Cerebral visual impairment: genetic diagnoses and phenotypic associations.

BACKGROUND: Cerebral visual impairment (CVI) is the most common form of paediatric visual impairment in developed countries. CVI can arise from a host of genetic or acquired causes, but there has been limited research to date on CVI in the context of genetic disorders. METHODS: We carried out a retrospective analysis of genotypic and phenotypic data for participants with CVI within the DECIPHER database and 100 000 Genomes Project (100KGP). RESULTS: 158 individuals with CVI were identified across both cohorts. Within this group, pathogenic or likely pathogenic sequence variants in 173 genes were identified. 25 of these genes already have known associations with CVI, while the remaining 148 are candidate genes for this phenotype. Gene ontology analysis of the CVI gene sets from both DECIPHER and 100KGP suggests that CVI has a similar degree of genetic heterogeneity to other neurodevelopmental phenotypes, and a strong association with genetic variants converging on ion channels and receptor functions. Individuals with a monogenic disorder and CVI have a higher frequency of epilepsies and severe neurodisability than individuals with a monogenic disorder but not CVI. CONCLUSION: This study supports the availability of genetic testing for individuals with CVI alongside other neurodevelopmental difficulties. It also supports the availability of ophthalmological screening for individuals with genetic diagnoses linked to CVI. Further studies could elaborate on the links between specific genetic disorders, visual maturation and broader neurodevelopmental characteristics.

Retinoblastoma in Asia: Clinical Presentation and Treatment Outcomes in 2112 Patients from 33 Countries.

PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Developing the OpenFlexure Microscope towards medical use: technical and social challenges of developing globally accessible hardware for healthcare.

The OpenFlexure Microscope is an accessible, three-dimensional-printed robotic microscope, with sufficient image quality to resolve diagnostic features including parasites and cancerous cells. As access to lab-grade microscopes is a major challenge in global healthcare, the OpenFlexure Microscope has been developed to be manufactured, maintained and used in remote environments, supporting point-of-care diagnosis. The steps taken in transforming the hardware and software from an academic prototype towards an accepted medical device include addressing technical and social challenges, and are key for any innovation targeting improved effectiveness in low-resource healthcare. This article is part of the Theo Murphy meeting issue 'Open, reproducible hardware for microscopy'.

Instant Detection of Synthetic Cannabinoids on Physical Matrices, Implemented on a Low-Cost, Ultraportable Device.

Synthetic cannabinoids (SCs) make up a class of novel psychoactive substances (NPS), used predominantly in prisons and homeless communities in the U.K. SCs can have severe side effects, including psychosis, stroke, and seizures, with numerous reported deaths associated with their use. The chemical diversity of SCs presents the major challenge to their detection since approaches relying on specific molecular recognition become outdated almost immediately. Ideally one would have a generic approach to detecting SCs in portable settings. The problem of SC detection is more challenging still because the majority of SCs enter the prison estate adsorbed onto physical matrices such as paper, fabric, or herb materials. That is, regardless of the detection modality used, the necessary extraction step reduces the effectiveness and ability to rapidly screen materials on-site. Herein, we demonstrate a truly instant generic test for SCs, tested against real-world drug seizures. The test is based on two advances. First, we identify a spectrally silent region in the emission spectrum of most physical matrices. Second, the finding that background signals (including from autofluorescence) can be accurately predicted is based on tracking the fraction of absorbed light from the irradiation source. Finally, we demonstrate that the intrinsic fluorescence of a large range of physical substrates can be leveraged to track the presence of other drugs of interest, including the most recent iterations of benzodiazepines and opioids. We demonstrate the implementation of our presumptive test in a portable, pocket-sized device that will find immediate utility in prisons and law enforcement agencies around the world.

Photochemical Fingerprinting Is a Sensitive Probe for the Detection of Synthetic Cannabinoid Receptor Agonists; toward Robust Point-of-Care Detection.

