Non-syndromic retinal dystrophy associated with biallelic variation of SUMF1 and reduced leukocyte sulfatase activity.

Biallelic variants in SUMF1 are associated with multiple sulfatase deficiency (MSD), a rare lysosomal storage disorder typically diagnosed in early infancy or childhood, marked by severe neurodegeneration and early mortality. We present clinical and molecular characterisation of three unrelated patients aged 13 to 58 years with milder clinical manifestations due to SUMF1 disease variants, including two adult patients presenting with apparent non-syndromic retinal dystrophy. Whole genome sequencing identified biallelic SUMF1 variants in all three patients; Patient 1 homozygous for a complex allele c.[290G>T;293T>A]; p.[(Gly97Val);(Val98Glu)], Patient 2 homozygous for c.866A>G; p.(Tyr289Cys), and Patient 3 compound heterozygous for c.726-1G>C and p.(Tyr289Cys). Electroretinography indicated a rod-cone dystrophy with additional possible inner retinal dysfunction in all three patients. Biochemical studies confirmed reduced, but not absent, sulfatase enzyme activity in the absence of extra-ocular disease (Patient 1) or only mild systemic disease (Patients 2, 3). These cases are suggestive that non-null SUMF1 genotypes can cause an attenuated clinical phenotype, including retinal dystrophy without systemic complications, in adulthood.

Shwachman-Diamond syndrome associated with rod-cone dystrophy.

PURPOSE: To report a patient with Shwachman-Diamond syndrome and concomitant rod-cone dystrophy who underwent bone marrow transplantation. METHODS: Retrospective single case report. RESULTS: A female patient with Shwachman-Diamond syndrome was referred to a tertiary hospital to investigate possible pigmentary retinopathy at the age of 16. She described poor night vision and was found to have reduced visual acuity (6/20 right, 6/38 left). Over the ten-year follow-up period, her visual acuity remained relatively stable with no new visual symptoms. Optical coherence tomography revealed progressive, diffuse outer retinal thinning with disruption of the ellipsoid zone, which initially was relatively preserved subfoveally. Fundus autofluorescence images revealed generalised areas of hypoautofluorescence beyond the vascular arcades and a perimacular ring of increased autofluorescence. The flash electroretinogram was in keeping with a severe rod-cone dystrophy. The pattern visual evoked potential was abnormal but detectable indicating macular pathway dysfunction, suggesting encroachment into central macular regions but with some functional preservation. CONCLUSIONS: We report a patient with Shwachman-Diamond syndrome with severe early-onset rod-cone dystrophy noted at the age of 16. Slow anatomical progression has been observed over the subsequent ten years, with relative functional macular preservation to support a visual acuity of 6/36 in both eyes.

Detecting Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder Using Multimodal Time-Frequency Analysis with Machine Learning Using the Electroretinogram from Two Flash Strengths.

PURPOSE: Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are conditions that similarly alter cognitive functioning ability and challenge the social interaction, attention, and communication skills of affected individuals. Yet these are distinct neurological conditions that can exhibit diverse characteristics which require different management strategies. It is desirable to develop tools to assist with early distinction so that appropriate early interventions and support may be tailored to an individual's specific requirements. The current diagnostic procedures for ASD and ADHD require a multidisciplinary approach and can be lengthy. This study investigated the potential of electroretinogram (ERG), an eye test measuring retinal responses to light, for rapid screening of ASD and ADHD. METHODS: Previous studies identified differences in ERG amplitude between ASD and ADHD, but this study explored time-frequency analysis (TFS) to capture dynamic changes in the signal. ERG data from 286 subjects (146 control, 94 ASD, 46 ADHD) was analyzed using two TFS techniques. RESULTS: Key features were selected, and machine learning models were trained to classify individuals based on their ERG response. The best model achieved 70% overall accuracy in distinguishing control, ASD, and ADHD groups. CONCLUSION: The ERG to the stronger flash strength provided better separation and the high frequency dynamics (80-300 Hz) were more informative features than lower frequency components. To further improve classification a greater number of different flash strengths may be required along with a discrimination comparison to participants who meet both ASD and ADHD classifications and carry both diagnoses.

