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Imaging and Testing in Pediatric Retina

A Current Review of the Literature

Tsui, Edmund, MD; Schempf, Tadhg A., BS; Besirli, Cagri G., MD, PhD; Mehta, Nitish, MD; Modi, Yasha S., MD; Lee, Gregory D., MD; Dedania, Vaidehi S., MD

International Ophthalmology Clinics: January 2019 - Volume 59 - Issue 1 - p 15–37
doi: 10.1097/IIO.0000000000000260
Original Articles
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History of Retinal Imaging

In the diagnosis and management of pediatric patients with ophthalmologic disease, ophthalmologists often enlist various imaging modalities. Imaging of the retina, especially, is benefitted by the ability of a clinician to utilize the appropriate imaging techniques. There are many different methods to image the pediatric retina, and vast advancements have been made over the last several decades.

The history of retinal imaging dates back to 1851, when Hermann von Helmholtz developed the first ophthalmoscope to better visualize the contents of the globe.1 The first fundus camera that could provide a reliable 20-degree view of the retina was invented in 1926 by Carl Zeiss and J.W. Nordensen. It was improved several years later to view 30 degrees.2 Over the next several decades, clinicians were able to continue to improve upon this design to produce cameras that allowed a 75-degree field of view.1 The advent of the scanning laser ophthalmoscope in 1981 marked a leap forward in the precision of retinal imaging.3 This method of fundus photography was the main method of visualizing the posterior segment of the eye until the late 20th century. In 1997, the RetCam, a wide-angle camera with a 130-degree field of view, was made commercially available.1 As it is portable and used on supine patients, it is especially useful for pediatric patients, as discussed below.1

Imaging of the retina entered a “golden age” upon the introduction of optical coherence tomography (OCT) in 1991, which permitted noninvasive cross-sectional imaging of the retina with longitudinal and lateral spatial resolutions of several micrometers.4 This has provided clinicians with a valuable tool in the diagnosis and management of pediatric retinal disease, discussed below. The field of retinal imaging has continued to make vast strides in the last several decades, with perpetual improvements and innovation.

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Overview of Imaging Modalities

Clinical examination can often be supplemented by a variety of imaging modalities, which can serve to refine a differential diagnosis. In general, the utility of fundus photography for purposes of examination and documentation has been greatly enhanced by numerous advancements in technology. Oftentimes, fundus photography may be better tolerated in children than examination in the clinic, especially when visualizing the peripheral retina. In addition, children may also tolerate OCT better than funduscopic examination. One of the major limitations of several types of OCT (spectral domain—SD; swept source—SS) imaging is the need for fixation to obtain adequate imaging. With the advent of portable imaging devices, such as handheld OCT and handheld OCT angiography (OCTA), more detailed examinations at the bedside and during an examination under anesthesia can be performed.5 In addition, widefield OCT can allow the visualization of the peripheral retina, where previously OCT could not image due to loss of signal secondary to the curvature of the retina, backscattering and lens reflections.6

Ultra-widefield (UWF) imaging, which can capture up to 200 degrees of the retina in a single image, has been demonstrated to be useful in evaluating and documenting peripheral pathology. UWF angiography, including fluorescein angiography (FA) and indocyanine green (ICG) angiography, has also furthered our ability to visualize the peripheral retinal and choroidal vasculature. Understandably, intravenous access may not always be possible in pediatric patients, so it is permissible to mix fluorescein with a liquid for oral intake. This may also avoid the need for FA under general anesthesia,7 although as transit time is unknown, its utility may be limited.

In addition, functional testing in a cooperative patient, such as visual field testing, electroretinogram, visual evoked potentials, and electroculogram have important uses in the evaluation of retinal dystrophies and other inherited retinal disorders. Fundus autofluorescence (FAF), a noninvasive imaging technique, detects fluorophores, such as lipofuscin, and is thus useful for the evaluation of diseases involving the outer retina and retinal pigment epithelium (RPE). Alterations in lipofuscin metabolism or distribution can be detected with FAF, improving diagnostic ability. Lastly, classic noninvasive imaging modalities, such as B-scan ultrasonography, remain useful in the evaluation of intraocular masses and retinal detachments.

