Cortical Visual Impairment Research Articles

A Survey of Parents of Children With Cortical or Cerebral Visual Impairment: 2018 Follow-up

A Survey of Parents of Children With Cortical or Cerebral Visual Impairment: 2018 Follow-up

Profiling Children With Cerebral Visual Impairment Using Multiple Methods of Assessment to Aid in Differential Diagnosis

Cerebral (cortical) visual impairment (CVI), the primary cause of visual impairment in children in high-income countries, is increasing globally due to improved life-saving measures for premature and full-term infants. Yet the consequences of this condition are only beginning to be understood and addressed. According to the topography, site, and the extent of the pathology, the deficit may variably concern central visual functions, visual field, perception of movement, visual analysis, visual exploration, attention, or visual memory, as well as visual guidance of movement. Each affected child has a unique clinical picture, which needs to be identified and individually profiled. This is probably the underlying reason that CVI is commonly underdiagnosed or misdiagnosed, especially in children, and, as a consequence, the full range of potential behavioral outcomes are not identified and adequately addressed. The present paper shows how the use of multiple methods of assessment can improve understanding of children with CVI.

Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral cortical dysfunctions in the origin of the symptoms is poorly understood. CDD mouse models also display visual deficits, and cortical visual responses can be used as a robust biomarker in CDKL5 mutant mice. A deeper understanding of the circuits underlying the described visual deficits is essential for directing preclinical research and translational approaches. Here, we addressed this question in two ways: first, we performed an in-depth morphological analysis of the visual pathway, from the retina to the primary visual cortex (V1), of CDKL5 null mice. We found that the lack of CDKL5 produced no alteration in the organization of retinal circuits. Conversely, CDKL5 mutants showed reduced density and altered morphology of spines and decreased excitatory synapse marker PSD95 in the dorsal lateral geniculate nucleus and in V1. An increase in the inhibitory marker VGAT was selectively present in V1. Second, using a conditional CDKL5 knockout model, we showed that selective cortical deletion of CDKL5 from excitatory cells is sufficient to produce abnormalities of visual cortical responses, demonstrating that the normal function of cortical circuits is dependent on CDKL5. Intriguingly, these deficits were associated with morphological alterations of V1 excitatory and inhibitory synaptic contacts. In summary, this work proposes cortical circuit structure and function as a critically important target for studying CDD.

Mass spectrometric quantification of plasma glycosphingolipids in human GM3 ganglioside deficiency

BackgroundAmong Amish communities of North America, biallelic mutations of ST3GAL5 (c.694C > T) eliminate synthesis of GM3 and its derivative downstream a- and b-series gangliosides. Systemic ganglioside deficiency is associated with infantile onset psychomotor retardation, slow brain growth, intractable epilepsy, deafness, and cortical visual impairment. We developed a robust quantitative assay to simultaneously characterize glycan and ceramide moieties of plasma glycosphingolipids (GSLs) among ST3GAL5 c.694C > T homozygotes (n = 8), their heterozygous siblings (n = 24), and wild type control (n = 19) individuals. MethodsFollowing extraction and saponification of total plasma lipids, GSLs were purified on a tC18 cartridge column, permethylated, and subjected to nanospray ionization mass spectrometry utilizing neutral loss scanning and data-dependent acquisition. Plasma GSLs were quantified against appropriate synthetic standards. ResultsOur method demonstrated linearity from 5 to 250 μl of plasma. Recovery of synthetic GSLs spiked into plasma was 99–104% with no matrix interference. Quantitative plasma GSL profiles discriminated among ST3GAL5 genotypes: GM3 and GD3 were undetectable in ST3GAL5 c.694C > T homozygotes, who had markedly elevated lactosylceramide (19.17 ± 4.20 nmol/ml) relative to heterozygous siblings (9.62 ± 2.46 nmol/ml) and wild type controls (6.55 ± 2.16 nmol/ml). Children with systemic ganglioside deficiency had a distinctive shift in ceramide composition toward higher mass species. ConclusionsOur quantitative glycolipidomics method discriminates among ST3GAL5 c.694C > T genotypes, can reveal subtle structural heterogeneity, and represents a useful new strategy to diagnose and monitor GSL disorders in humans.

