Marfan Syndrome (MFS) is a hereditary disorder of connective tissue caused by mutations in the gene FBN1, which encodes the extracellular protein, fibrillin-1. FBN1 is involved in the regulation of multiple modulatory genes and growth factors throughout the connective tissue of the body. Mutations in FBN1 lead to progressive abnormalities of the cardiovascular, skeletal, and ocular systems. Ocular manifestations include: flattened cornea, ectopia lentis, increased axial length, glaucoma, cataract, and retinal detachment.
Examination of the posterior segment of the eye in MFS patients is often difficult due to limited pupillary dilation, lens subluxation, and young age. Observational studies have focused on clinical characteristics and surgical outcomes of patients with retinal detachments who are referred to large tertiary centers for further assessment.1–4 There are few studies that examine the clinical characteristics of the posterior segment of those patients with MFS, without retinal detachments.
Patients with MFS are at a high risk of vision-threatening retinal pathology, including retinal detachment. Previous studies have reported the incidence of retinal detachment ranging from 3.5% to 11% in MFS patients.1,2 Retinal detachment rates increase to between 8% and 38% in patients with ectopia lentis or who are status post lens surgery.1 Bilateral detachments are much more common in MFS patients than in the general population and occur in up to between 35% and 45% of patients. This suggests a possible genetic predisposition for detachment.2–4 Vitreoretinal sequelae are more common in patients with earlier onset of clinical findings, including ectopia lentis, increased axial length, and aphakia.1,2,4 Frequent examination is required in these patients given their high risk for retinal disease/pathology.
The Marfan Eye Consortium of Chicago was organized to study the clinical characteristics of a large group of MFS patients, using clinical examinations and modern imaging technologies of the anterior and posterior segments. The present study focuses on the posterior segment in two parts: describing key findings in clinical examinations, and defining the role of imaging in augmenting the clinical examination of this population. Peripheral retinal disease was detected in patients through both dilated ophthalmic examination and wide-field photographic imaging, using ultra-widefield technology by a scanning laser ophthalmoscope (Optos 200Tx; Optos PLC, Dunfermline, Scotland, United Kingdom). This technology allows wide-field retinal examination without the need for complete dilation. Therefore, it is a potentially useful tool for studying this group of patients who do not dilate well.5–10
Patients and Methods
Patients were examined during the National Marfan Foundation’s annual conference in Chicago, IL, in August 2012. As part of the annual conference, the Marfan Eye Consortium of Chicago — a collaborative effort between Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern Memorial Hospital, and the University of Illinois — was created to study the ocular manifestations of patients with MFS. Institutional review board approvals were obtained from the respective institutions. Informed consent was obtained from the patients and/or their guardians. All patients included in this study were diagnosed with MFS based on Ghent nosology, the current standard for diagnosis of MFS. Many subjects were examined as part of the Consortium; however, only those with MFS diagnosis were included in the study. Fifty-six patients were evaluated (total count: n = 110 eyes, two unrecorded data sets). For imaging of the posterior segment, color ultra-widefield retinal images were obtained using the Optos system. Of the 56 total patients, fundus photographs were available in 47 patients (93 eyes), which were used in the cohort and in imaging analysis.
Examination of the posterior segment was performed with a 20-Diopter (D) and/or 28-D lens and indirect ophthalmoscopy with small pupil capabilities by vitreoretinal specialists, utilizing scleral depression whenever possible. The examination was considered full if retina anterior to the vortex veins could be assessed in all four quadrants. Limitation to full examination was documented for each patient and compared to the ultra-widefield imaging.
The ultra-widefield color images were analyzed by a different vitreoretinal specialist, masked to the clinical examinations. Several images were captured for each eye, and all images for each eye were evaluated. Images were reviewed with V2 Vantage Dx software (Optos PLC, Dunfermline, Scotland, United Kingdom) and manipulated with standard digital enhancement techniques available within the V2 software. An average of two to four non-steered images were recorded per eye. Reported data combine the fundus findings from all images for each evaluated eye. The images were evaluated for field of view, comparison to standard 9-field imaging, and artifact.
Quadrants (superior, nasal, inferior, temporal) were considered visible if the fundus anterior to the equator, as located by equatorial vortex veins, could be evaluated in the images. The center of the image was set at the macula and divided into four quadrants (Figure 1).6–8,11 All images were used for final analysis of each eye. If one quadrant was not visible in one image but was in a subsequent image, that quadrant was considered visualized.