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Challenges in Imaging the Pediatric Patient

The clinician that is imaging the pediatric patient may encounter several challenges compared with adult patients. First, the decreased ability for many children to maintain fixation may introduce artifacts and limit the length of the scan. In addition, given that examinations may need to be performed under anesthesia or in the neonatal intensive care unit, portable imaging modalities may be necessary. Third, invasive modalities requiring intravenous delivery of dye may not be well-tolerated in many children. Therefore, it is useful to have a broad armamentarium of imaging modalities and techniques to be used in different settings. Table 1 enumerates a variety of noninvasive and invasive testing that can be used to evaluate retinal disease, especially in the pediatric population. The purpose of this review is to discuss several imaging modalities in the management of pediatric retinal disease and the current body of literature describing their utility.

Table 1

Table 1

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Retinopathy of Prematurity (ROP)

ROP is one of the leading causes of vision loss in children. Routine screening examination for clinical staging and prompt intervention is needed to prevent permanent vision loss. While binocular indirect ophthalmoscopy is utilized in the evaluation of all ROP patients, adjunctive testing can be a helpful aid. Photographic documentation aids the clinician in identifying and monitoring patients at risk for ROP (Fig. 1). The utility of fundus photography in ROP screening has also played an important role in the development of telemedicine programs in ROP evaluation.8–10 Given that these exams are often performed in neonatal intensive care unit settings, portable fundus photography systems, such as the RetCam (Clarity Medicine Systems, Pleasanton, CA) or ICON (Phoenix Technology Group, Pleasanton, CA), have been utilized. Given the limited number of trained ophthalmologists to screen for ROP, there have been efforts to utilize trained nonophthalmologist readers and images taken by nonphysicians.11 In addition, comparison of multiple images may demonstrate a change in disease status, especially progression, that is not evident when comparing images taken within a short time frame. As such, advances including widefield imaging have continued to expand the boundaries of ROP management. The Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP) initiative is an ongoing telemedicine initiative to screen high-risk infants for ROP. The SUNDROP initiative is considered a landmark validation of the role of telemedicine in the diagnosis of ROP.8 The 6-year results reported that remote interpretation of widefield images had a sensitivity of 100% and specificity of 99.8% as compared with bedside binocular indirect ophthalmoscopy.8 While this technology is quite accurate and offers a promising method for the evaluation of ROP, there are limitations to such technology. Fierson et al12 reported that the current body of literature did not support the idea that remote widefield fundus photography screening is at a point at which it is capable of completely replacing traditional indirect ophthalmoscopy by an in-person trained ophthalmologist. While this technology may decrease the number of bedside examinations that need to be performed, when image quality is inadequate or results are equivocal, a provider must examine the patient at the bedside. There clearly exists a role for this technology, especially in the ever-growing field of telemedicine, but widefield fundus photography warrants further investigation before clinicians may know its full utility for the screening and diagnosis of ROP.

Figure 1

Figure 1

OCT in ROP has shed further insight into the retinal microstructure demonstrating a persistence of the inner retinal layers within the fovea (fovea plana), delays in photoreceptor development, and thinning of the photoreceptor.5 During an examination under anesthesia or bedside examination, handheld SD-OCT may also be a useful adjunct to binocular indirect ophthalmoscopy. Studies investigating the utility of handheld SD-OCT have revealed subclinical findings, such as preretinal tissue, retinal cystoid structures or schisis, cystoid macular edema, and retinal architectural abnormalities, which may not be visible on clinical examination.5,13 Chavala et al14 performed a study in 2009 to evaluate if handheld SD-OCT would provide an alternative for nonsedated neonates. They described that handheld SD-OCT was able to achieve adequate linear and volumetric imaging in 3 patients (1 without sedation and 2 under anesthesia), identifying retinoschisis and preretinal structures not identified by ophthalmoscopy.14 Notably, however, this study did not address the number of patients the investigators had attempted to image in order to visualize these features. Lee et al13 described a series of 76 eyes from 38 newborns with ROP, that were imaged by handheld SD-OCT, and found that it visualized certain subclinical features, but was inadequate to establish the stage or zone due to its smaller field of view. Furthermore, the utilization of handheld OCT can help identify and monitor possible prognostic biomarkers, such as the presence of cystoid macular edema. A drawback of handheld OCT is the skill required to obtain an image. As the handpiece is bulky and image quality is dramatically affected by small variations in refractive error and examiner movement, images cannot be rapidly obtained, especially by an inexperienced examiner.

