Viral Sheth

The Functional Significance of Foveal Abnormalities in Albinism Measured Using Spectral-Domain Optical Coherence Tomography

PURPOSE The relationship between foveal abnormalities in albinism and best-corrected visual acuity (BCVA) is unclear. High-resolution spectral-domain optical coherence tomography (SD OCT) was used to quantify foveal retinal layer thicknesses and to assess the functional significance of foveal morphologic features in patients with albinism. DESIGN Cross-sectional study. PARTICIPANTS Forty-seven patients with albinism and 20 healthy control volunteers were recruited to the study. METHODS Using high-resolution SD OCT, 7×7×2-mm volumetric scans of the fovea were acquired (3-μm axial resolution). The B scan nearest the center of the fovea was identified using signs of foveal development. The thickness of each retinal layer at the fovea and foveal pit depth were quantified manually using ImageJ software and were compared with BCVA. MAIN OUTCOME MEASURES Total retinal thickness, foveal pit depth, photoreceptor layer thickness, and processing layer thickness in relation to BCVA. RESULTS Total photoreceptor layer thickness at the fovea was correlated highly to BCVA (P = 0.0008; r = -0.501). Of the photoreceptor layers, the outer segment length was correlated most strongly to BCVA (P<0.0001; r = -0.641). In contrast, there was no significant correlation between either total retinal thickness or pit depth and BCVA (P>0.05). This was because of an inverse correlation between total photoreceptor layer thickness and total processing layer thickness (P<0.0001; r = -0.696). CONCLUSIONS Neither the total retinal thickness nor the pit depth are reliable indicators of visual deficit, because patients with similar overall retinal thickness had widely varying foveal morphologic features. In albinism, the size of the photoreceptor outer segment was found to be the strongest predictor of BCVA. These results suggest that detailed SD OCT images of photoreceptor anatomic features provide a useful tool in assessing the visual potential in patients with albinism. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Potential of Handheld Optical Coherence Tomography to Determine Cause of Infantile Nystagmus in Children by Using Foveal Morphology

OBJECTIVE To investigate the feasibility of handheld (HH) ultra-high-resolution spectral-domain optical coherence tomography (SD-OCT) in young children with nystagmus, to determine its sensitivity and specificity in classifying foveal abnormalities, and to investigate its potential to determine the cause of infantile nystagmus with the use of foveal morphology. DESIGN Prospective, case-control study. PARTICIPANTS AND CONTROLS A total of 50 patients with nystagmus and 50 healthy control subjects (mean age, 3.2 years; range, 0-8 years). METHODS Each patient was scanned using HH SD-OCT (Bioptigen Inc., Research Triangle Park, NC) without sedation, and foveal morphology was classified into 1 of 4 categories: (1) typical foveal hypoplasia (predicting clinical diagnosis of albinism, PAX6 mutations, or isolated foveal hypoplasia); (2) atypical foveal hypoplasia (predicting achromatopsia); (3) other foveal changes (corresponding to retinal dystrophies); and (4) normal fovea (predicting idiopathic or manifest latent nystagmus). An independent interpretation of the HH SD-OCT scans by masked examiners was performed, and the sensitivity and specificity of the predicted diagnosis were calculated. MAIN OUTCOME MEASURES The success rate of image acquisition and sensitivity and specificity of the HH SD-OCT in classifying foveal abnormalities. RESULTS In 94% of examinations, HH SD-OCT was successful. Twenty-three patients had typical foveal hypoplasia (category 1). Of these patients, 21 were diagnosed with albinism and 2 were diagnosed with PAX6 mutations. Five patients were classified as atypical (category 2) and diagnosed with achromatopsia. Six patients had other abnormal foveal morphology (category 3) and were diagnosed with retinal dystrophy. Sixteen patients had normal foveal morphology (category 4). Of these patients, 12 were diagnosed with idiopathic nystagmus and 4 were diagnosed with manifest latent nystagmus. Sensitivities of HH SD-OCT for classifying typical or atypical foveal hypoplasia, other abnormal foveal morphology, and normal morphology were 92.8%, 86.7%, 41.1%, and 88.4%, respectively, with specificities of 91.4%, 94.8%, 97.7% and 95.1%, respectively. CONCLUSIONS We demonstrate excellent feasibility of HH SD-OCT in the diagnosis of conditions associated with infantile nystagmus. The HH SD-OCT classification of foveal abnormalities was highly sensitive and specific. This classification was used to determine the underlying cause of infantile nystagmus. Handheld SD-OCT in early childhood can facilitate focused investigations and earlier diagnosis. This is important in an era when potentially time-sensitive treatment, such as gene therapy, is imminent.

