Prospective study of pediatric patients presenting with idiopathic infantile nystagmus-Management and molecular diagnostics.

Idiopathic infantile nystagmus (IIN) is an inherited disorder occurring in the first 6 months of life, with no underlying retinal or neurological etiologies and is predominantly caused by mutations in the FRMD7 gene. IIN poses a diagnostic challenge as underlying pre-symptomatic "multisystem" disorders varying from benign to life-threatening should first be ruled out before nystagmus can be labeled as idiopathic. A multidisciplinary approach including multimodal ocular investigations and next-generation sequencing with whole-genome sequencing (WGS) or targeted gene panel testing is required to delineate the exact etiology. We report the clinical and genetic outcomes of 22 patients, from 22 unrelated families of diverse ethnicities, with IIN seen in the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between 2016 and 2022. Thirty-six percent (8/22) received a confirmed molecular diagnosis with eight mutations identified in two genes (seven in FRMD7 including one novel variant c.706_707del; p. [Lys236Alafs*66], and one in GPR143). This study expands the mutational spectrum of IIN and highlights the significant role of an integrated care pathway and broader panel testing in excluding underlying pathologies.

Crowding changes appearance systematically in peripheral, amblyopic, and developing vision.

Visual crowding is the disruptive effect of clutter on object recognition. Although most prominent in adult peripheral vision, crowding also disrupts foveal vision in typically developing children and those with strabismic amblyopia. Do these crowding effects share the same mechanism? Here we exploit observations that crowded errors in peripheral vision are not random: Target objects appear either averaged with the flankers (assimilation) or replaced by them (substitution). If amblyopic and developmental crowding share the same mechanism, then their errors should be similarly systematic. We tested foveal vision in children aged 3 to 8 years with typical vision or strabismic amblyopia and peripheral vision in typical adults. The perceptual effects of crowding were measured by requiring observers to adjust a reference stimulus to match the perceived orientation of a target "Vac-Man" element. When the target was surrounded by flankers that differed by ± 30°, all three groups (adults and children with typical or amblyopic vision) reported orientations between the target and flankers (assimilation). Errors were reduced with ± 90° differences but primarily matched the flanker orientation (substitution) when they did occur. A population pooling model of crowding successfully simulated this pattern of errors in all three groups. We conclude that the perceptual effects of amblyopic and developing crowding are systematic and resemble the near periphery in adults, suggesting a common underlying mechanism.

Ocular myasthenia gravis saccades as a measure of extraocular muscle function.

Background: It is important to understand the pathophysiology of ocular myasthenia gravis (OMG) to improve treatment. Aim: To use modern video-oculography to characterise saccadic eye movements in patients with OMG, including anti-AChR, anti-MuSK, anti-LRP4, and seronegative OMG. Methods: In total, 21 patients with OMG and five age-matched healthy control subjects underwent video-oculography. Participants performed a sequence of horizontal saccades (3 minutes each) at ±5°, ± 10°, and ±20°, followed by 3 minutes of saccades directed at randomly presented targets at ±5°, ± 10°, and ±15°. We recorded the direction, amplitude, duration, peak, and average velocity of each saccade for each task for each participant. Results: Saccadic amplitude, duration, and average velocity were all lower in OMG patients than in control subjects (p < 0.021). Saccadic amplitude and velocity decreased over time, but this decrease was similar in OMG patients and control subjects. Fixation drift and ocular disparity tended to be greater in OMG patients than in control subjects. Saccadic intrusions occurred more frequently in OMG patients than in control subjects (p < 0.001). No significant effects of time or group by time on fixation drift or ocular disparity were found. Discussion: Saccadic velocities in OMG patients differed from those in normal control subjects, which suggests that OMG affects fast-twitch fibres, although fast-twitch fibres were still able to generate "twitch" or "quiver" movements in the presence of even severe ophthalmoplegia. Slow-twitch muscle fibres involved in gaze holding were also affected, accounting for increased fixation drift following saccades. Our objective finding of increased fixation drift and a larger number of saccadic intrusions mirror our anecdotal experience of patients with OMG who report significant diplopia despite minimal ophthalmoplegia on examination. Such microsaccades may be a surrogate for compensation of a gaze-holding deficit in MG.

