Familial Retinal Arterial Macroaneurysms with Peripheral Retinal Ischemia: A Characterization on Ultra-Widefield Fluorescein Angiography

Abstract

Retinal arterial macroaneurysm with supravalvular pulmonic stenosis (RAMSVPS), also known as familial retinal arterial macroaneurysm syndrome, is an autosomal recessive disorder associated with many life-threatening complications. The disease is characterized by progressive multiple retinal arterial macroaneurysms, retinal arterial beading, and recurrent vitreous hemorrhage. Here, we describe the first case of RAMSVPS associated with peripheral ischemia evident on ultra-widefield fluorescein angiography. A 23-year-old otherwise healthy woman presented to our ophthalmology emergency room with a 1-week history of right eye floaters and decreased vision. Dilated fundoscopic examination showed right eye vitreous and preretinal hemorrhage with bilateral active and involuted retinal arterial macroaneurysms, arterial beading, and sclerosed vessels. Ultra-widefield fluorescein angiography demonstrated multiple macroaneurysms on the optic discs and along the major retinal arteries in addition to significant peripheral retinal ischemia in both eyes. Echocardiography showed severe supravalvular pulmonic stenosis that required urgent pulmonary valvuloplasty. Indeed, peripheral retinal ischemia is an additional finding in RAMSVPS.

Introduction

Retinal arterial macroaneurysm with supravalvular pulmonic stenosis (RAMSVPS), also known as familial retinal arterial macroaneurysm syndrome, is a genetic disorder that has been described initially in multiple unrelated Saudi families.[1] The disease is characterized by progressive multiple retinal arterial macroaneurysms, retinal arterial beading, and recurrent vitreous hemorrhage.[2] The disease is inherited as an autosomal recessive pattern, and the causal mutation was identified as a founder splicing mutation in the insulin-like growth factor-binding protein 7 (IGFBP-7).[1] Valvular or supravalvular pulmonic stenosis is the most consistent finding in patients with RAMSVPS.[3] Other associated systemic complications included liver cirrhosis, renal hypoplasia, and stroke.[3] Four patients in a recent case series died prematurely due to cardiovascular and cerebral complications.[3] Hence, early diagnosis and multidisciplinary management are of paramount importance to prevent systemic complications and death.

The most common presenting findings in patients with RAMSVPS are recurrent vitreous hemorrhage and/or subretinal exudation.[4] Other ocular findings are including sclerosed retinal vessels, peripheral vascular telangiectasia, exudative retinal detachment, gliotic tissue proliferation, and the presence of remnant hyaloid artery.[3]

The first case of retinal arterial macroaneurysm in a young patient associated with congenital pulmonary stenosis was initially described in 1993 by Abu El-Asrar et al.[5] Thereafter, a mutation in the IGFBP-7 gene was found to be the underlying genetic cause of this disease.[1,3] Recent advances in multimodal retinal imaging led to novel insights in the retinal disease pathogenesis. In this study, we describe for the first time the presence of peripheral retinal ischemia in a patient with RAMSVPS that was evident on ultra-widefield fluorescein angiography.

Case Report

A 23-year-old otherwise healthy woman presented to our ophthalmology emergency room with a 1-week history of right eye floaters and decreased vision. Her past ocular and medical history was unremarkable. Family history disclosed that her older brother died at the age of 9 due to unknown cardiac cause. Upon examination, her visual acuity was 20/60 in the right eye and 20/25 in the left eye. Intraocular pressure was 12 mmHg in the right eye and 14 mmHg in the left eye. The anterior segment was normal in both eyes. Dilated fundoscopic examination showed right eye vitreous and preretinal hemorrhage and bilateral arterial macroaneurysms (active and involuted), retinal arterial beading, and sclerosed retinal vessels [Figure 1a–c]. No macular edema was detected on optical coherence tomography in either eye. Ultra-widefield fluorescein angiography demonstrated multiple macroaneurysms on the optic discs and major retinal arterioles in addition to a significant peripheral retinal ischemia in both eyes [Figure 1d and e]. The patient underwent laser photocoagulation to the peripheral avascular retina in both eyes.

Figure 1.

(a) Fundus photo of the right eye showing an active microaneurysm with preretinal and subretinal hemorrhage. (b) Fundus photo of the right eye showing multiple active and involuted macroaneurysms along with a sclerosed retinal vessel. (c) Fundus photo of the left eye showing multiple macroaneurysms. (d and e) Ultra-widefield fluorescein angiography demonstrating multiple macroaneurysms along major retinal arteries in addition to significant peripheral retinal ischemia in both eyes

Systemic workup included echocardiography which showed severe supravalvular pulmonic stenosis with a peak gradient of 70–80 mmHg that required urgent pulmonary valvuloplasty. Other cardiac findings included small patent ductus arteriosus with normal right ventricular function. Abdominal ultrasound imaging demonstrated cirrhotic liver features with splenomegaly but normal kidneys. Magnetic resonance imaging of the brain and neck vessels was unremarkable. Genetic testing of the patient showed splicing mutation of IGFBP-7 with autosomal recessive inheritance.

At 12-month follow-up, dilated fundus examination showed complete resolution of the vitreous and preretinal hemorrhage in the right eye and the macroaneurysms in both eyes. Two months later, the patient presented to our ophthalmology emergency room with decreased vision in the left eye. Dilated fundus examination revealed thick submacular hemorrhage and preretinal hemorrhage in the left eye [Figure 2a]. The patient underwent pars plana vitrectomy with intravitreal injection of tissue plasminogen activator and perfluoropropane 16% gas tamponade. At 4-month follow-up, the thick submacular hemorrhage was squeezed away from the macula resulting in improving visual acuity to 20/20 [Figure 2b].

Figure 2.

(a) Fundus photo of the left eye showing subretinal hemorrhage along with preretinal hemorrhage 1 year after her initial presentation. (b) Fundus photo of the left eye after surgical management showing how the subretinal blood was squeezed away from the macula

Discussion

RAMSVPS is a life-threatening condition and a higher likelihood that an ophthalmologist is the first to encounter these patients. In a recent and largest series of RAMSVPS, the reported systemic complications were cardiac, liver, brain, and renal involvement. Hence, prompt investigations must include cardiac echocardiography, abdominal ultrasound, and head-and-neck magnetic resonance imaging looking for vascular abnormalities.[3]

The current patient presented with vitreous and preretinal hemorrhage and then 1 year later submacular hemorrhage. This is consistent with what has been reported by Alkuraya et al., who demonstrated that recurrent bleeding might occur in 55%–59% of the patients.[3] Histopathological studies of idiopathic retinal macroaneurysms revealed multiple linear breaks in the retinal arterial vascular wall which lead to exudation as well as rupture and hemorrhage.[6] Similar studies are needed in RAMSVPS to better understand the natural history of these macroaneurysms.

Ultra-widefield fluorescein angiography gives the advantage of detecting peripheral retinal ischemia and neovascularization. Previous reports on RAMSVPS have not utilized the use of ultra-widefield fluorescein angiography to assess peripheral retinal perfusion. Our findings expand the spectrum of retinal vascular abnormalities in RAMSVPS. We do believe that such imaging modality is crucial as an investigative tool in patients diagnosed with RAMSVPS.

In conclusion, ophthalmologists should be aware of the different fundoscopic and angiographic manifestations of RAMSVPS. Early diagnosis, systemic workup, and multidisciplinary management is crucial to prevent systemic complications and death.

Disclosure

The case was part of a large retrospective chart review.[3] However, in this report, we have presented the full descriptive and photographic details.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.