Monitoring compliance to topical therapy in children and young people with uveitis.

BACKGROUND/OBJECTIVES: Uveitis in children and young people (CYP) is a rare but potentially debilitating condition. Steroid eye drops are the first step in treatment and poor compliance may result in vision-threatening complications. This study aims to measure compliance with prescribed eye drops prospectively in a child-specific manner. SUBJECTS/METHODS: Patients aged 0-18 years attending a tertiary paediatric uveitis clinic using steroid drops were recruited. Both the CYP, and person with parental responsibility (PPR) completed questionnaires about compliance. A subgroup had bottles of Prednisolone 1% drops dispensed and weighed at the first appointment and reweighed at follow-up. The weight reduction was compared with expected weight change over the interval. RESULTS: The study was completed by 42 patients of the 50 patients recruited. Thirty-one CYP and their respective PPR completed both questionnaires, 11 completed only one questionnaire (9 CYP, 2 PPR). Drop errors for all eye drops were reported more than "once a week" by 13/39 CYP (33.3%, 95% CI: 19.1%-50.2% of respondents), and 3/31 PPR (9.7%, CI: 19.1%-50.2% of respondents). Many PPR could not recall prescribed drop frequency (n = 13/31, 40.6%, CI: 23.7%-59.4% of respondents). Twelve patients had bottles weighed and returned. Insufficient weight reduction was found in 9 (75%, CI: 42.8%-94.5%). Within the eye drop weighing subgroup three participants (25%, CI: 5.5%-57.2%) used <50% the expected weight of drops. CONCLUSIONS: This study demonstrated poor eye drop compliance in CYP with uveitis. Self-reported compliance was unreliable in this population. Worryingly, some patients miss more than 50% of drops and may suffer sub-optimal disease control.

The Role of Genetic Testing in Children Requiring Surgery for Ectopia Lentis.

Non-traumatic ectopia lentis can be isolated or herald an underlying multisystemic disorder. Technological advances have revolutionized genetic testing for many ophthalmic disorders, and this study aims to provide insights into the clinical utility of genetic analysis in paediatric ectopia lentis. Children that underwent lens extraction for ectopia lentis between 2013 and 2017 were identified, and gene panel testing findings and surgical outcomes were collected. Overall, 10/11 cases received a probable molecular diagnosis. Genetic variants were identified in four genes: FBN1 (associated with Marfan syndrome and cardiovascular complications; n = 6), ADAMTSL4 (associated with non-syndromic ectopia lentis; n = 2), LTBP2 (n = 1) and ASPH (n = 1). Parents appeared unaffected in 6/11 cases; the initial presentation of all six of these children was to an ophthalmologist, and only 2/6 had FBN1 variants. Notably, 4/11 cases required surgery before the age of 4 years, and only one of these children carried an FBN1 variant. In summary, in this retrospective cohort study, panel-based genetic testing pointed to a molecular diagnosis in >90% of paediatric ectopia lentis cases requiring surgery. In a subset of study participants, genetic analysis revealed changes in genes that have not been linked to extraocular manifestations and highlighted that extensive systemic investigations were not required in these individuals. We propose the introduction of genetic testing early in the diagnostic pathway in children with ectopia lentis.

Paracentral Acute Middle Maculopathy in A Young Girl Treated with Interferon-Beta for Nasopharyngeal Carcinoma.

PURPOSE: To describe a case of interferon-beta retinopathy associated with paracentral acute middle maculopathy. CASE REPORT: A 15-year-old girl with Epstein-Barr virus-positive advanced nasopharyngeal carcinoma WAS REFERRED with reduced visual acuity. Multimodal imaging findings, including optical coherence tomography angiography, at presentation and evolution following cessation of interferon therapy are presented. CONCLUSION: The presentation of paracentral acute middle maculopathy in this patient supports the presumed ischaemic pathogenesis in interferon retinopathy. The imaging findings provide evidence of deep capillary plexus involvement in interferon retinopathy with evolution to permanent structural damage within the inner nuclear layer.

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders.

PURPOSE: A key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs). METHODS: Two hundred one unrelated children (0-5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011-2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing. RESULTS: The diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism). CONCLUSION: Genetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.

Clinical and genetic variability in children with partial albinism.