Schematic of the quadrants (superior, nasal, inferior, temporal) used for analysis. The lines were drawn through the fovea for reference. Each quadrant was considered visible if the fundus beyond the equator, as located by equatorial vortex veins, could be evaluated in the image.
Standard 9-field fundus photos, the current preferred method for posterior segment imaging, were not taken in this study. A theoretical comparison was made in order to evaluate the far peripheral views by the ultra-widefield photography. The disc diameter (DD) of each Optos photo was used as the metric for each patient’s set of fundus images. The V2 Vantage pixel measurement option was used for analysis of all fundus photos. An ideal standard 9-field was superimposed on the Optos ultra wide-field images for comparison (Figure 2). If there was complete blockage of one field, it was considered significant and reported. In the standard 9-field, the images span approximately 10 DD superior, 10 DD inferior, 10 DD temporal, and 7 DD nasal to optic nerve.
Representative standard 9-field superimposed on an ultra-widefield image. Artifacts that obscured a complete quadrant were considered significant and were reported. Imaging artifacts included lashes, eyelid, and fingers (holding lids or lashes). Physiologic artifact that distorted image analysis refers to a subluxed lens that blurred the image, leaving retinal details unable to be visualized.
Clinical examination of the 56 Marfan subjects (age range: 3–56 years; mean: 20 years) revealed vitreoretinal pathology in 21 of 110 eyes (19%). None of the subjects had any posterior segment pathology requiring acute treatment at the study. The fellow eyes of the two subjects with unilateral retinal detachment had evidence of treated retinal tears (Figure 3 and 4). In six eyes, there was white-without-pressure (WWP) without additional vitreoretinal pathology (Figure 5). All of the six eyes with WWP were phakic, and all with concurrent subluxed lens. Of the five eyes previously treated with laser for retinal tears, three had subluxed lenses. Two eyes with a history of retinal detachment repair had concurrent subluxed lenses.
Ultra-widefield image demonstrating scleral buckle effect and laser retinopexy.
Ultra-widefield image demonstrating chorioretinal scars from previous laser.
Ultra-widefield image demonstrating white-without-pressure in the far temporal peripheral retina.
The mean axial length of subjects in this study, excluding eyes with a scleral buckle, was 25.32 mm ± 1.32 mm. The mean axial length of eyes with previous retinal tears was not statistically different compared to eyes with retinal detachments treated with a scleral buckle (25.72 mm ± 1.82 mm and 25.5 mm ± 3.30 mm, respectively).
Ultra-Widefield Imaging Findings
Of the 56 subjects who were able to undergo clinical examination, 47 completed both the clinical examination and the ultra-widefield imaging for direct comparison. In total, 93 eyes (one subject was monocular) were analyzed. First, the visibility of quadrants was assessed. The superior quadrant was visible in 88%, temporal quadrant in 87%, nasal quadrant in 69%, and the inferior quadrant in 50% of eyes. Although some fields were blocked, we did not perform steered imaging, which may have allowed better visualization of these areas. Of the 93 eyes analyzed, 7% had an external artifact large enough to block 100% of a schematic quadrant (Figure 1). The artifacts consisted of lashes or lids during imaging. In another 7% of eyes, subluxed lenses created an internal optical artifact large enough to prevent accurate evaluation of the fundus photograph due to significant distortion of the image (Figure 6).
Ultra-widefield image demonstrating subluxed lens. This patient was 7 years old at the time of imaging.
To evaluate the outcomes from ultra-widefield imaging, we compared these images to accepted standard 9-field. Thirty-two percent of eyes (n = 30) had one or more fields blocked (average: 3; Figure 2). Inferior and nasal fields were blocked more frequently than superior or temporal fields. This was due to external artifact of lashes or lids (Figure 7).
Ultra-widefield image demonstrating lash artifact inferiorly, obstructing the view of inferior lattice, which had been detected in clinical examination.
Ultra-widefield images showed posterior segment pathology in 16 of 93 eyes compared to 19 of 93 eyes on clinical examination (Table 1); some eyes had multiple pathologies. WWP was significantly more evident on clinical examination compared to ultra-widefield imaging (1 eye vs. 6 eyes, respectively).
Retinal Pathology: Optos Ultra-Widefield Imaging Compared to Clinical Exam Findings
Table 1 demonstrates the various pathologic findings seen on examination and imaging. The retinal pathology ranged from small peripheral chorioretinal scars to large previous retinal detachment repair and scleral buckling (Figures 3, 4, and 8). Using the clinical examination and photographic documentation, no patient had evidence of active pathology that needed emergent treatment. Overall, 7.5% eyes had sustained previous retinal tears with or without retinal detachment repair.