With synthetic cannabinoid receptor agonist (SCRA) use still prevalent across Europe and structurally advanced generations emerging, it is imperative that drug detection methods advance in parallel. SCRAs are a chemically diverse and evolving group, which makes rapid detection challenging. We have previously shown that fluorescence spectral fingerprinting (FSF) has the potential to provide rapid assessment of SCRA presence directly from street material with minimal processing and in saliva. Enhancing the sensitivity and discriminatory ability of this approach has high potential to accelerate the delivery of a point-of-care technology that can be used confidently by a range of stakeholders, from medical to prison staff. We demonstrate that a range of structurally distinct SCRAs are photochemically active and give rise to distinct FSFs after irradiation. To explore this in detail, we have synthesized a model series of compounds which mimic specific structural features of AM-694. Our data show that FSFs are sensitive to chemically conservative changes, with evidence that this relates to shifts in the electronic structure and cross-conjugation. Crucially, we find that the photochemical degradation rate is sensitive to individual structures and gives rise to a specific major product, the mechanism and identification of which we elucidate through density-functional theory (DFT) and time-dependent DFT. We test the potential of our hybrid "photochemical fingerprinting" approach to discriminate SCRAs by demonstrating SCRA detection from a simulated smoking apparatus in saliva. Our study shows the potential of tracking photochemical reactivity via FSFs for enhanced discrimination of SCRAs, with successful integration into a portable device.

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.

Different Characteristics of Pre-Pubertal and Post-Pubertal Idiopathic Intracranial Hypertension: A Narrative Review.

Idiopathic intracranial hypertension (IIH) affects both children and adults. There are currently no clinical trials in IIH for those who are adolescents or children. The aims of this narrative review were to characterise the differences between pre- and post-pubertal IIH and to highlight the need to be more inclusive in clinical trial planning and recruitment. A detailed search of the scientific literature was performed using the PubMed database, from inception until 30 May 2022 using keywords. This included English language papers only. The abstracts and full texts were reviewed by two independent assessors. The literature revealed that the pre-pubertal group had a more variable presentation. The presenting features in the post-pubertal paediatric group were more akin to adults with headache as the dominant feature. They were also more likely to be female and have an increased body mass index. A clear limitation of the literature was that a number of paediatric studies had variable inclusion criteria, including secondary causes of raised intracranial pressure. Pre-pubertal children do not display the same predilection towards the female sex and obesity as post-pubertal children, who have a similar phenotype to the adult cohort. Inclusion of adolescents in clinical trials should be considered given the similar phenotype to adults. There is a lack of consistency in the definition of puberty, making the IIH literature difficult to compare. Inclusion of secondary causes of raised intracranial pressure has the potential to confound the accuracy of analysis and interpretation of the results.

Multi-modal microscopy imaging with the OpenFlexure Delta Stage.

Microscopes are vital pieces of equipment in much of biological research and medical diagnostics. However, access to a microscope can represent a bottleneck in research, especially in lower-income countries. 'Smart' computer controlled motorized microscopes, which can perform automated routines or acquire images in a range of modalities are even more expensive and inaccessible. Developing low-cost, open-source, smart microscopes enables more researchers to conceive and execute optimized or more complex experiments. Here we present the OpenFlexure Delta Stage, a 3D-printed microscope designed for researchers. Powered by the OpenFlexure software stack, it is capable of performing automated experiments. The design files and assembly instructions are freely available under an open licence. Its intuitive and modular design-along with detailed documentation-allows researchers to implement a variety of imaging modes with ease. The versatility of this microscope is demonstrated by imaging biological and non-biological samples (red blood cells with Plasmodium parasites and colloidal particles in brightfield, epi-fluorescence, darkfield, Rheinberg and differential phase contrast. We present the design strategy and choice of tools to develop devices accessible to researchers from lower-income countries, as well as the advantages of an open-source project in this context. This microscope, having been open-source since its conception, has already been built and tested by researchers around the world, promoting a community of expertise and an environment of reproducibility in science.

Fast, high-precision autofocus on a motorised microscope: Automating blood sample imaging on the OpenFlexure Microscope.

