Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Optical Coherence Tomography Angiography of Familial Retinal Arteriolar Tortuosity

Audrey Giocanti-Auregan, MD, PhD; Alain Gaudric, MD; Frédérique Buffon, MD; Manuele Mine, MD; Corinne Delahaye-Mazza, MD; Salomon Y. Cohen, MD, PhD; Ali Erginay, MD; Hugues Chabriat, MD, PhD; Elisabeth Tournier Lasserve, MD, PhD; Valérie Krivosic, MD

Abstract

BACKGROUND AND OBJECTIVE:

To analyze the location of familial retinal arterial tortuosity (fRAT) in the three-dimensional structure of retinal capillaries.

PATIENTS AND METHODS:

Retrospective observational study. Twelve eyes of six patients (two of whom were brothers) were imaged by optical coherence tomography angiography (OCTA). The data from their ocular and systemic examinations were recorded.

RESULTS:

OCTA imaging clearly showed increased tortuosity of second- and third-order retinal arteries in all cases, visible in the superficial vascular plexus (SVP) up to the arteriole termination in the capillaries. No change was visible in the deep capillary plexus (DCP).

CONCLUSIONS:

OCTA shows that fRAT affects all the course of the arterioles up to the capillaries in the SVP. The DCP does not show arteriolar tortuosity because it does not contain arterioles.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:397–401.]

Abstract

BACKGROUND AND OBJECTIVE:

To analyze the location of familial retinal arterial tortuosity (fRAT) in the three-dimensional structure of retinal capillaries.

PATIENTS AND METHODS:

Retrospective observational study. Twelve eyes of six patients (two of whom were brothers) were imaged by optical coherence tomography angiography (OCTA). The data from their ocular and systemic examinations were recorded.

RESULTS:

OCTA imaging clearly showed increased tortuosity of second- and third-order retinal arteries in all cases, visible in the superficial vascular plexus (SVP) up to the arteriole termination in the capillaries. No change was visible in the deep capillary plexus (DCP).

CONCLUSIONS:

OCTA shows that fRAT affects all the course of the arterioles up to the capillaries in the SVP. The DCP does not show arteriolar tortuosity because it does not contain arterioles.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:397–401.]

Introduction

Familial retinal arteriolar tortuosity (fRAT) is characterized by tortuosity of second- and third-order retinal arterioles.1 fRAT is usually described as an isolated retinal disease with autosomal dominant inheritance. However, fRAT has also been reported in association with cerebral small vessel disease (SVD) in patients with mutations in the COL4A1 gene.2,3 The clinical spectrum of COL4A1 mutations has been further extended and includes hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC syndrome).4 Mutations in the COL4A2 gene have also been described in patients with cerebral SVD.5

Optical coherence tomography angiography (OCTA) may be used to analyze the superficial vascular plexus (SVP) and deep capillary complex composed of intermediate (ICP) and deep capillary plexuses (DCP) in the macular region. We report here the results of the detailed analysis of the SVP and DCP in fRAT patients.

Patients and Methods

Twelve eyes of six patients were included in this retrospective case series. One patient was diagnosed while he was examined for possible early age-related macular degeneration. Two normotensive patients aged under 50 years who had stroke were diagnosed with fRAT during their extensive etiological workup. The brother of one of these patients was also investigated after his relative was diagnosed with fRAT. One patient was diagnosed when investigating his COL4A1 phenotype after his daughter developed an intracranial hemorrhage in early childhood. The latter had HANAC syndrome.

Patient charts were reviewed and data from their ophthalmic and general examinations were collected. All patients had a clinical examination with best-corrected visual acuity measurement, slit-lamp examination of the anterior segment and posterior pole, fundus photography (TRC50DX; Topcon Medical Systems, Oakland, NJ), and OCTA. The diagnosis of fRAT was based on fundus examination and photography showing an increased tortuosity of second- and third-order arterioles. The blood column caliber, vessel branching, venous system, and large retinal arteries were normal. All subjects were imaged by OCTA using the AngioVue OCTA device (Optovue; Freemont, CA). Scanning areas of 3 mm × 3 mm and 6 mm × 6 mm were recorded. Preset parameters were used to segment the SVP and DCP. The images of the DCP were processed with the beta version of the Projection Artifact Removal software, which removes the projection of the SVP and allows separating the intermediate capillary plexus from the DCP (AngioAnalytics Research Software version 2016.200.0.37; Optovue, Freemont, CA).

Results

In this series of 12 eyes of six patients with fRAT, with a mean age of 53.5 years, the diagnosis was made on fundus examination and showed bilateral tortuosity of the second- and third-order retinal arteries. In all eyes, OCTA showed the arterial tortuosity laying in the SVP, although there was no vessel tortuosity in the DCP (Figure 1). Patient clinical characteristics are summarized in the Table, and two cases are detailed below.