OCTA provides a noninvasive modality to image the retinal vasculature in ROP. Vinekar et al15 described the use of OCTA in the management of a premature girl with aggressive posterior ROP, which adequately quantified changes in vascular characteristics over time. This was one of the first described cases of the use of OCTA in an infant.15 Notably, the infant was held in place and swaddled to avoid motion, as OCTA is more sensitive to motion than OCT. The authors also note that obtaining OCTA imaging in infants was challenging and may be limited due to a short scan length and lack of image registration. Campbell et al16 described a similar, more recent, study of four neonates with ROP, in whom both prototype handheld SD-OCT and OCTA were able to achieve adequate imaging. These studies emphasize the possibility of a future commercially available device to achieve imaging of neonates with ROP. This technology can guide further characterization of patterns of retinal neovascularization. With a detailed knowledge of a patient’s vascular anatomy, treatment modalities such as laser photocoagulation versus anti-vascular endothelial growth factors (VEGF) treatments could be more directly utilized for each individual patient.

The role of FA in ROP remains unclear since the gold standard has long been clinical examination by indirect ophthalmoscopy. Klufas and colleagues found that the addition of FA to color fundus photography increased the sensitivity of diagnosis for stage 3 or worse disease. The authors also found that FA image availability may improve intergrader agreement in the diagnosis of treatment-requiring ROP.17 In addition, it may be difficult to accurately determine the borders of the avascular zones in the peripheral retina using indirect ophthalmoscopy or widefield retinal imaging images, so FA may be a useful adjunct to visualize the borders of nonperfusion.18 Finally, with the increasing use of intravitreal anti-VEGF for the treatment of ROP, anomalies in vascular development can be better identified and understood with the use of FA.19

Ocular ultrasound can also be used in the management of ROP. Muslubas et al20 described a series of 300 eyes from 150 patients with stage 5 ROP, and found that ultrasound was useful to visualize the retinal detachment configuration required for surgery, and is important for visualizing other features, including subretinal hemorrhage, reduced axial length, and posteriorly and anteriorly closed funnel configuration. Ron and colleagues describe that B-scan ultrasonography was able to visualize a dilated superior ophthalmic vein in 95% of patients with ROP, while only 16% of patients without ROP showed this finding. While a dilated superior ophthalmic vein is not diagnostic of ROP, the authors hypothesize that B-scan ultrasonography could be utilized as a supplemental imaging modality when diagnosing and managing patients with ROP, as it identifies a clinical feature that presents significantly more commonly in patients with ROP.21 Another feature of ultrasound that has been utilized in the diagnosis of ROP has been color Doppler. Hartenstein et al22 reported on a series of 8 preterm infants with ROP, and demonstrated a significantly increased mean central retinal vein maximum velocity relative to premature control infants without ROP. This imaging modality offers potentially valuable, rapid, and cost-effective supplementary tools for the ophthalmologist that is evaluating a pediatric patient, especially when sedation or anesthesia is not desirable. Despite these novel findings, B-scan ultrasonography is not routinely used for the screening and treatment of ROP.

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Sickle Cell Retinopathy (SCR)

Sickle cell disease is the most commonly inherited blood disorder and SCR can lead to numerous occlusive retinal vascular changes. Vascular tortuosity and peripheral retinal neovascularization is seen in SCR, which leads to the classic sea-fan retinopathy (Fig. 2A). Subsequently, vitreous hemorrhage or retinal detachments can occur. FA can reveal peripheral retinal vascular occlusions, as well as arteriovenous anastomoses (Fig. 2B). Studies using SD-OCT have provided more information about foveal anatomy and have demonstrated that the macula is significantly thinner in sickle cell eyes due to macular ischemia compared to normal eyes (Fig. 2C).23,24 Further these studies demonstrate that the temporal macula is most significantly affected, along with a lower macular volume and decreased choroidal thickness compared to normal eyes. As SCR is first detectable at the retinal perimeter, widefield OCT can aid in early diagnosis and management, especially in younger children when examination of the peripheral retina is difficult. This noninvasive imaging modality is especially useful for diagnosing and prognosticating disease severity, especially in patients that cannot tolerate FA. Mathew et al24 demonstrated that eyes with discrete areas of macular thinning were more likely to have proliferative SCR.