The OpenFlexure Microscope is a 3D-printed, low-cost microscope capable of automated image acquisition through the use of a motorised translation stage and a Raspberry Pi imaging system. This automation has applications in research and healthcare, including in supporting the diagnosis of malaria in low-resource settings. The plasmodium parasites that cause malaria require high magnification imaging, which has a shallow depth of field, necessitating the development of an accurate and precise autofocus procedure. We present methods of identifying the focal plane of the microscope, and procedures for reliably acquiring a stack of focused images on a system affected by backlash and drift. We also present and assess a method to verify the success of autofocus during the scan. The speed, reliability and precision of each method are evaluated, and the limitations discussed in terms of the end users' requirements.

Prognostic value of transient pattern visual evoked potentials in children with cerebral visual impairment.

AIM: To investigate whether pattern reversal visual evoked potentials (PRVEPs) could predict future visual acuity in infants with cerebral visual impairment (CVI). METHOD: Fifty-five children (27 males, 28 females) with severe CVI seen in the ophthalmology department of a specialist children's hospital were identified retrospectively. Behavioural visual acuity and visual evoked potentials (VEPs) at presentation (time 1, T1) were compared with final visual acuity at late preschool/early school age (time 2, T2). Predictors of visual acuity at T2 were identified using univariate and multivariate logistic and linear regression analysis. RESULTS: Median age was 14 months at T1 (range: 6-44mo) and 63 months at T2 (range: 29-150mo). The presence of a PRVEP produced by a check width of 50' (minutes of arc) or smaller (T1) predicted (p=0.05) the presence of measurable preferential looking acuity at T2. The presence of PRVEP to check widths of 25' or smaller (T1) predicted (p=0.02) better preferential looking acuity (logMAR-equivalent) scores at T2. The latter association was independent of presenting acuity at T1. INTERPRETATION: The presence of PRVEPs to check widths of 50' and 25' in infancy provided useful information. VEPs in young children with CVI may have prognostic value regarding future acuity.

Combining development, capacity building and responsible innovation in GCRF-funded medical technology research.

Development-oriented funding schemes such as the UK Global Challenges Research Fund (GCRF) have opened up opportunities for collaborations between low-middle income countries (LMICs) and high-income country (HIC) researchers. In particular, funding for medical technology research has seen a rise in previously under-represented disciplines such as physics and engineering. These collaborations have considerable potential to advance healthcare in LMICs, yet can pose challenges experienced to researchers undertaking these collaborations. Key challenges include a lack of tradition of HIC/LMIC collaborations within participating departments, lack of experience with development agendas, designing contextually-appropriate technologies and ensuring long-term viability of research outputs. This paper reflects on these key challenges, using the experiences of the authors on the Open Laboratory Instrumentation (OLI) project as a focalizing lens. This project was a GCRF-funded collaboration between physicists in the UK and engineers in Tanzania to develop an open-source, 3D-printed, fully-automated laboratory microscope. The paper highlights key ethics lessons learnt.

International travel to obtain medical treatment for primary retinoblastoma: A global cohort study.

Early diagnosis and treatment of retinoblastoma (Rb), the most common intraocular malignancy, can save both the child's life and vision. However, access to services and hence chances for survival and preserving the eye and its vision vary widely across the globe. Some families have to, or make a choice to, leave their home country to seek planned medical treatment abroad. We aimed to investigate how frequently this cross-border travel occurs and the factors associated with it. A total of 278 Rb centres in 153 countries were recruited to participate in a global cross-sectional analysis of newly diagnosed Rb patients in 2017. Number and proportions of children who travelled from their home country for treatment were analysed by country, continent, socioeconomic stratum and clinical and demographic features. The cohort included 4351 new patients of whom 223 [5.1%, 95% confidence interval 4.5-5.8] were taken across country borders for planned medical treatment. Independently significant predictors of travelling across borders included: being from a country with a smaller population, being from a country classified as low socioeconomic status, having bilateral Rb and having intraocular disease without extraocular spread. The factors that determine international travel for Rb treatment are complex and deserve further investigation. We may need to rethink the way services are delivered in the light of the threat of severe curtailment of international travel from pandemics like corona virus disease 2019.

Visual function subtyping in children with early-onset cerebral visual impairment.