Individuals who have ocular features of albinism and skin pigmentation in keeping with their familial background present a considerable diagnostic challenge. Timely diagnosis through genomic testing can help avert diagnostic odysseys and facilitates accurate genetic counselling and tailored specialist management. Here, we report the clinical and gene panel testing findings in 12 children with presumed ocular albinism. A definitive molecular diagnosis was made in 8/12 probands (67%) and a possible molecular diagnosis was identified in a further 3/12 probands (25%). TYR was the most commonly mutated gene in this cohort (75% of patients, 9/12). A disease-causing TYR haplotype comprised of two common, functional polymorphisms, TYR c.[575 C > A;1205 G > A] p.[(Ser192Tyr);(Arg402Gln)], was found to be particularly prevalent. One participant had GPR143-associated X-linked ocular albinism and another proband had biallelic variants in SLC38A8, a glutamine transporter gene associated with foveal hypoplasia and optic nerve misrouting without pigmentation defects. Intriguingly, 2/12 individuals had a single, rare, likely pathogenic variant in each of TYR and OCA2 - a significant enrichment compared to a control cohort of 4046 individuals from the 100,000 genomes project pilot dataset. Overall, our findings highlight that panel-based genetic testing is a clinically useful test with a high diagnostic yield in children with partial/ocular albinism.

Craniofacial linear scleroderma associated with retinal telangiectasia and exudative retinal detachment.

Linear scleroderma is a characteristic form of scleroderma that typically affects children. Ocular manifestations may be present, especially when the frontoparietal area of the head is affected. We present the case of a 5-year-old boy with craniofacial linear scleroderma ("en coup de sabre") who developed exudative retinal detachment. Angiographic and neuroimaging findings are presented, and the importance of regular fundus examination is highlighted.

Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease.

PURPOSE: To assess the clinical usefulness of genetic testing in a pediatric population with inherited retinal disease (IRD). DESIGN: Single-center retrospective case series. PARTICIPANTS: Eighty-five unrelated children with a diagnosis of isolated or syndromic IRD who were referred for clinical genetic testing between January 2014 and July 2016. METHODS: Participants underwent a detailed ophthalmic examination, accompanied by electrodiagnostic testing (EDT) and dysmorphologic assessment where appropriate. Ocular and extraocular features were recorded using Human Phenotype Ontology terms. Subsequently, multigene panel testing (105 or 177 IRD-associated genes) was performed in an accredited diagnostic laboratory, followed by clinical variant interpretation. MAIN OUTCOME MEASURES: Diagnostic yield and clinical usefulness of genetic testing. RESULTS: Overall, 78.8% of patients (n = 67) received a probable molecular diagnosis; 7.5% (n = 5) of these had autosomal dominant disease, 25.4% (n = 17) had X-linked disease, and 67.2% (n = 45) had autosomal recessive disease. In a further 5.9% of patients (n = 5), a single heterozygous ABCA4 variant was identified; all these participants had a spectrum of clinical features consistent with ABCA4 retinopathy. Most participants (84.7%; n = 72) had undergone EDT and 81.9% (n = 59) of these patients received a probable molecular diagnosis. The genes most frequently mutated in the present cohort were CACNA1F and ABCA4, accounting for 14.9% (n = 10) and 11.9% (n = 8) of diagnoses respectively. Notably, in many cases, genetic testing helped to distinguish stationary from progressive IRD subtypes and to establish a precise diagnosis in a timely fashion. CONCLUSIONS: Multigene panel testing pointed to a molecular diagnosis in 84.7% of children with IRD. The diagnostic yield in the study population was significantly higher compared with that in previously reported unselected IRD cohorts. Approaches similar to the one described herein are expected to become a standard component of care in pediatric ophthalmology. We propose the introduction of genetic testing early in the diagnostic pathway in children with clinical and/or electrophysiologic findings, suggestive of IRD.

Optic neuropathy in methylmalonic acidemia and propionic acidemia.

BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare hereditary disorders of protein metabolism, manifesting early in life with ketoacidosis and encephalopathy and often resulting in chronic complications. Optic neuropathy (ON) has been increasingly recognised in both conditions, mostly through isolated case reports or small cases series. We here report the clinical features and visual outcomes of a case series of paediatric patients with a diagnosis of MMA or PA. METHODS: Retrospective observational case series. A database of patients attending the Willink Biochemical Genetics unit in Manchester was interrogated. Fifty-three patients had a diagnosis of either isolated MMA or PA, of which 12 had been referred for ophthalmic review. RESULTS: Seven patients had clinical findings compatible with ON. Visual outcomes in these patients were poor, with slow clinical progression or stability over time in five cases with follow-up. Presentation was acute in a context of metabolic crisis in two of the cases. Four patients with ON had electrodiagnostics showing absent pattern evoked potentials, with one showing a preserved flash response. All four showed marked attenuation of the dark-adapted electroretinogram with better preservation of the light-adapted response. CONCLUSIONS: Our study suggests that ON is under-reported in patients with MMA and PA. Clinical presentation can be acute or insidious, and episodes of acute metabolic decompensation appear to trigger visual loss. Photoreceptor involvement may coexist. Active clinical surveillance of affected patients is important as comorbidities and cognitive impairment may delay diagnosis.