Figure 2

Figure 2

Cho and Kiss25 investigated 12 eyes of 6 pediatric patients with SCR, showing that in all but 1 eye, UWF fundus photography and UWF FA was able to identify peripheral vascular changes that had been missed on clinical examination. Although retinal imaging does not take the place of a complete clinical examination, these imaging modalities enhance detection of peripheral vascular remodeling. Compared with conventional FA, UWF imaging has allowed clinicians to better monitor peripheral neovascularization and guide laser photocoagulation. This is especially beneficial in children that are able to cooperate for FA, but not long enough to obtain the 7-standard ETDRS fields. The utility of ICG angiography has not been fully elucidated in the evaluation of SCR, as limited studies have been performed.26

The use of OCTA has been investigated in adolescent and adult patients with SCR.27 OCTA has been shown to be very sensitive in detecting early retinal ischemia, likely even more so than traditional FA.28 As with UWF FA and SD-OCT, OCTA was shown by Pahl et al29 to detect macular thinning and blood flow abnormalities not previously detected by conventional biomicroscopy. The use of multimodal imaging may continue to enhance screening for SCR, particularly for children; however, more investigation into its utility is required.

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Familial Exudative Vitreoretinopathy (FEVR)

FEVR is an inherited retinal disorder that demonstrates anomalous or incomplete retinal angiogenesis. This was first described in 1969 by Criswick and Schepens.30 Classic findings include retinal neovascularization, peripheral retinal avascularity, dragging of the vasculature, and tractional retinal detachments (Figs. 3A, B). Thorough clinical examination is required for staging of FEVR. Patients have demonstrated similar findings to ROP; however, patients with FEVR were generally full-term and did not require supplemental oxygen. In addition to clinical examination, FA is an important imaging modality to determine areas of avascularity and ischemia (Figs. 3C, D). FA may also be used for screening family members for subtle peripheral vascular pathology. Yonekawa et al,31 in the largest series of SD-OCT evaluation of FEVR patients, described a broad spectrum of new microstructural findings in FEVR. This included posterior hyaloidal organization, vitreomacular traction, cystoid macular edema, intraretinal exudates, and disruption of the ellipsoid zone. Cystoid macular edema associated with FEVR exhibits leakage on FA. Using FAF, areas that showed disruption of the outer retinal layers demonstrated hypoautofluorescence due to disruption and loss of RPE.31 Kashani et al32 also investigated the angiographic findings in FEVR using widefield FA. They found a wide range of new and/or under-recognized findings that have led to a more complete characterization of early FEVR.32 These findings include aberrant circumferential vessels, vascular tortuosity, peripheral and central telangiectasias, late phase-disc leakage, and capillary agenesis. Furthermore, they also described venous-venous shunting, delayed arteriovenous transit, and delayed or absent choroidal perfusion.32 Imaging is necessary for the management of FEVR, as early signs of disease activity may not be recognized on clinical examination. UWF FA can also aid in the guidance of laser photocoagulation in FEVR.33 FA has become critical for monitoring patients with FEVR as areas of late-phase angiographic posterior and peripheral vascular leakage (LAPPEL) may indicate capillary inflammatory changes, before the onset of capillary drop-out and neovascularization.34 This is especially useful in children that are unable to cooperate for intravenous fluorescein, but can consume oral fluorescein, as these findings are noted in the later phases of angiography. Identification of areas of LAPPEL can result in early intervention, where topical therapy, such as corticosteroids and/or nonsteroidal anti-inflammatory eye drops, may provide benefit, before the need for more invasive treatments arise.34

