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Personalised stroke evaluation and management: tailoring individualised patient care for hereditary haemorrhagic telangiectasia
  1. Zackary Park1,
  2. Randy Dunston1,2 and
  3. Tamra Ranasinghe1,2
  1. 1Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
  2. 2Neurology, Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, USA
  1. Correspondence to Mr Zackary Park; zackarypark{at}gmail.com

Summary

Hereditary haemorrhagic telangiectasia (HHT) has an estimated prevalence of 1 in 5000–8000 individuals globally with pulmonary arteriovenous malformations (PAVMs) affecting approximately 15%–50% of HHT patients. Ischaemic stroke is a known complication of PAVMs that affects ≤30% of patients with PAVMs. Studies have shown that patients with PAVMs have ischaemic stroke a decade earlier than routine stroke. The predominant mechanism of ischaemic stroke in HHT patients is paradoxical embolism due to PAVMs, but most HHT-related PAVMs are asymptomatic. Additionally, HHT is often underdiagnosed in patients and poses a challenge to physicians due to its rarity. We present a case of a patient with ischaemic stroke who was subsequently diagnosed with HHT and found to have a PAVM on further evaluation. This case highlights the importance of using an individualised patient-centred stroke evaluation and screening for PAVMs in patients who had a stroke with possible or suspected HHT and definite HHT.

  • Neurology
  • Stroke
  • Genetics
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Background

Hereditary haemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a rare autosomal dominant genetic disorder that predisposes individuals to abnormal blood vessel formation in multiple organ systems. HHT is estimated to affect 1 in 5000–8000 individuals worldwide and can affect people of all races and genders.1–3 However, the underdiagnosis of HHT patients continues to be a widespread phenomenon likely due to its rarity and lack of clinical awareness of the disease.4 Previous figures revealed that a significant portion of HHT patients in the USA, possibly as high as 90%, continue to lack a conclusive diagnosis and adequate monitoring.4 The pathognomic vascular lesions in HHT are telangiectasias and arteriovenous malformations (AVMs), which are often seen on the skin and mucous membranes and in internal organs, such as the lungs, brain and liver leading to complications known as pulmonary AVMs (PAVMs), cerebral AVMs (CAVMs) and hepatic AVMs, respectively (figure 1).1 3 Furthermore, previous reports have documented associated neurological manifestations in HHT patients with PAVMs, including cerebral abscess, migraine, stroke and transient ischaemic attack.3 5

Figure 1

Graphical representation of the vascular complications of hereditary haemorrhagic telangiectasia, including cerebral arteriovenous malformations (A), skin and mucous telangiectasias (B), pulmonary arteriovenous malformations (C) and hepatic arteriovenous malformations (D), illustrated by Minaanandag on the Fiverr application.

A PAVM is an abnormal connection between a pulmonary artery and pulmonary vein that bypasses the normal pulmonary capillary bed which may lead to an intrapulmonary right-to-left shunt in the setting of low resistance and high blood flow. If untreated, these malformed connections can lead to various complications, such as cerebral abscess, stroke, paradoxical emboli and hypoxaemia.1 3 A strong association has been documented between a single PAVM with a feeding artery (FA) diameter exceeding 3 mm and neurological complications, with increased prevalence in patients with multiple PAVMs.3 6 This suggests that a greater number of malformations increases the predisposition for paradoxical embolisation. Acute ischaemic stroke is a known complication of HHT that affects ≤30% of patients with PAVMs.1 Overall, PAVMs are estimated to be prevalent in 15%–50% of HHT patients and are often symptomatic, and HHT eventually manifests in roughly 80%–90% of patients who present with PAVMs.6 Embolisation of PAVMs has been proven to be a safe and effective treatment.7 We present a case of acute ischaemic stroke secondary to paradoxical embolism in an HHT patient in order to discuss the importance of an individualised patient-centred stroke evaluation.

Case presentation

A woman in her 50s with a history of chronic epistaxis presented with lightheadedness, dizziness, gait instability, occipital headaches and dyspnoea on exertion for the past 2–3 months. Her vitals on arrival were within normal limits; blood pressure was 128/63 mmHg, heart rate was 80 beats per minute, respiratory rate was 18 breaths per minute and she was afebrile. There were no pertinent abnormal findings on the physical exam, including skin or mucosal telangiectasias. She reported a family history of an immediate family member with HHT.