Full-field stimulus threshold testing: a scoping review of current practice.

The full-field stimulus threshold (FST) is a psychophysical measure of whole-field retinal light sensitivity. It can assess residual visual function in patients with severe retinal disease and is increasingly being adopted as an endpoint in clinical trials. FST applications in routine ophthalmology clinics are also growing, but as yet there is no formalised standard guidance for measuring FST. This scoping review explored current variability in FST conduct and reporting, with an aim to inform further evidence synthesis and consensus guidance. A comprehensive electronic search and review of the literature was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews (PRISMA-ScR) checklist. Key source, participant, methodology and outcomes data from 85 included sources were qualitatively and quantitatively compared and summarised. Data from 85 sources highlight how the variability and insufficient reporting of FST methodology, including parameters such as units of flash luminance, colour, duration, test strategy and dark adaptation, can hinder comparison and interpretation of clinical significance across centres. The review also highlights an unmet need for paediatric-specific considerations for test optimisation. Further evidence synthesis, empirical research or structured panel consultation may be required to establish coherent standardised guidance on FST methodology and context or condition dependent modifications. Consistent reporting of core elements, most crucially the flash luminance equivalence to 0 dB reference level is a first step. The development of criteria for quality assurance, calibration and age-appropriate reference data generation may further strengthen rigour of measurement.

First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

ISCEV standard pattern reversal VEP development: paediatric reference limits from 649 healthy subjects.

PURPOSE: To establish the extent of agreement for ISCEV standard reference pattern reversal VEPs (prVEPs) acquired at three European centres, to determine any effect of sex, and to establish reference intervals from birth to adolescence. METHODS: PrVEPs were recorded from healthy reference infants and children, aged 2 weeks to 16 years, from three centres using closely matched but non-identical protocols. Amplitudes and peak times were modelled with orthogonal quadratic and sigmoidal curves, respectively, and two-sided limits, 2.5th and 97.5th centiles, estimated using nonlinear quantile Bayesian regression. Data were compared by centre and by sex using median quantile confidence intervals. The 'critical age', i.e. age at which P100 peak time ceased to shorten, was calculated. RESULTS: Data from the three centres were adequately comparable. Sex differences were not clinically meaningful. The pooled data showed rapid drops in P100 peak time which stabilised by 27 and by 34 weeks for large and small check widths, respectively. Post-critical-age reference limits were 87-115 ms and 96-131 ms for large and small check widths, respectively. Amplitudes varied markedly and reference limits for all ages were 5-57 µV and 3.5-56 µV for large and small check widths, respectively. CONCLUSIONS: PrVEP reference data could be combined despite some methodology differences within the tolerances of the ISCEV VEP Standard, supporting the clinical benefit of ISCEV Standards. Comparison with historical data is hampered by lack of minimum reporting guidelines. The reference data presented here could be validated or transformed for use elsewhere.

Group comparisons of the individual electroretinogram time trajectories for the ascending limb of the b-wave using a raw and registered time series.

OBJECTIVES: The electroretinogram is a clinical test commonly used in the diagnosis of retinal disorders with the peak time and amplitude of the a- and b-waves used as the main indicators of retinal function. However, subtle changes that affect the shape of the electroretinogram waveform may occur in the early stages of disease or in conditions that have a neurodevelopmental or neurodegenerative origin. In such cases, we introduce a statistical approach to mathematically model the shape of the electroretinogram waveform that may aid clinicians and researchers using the electroretinogram or other biological signal recordings to identify morphological features in the waveforms that may not be captured by the time or time-frequency domains of the waveforms. We present a statistical graphics-based analysis of the ascending limb of the b-wave (AL-b) of the electroretinogram in children with and without a diagnosis of autism spectrum disorder (ASD) with a narrative explanation of the statistical approach to illustrate how different features of the waveform based on location and scale derived from raw and registered time series can reveal subtle differences between the groups. RESULTS: Analysis of the raw time trajectories confirmed findings of previous studies with a reduced and delayed b-wave amplitude in ASD. However, when the individual time trajectories were registered then group differences were visible in the mean amplitude at registered time ~ 0.6 suggesting a novel method to differentiate groups using registration of the ERG waveform.