Figure 3

Figure 3

As was mentioned earlier, FEVR may resemble ROP on clinical examination. Typically the diagnosis of FEVR is made in full-term infants, although with advances in imaging and a better understanding of both diseases, it is being realized that patients that may otherwise have been diagnosed with ROP, due to a history of prematurity, actually have FEVR. John et al35 described FA findings characteristic of FEVR in premature patients, a distinction that can have a significant impact on initial treatment, as well as lifelong management. As FEVR may mimic other forms of pediatric and adult vitreoretinopathies, careful examination, supplemented by imaging, is crucial for diagnosis.

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Persistent Fetal Vasculature (PFV)

PFV presents with a broad spectrum of findings and results from a failure of the fetal vasculature system to undergo involution.36 Pathology seen in PFV can be found in the anterior segment, posterior segment, or both. For the purpose of this review, posterior segment subtypes will be discussed. Posterior PFV is due to the persistence of posterior tunica and hyaloid vasculature. This can involve the retina, vitreous and optic nerve. Direct visualization of the persistent vasculature remnant is most reliable for diagnosis. If there is poor visualization, B-scan ultrasonography is recommended to rule out intraocular masses and/or retinal detachments (Figs. 3A, B). B-scan ultrasound can be especially useful in identifying calcifications within a lesion, such as retinoblastoma, guiding a diagnosis. On funduscopic examination, a broad variety of findings can be observed, including a fibrovascular stalk, retinal folds, macular dragging, and retinal detachments. Utilizing SD-OCT, De La Huerta et al37 reported that the main findings in posterior PFV include posterior hyaloidal organization, vitreoretinal traction, vitreopapillary traction, diminished foveal contour, foveal displacement, and disruption of the ellipsoid zone. In eyes with foveal displacement, FA demonstrated altered macular vasculature and confirmed nasal displacement of the fovea. Utilization of FA can demonstrate the presence of abnormal retinal vasculature and also reveal active blood flow in the vessels within the fibrovascular stalk, which is an important consideration for surgical decision-making.38 In addition to its use early in diagnosis, B-scan ultrasonography is also employed in the preoperative assessment of PFV and can also be utilized to assess for tractional retinal detachments (Fig. 4).39

Figure 4

Figure 4

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Coats Disease

Coats disease is an idiopathic retinal disease characterized by yellow retinal exudations and telangiectasias (Figs. 5A, C). Funduscopic examination is used to characterize Coats disease into different stages and is typically sufficient for diagnosis.40 However, given the broad spectrum of presentations and findings in Coats disease, it is important to rule out other disease entities, particularly retinoblastoma. Close monitoring and careful examination is required to prevent vision loss from exudative retinal detachment. Examination under anesthesia and ancillary imaging may provide further information for monitoring progression. B-scan ultrasonography may be used to confirm a retinal detachment and to rule out underlying intraocular masses.41 OCT will demonstrate retinal thickening in affected areas, fibrosis-induced retinal traction, exudative deposits (both intraretinal and subretinal), ellipsoid zone disruption, and external limiting membrane disruption.42–44 These retinal microstructural abnormalities may contribute to disease stratification and determining visual prognosis.

Figure 5

Figure 5

Vascular changes are typically seen in the peripheral retina and these can be highlighted with FA. FA demonstrates early hyperfluorescence of the telangiectasias and, in some cases, macular edema (Fig. 5B).41 FA will also reveal dilated, tortuous vessels (Fig. 5D) and adjacent areas of capillary dropout. In the early phase, areas of exudation will be hypofluorescent due to blockage with mild late staining. Ultimately, the use of UWF FA can help guide clinicians regarding targets for laser photocoagulation. On UWF autofluorescence, it has been noted that Coats disease demonstrates a diffuse background hypoautofluorescence compared to the fellow eye.42