Ultra-widefield image demonstrating a small area of lattice with an atrophic hole in the far temporal peripheral retina. Patient was 16 years old at the time of exam. Lattice was noted on clinical exam.
In 10 patients, the clinical exam was suboptimal (due to young age, small pupil, and limited cooperation; Figures 9 and 10). Table 2 compares posterior segment views for these challenging examinations. Six of the 10 incomplete clinical examinations were due to lack of pupillary dilation; ultra-widefield imaging was superior in all six small pupil examinations. Only the central posterior pole could be viewed in four subjects; these four subjects were able to be imaged by Optos ultra-widefield (Table 2).
Ultra-widefield image demonstrating the large area of peripheral retina not otherwise able to be visualized with indirect ophthalmoscopy. Patient was a 3-year-old who was uncooperative in the clinical examination.
Ultra-widefield image demonstrating the greater extent of peripheral retina compared to the suboptimal clinical examination. Patient was 5 years old at the time and had a small, poorly dilated pupil.
Posterior Fundus View: Optos Ultra-Widefield Compared to Clinical Examination in 10 Difficult Cases
In this large, cross-sectional case series, we analyzed the posterior segment of patients with MFS in order to evaluate the prevalence of peripheral retinal disease. The clinical exam revealed similar posterior segment pathology as noted in previous literature, with improved detection of peripheral retinal disease with the aid of Optos imaging. This is the first time this imaging modality has been studied in MFS patients.
Our clinical examination revealed posterior segment pathology in 19% of eyes. We also noted that seven eyes (6.3%) had evidence of previous tear with or without retinal detachment (n = 2). This is similar to the range reported (3.5% to 11%) by previous studies.1,2 Five of these seven eyes (70%) had dislocated lenses. The two patients with previous retinal detachment had subluxed lenses. Previous reports have demonstrated that MFS patients have increased rates (8% to 38%) of retinal detachments with subluxed lenses or following lens replacement surgery.1 This study further demonstrates an increased incidence of posterior segment pathology in the setting of anterior segment disease in this group of patients and the need for closer follow-up in patients with anterior segment changes. Since retinal detachment repair in our cohort was achieved by scleral buckle, which alters the axial length toward myopia, we cannot draw conclusions regarding the role of increased axial length in predisposing to vitreoretinal sequelae.1,2
All six subjects with clinically evident WWP had subluxed lenses. No additional posterior segment pathology was noted in these eyes. The specific etiology of WWP remains unknown. It has been suggested that WWP is a manifestation of peripheral vitreous traction or is an abnormal reflex from a structurally normal vitreoretinal interface, possibly in relation to the lens,12 although recent studies have demonstrated OCT findings with distinct hyper-reflectance of the ellipsoid portion of the photoreceptor outer segment in areas of WWP and changes in ultra-widefield fluorescein angiography. The relationship of these findings to vitreous traction remains unknown.12,13 In our study, we could not correlate the location of WWP to the degree of lens subluxation or any other clinical findings in the examination.
In the second part of the study, we evaluated the peripheral retinal anatomy of the patients using ultra-widefield imaging. We compared the widefield imaging to conventional standard 9-field imaging and demonstrated an improved visualization of the peripheral retina. A smaller number of images are needed for peripheral retinal analysis compared to conventional standard 9-field photography (two to four, compared to 10, respectively). The fewer number of images also shortens examination time for young and uncooperative patients. In addition, ultra-widefield imaging can aid in the visualization of the posterior segment, even compared to the visualization by experienced retina specialists. We did not use steered examinations by the Optos imaging system, which can further allow adequate evaluation of the peripheral fundus and overcome artifacts.
This technology could prove a valuable tool in the examination of these patients in clinics where access to retinal specialists is limited. The ultra-widefield imaging cannot be used as a replacement for the clinical exam since photography alone is not a sensitive method for detecting peripheral retinaI disease in MFS; however, the technology can offer a fast complement to the clinical retinal evaluation, which could prove instrumental in the early detection and treatment of these patients with poorly dilating pupils who are typically younger at time of diagnoses and exam. This is crucial for affording the patient the best possible visual outcome.
Although examination with indirect ophthalmoscopy may not be sufficient for complete examination, this is the largest case study to report on posterior segment findings without the bias of referral for retinal detachment repair seen in large centers.1,2 A potential limitation of this study relates to the recruitment bias of mildly affected patients with confirmed diagnosis at the time of the annual meeting of The Marfan Foundation.
