those who do not demonstrate a higher risk PFO variant may elect for either medical therapy or closure, based on a personalized risk assessment in consultation with a neurologist and cardiologist.

In our case, and in reference to this approach, it was reasonable that closure was offered to the pilot. While no high-risk features such as ASA were present, it was noted there was a small, nonsignificant bidirectional shunt. The PASCAL classification would suggest that the pilot may benefit from closure, with acknowledgment of a 1.5% risk of developing AF. However, further provocation testing could be performed to reveal whether there are dynamic changes in the shunt. If there were no significant flow changes, it would be reasonable to consider medical therapy as the optimal treatment. As the pilot is already able to fly solo in LSA under RAAus rules, it would be reasonable to consider the lifting of a copilot restriction for a Class 2 medical to allow private operations in general aviation aircraft.

It is hoped that this case will serve to assist in the development of a possible future consensus statement on the certification of pilots following paradoxical stroke associated with PFO, with discourse on the appropriate acceptable risk profile and thus restriction for private operations. This will provide greater clarity to both regulators and pilots on what the best practice approach should be regarding aeromedical certification in cases with small strokes, full recovery, and PFOs without high-risk characteristics on echocardiography.