Causes of childhood low vision and blindness in New Zealand.

This is the first national study on childhood visual impairment in a developed nation, New Zealand, describing prevalence, aetiology and preventable causes of low vision and blindness in children. Causes of childhood blindness vary between regions. This study aimed to present region-specific data on epidemiology of childhood blindness affecting a developed nation, New Zealand. Retrospective data analysis. All children enrolled with the Blind and Low Vision Education Network New Zealand (BLENNZ) with best-corrected visual acuity ≤6/18, or binocular visual field <10°. 1000 out of 1321 children with visual impairment enrolled with BLENNZ were included. The principal cause of visual loss was determined, and the severity of visual loss categorized as low vision, or blindness according to the World Health Organization criteria. Main outcome measures were degree of visual impairment, aetiology of visual impairment and treatment modalities for visual rehabilitation. The calculated prevalence of childhood blindness and low vision was 0.05% and 0.06%. Principle causes of blindness were cortical visual impairment (31.5%), optic nerve atrophy (16.5%) and optic nerve hypoplasia (9.0%). The main preventable causes of blindness were neonatal trauma/asphyxia (31.5%), retinopathy of prematurity (18.2%) and non-accidental injury (10.3%). This is the first national report on prevalence of childhood low vision and blindness in New Zealand. The prevalence and leading causes of low vision and blindness found in this study were comparable to other developed nations; however, preventable causes of low vision and blindness appeared unique to New Zealand.

Cerebralno oštećenje vida - dijagnostički kriterijumi i elementi tretmana

Cortical visual impairment is a leading cause of difficulties in visual functioning in premature children and children with cerebral palsy. Bearing in mind that a large part of the brain is involved in regulating visual-perceptive activities, the factors which influence its structure and functioning are a common cause of visual impairment. Complex neurological and neuro-ophthalmological basis of cortical visual impairment requires a transdisciplinary approach, as the most effective one for making accurate diagnosis and planning treatment. Introducing a separate code for cortical visual impairment in the International Classification of Diseases can simplify the diagnostics, formation of uniform diagnostic criteria, and provide evidence-based treatment involvement. Determining the presence of neurological impairment and a detailed assessment of visual functioning facilitate the creation of intervention programs and a "friendly environment" for working and daily functioning, based on individual needs of a child.

Human Parechovirus 3 in Infants: Expanding Our Knowledge of Adverse Outcomes.

Human parechovirus particularly genotype 3 (HPeV3) is an emerging infection affecting predominantly young infants. The potential for neurologic sequelae in a vulnerable subset is increasingly apparent. A review of 2 epidemics of human parechovirus (HpeV) infection in 2013 and in 2015 in Queensland, Australia, was undertaken, with an emphasis on identifying adverse neurodevelopmental outcome. All hospitalized cases with laboratory-confirmed HPeV infection between October 2013 June 2016 were identified. Clinical, demographic, laboratory and imaging data were collected and correlated with reported developmental outcome. Laboratory-confirmed HPeV infections were identified in 202 patients across 25 hospitals; 86.6% (n = 175) were younger than 3 months 16.3% (n = 33) received intensive care admission. Of 142 cerebrospinal fluid samples which were HPeV polymerase chain reaction positive, all 89 isolates successfully genotyped were HPeV3. Clinical information was available for 145 children; 53.1% (n = 77) had follow-up from a pediatrician, of whom 14% (n = 11) had neurodevelopmental sequelae, ranging from hypotonia and gross motor delay to spastic quadriplegic cerebral palsy and cortical visual impairment. Of 15 children with initially abnormal brain magnetic resonance imaging, 47% (n = 7) had neurodevelopmental concerns, the remainder had normal development at follow-up between 6 and 15 months of age. This is the largest cohort of HPeV3 cases with clinical data and pediatrician-assessed neurodevelopmental follow-up to date. Developmental concerns were identified in 11 children at early follow-up. Abnormal magnetic resonance imaging during acute infection did not specifically predict poor neurodevelopmental in short-term follow-up. Continued follow-up of infants and further imaging correlation is needed to explore predictors of long-term morbidity.

