Advances in retinal imaging have considerably affected our skills in completing a comprehensive outpatient pediatric retinal examination. Children with inherited retinal disease can benefit from early diagnosis and careful monitoring of most sight-threatening retinal diseases. Indirect funduscopy, visual field tests, and electrophysiologic tests such as electroretinogram and multifocal electroretino-gram are gold standard examinations for children with retinal disease.1–3 However, examination of the peripheral retina in pediatric patients in the clinic is challenging and binocular indirect ophthalmoscopic examination requires a skilled examiner, especially in the presence of nystagmus, photophobia, or limited cooperation on the part of children. A swift fundus examination is required, keeping the child attentive enough to get the useful retinal details to make an accurate diagnosis.
Ultra-wide–field color fundus (UWF-CF) imaging has become a useful tool for imaging pediatric retinal diseases, especially those affecting the periphery, such as familial exudative vitreoretinopathy, Coats disease, and incontinentia pigmenti.4,5 Non-contact UWF fundus autofluorescence (UWF-FAF) retinal imaging provides high-resolution images with a shorter capture time. According to recent studies, FAF is a useful method to assist in the diagnosis and progression of a wide variety of inherited and acquired retinal diseases, which is particularly useful at stages when fundus changes are not particularly evident in routine examination.6,7 This imaging technique detects fluorophores, naturally occurring molecules that absorb and emit light of specified wavelengths.8 FAF in the retinal pigment epithelium shows changes of the distribution of lipofuscin. FAF may be increased with active dystrophic processes and is decreased if retinal pigment epithelium cells are lost or autofluorescence is blocked.9,10
This study assessed the ease and utility of UWF-FAF in detecting difficult-to-examine children in clinic with suspected inherited retinal disease. The main outcome measure was to assess the sensitivity of UWF-FAF, UWF-CF photography, and clinical examination in diagnosing the disease. We hypothesized that UWF-FAF has higher sensitivity to detect disease than color fundus photography or clinical examination.
Patients and Methods
This was a retrospective observational study performed the Moorfields Eye Hospital in Dubai, United Arab Emirates. The provisional diagnosis of retinal dystrophy was based on a family history of inherited retinal disease, progressive decline in visual acuity, poor night vision, photosensitivity, eye movement abnormalities, and atypical findings on retinal examination. The best corrected visual acuity and refractive error were measured. Children were examined clinically (dilated eye examination with both direct and indirect ophthalmoscopy) and then underwent UWF-CF and UWF-FAF imaging using the Optos Tx-200 imaging system (Optos, Dunfermline, United Kingdom) at Moorfields Eye Hospital, Dubai, United Arab Emirates. Informed consent was obtained from parents under the Moorfields Eye Hospitals UAE approved protocol prior to any imaging.
Children underwent imaging after their routine clinical examination, including dilation with 1% cyclopentolate and 2.5% phenylepinephrine. Patients were seated in front of the scanning laser ophthalmoscope and the chin and forehead rest was used as a standard interface. Children younger than 2 years were assisted by their parents for proper positioning. Retinal images were obtained when the eye was in the optimal position. Through a fully dilated pupil, images of the posterior pole, equatorial retina, and periphery were obtained. Low-powered laser wavelengths (532 and 633 nm) allowed simultaneous color, green-free, red-free, and green imaging, as well as wide-field autofluorescence. Exclusion criteria were poor fixation and poor quality image.
Two image graders were masked to the patient's identity. The presence of hyperautofluorescent ring (Figures 1–2), retinal hyperautofluorescent flecks (Figures 3–4), or hypoautofluorescence of the atrophic retinal area (Figure 5) on UWF-FAF or UWF-CF photographs classified the finding as “disease present.” The consensus of presence or absence of disease was agreed upon in all cases by both clinical examination and UWF-FAF and UWF-CF imaging. The outcome was “disease present” or “disease absent.” We calculated sensitivity of the test using SPSS software package (SPSS, Inc., Chicago, IL) and set a P value of less than .05 as the level of statistical significance and Cohen's kappa statistics for inter-rater reliability.
Right eye of a 4-year-old child with a relatively normal-looking color fundus photograph (left panel). The right panel shows ultra-wide–field fundus autofluorescence demonstrating a hyperautofluorescent ring, characteristic of rod cone dystrophy (white arrow).
Left eye of the same patient as in Figure 1 shows a relatively normal-looking color fundus photograph (left panel). The right panel shows ultra-wide–field fundus autofluorescence demonstrating a hyperautofluorescent ring (white arrow).
Retinal imaging of an 8-year-old boy with retinitis pigmentosa as part of Bardet-Beidel syndrome. The left panel (right eye) shows a parafoveal hyperautofluorescent ring with retinal flecks (white arrow) in the vascular arcades presenting with both hyperautofluorescence and hypoautofluorescence. The right panel (left eye) has identical findings.
Left eyes of two siblings born to consanguineous parents with unexplained vision loss. Upper panels show a 1.5-year-old infant in whom ultra-wide–field fundus autofluorescence (right panel) demonstrates widespread loss and atrophy (white arrow) in comparison to normal color fundus photography (left panel). Similar findings were observed in his 2.5-year-old sibling (lower panels). Diagnosis of autosomal recessive retinitis pigmentosa was made.
A 3-year-old child is found to have retinal findings on examination. Upper left panel shows left color fundus photograph with deposits along the inferior arcade (white arrow), which on fundus autofluorescence (FAF) (upper right panel) correspond to hyperautofluorescent flecks with formation of ring visible only on FAF. Lower left panel shows a color fundus photograph of the patient's right eye showing symmetrical condition to the fellow eye (white arrow). Lower right panel shows FAF with formation of few flecks but a larger area of hypoautofluorescence along the inferior arcade (white arrow).