Retinal electrophysiology in central nervous system disorders. A review of human and mouse studies.

The retina and brain share similar neurochemistry and neurodevelopmental origins, with the retina, often viewed as a "window to the brain." With retinal measures of structure and function becoming easier to obtain in clinical populations there is a growing interest in using retinal findings as potential biomarkers for disorders affecting the central nervous system. Functional retinal biomarkers, such as the electroretinogram, show promise in neurological disorders, despite having limitations imposed by the existence of overlapping genetic markers, clinical traits or the effects of medications that may reduce their specificity in some conditions. This narrative review summarizes the principal functional retinal findings in central nervous system disorders and related mouse models and provides a background to the main excitatory and inhibitory retinal neurotransmitters that have been implicated to explain the visual electrophysiological findings. These changes in retinal neurochemistry may contribute to our understanding of these conditions based on the findings of retinal electrophysiological tests such as the flash, pattern, multifocal electroretinograms, and electro-oculogram. It is likely that future applications of signal analysis and machine learning algorithms will offer new insights into the pathophysiology, classification, and progression of these clinical disorders including autism, attention deficit/hyperactivity disorder, bipolar disorder, schizophrenia, depression, Parkinson's, and Alzheimer's disease. New clinical applications of visual electrophysiology to this field may lead to earlier, more accurate diagnoses and better targeted therapeutic interventions benefiting individual patients and clinicians managing these individuals and their families.

Assessment of digital light processing (DLP) projector stimulators for visual electrophysiology.

INTRODUCTION: Visual electrophysiology tests require the use of precise and calibrated visual display units (VDUs). Existing VDUs for presenting structured stimuli are now mostly obsolete, with modern solutions limited or unsuitable for clinical testing. Digital light processing (DLP) laser projectors have recently become commercially available and this study aimed to assess their suitability as VDUs for visual electrophysiology testing. METHODS: This study consisted of two sections. The first was a photometric study of two DLP laser projectors (Viewsonic LS831WU and HiSense 100L5FTUK) to assess luminance, contrast, spectral and temporal characteristics of the stimulus. The second was a physiological study comparing pattern electroretinograms (PERG) and visual evoked potentials (PVEPs) amplitudes and peak-times recorded using a DLP laser projector, photometrically and spatially matched to existing plasma VDUs at our institution (Pioneer Electronics Corporation, PDP422MXE). RESULTS: The Viewsonic DLP laser projector was capable of high luminance levels (0-587.5 cd/m2) whilst maintaining contrast above 93%. The temporal properties showed fast rise and fall times of 0.5-1 ms and 0.5-1 ms, respectively, without any transient luminance change with reversals. The device required a warm-up time of at least 2 min until reaching near maximal luminance. The second (Hisense) device was observed to have a detrimental input lag jitter so was not used for any further analysis. PERGs and PVEPs showed high agreement and correlation (r = 0.766-0.905) between the Viewsonic DLP device and existing plasma VDUs. No significant differences were observed for P50 and P100 peak-time (p = > 0.05), however P50, N95 and P100 amplitudes were all significantly larger for the DLP device (p = < 0.05). DISCUSSION: The DLP laser projector tested in this study is a viable and practical replacement VDU for clinical electrophysiology tests of vision. The device is easily capable of meeting ISCEV standards, and showed PERG and PVEP amplitudes larger than existing systems despite photometric and spatial matching. The DLP laser projectors are capable of very large field sizes so are beneficial for paediatric testing or those wishing to examine large field responses. Importantly, it was observed that some devices may suffer input lag jitter, therefore, individual calibration and assessment of DLP projection systems is an important consideration before clinical implementation.

