Paradoxical Embolism in a Case of Hereditary Hemorrhagic Telangiectasia: Case Report with Literature Review
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.288990
Source of Support: None, Conflict of Interest: None
Keywords: Embolic stroke, hereditary hemorrhagic telangiectasia, paradoxical embolism, pulmonary arteriovenous malformation
Cardioembolic stroke is responsible for about 14-30% of all ischemic stroke cases , Paradoxical embolization is a well-recognized cause of ischemic stroke. Paradoxical emboli are often attributed to patent foramen ovale (PFO), while pulmonary arteriovenous malformations (PAVM) or fistula are another less common source of right-to-left shunt. In this case report, we highlight the occurrence of paradoxical embolism in a patient with hereditary hemorrhagic telangiectasia (HHT) due to PAVM.
A 48-year-old male reported with a history of acute onset giddiness and swaying while walking on admission. He was a chronic smoker with 18 pack-years of smoking. He had no other vascular risk factors. The neurological examination confirmed right hemiparesis and positive cerebellar signs on the left side. In view of the acute presentation, the possibility of a stroke was considered.
His magnetic resonance imaging (MRI) of the brain showed left cerebellar infarct with vermis involvement and left middle cerebral artery territory cortical infarct [Figure 1]: Panel d and g]. His MR angiogram was normal. In view of the multiple arterial territory infarcts with normal vessels on imaging, the possibility of an embolic stroke was considered. His ECG, 24 h Holter monitoring and 2D echocardiogram (ECHO) didn't reveal any cardiac abnormalities including a patent foramen ovale (PFO). However, a transesophageal ECHO including study with agitated saline to look for an embolic source was not done. His laboratory workup was within normal limits except for higher hemoglobin (17.2 g/dL) and hematocrit (51%). His viral markers, antinuclear antibody (ANA) profile and serum homocysteine did were normal.
On clinical examination, the patient had significant clubbing with low arterial oxygen saturation (PaO2-85.5 mm Hg) [Figure 1]: Panel a and b] But he had no respiratory complaints and his cardiac evaluation was normal. Hence, the possibility of an extracardiac, right-to-left shunt was considered. His chest X-ray showed non-homogenous opacity over the bilateral lower zone. We proceeded further with a CT of the chest with contrast, which revealed PAVM in the antero-basal segment of the right lower lobe and a lateral basal segment of the left lower lobe. [Figure 2] Both lesions were fed by a single segmental branch of the lower lobar pulmonary artery and drained by a single branch of the inferior pulmonary vein. Even though pulmonary angiogram is the gold standard for the diagnosis of pulmonary AVM, it was not done in our patient. Additionally, he had splenic hemangiomas.
In the past, the patient reported recurrent epistaxis from his late twenties. An AVM over his left leg was noted six years back. [Figure 1], panel c] He underwent surgical correction of the leg AVM after six months of detection but had a recurrence. With this significant history of epistaxis and multiple vascular malformations, the possibility of an inherited vascular abnormality was explored. A four-generation family tree was traced and showed a strong family history of epistaxis and hemoptysis [Figure 3]. His elder brother had a history of epistaxis, hemoptysis, nail bed hemorrhage and hematuria. On evaluation, he had pulmonary AVM for which surgical correction was done but succumbed to the illness after 5-month following a massive bout of hemoptysis at the age of 58. The rest of the involved family members were having epistaxis or hemoptysis.
The patient was treated with antiplatelet and statins. He was functionally independent at a 1-month follow-up and had no recurrence at a 6-month follow-up. Our patient fulfilled all four of the Curacao criteria  for the diagnosis of definite HHT. The genetic evaluation was not done in our patient. However, in view of the possible recurrence of embolic stroke, he was transferred to a higher center for surgical correction of pulmonary AV fistula.
Paradoxical embolization is a relatively rare event, representing 2% of arterial emboli. The most common cause of right-to-left shunt in adult patients is PFO, the incidence of which has been reported in up to 25–35% of the normal population., PFO can be detected by contrast ECHO with agitated saline by the presence of bubbles within the left atrium., Once considered rare by autopsy studies, population-wide thoracic CT screenings estimates a PAVM prevalence of 1 in 2630. Up to 80% of PAVMs occur in patients with HHT.
HHT is an inherited vascular abnormality where abnormal telangiectatic capillaries result in frequent bleeding episodes, primarily from the nose and the gastrointestinal tract. Also known as Osler-Weber-Rendu disease, it is a rare autosomal dominant genetic disorder with a prevalence of 1 in 5-8000. AVMs in the lung, brain, and liver may also occur in HHT. The telangiectasia can often be visualized on the oral and nasal mucosa. Signs and symptoms develop over time. Epistaxis begins on average, at the age of 12 and occurs in more than 95% of affected individuals by middle age.
Approximately 15–35% of HHT patients have PAVMs, and 50–85% of PAVMs patients have HHT. Most of the patients with PAVMs remain asymptomatic over the course of their lifetime, but about 30% of patients have complications related to the central nervous system including seizure, migraine, brain abscess, transient ischemic attack, and ischemic stroke.
HHT is usually caused by mutations in endoglin (eng, HHT type 1), ACVRL1/ALK1 (HHT type 2), or SMAD 4 (HHT with juvenile polyposis). PAVMs are particularly common in HHT1, with 85% of “eng” mutation carriers demonstrating right-to-left shunts on contrast ECHO. Additionally, ACVRL1 on chromosome 9q33-34 (HHT2) is associated with pulmonary AVM in 40% of cases. A recent study by Akagawa et al. identified a heterozygous c. 685delG mutation resulting in immediate premature termination (p.Ala229 ProfsTer6) in “eng.”
PAVM is a well-recognized cause of paradoxical brain embolism because of the continuous right-to-left shunt. Brain infarction associated with PAVMs most likely occurs in patients with feeding arteries of more than a 3-mm diameter. Patients with HHT are at increased risk for both bleeding and clotting events. Any anticoagulation recommendations must take into account the bleeding risks associated with HHT. Because of these competing complications, hematologists are often faced with difficult clinical decisions., Embolization therapy has become the standard approach for treating PAVMs. Embolization therapy is currently recommended only for PAVMs with feeding arteries greater than 3 mm in diameter. Surgical techniques used to treat PAVMs include vascular ligation, local excision, lobectomy, and pneumonectomy. The major advantages of percutaneous closure over surgery include low morbidity and short hospitalization stay. Embolotherapy involves the use of coils, detachable balloons, and devices. After successful occlusion of feeding arteries, remodeling leads to PAVM regression with the return of former feeding and draining vessels to normal size and risk of ischemic stroke is reduced following therapy.
Arterial ischemic stroke occurring in multiple arterial territories with normal vessels on imaging should prompt us to think of an embolic cause. Paradoxical embolism even though rare should be considered and extra-cardiac causes are to be explored in the etiology. Our case highlights the importance of clinical examination, well-documented family history, supportive clinical investigations, and imaging studies in the evaluation of a cryptogenic stroke.
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[Figure 1], [Figure 2], [Figure 3]