Factors Associated With Lack of Vision Improvement in Children With Cortical Visual Impairment.

Improvement in vision has been noted in children with cortical visual impairment (CVI), resulting from disparate types of brain injury. The purpose of our study was to determine the risk factors associated with poor recovery of vision in this group of patients. Case records of children who were born before 2010 with at least 4 follow-up visits for CVI were reviewed for underlying etiologies of CVI, visual acuity (VA), and associated neurological and ophthalmological disorders. VA was assessed in 6 qualitative grades. Changes in VA were recorded as the difference between the grades of VA at presentation and the last follow-up visit. The outcome was calculated as a ratio of actual improvement to potential improvement in grades of qualitative VA. Multiple linear regression determined factors associated with lack of vision improvement in all children and based on etiology. Fifty-three children with CVI were identified. The median age at presentation was 13.6 months (range: 2.9-76.4 months) and the median follow-up was 5.8 years (1.1-16.3 years). CVI resulted from central nervous system (CNS) malformation (9.4%), hypoxic/inflammatory injury (15.1%), seizures (24.5%), and combined causes (51.0%). Vision improvement was noted in 83% of children. Lack of VA improvement was associated with older age at presentation in all children with CVI and within each etiological group except CNS malformation. None of the other investigated variables were associated with poor recovery of VA. Most of the children with CVI showed improvement in vision. Older age at presentation, but not etiology of CVI, was associated with poor improvement in VA.

Neuro-Ophthalmology at a Tertiary Eye Care Centre in India.

Neuro-ophthalmology as a specialty is underdeveloped in India. The aim of our study was to determine the spectrum and profile of patients presenting to a tertiary eye care center with neuro-ophthalmic disorders. A retrospective hospital-based study was conducted, and records of all patients seen at the neuro-ophthalmology clinic of Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India, over a 1-year period were retrieved and evaluated. Of a total of 30,111 patients referred to various specialty clinics in a span of 1 year, 1597 (5%) were referred for neuro-ophthalmology evaluation. The mean patient age was 30.8 ± 19.5 years, with a male dominance (M:F = 2.02:1). Among these patients, optic nerve disorders were noted in 63.8% (n = 1,020), cranial nerve palsy in 7% (n = 114), cortical visual impairment in 6.5% (n = 105), and others (eye/optic nerve hypophasia, blepharospasm, and optic disc drusen) in 6% (n = 95). Among the patients with optic nerve disorders, optic neuropathy without disc edema/(traumatic optic neuropathy, hereditary, tumor-related, retrobulbar neuritis, toxic, and idiopathic) was noted in 42.8% (n = 685) and optic neuropathy with disc edema (ischemic optic neuropathy, papilledema, post-papilledema optic atrophy, papillitis, neuroretinitis, and inflammatory optic neuropathy) in 20.9% (n = 335). Sixteen percent of patients (n = 263) were incorrect referrals. The neuro-ophthalmic clinic constitutes a significant referral unit in a tertiary eye care center in India. Traumatic and ischemic optic neuropathies are the most common diagnoses. Neuro-ophthalmology requires further development as a subspecialty in India to better serve the nation's population.

Attitudes concerning cortical visual impairment among pediatric ophthalmologists and teachers of the visually impaired

Attitudes concerning cortical visual impairment among pediatric ophthalmologists and teachers of the visually impaired

Tubulin mutations and ophthalmic manifestations: a pediatric case series

Tubulinopathies are a wide and overlapping range of brain malformations caused by six known gene mutations of different tubulin isotypes. Brain abnormalities include a range of lissencephalies and polymicrogyria-like cortical dysplasias with additional structural cerebral anomalies. Ocular findings involve associated cortical visual impairment, Congenital fibrosis of extraocular muscles (CFEOM) and associated ptosis, strabismus, and less commonly optic nerve hypoplasia. We present an observational case series of children diagnosed with a tubulinopathy, with emphasis on ophthalmic manifestations.