Is RPGR-related retinal dystrophy associated with systemic disease? A case series.

BACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.

Pattern visual evoked potentials show an inferior-superior topographic shift through maturation in childhood.

The pattern-reversal visual evoked potential (prVEP) is an established routine clinical test. Its objectivity is particularly valuable for assessing visual pathway function in children. International standards specify at a minimum that an active electrode is placed on the occiput at Oz, but we find an additional inferior electrode at the inion (Iz) provides larger and more sensitive prVEPs in young persons. This study assesses the significance and age-dependence of these observations. PrVEPs were recorded from 1487 patients considered ophthalmologically normal aged <20 years old, to a range of check widths including International Society for Clinical Electrophysiology of Vision (ISCEV) standard large (50') and small (12.5') check widths. P100 peak-time and amplitude from both electrode sites were analysed. A subset of 256 children were studied longitudinally by fitting logistic regression models including a random effect on subjects. PrVEPs were largest over the Iz electrode for the majority of infants and children. This transitioned with age to become equal or smaller at Oz as a function of check width. For ISCEV standard large and small check widths, transition periods were ∼8 and ∼12 years of age, respectively. We estimated abnormal result classifications of 3.7% with use of an Oz electrode alone, which decreases to 0.0-0.5% when adding or using an Iz electrode. The inferior dominance of prVEP topography in children may be explained by age-related anatomical changes altering the cortical dipole, combined with physiological maturation of the neural generators of the prVEP. We recommend the Iz electrode is used routinely in recording of prVEPs in children. KEY POINTS: Pattern visual evoked potentials (PVEPs) are an established clinical test which provide objective assessment of visual pathway function. These are particularly valuable in providing objective information of vision in children. International standards specify the active recording electrode should be placed at the mid-occiput (Oz), but we find that pattern-reversal visual evoked potential amplitudes are larger for a lower placed electrode (Iz) in young persons. This was assessed in 1487 patients who had simultaneous PVEP recording at both electrode positions, and it was found that the majority of PVEPs in children were larger over the Iz electrode. The developmental differences in PVEP distribution transitioned to be equal between Iz and Oz with increasing age as a function of check width, at ∼8 and ∼12 years old for large and small check widths, respectively. These differences will improve diagnostic accuracy of paediatric PVEPs. We hypothesise these changes reflect developmental anatomical and neurophysiological changes altering the PVEP dipole.

Electrophysiological assessment of nutritional optic neuropathy: a case report.

PURPOSE: To report an unexpectedly asymmetric, progressive nutritional optic neuropathy associated with vitamin A deficient optic canal hyperostosis in a 15-year-old female with a long history of a restricted diet. METHODS: We performed comprehensive ophthalmic assessments in a fifteen-year-old female with a long history of restricted eating who presented with suspected nutritional optic neuropathy, predominantly affecting the right eye vision. RESULTS: A review of computerised tomography and magnetic resonance imaging revealed bilateral optic canal hyperostosis likely associated with vitamin A deficiency. Electrodiagnostic tests and optical coherence tomography provided structure-function evidence of bilateral retinal ganglion cell dysfunction and notably revealed severe loss of temporal fibres in the left eye which showed cecocentral scotoma but normal visual acuity. Although selective damage of the papillomacular bundle has been well-documented in nutritional and toxic optic neuropathies, compressive optic canal hyperostosis secondary to nutritional deficiency has been rarely reported. CONCLUSIONS: Nutritional deficiencies are increasing in high-income countries and may be linked to the rise of gastrointestinal disorders, strict vegan and vegetarian diets and avoidant restrictive food intake disorder (ARFID) associated with conditions such as depression and autism spectrum syndrome (ASD). Our findings highlight the value of electrodiagnostic testing alongside imaging in complex nutritional optic neuropathies to help monitor, guide treatment and preserve remaining sight in a child.