Optical coherence tomography angiography (OCTA) of the right eye of a patient with familial retinal arteriolar tortuosity, Case 2. Color (A) and red-free (B) images of the posterior pole showing a focus of pigmentary clumping, and multiple arteriolar tortuosities and loops. (C) OCTA of the superficial vascular plexus (SVP) shows with more detail and contrast the arteriolar tortuosity and loops up to the last division of arterioles in the vicinity of the foveal avascular zone. (D) OCTA of the deep capillary plexus (DCP) in a 6 mm × 6 mm cube showing that the pattern of the capillary network is normal. Only a few projections of the superficial arterioles are seen in some locations. (E) B-scan corresponding to the segmentation of the SVP with the flow signal in red. (F) B-scan corresponding to the segmentation of the DCP with the flow signal in red.

Figure 1.

Optical coherence tomography angiography (OCTA) of the right eye of a patient with familial retinal arteriolar tortuosity, Case 2. Color (A) and red-free (B) images of the posterior pole showing a focus of pigmentary clumping, and multiple arteriolar tortuosities and loops. (C) OCTA of the superficial vascular plexus (SVP) shows with more detail and contrast the arteriolar tortuosity and loops up to the last division of arterioles in the vicinity of the foveal avascular zone. (D) OCTA of the deep capillary plexus (DCP) in a 6 mm × 6 mm cube showing that the pattern of the capillary network is normal. Only a few projections of the superficial arterioles are seen in some locations. (E) B-scan corresponding to the segmentation of the SVP with the flow signal in red. (F) B-scan corresponding to the segmentation of the DCP with the flow signal in red.

Clinical Characteristics of the Patients

Table:

Clinical Characteristics of the Patients

Case 1

A 45-year-old man presented with a stroke with sudden right hemiplegia and aphasia due to a deep hematoma of the left internal capsule. No arteriovenous malformation nor high blood pressure were identified. The diagnosis of fRAT was made during the etiologic workup. After a few months, the patient totally recovered from his neurological deficit. Genetic analysis revealed a COL4A1 mutation (p.M1I). Visual acuity (VA) was 20/20 in both eyes. Fundus examination showed mild increased bilateral tortuosity of the small terminal arterioles near the fovea. OCTA of both eyes showed more clearly the arteriolar tortuosity in the SCP. There was no abnormal vessel tortuosity in the DCP.

Case 4

A 66-year-old patient was asked to perform a complete investigation after a COL4A2 (p.G560E) mutation had been identified in his brother. He had multiple cardiovascular risk factors such as obesity, type 2 diabetes, high blood pressure, hypercholesterolemia, and sleep apnea. He also had a medical history of atrial fibrillation treated with anticoagulants. He was carrying the same COL4A2 mutation as his brother. His VA was 20/20 in both eyes, and fundus examination also showed mild increased bilateral tortuosity of the second- and third-order retinal arterioles. OCTA of both eyes clearly showed the increased tortuosity of the small arterioles in the SVP but no anomaly in the DCP. The capillary vortex organization of the DCP was normal (Figure 2).

Optical coherence tomography angiography (OCTA) of the right eye of a patient with familial retinal arteriolar tortuosity, Case 4. (A) OCTA of the superficial vascular plexus (SVP) showing the retinal arteriolar tortuosity in a 3 mm × 3 mm cube, less marked than in Case 1. (C) B-scan corresponding to the segmentation of the SVP with the flow signal in red. (B) OCTA segmentation of the deep capillary plexus (DCP) without any projection artifact showing the unchanged pattern of capillary vortexes (yellow arrows). (D) B-scan corresponding to the segmentation of the DCP with the flow signal in red.

Figure 2.

Optical coherence tomography angiography (OCTA) of the right eye of a patient with familial retinal arteriolar tortuosity, Case 4. (A) OCTA of the superficial vascular plexus (SVP) showing the retinal arteriolar tortuosity in a 3 mm × 3 mm cube, less marked than in Case 1. (C) B-scan corresponding to the segmentation of the SVP with the flow signal in red. (B) OCTA segmentation of the deep capillary plexus (DCP) without any projection artifact showing the unchanged pattern of capillary vortexes (yellow arrows). (D) B-scan corresponding to the segmentation of the DCP with the flow signal in red.

Discussion

In fRAT, the disruption of the extracellular matrix of the arterial wall may be the cause of tortuosity of retinal arterioles.6,7 Collagen types IV alpha-1 and 2 (COL4A1 and COL4A2) are abundant and ubiquitous basement membrane proteins and major components of basement membranes. COL4A1 mutations weaken the vessel wall and lead to a phenotype of retinal arteriolar abnormalities in mice, fRAT and cerebral SVD.8 Furthermore, the microvasculature is likely to bleed in the brain and retina.1,9,10 In our series of six cases of fRAT, two patients had a mutation in the COL4A2 gene with retinal tortuosity similar to that found in patients with a COL4A1 mutation.