Investigations

Initial diagnostic workup: serum white cell count 8.4 × 109/L, haemoglobin 57 g/L, platelets 799 × 109/L, basic metabolic panel was unremarkable, low-density lipoprotein 82 mg/dL, haemoglobin A1C 5.4%, iron 14 µg/dL, total iron-binding capacity 566 µg/dL, unsaturated iron-binding capacity >450 µg/dL, transferrin 404 mg/dL, ferritin 4 ng/mL and reticulocyte % was within normal limits. ECG showed normal sinus rhythm.

CT of the brain without contrast demonstrated a hypodensity in the right cerebellar hemisphere. MRI of the brain showed multiple acute infarcts in the right cerebellar hemisphere and remote infarcts in the left cerebellar hemisphere (figure 2A). MR angiography of the head and neck demonstrated no significant flow limiting stenosis or occlusions. A transthoracic echocardiogram with agitated saline contrast was performed to evaluate for a possible shunt. Injection of agitated saline demonstrated a severe right to left shunt within five heart beats. The Risk of Paradoxical Embolism (RoPE) score was determined to be 6, which was suggestive of a 62% chance that her stroke was due to her patent foramen ovale.8 Upper extremity ultrasound Doppler and lower extremity ultrasound Doppler were negative for deep vein thrombosis.

Figure 2

MRI brain diffusion-weighted imaging demonstrating multiple right cerebellar infarctions, depicted blue arrows (A). CT chest angiogram demonstrating pulmonary arteries with a single dilated 4.5 mm feeding artery and a single dilated, early filling, draining vein with a dominant intervening aneurysm measuring approximately 2.0×3.3×2.7 cm, depicted by blue arrow (B, C). Yellow arrow depicts a crescentic thrombus along the posteromedial wall of the aneurysm (C).

Given the history of recurrent epistaxis and a first-degree relative with HHT, the patient was screened for HHT using the Curaçao Diagnostic Criteria for HHT.9 She met two of the four Curaçao criteria, suggestive of possible HHT.9 Therefore, we proceeded to screen with digital subtraction angiography (DSA) to evaluate for CAVMs. The DSA demonstrated a 4 mm left superior hypophyseal artery aneurysm, without CAVMs, but visualised multiple mucosal telangiectasias filling from the palatine and sphenopalatine arteries. The presence of mucosal telangiectasias fulfilled the third criteria to diagnose our patient with definite HHT.9 To further screen for PAVMs, a CT angiography (CTA) of the chest was obtained, which demonstrated a right lower lobe PAVM with a 3.3 cm aneurysm and a thrombus (figure 2B,C). The size of the FA of the PAVM was 4.5 mm in diameter. The presence of the PAVM fulfilled the fourth criteria and further supported her diagnosis of definite HHT.9

Differential diagnosis

Aetiology of the embolic appearing right cerebellar stroke with a prior left cerebellar stroke is suggestive of embolic stroke of unknown source (ESUS). In such cases, the patient requires a comprehensive stroke evaluation. Cardioembolic aetiologies in the differential diagnosis include evaluating for atrial fibrillation, cardiac thrombi, valvular vegetations, cardiac myxomas and PFO (patent foramen ovale). Given her relatively young age an underlying hypercoagulability such as lupus should be considered. In older ESUS patients an underlying malignancy should be included in the differential diagnosis. Further, the carotid arch should be evaluated for soft ulcerated plaques.

Due to the history of epistaxis, a first-degree relative with HHT, the presence of telangiectasias and her CTA chest findings, the clinical suspicion was of HHT with a PAVM. Although genetic testing was not performed, the Curaçao Diagnostic Criteria for HHT supported a diagnosis of definite HHT.9 The aetiology of her stroke was attributed to the PAVM with an aneurysm and a thrombus rather than due to the PFO.

Treatment

The patient was transfused with packed red blood cells with a subsequent haemoglobin of 81 g/L. She was involved in a risk-versus-benefit discussion, and despite her low haemoglobin and epistaxis, she was initiated on therapeutic intravenous heparin for the thrombus within the aneurysm and underwent embolisation of the PAVM by interventional radiology (figure 3).