Use of Flow Cytometry for Diagnosis of Epilepsy Associated With Homozygous PIGW Variants

BackgroundBiallelic variants in PIGW have been suggested to cause infantile spasms and hyperphosphatasia. PIGW encodes for a protein involved in the third step of glycosylphosphatidylinositol (GPI) synthesis. GPI anchored proteins are increasingly recognized as important structures for cellular interactions and neuronal development. MethodsMolecular testing of PIGW was performed followed by fluorescence activating cell sorting analysis of granulocytes, lymphocytes, and monocytes, and compared to controls. FindingsAn infant was homozygous for variants in PIGW (c.199C>G; p.Pro67Ala) with an associated phenotype of infantile spasms, myoclonic seizures, cortical visual impairment, developmental delay, and minor dysmorphic features. Alkaline phosphatase levels ranged from normal to mildly elevated. Flow cytometric studies showed significantly decreased expression of important GPIs, providing functional evidence of pathogenicity. ConclusionOur data provide further evidence of a novel autosomal recessive PIGW-related epilepsy disorder. Flow cytometry provided functional evidence of the pathogenicity of homozygous variants of uncertain significance in PIGW, and supports the use of flow cytometry as a functional tool to demonstrate decreased surface expression of GPI anchored proteins in individuals with variants of unknown significance.

A 5-year retrospective record review of hospital-based low-vision rehabilitation in Thailand.

PurposeTo investigate the quality-of-life-related goals of low-vision patients, the causes of visual impairment, and the low-vision rehabilitation services at a Thai national tertiary referral center.Subjects and methodsA review was conducted on the medical records of patients attending the Low Vision Rehabilitation Clinic, Siriraj Hospital, Bangkok, Thailand, between 2012 and 2016.ResultsA total of 992 patient records were included, comprising of 760 adults (aged over 15 years) and 232 children (aged ≤15), with a mean age of 52.2 and 5.4 years, respectively. The retina was the most common anatomic site of visual impairment. Among the adults, the most common ocular condition was retinitis pigmentosa (28.3%), followed by age-related macular degeneration (10.3%), glaucoma (10.0%), and diabetic retinopathy (9.6%). As for the children, the most common ocular conditions were cortical visual impairment (17.7%), optic nerve hypoplasia (13.4%), and retinopathy of prematurity (9.5%). More patients had low vision (a visual acuity of <6/18–3/60) than blindness (a visual acuity below 3/60). The most commonly stated goals among the adults were reading, writing, and performing near tasks (34.7%), and independent mobility (21.3%), whereas for children, the most frequently indicated goal was visual and developmental stimulation (38.4%). The services most often provided for the adults were the prescribing of visual aid devices (51.8%) and orientation and mobility training (40.7%), while the children most often received visual and developmental stimulation provided by a multidisciplinary team (33.8%). The Thai Government’s Universal Health Care Coverage scheme was the most commonly used medical insurance.ConclusionData from this study can be used to improve low-vision patient care and rehabilitation services, and as input to the further development of national health care policies for low-vision patients.

Evaluation of Vision Behaviors in Children with Cortical Visual Impairment Due to Cerebral Palsy (CP)

Evaluation of Vision Behaviors in Children with Cortical Visual Impairment Due to Cerebral Palsy (CP)

Book Review: Cortical Visual Impairment: An Approach to Assessment and Intervention

Book Review: Cortical Visual Impairment: An Approach to Assessment and Intervention