Electrophysiological and fundoscopic detection of intracranial hypertension in craniosynostosis.

AIMS: To assess the diagnostic accuracy of fundoscopy and visual evoked potentials (VEPs) in detecting intracranial hypertension (IH) in patients with craniosynostosis undergoing spring-assisted posterior vault expansion (sPVE). METHODS: Children with craniosynostosis undergoing sPVE and 48-hour intracranial pressure (ICP) monitoring were included in this single-centre, retrospective, diagnostic accuracy study. Data for ICP, fundoscopy and VEPs were analysed. Primary outcome measures were papilloedema on fundoscopy, VEP assessments and IH, defined as mean ICP > 20 mmHg. Diagnostic indices were calculated for fundoscopy and VEPs against IH. Secondary outcome measures included final visual outcomes. RESULTS: Fundoscopic examinations were available for 35 children and isolated VEPs for 30 children, 22 of whom had at least three serial VEPs. Sensitivity was 32.1% for fundoscopy (95% confidence intervals [CI]: 15.9-52.4) and 58.3% for isolated VEPs (95% CI 36.6-77.9). Specificity for IH was 100% for fundoscopy (95% CI: 59.0-100) and 83.3% for isolated VEPs (95% CI: 35.9-99.6). Where longitudinal deterioration was suspected from some prVEPs but not corroborated by all, sensitivity increased to 70.6% (95% CI: 44.0-89.7), while specificity decreased to 60% (95% CI: 14.7-94.7). Where longitudinal deterioration was clinically significant, sensitivity decreased to 47.1% (23.0-72.2) and specificity increased to 100% (47.8-100). Median final BCVA was 0.24 logMAR (n = 36). UK driving standard BCVA was achieved by 26 patients (72.2%), defined as ≥0.30 logMAR in the better eye. CONCLUSION: Papilloedema present on fundoscopy reliably indicated IH, but its absence did not exclude IH. VEP testing boosted sensitivity at the expense of specificity, depending on method of analysis.

Detecting Autism Spectrum Disorder Using Spectral Analysis of Electroretinogram and Machine Learning: Preliminary results.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that impacts language, communication and social interactions. The current diagnostic process for ASD is based upon a detailed multidisciplinary assessment. Currently no clinical biomarker exists to help in the diagnosis and monitoring of this condition that has a prevalence of approximately 1%. The electroretinogram (ERG), is a clinical test that records the electrical response of the retina to light. The ERG is a promising way to study different neurodevelopmental and neurodegenerative disorders, including ASD. In this study, we have proposed a machine learning based method to detect ASD from control subjects using the ERG waveform. We collected ERG signals from 47 control (CO) and 96 ASD individuals. We analyzed ERG signals both in the time and the spectral domain to gain insight into the statistically significant discriminating features between CO and ASD individuals. We evaluated the machine learning (ML) models using a subject independent cross validation-based approach. Time-domain features were able to detect ASD with a maximum 65% accuracy. The classification accuracy of our best ML model using time-domain and spectral features was 86%, with 98% sensitivity. Our preliminary results indicate that spectral analysis of ERG provides helpful information for the classification of ASD.

Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect.

Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by deficiency of the ubiquitously expressed SMN protein. Here, we present a retinal vascular defect in patients, recapitulated in SMA transgenic mice, driven by failure of angiogenesis and maturation of blood vessels. Importantly, the retinal vascular phenotype was rescued by early, systemic SMN restoration therapy in SMA mice. We also demonstrate in patients an unfavorable imbalance between endothelial injury and repair, as indicated by increased circulating endothelial cell counts and decreased endothelial progenitor cell counts in blood circulation. The cellular markers of endothelial injury were associated with disease severity and improved following SMN restoration treatment in cultured endothelial cells from patients. Finally, we demonstrated autonomous defects in angiogenesis and blood vessel formation, secondary to SMN deficiency in cultured human and mouse endothelial cells, as the underlying cellular mechanism of microvascular pathology. Our cellular and vascular biomarker findings indicate microvasculopathy as a fundamental feature of SMA. Our findings provide mechanistic insights into previously described SMA microvascular complications, and highlight the functional role of SMN in the periphery, including the vascular system, where deficiency of SMN can be addressed by systemic SMN-restoring treatment.

Discrete Wavelet Transform Analysis of the Electroretinogram in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Background: To evaluate the electroretinogram waveform in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) using a discrete wavelet transform (DWT) approach. Methods: A total of 55 ASD, 15 ADHD and 156 control individuals took part in this study. Full field light-adapted electroretinograms (ERGs) were recorded using a Troland protocol, accounting for pupil size, with five flash strengths ranging from -0.12 to 1.20 log photopic cd.s.m-2. A DWT analysis was performed using the Haar wavelet on the waveforms to examine the energy within the time windows of the a- and b-waves and the oscillatory potentials (OPs) which yielded six DWT coefficients related to these parameters. The central frequency bands were from 20-160 Hz relating to the a-wave, b-wave and OPs represented by the coefficients: a20, a40, b20, b40, op80, and op160, respectively. In addition, the b-wave amplitude and percentage energy contribution of the OPs (%OPs) in the total ERG broadband energy was evaluated. Results: There were significant group differences (p < 0.001) in the coefficients corresponding to energies in the b-wave (b20, b40) and OPs (op80 and op160) as well as the b-wave amplitude. Notable differences between the ADHD and control groups were found in the b20 and b40 coefficients. In contrast, the greatest differences between the ASD and control group were found in the op80 and op160 coefficients. The b-wave amplitude showed both ASD and ADHD significant group differences from the control participants, for flash strengths greater than 0.4 log photopic cd.s.m-2 (p < 0.001). Conclusion: This methodological approach may provide insights about neuronal activity in studies investigating group differences where retinal signaling may be altered through neurodevelopment or neurodegenerative conditions. However, further work will be required to determine if retinal signal analysis can offer a classification model for neurodevelopmental conditions in which there is a co-occurrence such as ASD and ADHD.

The electroretinogram b-wave amplitude: a differential physiological measure for Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent childhood neurodevelopmental disorder. It shares some genetic risk with Autism Spectrum Disorder (ASD), and the conditions often occur together. Both are potentially associated with abnormal glutamate and GABA neurotransmission, which can be modelled by measuring the synaptic activity in the retina with an electroretinogram (ERG). Reduction of retinal responses in ASD has been reported, but little is known about retinal activity in ADHD. In this study, we compared the light-adapted ERGs of individuals with ADHD, ASD and controls to investigate whether retinal responses differ between these neurodevelopmental conditions. METHODS: Full field light-adapted ERGs were recorded from 15 ADHD, 57 ASD (without ADHD) and 59 control participants, aged from 5.4 to 27.3 years old. A Troland protocol was used with a random series of nine flash strengths from -0.367 to 1.204 log photopic cd.s.m-2. The time-to-peak and amplitude of the a- and b-waves and the parameters of the Photopic Negative Response (PhNR) were compared amongst the three groups of participants, using generalised estimating equations. RESULTS: Statistically significant elevations of the ERG b-wave amplitudes, PhNR responses and faster timings of the b-wave time-to-peak were found in those with ADHD compared with both the control and ASD groups. The greatest elevation in the b-wave amplitudes associated with ADHD were observed at 1.204 log phot cd.s.m-2 flash strength (p < .0001), at which the b-wave amplitude in ASD was significantly lower than that in the controls. Using this measure, ADHD could be distinguished from ASD with an area under the curve of 0.88. CONCLUSIONS: The ERG b-wave amplitude appears to be a distinctive differential feature for both ADHD and ASD, which produced a reversed pattern of b-wave responses. These findings imply imbalances between glutamate and GABA neurotransmission which primarily regulate the b-wave formation. Abnormalities in the b-wave amplitude could provisionally serve as a biomarker for both neurodevelopmental conditions.

