Visual Abnormalities and Sensory Integration in Infantile Nystagmus

Introduction: Individuals with albinism and IIN demonstrate retinal structural abnormalities. However, there are no consistent functional retinal differences apparent using full-field flash electroretinography (ffERG). This thesis aims to investigate abnormalities in albinism and IIN at: (i) early stages of visual processing (i.e. retinal deficits) using ffERG; (ii) late stages of visual processing, where the brain integrates visual inputs with other sensory to control posture, using Computerized Dynamic Posturography (CDP). Methods: ffERG and OCT were used to measure functional and structural retinal deficits, respectively. Binocular pupil tracker was used to characterise nystagmus to investigate its effect on ffERG responses. CDP was used to evaluate sensory organization during postural control. Results: Patients with IIN had significant smaller a- and b-wave amplitudes under photopic condition compared to healthy controls. However, individuals with albinism were relatively normal. Test-retest showed that ffERG testing is mostly reliability despite nystagmus being present. Photopic a-wave amplitudes were correlated with combined photoreceptor layer thickness and scotopic S.F. b-wave amplitudes were correlated with the inner nuclear layer thickness. Patients with albinism and IIN have relative good overall postural control. However, both groups present lower visual score and higher somatosensory score than controls. The albinism group also had a higher vestibular sensory score. Conclusion: Reductions of photopic a- and b-wave amplitudes in IIN indicate a subclinical retinal deficit, which has not been previously detected. Interestingly, participants with albinism did not show abnormalities probably due to hypopigmentation shifting the baseline of ERG responses into normal ranges. Correlations between ffERGs and OCT measurements suggest ffERG may contain useful information in albinism and open up an interesting field for future study. Brain plasticity can rearrange the weighting of sensory inputs in both patient groups with the albinism group attaching a stronger weighting to vestibular cues than the other two groups

Our current understanding of clinical characteristics and the genetics of patients with albinism

Introduction: Albinism is a heterogenous disease with variable phenotypic and genotypic presentations. Diagnosis can be challenging and clinical evaluation strategies vary. Areas covered: This review examines the phenotypic and genotypic characteristics of albinism and discusses evaluation strategies used to assess its variable clinical presentations. Additionally, it explores the challenges faced by clinicians in diagnosing albinism and issues related to genetic testing, interpretation and subsequent counseling of affected patients and their families. It is important to note that although current management of albinism is mainly supportive and focuses on optimizing vision, there are emerging therapies with promising translational benefit. Expert opinion: Ongoing research in the field of albinism is benefiting from recent advances, particularly in retinal imaging and phenotyping. Similarly, access to advanced technologies like next-generation and long-read sequencing has improved diagnostic accuracy for previous cases with missing heritability. Deeper genotyping and phenotyping as well as multicentre collaborative approaches have allowed better understanding of genotype-phenotype correlations. There is still a need for more research on the psychosocial aspects of albinism. Encouraging involvement of patients and the public in determining research priorities in this area is essential for a better understanding of the psychosocial impact on individuals with albinism

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 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.</p

Reliability and Recommended Settings for Pediatric Circumpapillary Retinal Nerve Fiber Layer Imaging Using Hand-Held Optical Coherence Tomography

To investigate feasibility and reliability of 3-dimensional full circumpapillary retinal nerve fiber layer (cpRNFL) analysis in children, with and without glaucoma, without the use of sedation and to recommend a protocol for hand-held optical coherence tomography use.A cohort of pediatric glaucoma patients and normal children were imaged with hand-held optical coherence tomography to assess the feasibility of obtaining full cpRNFL. Two consecutive scans were acquired in a smaller sample to investigate test-retest repeatability and interassessor reproducibility. The cpRNFL thickness was assessed in four quadrants, at several visual angles from the optic nerve center.Scanning was attempted in both eyes of 90 children with pediatric glaucoma and 180 controls to investigate feasibility (mean age, 6.98 ± 4.42 years). Scanning was not possible in 68 eyes of glaucoma children mainly owing to nystagmus, unclear optical media, or high refractive errors. Where three-dimensional imaging was possible, success at obtaining full cpRNFL was 67% in children with glaucoma and 89% for controls. Seventeen children with pediatric glaucoma and 34 controls contributed to reliability analysis (mean age, 6.3 ± 3.63 years). For repeatability intraclass correlation coefficients across quadrants ranged from 0.63 to 0.82 at 4° and improved to 0.88 to 0.94 at 6°. Intraclass correlation coefficients for reproducibility were also highest at 6° (>0.97 across all quadrants).We demonstrate that acquisition and measurement of cpRNFL thickness values using 3-dimensional hand-held optical coherence tomography volumes in awake children is both feasible and reliable and is optimal at 6° from optic nerve center.Our recommended protocol provides guidance on how pediatric optic nerve pathologies are managed by clinicians.</p

Retinal imaging technologies in cerebral malaria: a systematic review

Background Cerebral malaria (CM) continues to present a major health challenge, particularly in sub-Saharan Africa. CM is associated with a characteristic malarial retinopathy (MR) with diagnostic and prognostic significance. Advances in retinal imaging have allowed researchers to better characterize the changes seen in MR and to make inferences about the pathophysiology of the disease. The study aimed to explore the role of retinal imaging in diagnosis and prognostication in CM; establish insights into pathophysiology of CM from retinal imaging; establish future research directions. Methods The literature was systematically reviewed using the African Index Medicus, MEDLINE, Scopus and Web of Science databases. A total of 35 full texts were included in the final analysis. The descriptive nature of the included studies and heterogeneity precluded meta-analysis. Results Available research clearly shows retinal imaging is useful both as a clinical tool for the assessment of CM and as a scientific instrument to aid the understanding of the condition. Modalities which can be performed at the bedside, such as fundus photography and optical coherence tomography, are best positioned to take advantage of artificial intelligence-assisted image analysis, unlocking the clinical potential of retinal imaging for real-time diagnosis in low-resource environments where extensively trained clinicians may be few in number, and for guiding adjunctive therapies as they develop. Conclusions Further research into retinal imaging technologies in CM is justified. In particular, co-ordinated interdisciplinary work shows promise in unpicking the pathophysiology of a complex disease.</p