This familial disorder was initially described using fundus photography and fluorescein angiography (FA).1 OCTA now shows the increased tortuosity of perifoveal terminal arterioles with a high contrast. In our cases, retinal arteriolar tortuosity was only detected in the SVP segmentation, whereas no vascular abnormality was found in the DCP of any eye of our six patients. We were able to highlight this difference using the recent evolution of the AngioAnalytics software including projection artifact removal, which allows completely differentiating the DCP from the SVP. Retinal arterioles were tortuous up to capillaries surrounding the foveal avascular zone. In the cases in which the arterioles were the most tortuous, some loops penetrated into the inner nuclear layer and were then slightly visible encroaching the inner portion of the DCP (intermediate plexus). Unlike the SVP, the DCP is organized into polygonal units (capillary vortexes) converging to venules that drain into the superficial veins and receive their arteriolar supply via vertical capillaries coming from the SVP.11–14 As no vascular tortuosity was visible in the intermediate and deep capillary plexuses, the hypothesis that the DCP does not contain arterioles is supported. The fact that the DCP is located on the venous side of the retinal circulation has implications in the understanding of other retinal vascular diseases such as diabetic retinopathy.

In the present report, fRAT appeared to be limited to the SVP in all cases. OCTA provides a high contrast of the vessels and enhances the visibility of the perifoveal arterioles tortuosity and thus facilitates the diagnosis of fRAT without using FA. The fact that arteriolar tortuosity is restricted to the SVP supports the finding that the DCP is located on the venous side of the retinal circulation.15

References

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Clinical Characteristics of the Patients

Case Clinical Context Sex Age Cardiovascular Risk Factors Cerebral Involvement Renal Involvement Genetic SVP DCP
1 Etiologic workup for a stroke with cerebral SVD M 45 None Stroke, deep hematoma of the left internal capsule No COL4A1 mutation (p.M1I) +
2 Fundus examination for macular pigmentary clumping M 77 None No No Not done +
3 Etiologic workup for a stroke with cerebral SVD M 42 None Stroke No COL4A2 mutation (p.G560E) +
4 Familial genetic workup (brother of case 3) M 66 Obesity, type 2 diabetes, high blood pressure, hypercholesterolemia and sleep apnea No No COL4A2 mutation (p.G560E) +
5 Familial genetic workup (his daughter had an intracranial hemorrhage at the age of 6 months and was diagnosed COL4A1 carrier) M 29 None No No COL4A1 mutation (c.4546C>T p.R1516X) +
6 HANAC syndrome M 62 None Leukoencephalopathy, stroke Renal failure COL4A1 mutation (c.3G>T; p.M1I) +
Authors

From Service d'Ophtalmologie, AP-HP, Hôpital Avicenne, Université Paris 13, Bobigny, France (AGA); Service d'Ophtalmologie, AP-HP, Hôpital Lariboisière, Université Paris-Diderot, Sorbonne Paris Cité, France (AG, AE, VK); Centre de Référence des Maladies Vasculaires Rares du Cerveau et de l'OEil (CERVCO), Hôpital Lariboisière, AP-HP, Paris (AG, FB, HC, VK); Département de Neurologie, AP-HP, Hôpital Lariboisière, DHU-NeuroVasc, Université Paris-Diderot, Sorbonne Paris Cité, France (FB, HC); Service de Génétique, AP-HP, Hôpital Lariboisière, DHU-NeuroVasc Université Paris-Diderot, Sorbonne Paris Cité, France (MM, ETL); INSERM, U1161, F-75010 Paris (MM, ETL); Centre Ophtalmologique d'Imagerie et de Laser, Paris (AG, CDM, SYC); and Service d'Ophtalmologie, Hôpital Intercommunal, Université Paris-Est-Creteil, Creteil, France (SYC).

This work was presented as a paper at the 4th Annual OCT-Angiography Meeting held in Rome in December 2016.

Dr. Gaudric reports grants from Novartis and Bayer outside the submitted work. Dr. Krivosic reports grants from Novartis and personal fees from Bayer and Allergan outside the submitted work. Dr. Cohen reports grants from Alcon, Allergan, Bayer, Novartis, Roche, and Thea outside the submitted work. Dr. Erginay reports grants from Novartis, Bayer, and Allergan outside the submitted work. The remaining authors report no relevant financial disclosures.

Address correspondence to Valérie Krivosic, MD, Service d'Ophtalmologie, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France; email: vkrivosic@gmail.com.

Received: July 03, 2017
Accepted: November 01, 2017

10.3928/23258160-20180601-03

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