Eye movements elevate crowding in idiopathic infantile nystagmus syndrome.

Idiopathic infantile nystagmus syndrome is a disorder characterised by involuntary eye movements, which leads to decreased acuity and visual function. One such function is visual crowding - a process whereby objects that are easily recognised in isolation become impaired by nearby flankers. Crowding typically occurs in the peripheral visual field, although elevations in foveal vision have been reported in congenital nystagmus, similar to those found with amblyopia. Here, we examine whether elevated foveal crowding with nystagmus is driven by similar mechanisms to those of amblyopia - long-term neural changes associated with a sensory deficit - or by the momentary displacement of the stimulus through nystagmus eye movements. A Landolt-C orientation identification task was used to measure threshold gap sizes with and without either horizontally or vertically placed Landolt-C flankers. We assume that a sensory deficit should give equivalent crowding in these two dimensions, whereas an origin in eye movements should give stronger crowding with horizontal flankers given the predominantly horizontal eye movements of nystagmus. We observe elevations in nystagmic crowding that are above crowding in typical vision but below that of amblyopia. Consistent with an origin in eye movements, elevations were stronger with horizontal than vertical flankers in nystagmus, but not in typical or amblyopic vision. We further demonstrate the same horizontal elongation in typical vision with stimulus movement that simulates nystagmus. Consequently, we propose that the origin of nystagmic crowding lies in the eye movements, either through image smear of the target and flanker elements or through relocation of the stimulus into the peripheral retina.

Prospective Study of the Phenotypic and Mutational Spectrum of Ocular Albinism and Oculocutaneous Albinism.

Albinism encompasses a group of hereditary disorders characterized by reduced or absent ocular pigment and variable skin and/or hair involvement, with syndromic forms such as Hermansky-Pudlak syndrome and Chédiak-Higashi syndrome. Autosomal recessive oculocutaneous albinism (OCA) is phenotypically and genetically heterogenous (associated with seven genes). X-linked ocular albinism (OA) is associated with only one gene, GPR143. We report the clinical and genetic outcomes of 44 patients, from 40 unrelated families of diverse ethnicities, with query albinism presenting to the ocular genetics service at Moorfields Eye Hospital NHS Foundation Trust between November 2017 and October 2019. Thirty-six were children (≤ 16 years) with a median age of 31 months (range 2-186), and eight adults with a median age of 33 years (range 17-39); 52.3% (n = 23) were male. Genetic testing using whole genome sequencing (WGS, n = 9) or a targeted gene panel (n = 31) gave an overall diagnostic rate of 42.5% (44.4% (4/9) with WGS and 41.9% (13/31) with panel testing). Seventeen families had confirmed mutations in TYR (n = 9), OCA2, (n = 4), HPS1 (n = 1), HPS3 (n = 1), HPS6 (n = 1), and GPR143 (n = 1). Molecular diagnosis of albinism remains challenging due to factors such as missing heritability. Differential diagnoses must include SLC38A8-associated foveal hypoplasia and syndromic forms of albinism.

Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia.

Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies.

Use of a Binocular Optical Coherence Tomography System to Evaluate Strabismus in Primary Position.