Although Coats disease has a typically unilateral presentation, recent studies utilizing widefield imaging and OCTA have suggested that Coats disease is a highly asymmetric bilateral disease.42,45,46 Rabiolo et al,42 utilizing UWF FA, noted that in the majority of the clinically unaffected fellow eyes, retinal pathology, such as dilated intercapillary spaces with nonperfusion and telangiectatic capillaries, was observed at the most temporal quadrant. Studies with OCTA have described replacement of the foveal avascular zone with coarse vessels which may represent vascularized fibrosis, dilated capillary network, and aneurysmal dilatations in the macular capillary bed.42,47 Further supporting the notion that Coats disease may be highly asymmetric, recent studies using OCTA have found that clinically normal appearing fellow eyes demonstrate altered foveal vasculature at the superficial capillary plexus.45,48

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Combined Hamartoma of the Retina and RPE (CHRRPE)

CHRRPE is a congenital benign tumor that is characterized by an elevated lesion with glial proliferation and disorganized vascular and melanocytic tissue that arises from the retina and RPE. These lesions were first described by Gass in 1973.49 These are most commonly found in pediatric patients who present with strabismus or reduced visual acuity due to macular tumors.50 Funduscopic examination of CHRRPE demonstrates these lesions are elevated, have variable pigmentation, retinal traction, epiretinal membrane and have associated intraretinal corkscrew vessels (Figs. 6A, B).50–52 In general, OCT of these lesions reveal hyperreflective masses with thickening and disorganization of the inner retinal layers with overlying epiretinal membranes (Figs. 6C, D). Using enhanced-depth imaging (EDI) OCT, Arepalli et al53 demonstrated that these tumors are associated with epiretinal membranes with vitreoretinal traction that are in a saw-tooth or folded pattern. This traction leads to increased retinal thickness and EDI-OCT demonstrated reduced underlying choroidal thickness.53 In macular CHRRPE, Kumar et al54 identified a distinct pattern of the “omega sign,” which refers to an omega-shaped disorganization of the inner retinal layers, bordered posteriorly by the outer plexiform layer (OPL). By using clinical examination of location of lesion, fundus features and the previously mentioned OCT findings, Dedania et al55 proposed a new clinical classification system, which can help in determining follow-up interval and can guide discussion of prognosis with patients and their families, especially as many affected patients are young children.

Figure 6

Figure 6

FA of these lesions demonstrates early hyperfluorescence within the tumor itself along with increased intrinsic vascularity and tortuosity and distal vascular straightening.50,56 FAF demonstrates hypoautofluorescence due to the masking effect of the hamartoma.56 Often, thickened retinal and glial tissue may make it difficult to view the vasculature associated with the tumor on funduscopic examination, and utilization of OCTA allows for clearer visualization of the vascular networks. OCTA of these lesions demonstrate increased and disorganized vasculature within the tumor.56 OCT and clinical examination provide more detail regarding these lesions than ultrasonography, but for patients that may not be able to fixate or tolerate examination, ultrasonography typically demonstrates an isodense lesion without any evidence of acoustic shadowing or intralesional calcification.51

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Retinoblastoma

Retinoblastoma is the most common malignant intraocular tumor in pediatric patients (Fig. 7A). Historically, enucleation was the mainstay for retinoblastoma treatment; however, rapid advances in intra-arterial chemotherapy has minimized the need for enucleation. In addition, innovations in retinal imaging have helped improve diagnosis, guide management, and monitor response to treatment.57

Figure 7

Figure 7

Fundus photography of retinoblastoma can be useful for documentation pretreatment and posttreatment, but other imaging modalities discussed below may be helpful in management and posttreatment monitoring as well. B-scan ultrasonography is typically used as a confirmatory tool in the diagnosis of retinoblastoma. It can demonstrate a calcified mass in the concerning eye (Fig. 7B). It also helps to rule out involvement of the fellow eye. Magnetic resonance imaging may also used to rule out “trilateral” retinoblastoma. Ultrasound biomicroscopy is a useful modality to evaluate retinoblastoma as it can provide views anterior to the ora serrata, allowing for better staging of disease.