In Vivo Foveal Development Using Optical Coherence Tomography

PURPOSE To characterize the time course of normal foveal development in vivo in term infants and young children using handheld spectral-domain optical coherence tomography (HH-SDOCT). METHODS We obtained 534 HH-SDOCT scans from 261 infants, children, and young adults with a mean age of 4.9 years (range, 0-27 years). Each retinal layer was manually segmented in ImageJ and correlated with gestational age (GA) and visual acuity (VA). The developmental trajectories of each retinal layer at the fovea, parafovea, and perifovea were calculated using fractional polynomial modeling. RESULTS The central macular thickness (CMT) increases logarithmically between birth and 48.6 months GA. The foveal ganglion cell (GCL), inner plexiform, inner nuclear (INL), and outer plexiform layers decrease in thickness exponentially until 18 months GA. Interestingly, the parafoveal and perifoveal GCL and INL thicknesses initially decrease until 17 months GA and then increase in thickness until 65.5 GA. The foveal outer nuclear layer, inner segment, and outer segment of the photoreceptors increase in thickness logarithmically until 32.4, 26.9, and 45.3 months GA, respectively. The parafoveal and perifoveal outer retinal layers increase in thickness more gradually until 146 months GA. The thickness of the outer retinal layers and CMT were strongly correlated with VA, with r = 0.54 (P < 0.0001) and r = 0.52 (P < 0.0001), respectively. CONCLUSIONS We have modeled for the first time the complex, nonlinear developmental trajectories for each retinal layer and demonstrate that development continues until adolescence. Our description of normal development will be helpful in diagnosing, monitoring, and understanding pediatric retinal disease.

Abnormal retinal development associated with FRMD7 mutations

Idiopathic infantile nystagmus (IIN) is a genetically heterogeneous disorder, often associated with FRMD7 mutations. As the appearance of the retina is reported to be normal based on conventional fundus photography, IIN is postulated to arise from abnormal cortical development. To determine whether the afferent visual system is involved in FRMD7 mutations, we performed in situ hybridization studies in human embryonic and fetal stages (35 days post-ovulation to 9 weeks post-conception). We show a dynamic retinal expression pattern of FRMD7 during development. We observe expression within the outer neuroblastic layer, then in the inner neuroblastic layer and at 9 weeks post-conception a bilaminar expression pattern. Expression was also noted within the developing optic stalk and optic disk. We identified a large cohort of IIN patients (n = 100), and performed sequence analysis which revealed 45 patients with FRMD7 mutations. Patients with FRMD7 mutations underwent detailed retinal imaging studies using ultrahigh-resolution optical coherence tomography. The tomograms were compared with a control cohort (n = 60). The foveal pit was significantly shallower in FRMD7 patients (P < 0.0001). The optic nerve head morphology was abnormal with significantly decreased optic disk area, retinal nerve fiber layer thickness, cup area and cup depth in FRMD7 patients (P < 0.0001). This study shows for the first time that abnormal afferent system development is associated with FRMD7 mutations and could be an important etiological factor in the development of nystagmus.

Optic Nerve Head Development in Healthy Infants and Children Using Handheld Spectral-Domain Optical Coherence Tomography