Importance: Current clinical methods for assessing strabismus can be prone to error. Binocular optical coherence tomography (OCT) has the potential to assess and quantify strabismus objectively and in an automated manner. Objective: To evaluate the use of a binocular OCT prototype to assess the presence and size of strabismus. Design, Setting, and Participants: Fifteen participants with strabismus were recruited in 2016 as part of the EASE study from Moorfields Eye Hospital National Health Service Foundation Trust, London, England, and 15 healthy volunteers underwent automated anterior segment imaging using the binocular OCT prototype. All participants had an orthoptic assessment, including alternating prism cover test (APCT), before undergoing imaging. Simultaneously acquired pairs of OCT images, captured with 1 eye fixating, were analyzed using ImageJ (National Institutes of Health) to assess the presence and angle of strabismus. Main Outcomes and Measures: The direction and size of strabismus measured using binocular OCT was compared with that found using APCT. Results: The median age for participants with strabismus was 55 years (interquartile range [IQR], 33-66.5 years) and for the healthy group, 50 years (IQR, 41-59 years); 15 participants (50%) were women, and 25 participants (83.3%) were white. The median magnitude of horizontal deviation was 20∆ (IQR, 13-35∆) and for vertical deviation, 3∆ (IQR, 0-5∆). Binocular OCT imaging correctly revealed the type and direction of the deviation in all 15 participants with strabismus, including horizontal and vertical deviations. The APCT and OCT measurements were strongly correlated for the horizontal (Pearson r = 0.85; 95% CI, 0.60-0.95; P < .001) and vertical (r = 0.89; 95% CI, 0.69-0.96; P < .001) deviations. In the healthy cohort, 9 of 15 participants (60%) had a latent horizontal deviation on APCT results (median magnitude 2∆, range 2-4∆). Six (40%) had orthophoria. Horizontal deviations were observed on OCT imaging results in 12 of the 15 participants (80%), and a vertical deviation was visible in 1 participant (6.7%). Conclusions and Relevance: These findings suggest that binocular anterior segment OCT imaging can provide clinicians with a precise measurement of strabismus. The prototype can potentially incorporate several binocular vision tests that will provide quantitative data for the assessment, diagnosis, and monitoring of ocular misalignments.

Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression.

Purpose: Amblyopia is a common developmental visual impairment characterized by a substantial difference in acuity between the two eyes. Current monocular treatments, which promote use of the affected eye by occluding or blurring the fellow eye, improve acuity, but are hindered by poor compliance. Recently developed binocular treatments can produce rapid gains in visual function, thought to be as a result of reduced interocular suppression. We set out to develop an effective home-based binocular treatment system for amblyopia that would engage high levels of compliance but that would also allow us to assess the role of suppression in children's response to binocular treatment. Methods: Balanced binocular viewing therapy (BBV) involves daily viewing of dichoptic movies (with "visibility" matched across the two eyes) and gameplay (to monitor compliance and suppression). Twenty-two children (3-11 years) with anisometropic (n = 7; group 1) and strabismic or combined mechanism amblyopia (group 2; n = 6 and 9, respectively) completed the study. Groups 1 and 2 were treated for a maximum of 8 or 24 weeks, respectively. Results: The treatment elicited high levels of compliance (on average, 89.4% ± 24.2% of daily dose in 68.23% ± 12.2% of days on treatment) and led to a mean improvement in acuity of 0.27 logMAR (SD 0.22) for the amblyopic eye. Importantly, acuity gains were not correlated with a reduction in suppression. Conclusions: BBV is a binocular treatment for amblyopia that can be self-administered at home (with remote monitoring), producing rapid and substantial benefits that cannot be solely mediated by a reduction in interocular suppression.

Neuroplasticity and amblyopia: vision at the balance point.

PURPOSE OF REVIEW: New insights into triggers and brakes of plasticity in the visual system are being translated into new treatment approaches which may improve outcomes not only in children, but also in adults. RECENT FINDINGS: Visual experience-driven plasticity is greatest in early childhood, triggered by maturation of inhibitory interneurons which facilitate strengthening of synchronous synaptic connections, and inactivation of others. Normal binocular development leads to progressive refinement of monocular visual acuity, stereoacuity and fusion of images from both eyes. At the end of the 'critical period', structural and functional brakes such as dampening of acetylcholine receptor signalling and formation of perineuronal nets limit further synaptic remodelling. Imbalanced visual input from the two eyes can lead to imbalanced neural processing and permanent visual deficits, the commonest of which is amblyopia. SUMMARY: The efficacy of new behavioural, physical and pharmacological interventions aiming to balance visual input and visual processing have been described in humans, and some are currently under evaluation in randomised controlled trials. Outcomes may change amblyopia treatment for children and adults, but the safety of new approaches will need careful monitoring, as permanent adverse events may occur when plasticity is re-induced after the end of the critical period.Video abstracthttp://links.lww.com/CONR/A42.