OCT can help assess for clinically invisible tumors and optic nerve infiltration as well as assist in evaluation of the fovea and localization of the tumor microstructure. OCT is also useful in evaluating the response to laser therapy, monitoring tumor borders and recurrences at the edges. The use of handheld OCT at the time of examination under anesthesia has continued to further our understanding of these tumors. In a small case series, handheld SD-OCT was demonstrated to be useful in monitoring small macular retinoblastoma in infants.58 Handheld OCT can also evaluate posttreatment scars and scan the posterior pole for new tumors.59,60 Sequential imaging can be used to determine if tumors are progressing or regressing. A large case series demonstrated that handheld OCT directed treatment decisions, diagnosis, and follow-up in many of the evaluated cases.59

Autofluorescence may be useful in monitoring retinoblastoma following treatment or differentiating regressing calcific lesions from other tumors. Ramasubramanian et al61 demonstrated that autofluorescence of the retinoblastoma shows hyperautofluorescence within the calcified portion, while the noncalcified portions demonstrate variable autofluorescence. FA in retinoblastoma can identify neovascularization of the iris, large retinal vessel dilation, intrinsic tumor vessels, and retinal vessel leakage. This can help determine the extent of the lesion and distinguish retinoblastoma from other ocular tumors.62 FA can also evaluate the vascularity, residual tumor and/or recurrences within previously treated areas.

Lastly, the use of ERG in patients undergoing systemic or intra-arterial chemotherapy may be used as a proxy for visual function. Brodie et al63 demonstrated that infants undergoing systemic chemotherapy had significant increases in ERG amplitude. Brodie et al64 also demonstrated that retinal function may persist or even recover in those receiving selective ophthalmic artery chemotherapy infusion.

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Congenital X-linked Retinoschisis (CXLRS)

CXLRS is an inherited retinal disease, which is characterized by splitting of the retinal layers in the fovea or the periphery. This is typically a clinical diagnosis, although advances in imaging have furthered our understanding of the pathogenesis of this disease. Funduscopy demonstrates a classic spoke-wheel pattern within the macula (Fig. 8A) and the patient may also have vitreous veils (Fig. 8C) or vitreous hemorrhage. A classic finding on SD-OCT is intraretinal splitting and OCT is typically the imaging modality of choice for the diagnosis of CXLRS as it is noninvasive and has a fast acquisition time, especially if a single foveal scan can be obtained in an uncooperative child (Fig. 8B). OCT demonstrates that the splitting typically occurs in the inner nuclear layer (INL), OPL, outer nuclear layer (ONL), and less commonly in the ganglion cell layer.65 In addition, OCT has been instrumental in better understanding disease presentation. Recently, CXLRS has been classified into 4 phenotypes, based on not only clinical examination, but also OCT. Previously, the foveolamellar phenotype was under-recognized, as clinical findings can be subtle. These cystic spaces seen on OCT, when examined with FA, demonstrate typically normal findings without leakage within the macula. Autofluorescence typically demonstrates a pattern of spoke-wheel pattern of hyperautofluorescence and hypoautofluorescence within the macula that corresponds to the area of retinoschisis.66,67

Figure 8

Figure 8

Interestingly, using UWF imaging, Rao et al68 demonstrated that peripheral findings include fibrosis or retinal folds, bridging vessels, and vascular sheathing. Furthermore they found that 59% of eyes demonstrated extramacular leakage on FA. In further imaging of exudative compared with nonexudative retinoschisis, they found that widefield imaging confirmed leakage in both forms of retinoschisis.68 On ICG imaging, Souied et al69 reported a distinct hyperfluorescent stellate pattern associated with radial lines of hyperfluorescence. Padrón-Pérez and colleagues utilized SS-OCT and OCTA to study 18 eyes with CXLRS. They demonstrated that the hyporeflective spaces seen on SS-OCT were located in the INL and OPL. They also found that the external limiting membrane and ellipsoid portion of the inner segment defects were present in over two-thirds of eyes. OCTA can demonstrate petaloid nonreflective areas in the deep vascular plexus. En-face imaging demonstrated a spoke-like pattern in the foveal region and a reticular pattern in the parafoveal region at the level of the INL.65 SS-OCT imaging did not reveal abnormalities associated with the choriocapillaris, Sattler’s or Haller’s layers.