AIM: To develop a data-driven subgrouping method to identify and profile subtypes of early-onset childhood cerebral visual impairment (CVI). METHOD: Sixty-three children with suspected or diagnosed congenital CVI were recruited (28 males, 35 females, median age=8y, range=5-16y). Cognitive, basic, and higher-order vision functions were assessed and quality of life, functional vision questionnaire, neurodevelopmental, and ophthalmological data were collected. Cluster analysis and other statistical analyses were undertaken to determine and validate the subgrouping. RESULTS: Forty-three participants completing the full test battery were included in cluster analysis, revealing two subgroups. Group A1 (n=15) showed selective visual perception and visuomotor deficits. Group A2 (n=28) showed more severe and broader visual perception and visuomotor deficits, and variable visual acuity. A third, lower-functioning group, Group B (n=20), was differentiated and showed significant visual acuity reduction compared with Group A (p<0.001, V=0.69). External validation showed significant cooccurring ophthalmological (e.g. strabismus p<0.001, V=0.59) and motor impairment differences (χ2 =16.26, p<0.001, V=0.51) between the three groups. All groups had lowered parent-reported quality of life and everyday functional vision. INTERPRETATION: Statistical analyses revealed three subgroups with differentiated vision function characteristics on a gradient of severity. The subgrouping method provides the first steps in developing a novel classification system to underpin future clinical diagnostics and profiling of early-onset CVI. WHAT THIS PAPER ADDS: Three data-driven subgroups of vision function deficits were identified. A similar severity gradient was shown in cooccurring cognitive and neurodevelopmental deficits. Reported quality of life and functional vision difficulties were low across all groups.

Pattern of comorbidities in school-aged children with cerebral palsy in Cross River State, Nigeria.

BACKGROUND: To describe the pattern of comorbidities in school-aged children with cerebral palsy (CP) and to identify which, if any, were associated with poor school attendance. A cross-sectional study, using the key informant methodology, between December 2017 and July 2018 was conducted in Cross River State, Nigeria. Assessments, confirmation of CP and identification of systemic comorbidities using standard tools and questionnaires were performed. Children confirmed to have CP between the ages 4 to 15 years were included. RESULTS: Three hundred and eighty-eight children were confirmed to have CP, 59% males. The mean age was 9.2 years ± SD 4.0; 28% were non-ambulatory (gross motor function classification system (GMFCS) level IV-V) and spastic CP was seen in 70%. Comorbidities included Speech impairment 85%, feeding difficulties 86%, and swallowing difficulties 77%, learning difficulties 88%, abnormal behaviour 62%, visual acuity impairment 54%, objective perceptual visual disorders 46%, communication difficulties 45%, epilepsy 35%, hearing impairment 12% and malnutrition 51%. Learning difficulties (OR 10.1, p < 0.001; CI: 3.6-28.1), visual acuity impairment (OR 2.8, p = 0.002; CI: 1.5-5.3), epilepsy (OR 2.3, p = 0.009; CI:1.2-4.3) manual ability classification scale 4-5 (OR 4.7,p = 0.049; CI:1.0-22.2) and CP severity (GMFCS V-VI) OR 6.9 p = 0.002, CI: 2.0-24.0.) were seen as increasing the likelihood of poor school attendance. CONCLUSION: Comorbidities were common, and some were associated with limited school attendance. A multidisciplinary tailored approach to care, with application of available therapeutic interventions for comorbidities is suggested. This may be useful in reducing barriers to school attendance.

The OpenFlexure Block Stage: sub-100 nm fibre alignment with a monolithic plastic flexure stage.

As 3D printers become more widely available, researchers are able to rapidly produce components that may have previously taken weeks to have machined. The resulting plastic components, having high surface roughness, are often not suitable for high-precision optomechanics. However, by playing to the strengths of 3D printing-namely the ability to print complex internal geometries-it is possible to design monolithic mechanisms that do not rely on tight integration of high-precision parts. Here we present a motorised monolithic 3D-printed plastic flexure stage with sub-100 nm resolution that can perform automated optical fibre alignment.

Clinical use of the Insight Inventory in cerebral visual impairment and the effectiveness of tailored habilitational strategies.

