Visual Field Deficits in Albinism in Comparison to Idiopathic Infantile Nystagmus.

Purpose: This is the first systematic comparison of visual field (VF) deficits in people with albinism (PwA) and idiopathic infantile nystagmus (PwIIN) using static perimetry. We also compare best-corrected visual acuity (BCVA) and optical coherence tomography measures of the fovea, parafovea, and circumpapillary retinal nerve fiber layer in PwA. Methods: VF testing was performed on 62 PwA and 36 PwIIN using a Humphrey Field Analyzer (SITA FAST 24-2). Mean detection thresholds for each eye were calculated, along with quadrants and central measures. Retinal layers were manually segmented in the macular region. Results: Mean detection thresholds were significantly lower than normative values for PwA (-3.10 ± 1.67 dB, P << 0.0001) and PwIIN (-1.70 ± 1.54 dB, P < 0.0001). Mean detection thresholds were significantly lower in PwA compared to PwIIN (P < 0.0001) and significantly worse for left compared to right eyes in PwA (P = 0.0002) but not in PwIIN (P = 0.37). In PwA, the superior nasal VF was significantly worse than other quadrants (P < 0.05). PwIIN appeared to show a mild relative arcuate scotoma. In PwA, central detection thresholds were correlated with foveal changes in the inner and outer retina. VF was strongly correlated to BCVA in both groups. Conclusions: Clear peripheral and central VF deficits exist in PwA and PwIIN, and static VF results need to be interpreted with caution clinically. Since PwA exhibit considerably lower detection thresholds compared to PwIIN, VF defects are unlikely to be due to nystagmus in PwA. In addition to horizontal VF asymmetry, PwA exhibit both vertical and interocular asymmetries, which needs further exploration.

Phenotypic Features Determining Visual Acuity in Albinism and the Role of Amblyogenic Factors.

Albinism is a spectrum disorder causing foveal hypoplasia, nystagmus, and hypopigmentation of the iris and fundus along with other visual deficits, which can all impact vision. Albinism is also associated with amblyogenic factors which could affect monocular visual acuity. The foveal appearance in albinism can range from mild foveal hypoplasia to that which is indistinguishable from the peripheral retina. The appearance can be quickly and easily graded using the Leicester Grading System in the clinic. However, interquartile ranges of 0.3 logMAR for the grades associated with albinism limit the accuracy of the grading system in predicting vision. Here, we discuss the potential role of nystagmus presenting evidence that it may not be a major source of variability in the prediction of visual acuity. We also show that interocular differences in visual acuity are low in albinism despite high levels of amblyogenic factors indicating that active suppression of vision in one eye in albinism is uncommon.

CHIASM-Net: Artificial Intelligence-Based Direct Identification of Chiasmal Abnormalities in Albinism.

Purpose: Albinism is a congenital disorder affecting pigmentation levels, structure, and function of the visual system. The identification of anatomical changes typical for people with albinism (PWA), such as optic chiasm malformations, could become an important component of diagnostics. Here, we tested an application of convolutional neural networks (CNNs) for this purpose. Methods: We established and evaluated a CNN, referred to as CHIASM-Net, for the detection of chiasmal malformations from anatomic magnetic resonance (MR) images of the brain. CHIASM-Net, composed of encoding and classification modules, was developed using MR images of controls (n = 1708) and PWA (n = 32). Evaluation involved 8-fold cross validation involving accuracy, precision, recall, and F1-score metrics and was performed on a subset of controls and PWA samples excluded from the training. In addition to quantitative metrics, we used Explainable AI (XAI) methods that granted insights into factors driving the predictions of CHIASM-Net. Results: The results for the scenario indicated an accuracy of 85 ± 14%, precision of 90 ± 14% and recall of 81 ± 18%. XAI methods revealed that the predictions of CHIASM-Net are driven by optic-chiasm white matter and by the optic tracts. Conclusions: CHIASM-Net was demonstrated to use relevant regions of the optic chiasm for albinism detection from magnetic resonance imaging (MRI) brain anatomies. This indicates the strong potential of CNN-based approaches for visual pathway analysis and ultimately diagnostics.

Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.

Purpose: Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. Methods: We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Results: Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Conclusions: Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.

Clinical features and imaging characteristics in achiasmia.

Achiasmia is a rare visual pathway maldevelopment with reduced decussation of the axons in the optic chiasm. Our aim was to investigate clinical characteristics, macular, optic nerve and brain morphology in achiasmia. A prospective, cross-sectional, observational study of 12 participants with achiasmia [8 males and 4 females; 29.6 ± 18.4 years (mean ± standard deviation)] and 24 gender-, age-, ethnicity- and refraction-matched healthy controls was done. Full ophthalmology assessment, eye movement recording, a high-resolution spectral-domain optical coherence tomography of the macular and optic disc, five-channel visual-evoked responses, eye movement recordings and MRI scans of the brain and orbits were acquired. Achiasmia was confirmed in all 12 clinical participants by visual-evoked responses. Visual acuity in this group was 0.63 ± 0.19 and 0.53 ± 0.19 for the right and left eyes, respectively; most participants had mild refractive errors. All participants with achiasmia had see-saw nystagmus and no measurable stereo vision. Strabismus and abnormal head position were noted in 58% of participants. Optical coherence tomography showed optic nerve hypoplasia with associated foveal hypoplasia in four participants. In the remaining achiasmia participants, macular changes with significantly thinner paracentral inner segment (P = 0.002), wider pit (P = 0.04) and visual flattening of the ellipsoid line were found. MRI demonstrated chiasmatic aplasia in 3/12 (25%), chiasmatic hypoplasia in 7/12 (58%) and a subjectively normal chiasm in 2/12 (17%). Septo-optic dysplasia and severe bilateral optic nerve hypoplasia were found in three patients with chiasmic aplasia/hypoplasia on MRI. In this largest series of achiasmia patients to date, we found for the first time that neuronal abnormalities occur already at the retinal level. Foveal changes, optic nerve hypoplasia and the midline brain anomaly suggest that these abnormalities could be part of the same spectrum, with different manifestations of events during foetal development occurring with varying severity.

Abnormal foveal morphology in carriers of oculocutaneous albinism.

BACKGROUND/AIMS: To investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study. METHODS: Handheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured. RESULTS: Foveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL thickness (mean difference: 8.98 µm, p<0.001) at the central fovea compared with controls. BCVA of carriers was between -0.16 and 0.18 logMAR (mean: 0.0 logMAR). No significant differences in BCVA was noted between OCA carriers or controls (p=0.83). In the OCA carriers, we identified previously reported pathogenic variants in TYR, OCA2 and SLC45A2, novel OCA2 variants (n=3) and heterozygosity of the pathogenic TYR haplotype. CONCLUSION: We have, for the first time, identified foveal abnormalities in OCA carriers. This provides clinical value, particularly in cases where limited phenotype data are available. Our findings raise the possibility that previously reported mild cases of foveal hypoplasia or isolated foveal hypoplasia could correspond to OCA carrier status.

Retinal Development in Infants and Young Children With Albinism: Evidence for Plasticity in Early Childhood.

MEETING PRESENTATION: Presented at the 2016 Association for Research in Vision and Ophthalmology meeting and at the 2015 British Isles Paediatric, Ophthalmology and Strabismus Association meeting. PURPOSE: To investigate the time course of foveal development after birth in infants with albinism. DESIGN: Prospective, comparative cohort optical coherence tomography study. METHODS: Thirty-six children with albinism were recruited. All participants were between 0 and 6 years of age and were seen at Leicester Royal Infirmary. A total of 181 mixed cross-sectional and longitudinal optical coherence tomography examinations were obtained, which were analyzed for differences in retinal development in comparison to 297 cross-sectional control examinations. RESULTS: Normal retinal development involves migration of the inner retinal layers (IRLs) away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the outer retinal layers (ORLs) over time. In contrast to controls where IRL migration from the fovea was almost completed at birth, a significant degree of IRL migration was taking place after birth in albinism, before arresting prematurely at 40 months postmenstrual age (PMA). This resulted in a significantly thicker central macular thickness in albinism (Δ = 83.8 ± 6.1, P < .0001 at 69 months PMA). There was evidence of ongoing foveal ORL elongation in albinism, although reduced in amplitude compared with control subjects after 21 months PMA (Δ = -17.3 ± 4.3, P < .0001). CONCLUSIONS: We have demonstrated evidence of ongoing retinal development in young children with albinism, albeit at a reduced rate and magnitude compared with control subjects. The presence of a period of retinal plasticity in early childhood raises the possibility that treatment modalities, which aim to improve retinal development, could potentially optimize visual function in albinism.