UWF fundus image acquisition with the Optos imaging system was performed in a total of 124 eyes of 62 children from January 2015 through January 2018. All examinations were uneventful and took less than 10 minutes per patient for both eyes. Patients were aged between 1 and 13 years, with a mean age of 5.6 years. Of all 62 children, 30 were male and 32 were female. Twelve of the 124 eyes (9.7%) were excluded from the study because of poor fixation associated with nystagmus. One hundred twelve eyes of 59 patients met the inclusion criteria. All patients recorded significantly subnormal vision for their age with a mean visual acuity of 0.58 and 0.59 logarithm of the minimum angle of resolution (logMAR) for the right and left eye, respectively. Table 1 shows the proportions of ophthalmic findings on clinical examination and retinal imaging. Figures 1–5 show representative findings. Following are comparisons of the sensitivity of the imaging tests and clinical examination in detecting the disease: UWF-FAF versus UWF-CF (P < .001), UWF-FAF versus clinical examination (P < .0001), and UWF-CF versus clinical examination (P < .001). The agreement between graders for clinical examination, UWF-CF, and UWF-FAF was kappa = 0.88, 0.92, and 0.96, respectively.
Ophthalmic Findings on Clinical Examination and Retinal Imaging in 59 Children With Inherited Retinal Disease
Imaging technology in diagnostic fields of ophthalmology has seen revolutionary advances in the past two decades. The introduction of a non-invasive, high-speed, and high-resolution imaging system has advantages in assessing the retinal status in children in whom the assessment can be limited.11,12
The Retcam (Clarity Medical Systems, Pleasanton, CA) provides a UWF retinal image with fluorescein angiography for use in pediatric patients. It is most useful in retinopathy of prematurity surveillance and to examine the peripheral retina in neonatal intensive care units under anesthesia.13 However, it is a contact-based system and has limitations in outpatient settings. In contrast, the Optos imaging system is noninvasive and easy to operate in children with or without pupillary mydriasis. It takes an image in 0.25 second, which can overcome the challenge of eye movements when imaging young uncooperative children.14,15 FAF provides a topo-graphical map of the lipofuscin distribution and fluorophores in the outer retina, subretinal space, and retinal pigment epithelium. It distinguishes a parafoveal ring of increased autofluorescence and varying degrees of patchy hypoautofluorescence and hyperautofluorescence within the periphery in patients with retinitis pigmentosa. Abnormal FAF reflects loss of retinal function and is beneficial in monitoring disease progression.16
Several other studies have demonstrated advantages of UWF imaging over conventional fundus photography. UWF imaging, including autofluorescence mode, is superior to the conventional seven standard fields because it captures 3.2 times more retinal surface area.17–19 UWF-FAF combines the advantages of FAF and fields of view. Conditions such as familial exudative vitreoretinopathy (FEVR), characterized by asymptomatic peripheral retinal vascular changes during the early stages, have also benefited from UWF-FAF.20 It not only enhances the diagnostic sensitivity in staging patients whose retinal periphery appears normal on conventional funduscopy, but it also helps as a screening tool to assess asymptomatic family members of patients with FEVR.21
In the current study, UWF-FAF showed the highest sensitivity in detecting pathologic findings characteristic of inherited retinal dystrophies in our population compared to the same range for both fundus photography and clinical examination. Hyperautofluorescence ring is a sign exclusive to autofluorescence imaging, and in our opinion this was the cause of the difference in sensitivity of disease detection among the three studied modalities. Both retinal flecks and retinal atrophy, if large enough, can be detected on clinical examination and be observed on fundus photography. UWF fundus photography showed higher diagnostic yield compared to clinical examination, perhaps because the reader has more time to analyze details in images in comparison to swift clinical examination. Both retinal imaging modalities, and particularly FAF, have been instrumental in providing baseline documentation for subsequent monitoring but also for educating parents about the degree and extent of retinal involvement.
The limitations of this study include its retrospective nature, but with a focus on image analysis this has not interfered with our conclusions. We have not analyzed the optic disc, which can be affected in inherited retinal diseases. Because of early age and relative short duration of disease in many children, we have not observed changes to optic discs based on clinical examination. However, we also suspect that imaging would give us more information on the status of the optic nerve than clinical examination. We did not use intraobserver readings, but the differences in findings were robust enough for one evaluation only with consensus among examiners about the presence or absence of disease.
We have shown that UWF-FAF imaging is superior to fundus photography and clinical examination in detecting pathology in children with suspected inherited retinal diseases. It is a feasible and perhaps clinically essential tool to be used for this condition. This is the first study that focuses on comparisons of clinical examination and UWF-FAF retinal imaging in a pediatric population whose clinical conditions present a challenge for examiners.
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Ophthalmic Findings on Clinical Examination and Retinal Imaging in 59 Children With Inherited Retinal Disease
|Finding||UWF-FAF (%)||UWF-CF (%)||Clinical Examination (%)|
|Hyperautofluorescent ring||25 (42.4)||N/A||N/A|
|Retinal flecks||32 (54.2)||32 (54.2)||25 (42.3)|
|Retinal atrophy||14 (23.7)||8 (13.5)||4 (6.7)|
|Disease present||56 (94.9)||40 (67.7)||29 (49.1)|
|Disease absent||3 (5)||19 (32.2)||30 (50.8)|