AIM: To investigate the utility of the Insight Inventory (a structured clinical inventory completed by caregivers) for assessment of children with cerebral visual impairment; and to investigate effectiveness of tailored habilitational strategies derived from the responses to the Insight Inventory. METHOD: Fifty-one eligible children (26 males, 25 females; mean age 9y 5mo, SD 3y, range 5-16y) were recruited from Great Ormond Street Hospital, London. They underwent baseline assessment including neuro-ophthalmological and neuropsychological evaluations, and parent- and child-reported ratings on a questionnaire-based measure of quality of life. Parents also completed the Insight Inventory. On the basis of responses to the Inventory, families received individualized habilitational strategies. Follow-up assessments 6 months later included repeating the Insight Inventory and quality of life questionnaires. RESULTS: Correlations were found between the Insight Inventory and the Wechsler Intelligence Scale for Children, Fourth Edition, the Beery-Buktenica Test of Visual-Motor Integration, and the Benton Facial Recognition Test, suggesting that the Insight Inventory is an effective tool to estimate visual-perceptual difficulties. At 6 months follow-up, caregiver reports indicated significant improvements in the quality of life of children below the age of 12 years. INTERPRETATION: The Insight Inventory is a simple questionnaire which covers practical aspects of cognitive visual function in everyday life. It provides in-depth information about the aspects that children struggle with. It can also guide programmes of individualized habilitation strategies, which may enhance the quality of life of younger children. WHAT THIS PAPER ADDS: Questionnaire scores demonstrate biologically plausible correlations with formal neuropsychological tests of visual function. After administration of matched practical habilitational strategies, younger children showed improvement in quality of life and functional vision scores.

Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.

AIM: Optic neuritis may be monophasic or occur as part of a relapsing demyelinating syndrome (RDS), such as multiple sclerosis, aquaporin-4 antibody (AQP4-Ab) neuromyelitis optical spectrum disorder (NMOSD), or myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease. The aims of this study were to test whether clinical, electrophysiological, and microstructural parameters differ in multiple-sclerosis-associated optic neuritis (MS-ON) and antibody-associated optic neuritis (Ab-ON); to identify the clinical and paraclinical characteristics of children suffering worse long-term visual outcome of RDS-optic neuritis; and to explore the relationship between RNFL thickness and clinical parameters in RDS-optic neuritis. METHOD: Forty-two children with optic neuritis were retrospectively studied: 22 with multiple sclerosis (MS-ON) and 20 with antibody-associated demyelination (Ab-ON: MOG-Ab=16 and AQP4-Ab=4). Clinical and paraclinical features were analysed. RESULTS: Complete recovery of visual acuity was reported in 25 out of 42 children; eight out of 38 (21%) suffered moderate or severe visual impairment (logarithm of the minimum angle of resolution [logMAR]>0.5) in their worse eye, including four out of 38 who were blind (logMAR>1.3) in their worse eye (two with multiple sclerosis, two with AQP4-Ab NMOSD). None of the children with MOG-Ab were blind. Recurrence of optic neuritis was more common in the Ab-ON group than the MS-ON group (15 out of 20 vs seven out of 22, p=0.007). Retinal nerve fibre layer (RNFL) thickness at baseline inversely correlated with visual acuity at final follow-up (r=-0.41, p=0.008). There was no significant relationship between the number of episodes of optic neuritis and mean RNFL (r=-0.08, p=0.628), nor any significant relationship between the number of episodes of optic neuritis and visual impairment (r=0.03, p=0.794). INTERPRETATION: In children with RDS, long-term visual impairment inversely correlated with RNFL thickness, but not with the number of relapses of optic neuritis. Optical coherence tomography may have a role in assessing children with optic neuritis to monitor disease activity and inform treatment decisions. WHAT THIS PAPER ADDS: Long-term visual impairment is reported in 40% of children with a relapsing demyelinating syndrome following optic neuritis. Relapse of optic neuritis, occurring more frequently in the non-multiple-sclerosis group. Retinal nerve fibre layer thinning is associated with worse visual outcome. Optical coherence tomography can be used alongside clinical parameters as an objective measure of neuroretinal loss.