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia.

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM.

Structural Differences Across Multiple Visual Cortical Regions in the Absence of Cone Function in Congenital Achromatopsia.

Most individuals with congenital achromatopsia (ACHM) carry mutations that affect the retinal phototransduction pathway of cone photoreceptors, fundamental to both high acuity vision and colour perception. As the central fovea is occupied solely by cones, achromats have an absence of retinal input to the visual cortex and a small central area of blindness. Additionally, those with complete ACHM have no colour perception, and colour processing regions of the ventral cortex also lack typical chromatic signals from the cones. This study examined the cortical morphology (grey matter volume, cortical thickness, and cortical surface area) of multiple visual cortical regions in ACHM (n = 15) compared to normally sighted controls (n = 42) to determine the cortical changes that are associated with the retinal characteristics of ACHM. Surface-based morphometry was applied to T1-weighted MRI in atlas-defined early, ventral and dorsal visual regions of interest. Reduced grey matter volume in V1, V2, V3, and V4 was found in ACHM compared to controls, driven by a reduction in cortical surface area as there was no significant reduction in cortical thickness. Cortical surface area (but not thickness) was reduced in a wide range of areas (V1, V2, V3, TO1, V4, and LO1). Reduction in early visual areas with large foveal representations (V1, V2, and V3) suggests that the lack of foveal input to the visual cortex was a major driving factor in morphological changes in ACHM. However, the significant reduction in ventral area V4 coupled with the lack of difference in dorsal areas V3a and V3b suggest that deprivation of chromatic signals to visual cortex in ACHM may also contribute to changes in cortical morphology. This research shows that the congenital lack of cone input to the visual cortex can lead to widespread structural changes across multiple visual areas.

Detection of intracranial hypertension in children using optical coherence tomography: a systematic review.

OBJECTIVES: To evaluate the diagnostic capability of optical coherence tomography (OCT) in children aged under 18 years old with intracranial hypertension (IH). DESIGN: Systematic review. METHODS: We conducted a systematic review using the following platforms to search the keywords 'optical coherence tomography' and 'intracranial hypertension' from inception to 2 April 2020: Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, PubMed and Web of Science, without language restrictions. Our search returned 2729 records, screened by two independent screeners. Studies were graded according to the Oxford Centre for Evidence-Based Medicine and National Institutes of Health Quality Assessment Tool for observational studies. RESULTS: Twenty-one studies were included. Conditions included craniosynostosis (n=354 patients), idiopathic IH (IIH; n=102), space-occupying lesion (SOL; n=42) and other pathology (n=29). OCT measures included optic nerve parameters, rim parameters (notably retinal nerve fibre layer thickness) and retinal parameters. Levels of evidence included 2b (n=13 studies), 3b (n=4) and 4 (n=4). Quality of 10 studies was fair and 11 poor. There was inconsistency in OCT parameters and reference measures studied, although OCT did demonstrate good diagnostic capability for IH in craniosynostosis, IIH and SOL. CONCLUSIONS: This systematic review identified various studies involving OCT to assist diagnosis and management of IH in children with craniosynostosis, IIH, SOL and other pathology, in conjunction with established clinical measures of intracranial pressure. However, no level 1 evidence was identified. Validating prospective studies are, therefore, required to determine optimal OCT parameters in this role and to develop formal clinical guidelines. PROSPERO REGISTRATION NUMBER: CRD42019154254.

Feasibility and Repeatability of Handheld Optical Coherence Tomography in Children With Craniosynostosis.