Longitudinal Evaluation of Changes in Retinal Architecture Using Optical Coherence Tomography in Achromatopsia

PURPOSE. This prospective study investigates longitudinal changes in retinal structure in patients with achromatopsia (ACHM) using optical coherence tomography (OCT).  METHODS. Seventeen patients (five adults, 12 children) with genetically confirmed CNGA3- or CNGB3-associated ACHM underwent ocular examination and OCT over a follow-up period of between 2 and 9.33 years (mean = 5.7 years). Foveal tomograms were qualitatively graded and were segmented for quantitative analysis: central macular thickness (CMt), outer nuclear layer thickness (ONLt), and size of the foveal hyporeflective zone (vertical HRZ thickness: HRZt and horizontal HRZ width: HRZw) were measured. Data were analyzed using linear mixed regression models. Both age and visit were included into the models, to explore the possibility that the rate of disease progression depends on patient age. RESULTS. Fifteen of 17 patients (88%) showed longitudinal changes in retinal structure over the follow-up period. The most common patterns of progression was development of ellipsoid zone (EZ) disruption and HRZ. There was a significant increase in HRZt (P = 0.01) and HRZw (P = 0.001) between visits and no significant change in CMt and ONLt. Retinal parameters showed no difference in changes by genetic mutation (CNGA3 (n = 11), CNGB3 (n = 6)).  CONCLUSIONS. This study demonstrates clear longitudinal changes in foveal structure mainly in children, but also in adults with ACHM, over a long follow-up period. The longitudinal foveal changes suggest that treatment at an earlier age should be favored.</p

ERG Responses in Albinism, Idiopathic Infantile Nystagmus, and Controls

PurposeOur primary aim was to compare adult full-field ERG (ffERG) responses in albinism, idiopathic infantile nystagmus (IIN), and controls. A secondary aim was to investigate the effect of within-subject changes in nystagmus eye movements on ffERG responses.MethodsDilated Ganzfeld flash ffERG responses were recorded using DTL electrodes under conditions of dark (standard and dim flash) and light adaptation in 68 participants with albinism, 43 with IIN, and 24 controls. For the primary aim, the effect of group and age on ffERG responses was investigated. For the secondary aim, null region characteristics were determined using eye movements recorded prior to ffERG recordings. ffERG responses were recorded near and away from the null regions of 18 participants also measuring the success rate of recordings.ResultsFor the primary aim, age-adjusted photopic a- and b-wave amplitudes were consistently smaller in IIN compared with controls (P ConclusionsAge-adjusted photopic ffERG responses are significantly reduced in IIN adding to the growing body of evidence of retinal abnormalities in IIN. Differences between photopic responses in albinism and controls depend on age. Success at obtaining ffERG responses could be improved by recording responses at the null region

ERG Responses in Albinism, Idiopathic Infantile Nystagmus, and Controls

PurposeOur primary aim was to compare adult full-field ERG (ffERG) responses in albinism, idiopathic infantile nystagmus (IIN), and controls. A secondary aim was to investigate the effect of within-subject changes in nystagmus eye movements on ffERG responses.MethodsDilated Ganzfeld flash ffERG responses were recorded using DTL electrodes under conditions of dark (standard and dim flash) and light adaptation in 68 participants with albinism, 43 with IIN, and 24 controls. For the primary aim, the effect of group and age on ffERG responses was investigated. For the secondary aim, null region characteristics were determined using eye movements recorded prior to ffERG recordings. ffERG responses were recorded near and away from the null regions of 18 participants also measuring the success rate of recordings.ResultsFor the primary aim, age-adjusted photopic a- and b-wave amplitudes were consistently smaller in IIN compared with controls (P ConclusionsAge-adjusted photopic ffERG responses are significantly reduced in IIN adding to the growing body of evidence of retinal abnormalities in IIN. Differences between photopic responses in albinism and controls depend on age. Success at obtaining ffERG responses could be improved by recording responses at the null region

Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders

Background Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients. Results A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations. Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patients and 15 patients from 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES was performed in 122 CCDDs patients. Ten pathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM) and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes. Conclusions This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.</p

Predicting Acute and Post-Recovery Outcomes in Cerebral Malaria and Other Comas by Optical Coherence Tomography (OCT in CM) – A protocol for an observational cohort study of Malawian children

Cerebral malaria (CM) remains a significant global health challenge with high morbidity and mortality. Malarial retinopathy has been shown to be diagnostically and prognostically significant in the assessment of CM. The major mechanism of death in paediatric CM is brain swelling. Long term morbidity is typically characterised by neurological and neurodevelopmental sequelae. Optical coherence tomography can be used to quantify papilloedema and macular ischaemia, identified as hyperreflectivity. Here we describe a protocol to test the hypotheses that quantification of optic nerve head swelling using optical coherence tomography can identify severe brain swelling in CM, and that quantification of hyperreflectivity in the macula predicts neurodevelopmental outcomes post-recovery. Additionally, our protocol includes the development of a novel, low-cost, handheld optical coherence tomography machine and artificial intelligence tools to assist in image analysis