Prescribed computer games in addition to occlusion versus standard occlusion treatment for childhood amblyopia: a pilot randomised controlled trial.

BACKGROUND: Amblyopia ("lazy eye") is the commonest vision deficit in children. If not fully corrected by glasses, amblyopia is treated by patching or blurring the better-seeing eye. Compliance with patching is often poor. Computer-based activities are increasingly topical, both as an adjunct to standard treatment and as a platform for novel treatments. Acceptability by families has not been explored, and feasibility of a randomised controlled trial (RCT) using computer games in terms of recruitment and treatment acceptability is uncertain. METHODS: We carried out a pilot RCT to test whether computer-based activities are acceptable and accessible to families and to test trial methods such as recruitment and retention rates, randomisation, trial-specific data collection tools and analysis. The trial had three arms: standard near activity advice, Eye Five, a package developed for children with amblyopia, and an off-the-shelf handheld games console with pre-installed games. We enrolled 60 children age 3-8 years with moderate or severe amblyopia after completion of optical treatment. RESULTS: This trial was registered as UKCRN-ID 11074. Pre-screening of 3600 medical notes identified 189 potentially eligible children, of whom 60 remained eligible after optical treatment, and were enrolled between April 2012 and March 2013. One participant was randomised twice and withdrawn from the study. Of the 58 remaining, 37 were boys. The mean (SD) age was 4.6 (1.7) years. Thirty-seven had moderate and 21 severe amblyopia. Three participants were withdrawn at week 6, and in total, four were lost to follow-up at week 12. Most children and parents/carers found the study procedures, i.e. occlusion treatment, usage of the allocated near activity and completion of a study diary, easy. The prescribed cumulative dose of near activity was 84 h at 12 weeks. Reported near activity usage numbers were close to prescribed numbers in moderate amblyopes (94 % of prescribed) but markedly less in severe amblyopes (64 %). Reported occlusion usage at 12 weeks was 90 % of prescribed dose for moderate and 33 % for severe amblyopes. CONCLUSIONS: Computer-based games and activities appear acceptable to families as part of their child's amblyopia treatment. Trial methods were appropriate and accepted by families.

Visual acuity, crowding, and stereo-vision are linked in children with and without amblyopia.

PURPOSE: During development, the presence of strabismus and anisometropia frequently leads to amblyopia, a visual disorder characterized by interocular acuity differences. Although additional deficits in contrast sensitivity, crowding (the impaired recognition of closely spaced objects), and stereoacuity are common, the relationship between these abilities is unclear. METHODS: We measured the covariation between these four abilities in children 4 to 9 years of age (n = 72) with strabismus, anisometropia, or mixed strabismus/anisometropia, and unaffected controls. Children reported the orientation of a target (a modified "Pac-Man," similar to Landolt-C stimuli) using four "ghosts" as references. Using a modified staircase procedure we measured threshold size (acuity), contrast detection, foveal crowding (the minimum separation between target and ghost-flankers supporting accurate identification), and stereoacuity (with random-dot stereogram ghosts). RESULTS: Group averages revealed significant interocular differences (IODs) in acuity for all three clinical groups (0.2-0.3 log minutes), and significant crowding IODs for the strabismic and mixed groups (0.6 and 0.4°, respectively). Nonetheless, crowding IODs were correlated with acuity IODs in all four groups (r values between 0.43 and 0.59 and P < 0.05; P = 0.07 in the mixed group). Similarly, the occurrence of stereo-blindness (most common in strabismic and mixed groups) was associated with a significant increase in IODs for both acuity and crowding (each P < 0.05). No correlations were found with contrast detection. CONCLUSIONS: Our results demonstrate an association between IODs in acuity and crowding and, furthermore, between these IODs and the presence of stereo-vision. We suggest that the deficits derived from strabismus and anisometropia lay along a continuum with abilities observed during normal development.