Figure 3

Angiogram of the right lower lobe pulmonary artery revealing a large pulmonary arteriovenous malformation with an aneurysm, depicted by blue arrow, supplied by a single dilated 4.5 mm feeding artery (A). Pulmonary angiogram demonstrating a successful post coil embolisation of the pulmonary arteriovenous malformation and aneurysm (B, C).

Outcome and follow-up

The patient was discharged on antiplatelet therapy, a statin and oral iron replacement with a plan to follow up with otorhinolaryngology for the embolisation of her mucosal telangiectasias if she continued to have recurrent epistaxis. Doppler ultrasound of the liver was performed in the outpatient clinic to further evaluate for asymptomatic hepatic AVMs. A year after the PAVM embolisation, the patient has shown no recurrence of strokes and remains on aspirin 81 mg for secondary stroke prevention.

Discussion

Neurological disorders such as ischaemic stroke, cerebral haemorrhage and brain abscess are a known complication of HHT. One hypothesis that supports the increase in neurological complications in HHT patients is the increased prevalence of AVMs, particularly in the and the brain and lungs.5 10 Up to 23% of HHT patients develop cerebral vascular malformations with the most common being CAVMs, which carry the risk of possible rupture.11 The prevalence of CAVMs in the HHT population is approximately 10%–20%, and the risk of CAVM rupture in HHT patients is reported to be from 0.3% to 0.7% per year per lesion or 0.4% to 1.3% per year per patient.10 11 Some studies have reported the risk of CAVM rupture in HHT patients to be as high as 1.4%–2% per year.12 CAVM ruptures are a rare complication but can cause severe consequences and thus require screening with digital subtraction angiography as in our case or cerebral MRI, which is recommended for adults with possible or definite HHT by the Second International Guidelines for the Diagnosis and Management of HHT.7 11 More recently, some case reports have reported PAVMs causing cerebrovascular accidents in patients with HHT and without HHT.2 13–15 In our review of the literature, there are no recent studies or case reports that discuss the necessity of a patient-centred stroke evaluation in patients who present with signs and symptoms of HHT, especially in the setting of PAVMs.

PAVMs create right-to-left shunts via abnormal connections between pulmonary arteries and pulmonary veins that bypass the normal pulmonary capillary bed. These intrapulmonary shunts have been documented to manifest as dyspnoea, fatigue, cyanosis, polycythaemia and hypoxia but can also allow for the passage of emboli or bacteria to enter the cerebral circulation, which can result in ischaemic strokes and brain abscesses, respectively.1 3 10 PAVMs and PFOs share similar mechanisms in the development of brain infarction through right-to-left shunts. However, the shunt flow through PAVMs is continuous, whereas the flow though PFOs is intermittent when the right atrial pressure is increased. PAVMs are considered to have a higher probability than PFOs as a route of paradoxical embolisation.16 PAVMs are the most frequent cause of neurological symptoms in this population, with an estimated prevalence of 15%–50% in HHT patients, and between 25% and 33% of HHT patients with PAVMs will develop cerebral ischaemic symptoms.6 Notably, HHT patients with PAVMs who engage in scuba diving have an increased risk of decompression illness due to paradoxical gas embolism, which can lead to vascular obstruction and subsequent tissue ischaemia.17 Antibiotic prophylaxis for dental and surgical procedures is also strongly recommended for HHT patients with PAVMs. This precaution is based on the higher risk of brain abscess for these patients, which is several orders of magnitude higher than that for heart patients at risk for endocarditis.18 PAVMs are a rare finding, with studies showing 4.3%–7.6% of HHT admissions annually are related to a PAVM diagnosis but should be ruled out in all patients with HHT due to these reasons.19 Implementing proper standardised screening techniques for PAVMs is necessary for decreasing the risk of complications and preventing increased mortality.3 5

