Gail Maconachie

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.

Reading Strategies in Infantile Nystagmus Syndrome

PURPOSE The adaptive strategies adopted by individuals with infantile nystagmus syndrome (INS) during reading are not clearly understood. Eye movement recordings were used to identify ocular motor strategies used by patients with INS during reading. METHODS Eye movements were recorded at 500 Hz in 25 volunteers with INS and 7 controls when reading paragraphs of text centered at horizontal gaze angles of -20°, -10°, 0°, 10°, and 20°. At each location, reading speeds were measured, along with logMAR visual acuity and nystagmus during gaze-holding. Adaptive strategies were identified from slow and quick-phase patterns in the nystagmus waveform. RESULTS Median reading speeds were 204.3 words per minute in individuals with INS and 273.6 words per minute in controls. Adaptive strategies included (1) suppression of corrective quick phases allowing involuntary slow phases to achieve the desired goal, (2) voluntarily changing the character of the involuntary slow phases using quick phases, and (3) correction of involuntary slow phases using quick phases. Several individuals with INS read more rapidly than healthy control volunteers. CONCLUSIONS These findings demonstrate that volunteers with INS learn to manipulate their nystagmus using a range of strategies to acquire visual information from the text. These strategies include taking advantage of the stereotypical and periodic nature of involuntary eye movements to allow the involuntary eye movements to achieve the desired goal. The versatility of these adaptations yields reading speeds in those with nystagmus that are often much better than might be expected, given the degree of foveal and ocular motor deficits.

Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects.

Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.

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.

Association Between Adherence to Glasses Wearing During Amblyopia Treatment and Improvement in Visual Acuity

Importance Occlusion dose monitors have helped establish that better adherence to occlusion is associated with improved visual outcomes in patients undergoing amblyopia treatment. However, the role of adherence to glasses wearing is unknown. Objectives To establish the feasibility and reliability of objectively monitoring adherence to glasses wearing using age-based norms, establish the association between adherence to glasses wearing and improvement in visual acuity (VA) after optical treatment and occlusion therapy, and analyze the effect of age, sex, refractive errors, type of amblyopia, and adherence to glasses wearing on improvement in VA. Design, Setting, and Participants A prospective, observational, nonmasked, cohort study was conducted between June 8, 2008, and June 30, 2013, among patients at a pediatric ophthalmology clinic of a tertiary care hospital who were newly diagnosed with anisometropic and/or strabismic amblyopia and had not undergone previous treatment. The study consisted of a glasses phase (18 weeks) and a patching phase (glasses and occlusion for 10 hours per day for 12 weeks). Reliability of the glasses monitors was assessed by comparing diary entries and monitor recordings in adults. Interventions Objective monitoring of glasses wearing and occlusion. Main Outcomes and Measures Adherence to glasses wearing (hours per day) and effect on VA. Results Among 20 children with anisometropia (mean [SD] age, 6.20 [2.16] years; 11 boys and 9 girls) and 20 with strabismic or mixed amblyopia (mean [SD] age, 4.90 [1.36] years; 10 boys and 10 girls), adherence to glasses wearing was successfully monitored in all but 1 patient. Agreement between diaries and monitored times wearing glasses in adults was high (intraclass correlation coefficient, 1.00; 95% CI, 0.999-1.00). Median (SD) adherence to glasses wearing was 70% (25.3%). A moderate correlation was observed between adherence to glasses wearing and percentage improvement in VA during the glasses phase (r = 0.462; P = .003). Multiple regression revealed that age (β = -0.535; P = .001), type of amblyopia (β = -0.347; P = .02), and adherence to glasses wearing (β = 0.287; P = .04) were independently associated with improvement in VA after the glasses phase and explained 42% of the variability (F3,35 = 8.457; P < .001). A strong correlation between glasses wearing and occlusion adherence was observed (r = 0.719; P < .001). Conclusions and Relevance The results suggest that adherence to glasses wearing is less than optimal and highly variable but is important in achieving good VA. This study emphasizes the importance of encouraging children to not only have good adherence to occlusion therapy but also to glasses wearing.

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.

The challenges of amblyopia treatment

The treatment of amblyopia, particularly anisometropic (difference in refractive correction) and/or strabismic (turn of one eye) amblyopia has long been a challenge for many clinicians. Achieving optimum outcomes, where the amblyopic eye reaches a visual acuity similar to the fellow eye, is often impossible in many patients. Part of this challenge has resulted from a previous lack of scientific evidence for amblyopia treatment that was highlight by a systematic review by Snowdon et al. in 1998. Since this review, a number of publications have revealed new findings in the treatment of amblyopia. This includes the finding that less intensive occlusion treatments can be successful in treating amblyopia. A relationship between adherence to treatment and visual acuity has also been established and has been shown to be influenced by the use of intervention material. In addition, there is growing evidence of that a period of glasses wearing only can significantly improve visual acuity alone without any other modes of treatment. This review article reports findings since the Snowdons report.