Purpose: To determine whether handheld optical coherence tomography (OCT) is feasible and repeatable in children with craniosynostosis. Methods: This was a prospective cross-sectional study. Children with syndromic and non-syndromic craniosynostosis 0 to 18 years of age were recruited between February 13, 2020, and October 1, 2020. Main outcome measures included feasibility (patient recruitment and handheld OCT success rates) and repeatability, which were assessed using intraclass correlation coefficients (ICCs) where repeated images of the optic nerve head (ONH) within the same visit were available. ONH parameters used for repeatability analysis included cup depth, width, and area; disc width; rim height; retinal thickness; retinal nerve fiber layer thickness; and Bruch's membrane opening minimum rim width. Results: Fifty children were approached, and all 50 (100%) were successfully recruited. Median age was 51.1 months (range, 1.9-156.9; interquartile range, 37.0-74.2), and 33 of the children (66%) were male. At least one ONH image was obtained in 43 children (86%), and bilateral ONH imaging was successful in 38 children (76%). Factors boosting the likelihood of success included good understanding and cooperation of the child and parent/guardian and availability of an assistant. Repeatability analysis was performed in 20 children, demonstrating good repeatability (ICC range, 0.77-0.99; the majority exceeded 0.90). OCT correctly identified two cases of intracranial hypertension, one of which was undetected by prior fundoscopy. Conclusions: Handheld OCT is feasible and repeatable in children with syndromic and non-syndromic forms of craniosynostosis. Translational Relevance: Our handheld OCT approach could be used for the clinical surveillance of children with craniosynostosis.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Discordant phenotypes in twins with infantile nystagmus.

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and triplets displayed FH. In three families, at least one parent had FH without nystagmus. FH alone may be insufficient to develop nystagmus. Whilst arrested optokinetic reflex pathway development is implicated in IN, discordant twins raise questions regarding where differences in development have arisen. In unaffected monozygotes therefore, genetic variants may predispose to oculomotor instability, with variable expressivity possibly responsible for the discordance observed.

Early Recognition of Raised Intracranial Pressure in Craniosynostosis Using Optical Coherence Tomography.

OBJECTIVE: Craniosynostosis can be associated with raised intracranial pressure (ICP), which can pose deleterious effects on the brain and vision if untreated. Estimating ICP in children is challenging, whilst gold standard direct intracranial measurement of ICP is invasive and carries risk. This systematic review aims to evaluate the role of optical coherence tomography (OCT), a noninvasive imaging technique, for detecting raised ICP in children with craniosynostosis. METHODS: The authors conducted a systematic review of the literature published from inception until 19 August, 2019 in the Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, and EMBASE. Eligible studies evaluated the role of OCT in detecting raised ICP in children aged 0 to 16 years with craniosynostosis. Main outcome measures were sensitivity and specificity of OCT parameters for raised ICP. Quality assessment was performed using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-sectional Studies. RESULTS: Out of 318 records identified, data meeting the inclusion criteria were obtained from 3 studies. The quality of 2 studies was poor whilst 1 was fair. Optical coherence tomography demonstrated higher sensitivity and specificity for detecting raised ICP compared to fundus examination, clinical history, radiological testing, and visual field testing. CONCLUSIONS: This systematic review demonstrated a lack of quality evidence for OCT as a screening tool for children with craniosynostosis. Further research is required to clarify the strength of OCT in this role and to determine which OCT parameters are most appropriate.

Detection of intracranial hypertension in children using optical coherence tomography: a systematic review protocol.