Purpose To determine feasibility of optic nerve head (ONH) imaging and to characterize ONH development in full-term infants without sedation using handheld spectral-domain optical coherence tomography (SD OCT). Design Prospective cross-sectional study. Participants Three hundred fifty-two children aged between 1 day and 13 years. Methods All participants were imaged using handheld SD OCT without sedation during a single scan session. The percentage of successful scans was calculated. Interexaminer reproducibility and differences between right and left eyes were assessed using intraclass correlation coefficients (ICCs). Images were analyzed using ImageJ software. The developmental trajectories over time for ONH parameters were calculated using fractional polynomial modelling. Main Outcome Measures Disc and cup diameter (expressed as distance in micrometers and visual angle in degrees), cup depth, Bruchs membrane opening–minimum rim width (BMO-MRW), retinal thickness, and retinal nerve fiber layer (RNFL; 1700 μm and 6° from the disc center). Results On average, 70% of participants were imaged successfully. Interexaminer reliability was excellent (ICC, >0.89) for diametric and retinal thickness parameters. Right and left eyes were similar for diametric measurements (ICC, >0.79), but more variable for nasal BMO-MRW, RNFL, and retinal thickness. The mean disc and cup diameter increase by 30% and 40%, respectively, between birth and 13 years of age when expressed as a distance measure, but remained constant (at 5°–5.5° and 2°, respectively) when expressed as a visual angle with reference to the eye nodal point. The peripapillary temporal RNFL demonstrated a marked initial decrease of nearly 35% between birth and approximately 18 months of age. This was followed by a slow increase up to 12 years of age when measured at 1700 μm from the disc center, although there was little change when measured at 6° from the disc center. Conclusions We demonstrated feasibility of handheld SD OCT imaging of the ONH in full-term infants and children without anaesthesia or sedation. This is the first in vivo handheld SD OCT study to describe the development of ONH parameters during the critical early years of visual maturation. Our results provide a normative database for use in routine practice and further studies of ONH pathologic features.

Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing

Infantile nystagmus (IN) is a genetically heterogeneous disorder arising from variants of genes expressed within the developing retina and brain. IN presents a diagnostic challenge and patients often undergo numerous investigations. We aimed to develop and assess the utility of a next-generation sequencing (NGS) panel to enhance the diagnosis of IN. We identified 336 genes associated with IN from the literature and OMIM. NimbleGen Human custom array was used to enrich the target genes and sequencing was performed using HiSeq2000. Using reference genome material (NA12878), we show the sensitivity (98.5%) and specificity (99.9%) of the panel. Fifteen patients with familial IN were sequenced using the panel. Two authors were masked to the clinical diagnosis. We identified variants in 12/15 patients in the following genes: FRMD7 (n=3), CACNA1F (n=2), TYR (n=5), CRYBA1 (n=1) and TYRP1 (n=1). In 9/12 patients, the clinical diagnosis was consistent with the genetic diagnosis. In 3/12 patients, the results from the genetic diagnoses (TYR, CRYBA1 and TYRP1 variants) enabled revision of clinical diagnoses. In 3/15 patients, we were unable to determine a genetic diagnosis. In one patient, copy number variation analysis revealed a FRMD7 deletion. This is the first study establishing the clinical utility of a diagnostic NGS panel for IN. We show that the panel has high sensitivity and specificity. The genetic information from the panel will lead to personalised diagnosis and management of IN and enable accurate genetic counselling. This will allow development of a new clinical care pathway for IN.

In Vivo Morphology of the Optic Nerve and Retina in Patients With Parkinson's Disease

Purpose To investigate optic nerve (ON) and macular morphology in patients with Parkinsons disease (PD) using spectral-domain optical coherence tomography (SD-OCT). Subjects Twenty-five participants with PD (19 males and 6 females; mean age 60.79; SD ± 9.24) and 25 sex-, age-, ethnicity-, and refraction-matched healthy controls. Methods A high-resolution SD-OCT device was used to acquire scans in 25 participants with PD (mean age 60.79; ± SD 9.24) and 25 sex-, age-, ethnicity-, and refraction-matched healthy controls. Main outcome measures included optic nerve head parameters (disc/cup diameters/areas, cup/rim volumes, cup depth, cup/disc ratio; peripapillary retinal nerve fiber layer [ppRNFL] thickness), retinal thickness (in inner and outer annuli around the foveal center) and thickness of individual retinal layers. Results Our study showed significant ppRNFL thinning in PD patients in all quadrants (P < 0.05) associated with a shallower optic cup (P = 0.03) as compared with controls. Foveal remodelling with retinal thinning (nasal and temporal segments in both annuli; and superior segment in outer annulus; P < 0.05), foveal pit widening (P = 0.05), central outer plexiform layer (OPL) thickening (P < 0.001), and nasal RPE thinning (P < 0.001) was also found in PD. The differences were more obvious in hemiretinae related to the predominantly affected cerebral hemisphere. Changes were more pronounced in advanced stages and longer PD duration. Conclusions Optic nerve changes in PD are likely to be caused by primary neurodegeneration. Central retinal thinning, pit widening, central OPL thickening, and RPE thinning indicate foveal remodelling. Specific changes of the fovea and thinning of individual retinal layers, correlating with disease severity and duration, indicate that ON and retinal changes have potential to be used as biomarkers for PD.