Although ERG was previously utilized in the diagnosis of CXLRS, it has experienced a decline in utilization due to advancements in retinal imaging. ERG can demonstrate a reduced b-wave amplitude with preservation of the negative a-wave, forming the classic “negative” ERG pattern that is associated with CXLRS.

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Optic Disc Drusen

Optic disc drusen are accumulations in the optic nerve that are composed of amino and nucleic acids, calcium, mucopolysaccharides, and iron (Fig. 9A).70,71 They have been reported in association with numerous systemic and ocular conditions, such as pseudoxanthoma elasticum, Alagille syndrome, and retinitis pigmentosa.70 As the presence of optic disc drusen, particularly buried optic disc drusen, can simulate optic disc edema, it is critical to utilize multimodal imaging in addition to the clinical examination for accurate diagnosis.

Figure 9

Figure 9

B-scan ultrasonography is considered the gold standard for detecting optic disc drusen and typically demonstrates a hyperechoic lesion with posterior shadowing (Fig. 9B).70 This may be of limited utility in younger children since optic disc drusen in children are often noncalcified and buried.70 In cases of buried, undetected drusen, B-scan ultrasonography could only identify drusen in 48% of cases.72 As the patient ages, optic disc drusen may become calcified, which allow for easier detection with B-scan ultrasonography.

Evaluating optic disc drusen with SD-OCT, several studies have shown hyperreflective lesions that are located posterior to the outer plexiform and ONLs.70 However, SD-OCT may be of limited utility when evaluating optic disc drusen since these drusen can be deeper. This leads to poor demarcation of the optic disc drusen with SD-OCT, as well as difficulty in assessing the posterior limits of the drusen.73 When utilizing EDI OCT and SS-OCT, Sato and colleagues, demonstrated that optic disc drusen were located in multiple different levels and most were located anterior to the lamina cribrosa. They report that the drusen appear as ovoid areas of lower reflectivity that are bordered by hyperreflective material and in almost half the cases also contained internal hyperreflective foci.74 A case report by Flores-Reyes et al75 utilizing OCTA analyzed the peripapillary vessel density in optic disc drusen and found that there was a focal decrease in vessel density within the area of the drusen.

FA has been utilized in the diagnosis of optic disc drusen, but its use may be limited due to the need for venipuncture. In general, FA demonstrates optic disc staining and may also demonstrate late filling of the peripapillary choriocapillaris.70,76 The utility of FA may be most appropriate to rule out optic disc edema since optic disc drusen are not associated with leakage.76,77 FAF demonstrates hyperautofluorescence associated with optic disc drusen.74 However, it is significantly more difficult to evaluate buried optic disc drusen with FAF as the overlying tissue masks the autofluorescence of the drusen.

Visual field testing is also important as visual field loss is well-associated with optic disc drusen. Slowly progressive visual field defects are more common in superficial disc drusen compared to buried disc drusen.70 A 36-month study by Lee and Zimmerman reported an annual rate of Goldmann visual field loss of 1.6%. They reported that younger patients had minimal field loss, while older patients were more likely to have moderate or severe visual field loss.78 It is important to understand the applications and limitations of each imaging modality in the assessment of optic disc drusen given that buried disc drusen may mimic optic disc edema and a misdiagnosis may subject the patient to further costly testing and/or anesthesia.

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Conclusions

Numerous advances in retinal imaging have permitted ophthalmologists to better diagnose and monitor patients, especially in pediatric patients that may not be able to complete a dilated fundus examination in the clinic. A broad armamentarium of multimodal imaging in addition to clinical examination will help the clinician refine their differential diagnosis. In particular, noninvasive imaging modalities, such as OCT angiography, have permitted high-resolution imaging of the pediatric retinal vasculature that could previously only be visualized with invasive angiography imaging. New innovations, such as handheld OCT, can reveal details regarding the retinal microstructure during bedside exams or examination under anesthesia. Lastly, B-scan ultrasonography is a modality that remains exceptionally useful in the evaluation of retinal detachment and intraocular masses, particular when the view to the retina is obscured. Each imaging modality is able to visualize a unique feature of a particular disease. The collective data is important for staging disease, determining follow-up, guiding treatment, and monitoring treatment response.

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