Editors' note: Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness

In “Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness,” authors Cavanaugh et al. assessed whether visual discrimination training improves performance on visual perimetry tests in chronic stroke patients with visual cortex involvement. They found that in adults with chronic cortical visual impairment, the blind field border appears to have enhanced plastic potential, which can be recruited by gaze-controlled visual discrimination training to expand the visible field. Drs. Wall and Schiefer express concerns regarding the study, explaining that Cavanaugh et al. may not have separated the potential effects of training on improving attention along the vertical meridian, that the Humphrey device does not adequately capture small eye movements, and that the retest variability below 15 dB has little predictive value, in addition to other confounding factors. Cavanaugh et al. defend their article, stating that Humphrey visual fields (HVFs) remain the clinical gold standard for measuring visual defects in hemianopia. They explain that a shift in attention does not automatically cause a shift in fixation, and that, in their study, they created maps with a resolution of 0.1° squared. They proposed a new approach to collecting and analyzing HVFs, while rigorously controlling for drifts in fixation, whether attention-induced or otherwise. In “Visual discrimination training improves Humphrey perimetry in chronic cortically induced blindness,” authors Cavanaugh et al. assessed whether visual discrimination training improves performance on visual perimetry tests in chronic stroke patients with visual cortex involvement. They found that in adults with chronic cortical visual impairment, the blind field border appears to have enhanced plastic potential, which can be recruited by gaze-controlled visual discrimination training to expand the visible field.

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency

Variants in the SPATA5 gene were recently described in a cohort of patients with global developmental delay, sensorineural hearing loss, seizures, cortical visual impairment and microcephaly. SPATA5 protein localizes predominantly in the mitochondria and is proposed to be involved in mitochondrial function and brain developmental processes. However no functional studies have been performed. This study describes five patients with psychomotor developmental delay, microcephaly, epilepsy and hearing impairment, who were thought clinically to have a mitochondrial disease with subsequent whole-exome sequencing analysis detecting compound heterozygous variants in the SPATA5 gene. A summary of clinical data of all the SPATA5 patients reported in the literature confirms the characteristic phenotype. To assess SPATA5’s role in mitochondrial dynamics, functional studies were performed on rat cortical neurons. SPATA5-deficient neurons had a significant imbalance in the mitochondrial fusion-fission rate, impaired energy production and short axons. In conclusion, SPATA5 protein has an important role in mitochondrial dynamics and axonal growth. Biallelic variants in the SPATA5 gene can affect mitochondria in cortical neurons and should be considered in patients with a neurodegenerative disorder and/or with clinical presentation resembling a mitochondrial disorder.

A pilot study regarding basic knowledge of "cortical visual impairment in children" among ophthalmologists.

Purpose:A pilot study was done to evaluate knowledge regarding “cortical visual impairment (CVI) in children” among ophthalmologists.Methods:This study was conducted during the annual conference of a zonal ophthalmological society. All ophthalmologists who attended the conference were requested to participate in this study. Those who agreed were given a validated questionnaire to assess knowledge regarding CVI. Cronbach's alpha of the questionnaire was 0.6. Participants were asked to respond to multiple choice questions by choosing the single best option. The responses obtained were then evaluated.Results:The total number of registered delegates in the conference was 448. A total of 103 ophthalmologists showed interest to participate in the study with a response rate of 22.9%. Only 89/103 interested delegates were included in the study as remaining were unaware of CVI. No participant gave correct answers to all questions. Although more than 80% of them knew the most common association (87%) and site of pathology (84%), only 52% were sure about clinical features and even lesser respondents (39%) knew that magnetic resonance imaging is the correct investigation of choice. The majority responded correctly that these children need eye examination (89%) and can be managed by rehabilitation through multidisciplinary approach (82%), but only 58% could recognize differential diagnoses and had a correct idea regarding the prognosis of CVI. There was no correlation between the number of patients diagnosed per month by the respondent with knowledge of the disease.Conclusion:In this pilot study, ophthalmologists were found to have limited knowledge regarding clinical features, investigation, differential diagnosis, and visual prognosis of CVI in children. There is a need to improve awareness regarding CVI among ophthalmologists.

Cortical visual impairment following cardiac arrest in a child with Salmonella myocarditis

Many patients suffering from enteric fever may face serious complications affecting any organ. Cortical blindness has been reported as a complication in three cases till date. We report a case of a 10-year-old male child, who presented with bilateral loss of vision 9 months after suffering from Salmonella myocarditis with a cardiac arrest, following which there was hypoxic insult to the brain. The child had a perception of light and was diagnosed with cortical visual impairment. As per literature search from Medline and Cochrane review, no such case has been reported in this age group till date.