Retinal development in albinism: a prospective study using optical coherence tomography in infants and young children.

BACKGROUND Retinal development normally involves migration of the inner retinal layers away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the photoreceptors over time. This process is arrested prematurely in albinism. However, because retinal development continues at least until the age of 4 years, when development arrests in albinism is uncertain. In this study we outlined the time course of retinal development in children with albinism. METHODS We studied 44 children with a diagnosis of albinism and 223 control participants. All participants were aged between 0 and 6 years. We obtained 219 mixed cross-sectional and longitudinal optical coherence tomography examinations in the albinism group and compared them with 558 control examinations. Retinal layer segmentation was performed with ImageJ software. Generalised linear mixed regression modelling was used to analyse group differences in retinal development. FINDINGS In the albinism group, inner retinal layer migration from the fovea was delayed and arrested prematurely, resulting in a significantly thicker central macular thickness than in the control group (p<0·0001). Whereas the central macular thickness increased with age in the control group, in the albinism group it initially decreased with age as a result of continuing regression of the inner retinal layers (p=0·041). The perifoveal retinal thickness was significantly decreased in albinism from a reduction of both inner (p<0·0001) and outer (p<0·0001) retinal layer thicknesses. There was evidence that the photoreceptor layers across the fovea were elongating in albinism, albeit at a reduced rate, compared with the control group. This difference was most apparent for the foveal photoreceptor inner segment (p=0·001). INTERPRETATION Our findings show that perturbations exist in several aspects of retinal development including the migration and differentiation of the neuronal cells within the retina. We showed continuing regression of the inner retinal layers and elongation of the photoreceptor layers suggesting residual plasticity of the developing albino retina. This finding is important because treatment at the earliest stages of the condition might normalise retinal development and optimise vision. FUNDING UK Medical Research Council (grant number MR/J004189/1), Ulverscroft Foundation, National Eye Research Centre, Nystagmus Network UK.

Characterization of Abnormal Optic Nerve Head Morphology in Albinism Using Optical Coherence Tomography.

PURPOSE To characterize abnormalities in three-dimensional optic nerve head (ONH) morphology in people with albinism (PWA) using spectral-domain optical coherence tomography (SD-OCT) and to determine whether ONH abnormalities relate to other retinal and clinical abnormalities. METHODS Spectral-domain OCT was used to obtain three-dimensional images from 56 PWA and 60 age- and sex-matched control subjects. B-scans were corrected for nystagmus-associated motion artefacts. Disc, cup, and rim ONH dimensions and peripapillary retinal nerve fiber layer (ppRNFL) thickness were calculated using Copernicus and ImageJ software. RESULTS Median disc areas were similar in PWA (median = 1.65 mm2) and controls (1.71 mm2, P = 0.128), although discs were significantly elongated horizontally in PWA (P < 0.001). In contrast, median optic cup area in PWA (0.088 mm2) was 23.7% of that in controls (0.373 mm2, P < 0.001), with 39.4% of eyes in PWA not demonstrating a measurable optic cup. This led to significantly smaller cup to disc ratios in PWA (P < 0.001). Median rim volume in PWA (0.273 mm3) was 136.6% of that in controls (0.200 mm3). The ppRNFL was significantly thinner in PWA compared with controls (P < 0.001), especially in the temporal quadrant. In PWA, ppRNFL thickness was correlated to ganglion cell thickness at the central fovea (P = 0.007). Several ONH abnormalities, such as cup to disc ratio, were related to higher refractive errors in PWA. CONCLUSIONS In PWA, ocular maldevelopment is not just limited to the retina but also involves the ONH. Reduced ppRNFL thickness is consistent with previous reports of reduced ganglion cell numbers in PWA. The thicker rim volumes may be a result of incomplete maturation of the ONH.

Hand-held optical coherence tomography imaging in children with anterior segment dysgenesis

Case 1: A 5-year-old patient was seen because of conjunctivitis. An irregular circular white structure located underneath of the endothelium anteriorly to the limbus was found incidentally (Fig. 2). Diagnosis of Axenfeld’s anomaly was made. Optical coherence tomography (OCT) angle scans demonstrated a prominent anteriorly displaced Schwalbe line. The patient had several small (less than 1 mm) zones of the iridocorneal adhesions originating from the angular part of the iris and fixed behind the displaced Schwalbe line (Fig. 2E, right) in both eyes.