Septo-optic dysplasia presenting with nystagmus, pseudo-disc edema, and fovea hypoplasia.

BACKGROUND: Septo-optic dysplasia (SOD) is a condition that affects the early development of the brain and eyes. It presents with a combination of optic nerve hypoplasia, brain midline structure abnormalities, and pituitary gland hypoplasia. METHODS: This is a case report of a 4-year-old male who presented with low amplitude horizontal nystagmus and decreased visual acuity 20/60 OU. Further imaging and electrophysiology were conducted to classify the ocular presentation. RESULTS: No iris transillumination was noted, but foveal hypoplasia and disc edema were evident on fundus examination. This prompted neurology consultation and MRI imaging. The MRI was consistent with the diagnosis of SOD showing hypoplasia of the optic nerves, chiasm, and tracts and an absent septum pellucidum, but with normal pituitary development and function. Lumbar puncture and intracranial pressure were normal. Genetic testing identified one pathogenic variant in the SLC45A2, indicating carrier status for oculocutaneous albinism type 4 (OCA4). Flash Visual Evoked Potentials (VEPs) were consistent with chiasm dysfunction or hypoplasia rather than the chiasmal misrouting of OCA. CONCLUSION: This case report further elaborates the phenotypic variation of SOD, with the finding of blurred disc margins, in the absence of the typical optic nerve double ring sign and with normal intracranial pressure. The findings of fovea hypoplasia and blond fundi lead to the suspicion of OCA either as a separate diagnosis with a second pathogenic variant in SCL45A2 not yet identified or in association with SOD. This case highlights the importance of electrophysiology to help distinguish chiasmal hypoplasia or dysfunction from OCA misrouting.

Visual outcomes in children with syndromic craniosynostosis: a review of 165 cases.

OBJECTIVE: To determine visual outcomes and prevalence of amblyogenic risk factors in children with Apert, Crouzon, Pfeiffer and Saethre-Chotzen syndromes. METHODS: We conducted a single-centre, retrospective chart review of patients assessed at our unit between October 2000 and May 2017. Our outcome measures were as follows: age at first and last examination, refraction, horizontal ocular alignment, alphabet pattern deviations, anterior segment appearance, fundus examination findings, visual evoked potentials (VEPs) and genetics. The study's primary endpoint was the proportion of children achieving best-corrected visual acuity (BCVA) ≥ 6/12 in the better eye at final visit, as per UK driving standards. RESULTS: 165 patients were included in this study. Breakdown of diagnoses was as follows: Crouzon (n = 60), Apert (n = 57), Pfeiffer (n = 14) and Saethre-Chotzen (n = 34). 98 patients were male. Of 133 patients with full BCVA data available, 76.7% achieved BCVA ≥ 6/12 in the better eye. Of 122 patients, anisometropia >1.00 dioptre sphere (DS) affected 18.9% and astigmatism ≥1.00DS in at least one eye affected 67.2%. Of 246 eyes, 48.4% had oblique astigmatism. Of 165 patients, 60 had exotropia and 12 had esotropia. 48 of 99 patients demonstrated 'V' pattern. On multivariable logistic regression, nystagmus (p = 0.009) and ON involvement (p = 0.001) were associated with decreased vision in the worse eye. Normal VEPs were associated with better BCVA (p = 0.036). CONCLUSION: There was a high prevalence of amblyogenic factors, however, the majority achieved BCVA ≥ 6/12 in their better eye. Optic neuropathy and nystagmus had the most significant impact on vision. VEPs can help the in overall assessment of visual function.