Given the severity of complications from PAVMs in the HHT population, current guidelines recommend that physicians screen all patients with possible or confirmed HHT for PAVMs.7 Prior modelling demonstrates that 25% of untreated patients with PAVMs would have a clinical stroke by age 65, losing up to nine extra healthy life-years per patient in a recent US nationwide analysis (2005–2014).20 Screening can be accomplished through CT with a modified angiography protocol or transthoracic contrast echocardiography (TTCE), which is the screening test of choice for PAVMs.21 Current indications for treatment of PAVMs include any PAVM with FA diameter ≥2–3 mm, increasing PAVM size, paradoxical emboli, symptomatic hypoxaemia or any other severe complication.22 Transcatheter embolisation is considered the gold standard for treatment of PAVMs, contrary to surgical excision which would sacrifice excess lung tissue, increase postprocedural mortality and lengthen hospital stays.7 Surgery is reserved for refractory cases which have failed embolotherapy. A compounding complication for HHT patients is the risk of hypercoagulable states due to recurrent iron loss through haemorrhage leading to increased levels of von Willebrand factor and factor VIII, resulting in a prothrombotic state.23 It is important to weigh the risks and benefits of anticoagulation in this patient population. Overall, PAVMs are curable, and the treatment of PAVMs has been shown to reduce the risk of ischaemic stroke.23 One study examined stroke rates in 219 patients with PAVMs before and after embolisation of all visible PAVMs and found a significant reduction of recurrent stroke (13.6% vs 0%, respectively) at a mean follow-up of 3.7 years.20 24 Per the consensus from the British Thoracic Society, the Cardiovascular and Interventional Radiological Society of Europe and the most recent Cochrane Database review, every visible PAVM on CT scans should be considered for endovascular treatment, regardless of the feeding diameter and even when asymptomatic.20 22 25 26 As of now, there are no prevailing secondary stroke prevention guidelines from the American Heart Association/American Stroke Association (AHA/ASA) specifically addressing PAVM embolisation. Additionally, there is a paucity of data on long-term antithrombotic therapy use for secondary stroke prevention post-PAVM embolisation. The international guidelines for HHT management recommend when indicated, using a single antiplatelet or anticoagulant therapy and avoiding dual antiplatelet therapy or a combination of antiplatelet plus anticoagulant.7

Although our patient had a large PFO and a high RoPE score, her stroke aetiology was likely secondary to the PAVM with a thrombus, which was treated appropriately with anticoagulation followed by embolisation. If she had not screened for PAVMs with the CTA chest, she would have undergone a PFO closure procedure in the outpatient setting and likely continued to have recurrent strokes due to the undiagnosed and untreated PAVM with a thrombus. Therefore, it is essential to use an individualised patient-centred stroke evaluation and screening for PAVMs in patients who had a stroke with possible or suspected HHT and definite HHT.

Conclusion

This case highlights the importance of using an individualised patient-centred stroke evaluation and thoroughly screening patients who had a stroke with HHT. HHT is often underdiagnosed in patients and poses a challenge to providers due to its rarity and the lack of clinical awareness of the disease. Current guidelines indicate that all patients with possible or confirmed HHT should be screened for PAVMs with the recommended screening modalities, which include CT with a modified angiography protocol or TTCE.

Learning points

  • Hereditary haemorrhagic telangiectasia (HHT) is frequently underdiagnosed in patients due to its rarity and lack of clinical awareness. An individualised patient-centred stroke evaluation, along with extensive screening for pulmonary arteriovenous malformations (PAVMs) in patients who had a stroke with HHT, is crucial for accurate diagnosis and timely intervention to prevent further complications.

  • Genetic testing plays a pivotal role in diagnosing HHT, an autosomal dominant disorder. Families with signs of HHT can have their diagnosis confirmed through genetic testing, making it invaluable for those who do not meet Curaçao criteria or are asymptomatic. This early identification allows for personalised care and the management of potential complications.

  • Ischaemic stroke in HHT patients can be caused by paradoxical embolism due to PAVMs, even though most HHT-related PAVMs are asymptomatic. The risk of stroke in HHT patients with untreated PAVMs increases with age, emphasising the importance of early screening and intervention.

  • Treatment decisions should be made after considering the patient’s overall health, risks and benefits and may involve interventions such as embolisation for PAVMs to reduce the risk of recurrent stroke. Regular follow-up and monitoring of the patient’s condition are crucial to ensure appropriate management.

Ethics statements

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References

Footnotes

  • Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: ZP, RD and TR. The following authors gave final approval of the manuscript: ZP, RD and TR.

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

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

  • Competing interests None declared.

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