In conclusion, we described here posterior segment findings that were consistent with previously reported literature. This study also highlights the importance of a complete ocular examination, especially among patients with subluxed lenses or a history of previous lens surgery. The ultra-widefield imaging obtained by the Optos system can be used to assist in fundus examination of MFS patients who are difficult to evaluate due to young age, inadequate dilation of the pupil, or lens subluxation. This tool can augment the clinical examination.
- Sharma T, Gopal L, Shanmugam MP, et al. Retinal detachment in Marfan syndrome: clinical characteristics and surgical outcome. Retina. 2002;22(4):423–428. doi:10.1097/00006982-200208000-00005 [CrossRef]
- Loewenstein A, Barequet IS, De Juan E Jr, Maumenee IH. Retinal detachment in Marfan syndrome. Retina. 2000;20(4):358–363. doi:10.1097/00006982-200007000-00006 [CrossRef]
- Nahum Y, Spierer A. Ocular features of Marfan syndrome: diagnosis and management. Isr Med Assoc J. 2008;10(3):179–181.
- Nemet AY, Assia EI, Apple DJ, Barequet IS. Current concepts of ocular manifestations in Marfan syndrome. Surv Ophthalmol. 2006;51(6):561–575. doi:10.1016/j.survophthal.2006.08.008 [CrossRef]
- Campbell JP, Leder HA, Sepah YJ, et al. Wide-field retinal imaging in the management of noninfectious posterior uveitis. Am J Ophthalmol. 2012;154(5):908–911.e2. doi:10.1016/j.ajo.2012.05.019 [CrossRef]
- Cho M, Kiss S. Detection and monitoring of sickle cell retinopathy using ultra wide-field color photography and fluorescein angiography. Retina. 2011;31(4):738–747.
- Tsui I, Franco-Cardenas V, Hubschman JP, Schwartz SD. Pediatric retinal conditions imaged by ultra wide field fluorescein angiography. Ophthalmic Surg Lasers Imaging Retina. 2013;44(1):59–67. doi:10.3928/23258160-20121221-14 [CrossRef]
- Witmer MT, Parlitsis G, Patel S, Kiss S. Comparison of ultra-widefield fluorescein angiography with the Heidelberg Spectralis non-contact ultra-widefield module versus the Optos Optomap. Clin Ophthalmol. 2013;7:389–394. doi:10.2147/OPTH.S41731 [CrossRef]
- Manivannan A, Plskova J, Farrow A, McKay S, Sharp PF, Forrester JV. Ultra-wide-field fluorescein angiography of the ocular fundus. Am J Ophthalmol. 2005;140(3):525–527. doi:10.1016/j.ajo.2005.02.055 [CrossRef]
- Prasad PS, Oliver SC, Coffee RE, Hubschman JP, Schwartz SD. Ultra wide-field angiographic characteristics of branch retinal and hemi-central retinal vein occlusion. Ophthalmology. 2010;117(4):780–784. doi:10.1016/j.ophtha.2009.09.019 [CrossRef]
- Leder HA, Campbell JP, Sepah YJ, et al. Ultra-wide-field retinal imaging in the management of non-infectious retinal vasculitis. J Ophthalmic Inflamm Infect. 2013;3(1):30. doi:10.1186/1869-5760-3-30 [CrossRef]
- Orlin A, Fatoo A, Ehrlich J, D’Amico DJ, Chan RP, Kiss S. Ultra-widefield fluorescein angiography of white without pressure. Clin Ophthalmol. 2013;7:959–964. doi:10.2147/OPTH.S43450 [CrossRef]
- Diaz RI, Sigler EJ, Randolph JC, Rafieetary MR, Calzada JI. Spectral domain optical coherence tomography characteristics of white-without-pressure. Retina. 2014;34(5):1020–1021. doi:10.1097/IAE.0000000000000012 [CrossRef]
Retinal Pathology: Optos Ultra-Widefield Imaging Compared to Clinical Exam Findings
|Optos (n)||Exam (n)||Viewed on Optos, Not Exam (n)||Seen on Exam, not Optos (n)|
|Previous Laser Scars||5||5||0||0|
|* Total (eyes)||22||26||4||8|
Posterior Fundus View: Optos Ultra-Widefield Compared to Clinical Examination in 10 Difficult Cases
|Patient (n)||Superior View by Optos||Superior Clinical Exam||Reason for Difficult Exam|
|1||X||Poor dilation, Age (5 years)|
|2||X||Age (3 years)|
|4||X||Age (4 years)|
|6||X||Cooperation, Age (13 years)|
|7||X||Cooperation, Age (15 years)|
|8||X||Poor dilation, Age (5 years)|