INTRODUCTION: Intracranial hypertension (ICH) in children can have deleterious effects on the brain and vision. It is notoriously difficult to estimate intracranial pressure (ICP) in children and existing methods deliver suboptimal diagnostic accuracy to be used as screening tools. Optical coherence tomography (OCT) may represent a valuable, non-invasive surrogate measure of ICP, as has been demonstrated in a number of associated conditions affecting adults. More recently, OCT has been employed within the paediatric age group. However, the role of OCT in detecting ICH in children has not been rigorously assessed in a systematic review for all relevant conditions. Here, we propose a systematic review protocol to examine the role of OCT in the detection of ICH in children. METHODS AND ANALYSIS: Electronic searches in the Cochrane Central Register of Controlled Trials, Medline, Embase, Web of Science and PubMed will identify studies featuring OCT in detecting ICH in children. Two independent screeners will identify studies for inclusion using a screening questionnaire. The systematic search and screening will take place between 2 April 2020 and 1 June 2020, while we aim to complete data analysis by 1 September 2020. Quality assessment will be performed using the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome measure is the sensitivity and specificity of OCT in detecting ICH in children. Secondary outcomes measures include conditions associated with ICH per study, direct ICP monitoring, sensitivity and specificity of other measures for ICP and OCT parameters used. ETHICS AND DISSEMINATION: Ethical approval is not required for the proposed systematic review as no primary data will be collected. The findings will be disseminated through presentations at scientific meetings and peer-reviewed journal publication. PROSPERO REGISTRATION NUMBER: CRD42019154254.

Reading Individual Words Within Sentences in Infantile Nystagmus.

Purpose: Normal readers make immediate and precise adjustments in eye movements during sentence reading in response to individual word features, such as lexical difficulty (e.g., common or uncommon words) or word length. Our purpose was to assess the effect of infantile nystagmus (IN) on these adaptive mechanisms. Methods: Eye movements were recorded from 29 participants with IN (14 albinism, 12 idiopathic, and 3 congenital stationary night blindness) and 15 controls when reading sentences containing either common/uncommon words or long/short target words. Parameters assessed included: duration of first foveation/fixation, number of first-pass and percentage second-pass foveations/fixations, percentage words skipped, gaze duration, acquisition time (gaze + nongaze duration), landing site locations, clinical and experimental reading speeds. Results: Participants with IN could not modify first foveation durations in contrast to controls who made longer first fixations on uncommon words (P < 0.001). Participants with IN made more first-pass foveations on uncommon and long words (P < 0.001) to increase gaze durations. However, this also increased nongaze durations (P < 0.001) delaying acquisition times. Participants with IN reread shorter words more often (P < 0.005). Similar to controls, participants with IN landed more first foveations between the start and center of long words. Reading speeds during experiments were lower in IN participants compared to controls (P < 0.01). Conclusions: People with IN make more first-pass foveations on uncommon and long words influencing reading speeds. This demonstrates that the "slow to see" phenomenon occurs during word reading in IN. These deficits are not captured by clinical reading charts.

The Effects of Feedback on Adherence to Treatment: A Systematic Review and Meta-analysis of RCTs.

CONTEXT: The aim of this systematic review is to determine whether providing feedback, guided by subjective or objective measures of adherence, improves adherence to treatment. EVIDENCE ACQUISITION: Data sources included MEDLINE, Embase, CINAHL, and PsycINFO, and reference lists of retrieved articles. Only RCTs comparing the effect of feedback on adherence outcome were included. Three independent reviewers extracted data for all potentially eligible studies using an adaptation of the Cochrane Library data extraction sheet. The primary outcome, change in adherence, was obtained by measuring the difference between adherence at baseline visit (prior to feedback) and at the last visit (post-feedback). EVIDENCE SYNTHESIS: Twenty-four studies were included in the systematic review, and 16 found a significant improvement in adherence in the intervention group (change in adherence range, -13% to +22%), whereas adherence worsened in the control group (change in adherence range, -32% to 10.2%). Meta-analysis included six studies, and the pooled effect showed that mean percentage adherence increased by 10.02% (95% CI=3.15%, 16.89%, p=0.004) more between baseline and follow-up in the intervention groups compared with control groups. Meta-regression confirmed that study quality, form of monitoring adherence, delivery of feedback, or study duration did not influence effect size. CONCLUSIONS: Feedback guided by objective or subjective measures of adherence improves adherence and, perhaps more importantly, prevents worsening of adherence over time even when only small absolute improvements in adherence were noted. Increased use of feedback to improve treatment adherence has the potential to reduce avoidable healthcare costs caused by non-adherence.

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.