Accuracy of Intraocular Pressure Measurement With the Icare Tonometer in Children.

PURPOSE: The aim of this study was to evaluate the difference between intraocular pressure (IOP) measurements in children with the Icare tonomer (IT) and applanation (AT), pneumatic (PT), or digital tonometers (TT). DESIGN: A randomized prospective trial of children younger than age 16 attending the pediatric ophthalmology department of Manchester Royal Eye Hospital was conducted. METHODS: Children had IOP measured twice, once with an IT and again with a TT, PT, or AT during the same clinic appointment. RESULTS: Forty-four children (88 eyes) were included, with a mean [range (R)] age of 57 (2-144) months. Twelve eyes had anterior segment pathology (ASP), defined as aniridia, congenital glaucoma, or Peters anomaly. Regardless of the presence or absence of ASP, total mean difference (MD), R, positive bias (PB), and limits of agreement (LOA) between IT and other instruments were as follows: PT: MD = 3.2, R = 0 to 8, PB = 2.9, LOA = -1.0 to 6.9; TT: MD = 2.6, R = 0 to 6, PB = 0.9, LOA = -1.8 to 3.5; and AT: MD = 1.4, R = -3 to 5, PB = 0.6, LOA = -4.2 to 7.3. In eyes with ASP, IT comparisons with PT were as follows: MD = 3.9, R = 0 to 8, PB = 3.9, LOA = -0.9 to 8.8. CONCLUSIONS: In children with ASP, IOP measured with IT is higher than expected when compared with other tonometers, in some cases by up to 8 mm Hg. We found an overestimation of IOP in children using the IT with a positive bias of 4 mm Hg. We propose that the IT overestimates IOP measurements in children compared with standard tonometers. Further work should be carried out on a much larger cohort to establish a suitable correction factor for such children.

Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy.

Leber hereditary optic neuropathy and autosomal dominant optic atrophy are the two most common inherited optic neuropathies. The latter has been associated with mutations in the OPA1 and OPA3 genes. To date, only six families with OPA3-associated dominant optic atrophy have been reported. In order to identify additional families, we performed Sanger sequencing of the OPA3 gene in 75 unrelated optic neuropathy patients. Affected individuals from two families were found to harbour the c.313C > G, p.(Gln105Glu) change in heterozygous state; this genetic defect has been previously reported in four dominant optic atrophy families. Intra- and interfamilial variability in age of onset and presenting symptoms was observed. Although dominant OPA3 mutations are typically associated with optic atrophy and cataracts, the former can be observed in isolation; we report a case with no lens opacities at age 38. Conversely, it is important to consider OPA3-related disease in individuals with bilateral infantile-onset cataracts and to assess optic nerve health in those whose vision fail to improve following lens surgery. The papillomacular bundle is primarily affected and vision is typically worse than 20/40. Notably, we describe one subject who retained normal acuities into the fifth decade of life. The condition can be associated with extraocular clinical features: two affected individuals in the present study had sensorineural hearing loss. The clinical heterogeneity observed in the individuals reported here (all having the same genetic defect in OPA3) suggests that the molecular pathology of the disorder is likely to be complex.

Congenital and infantile cataract: aetiology and management.

Congenital cataract is the commonest worldwide cause of lifelong visual loss in children. Although congenital cataracts have a diverse aetiology, in many children, a cause is not identified; however, autosomal dominant inheritance is commonly seen. Early diagnosis either on the post-natal ward or in the community is important because appropriate intervention can result in good levels of visual function. However, visual outcome is largely dependent on the timing of surgery when dense cataracts are present. Good outcomes have been reported in children undergoing surgery before 6 weeks of age in children with unilateral cataract and before 10 weeks of age in bilateral cases. Placement of an artificial intraocular lens implant after removal of the cataract has become established practice in children over 2 years of age. There remains debate over the safety and predictability of intraocular lens implantation in infants. Despite early surgery and aggressive optical rehabilitation, children may still develop deprivation amblyopia, nystagmus, strabismus, and glaucoma. The diagnosis and management of congenital cataracts has improved substantially over the past 30 years with a concurrent improvement in outcomes for affected children. Many aspects of the pre-, intra-, and postoperative management of these patients continue to be refined, highlighting the need for good quality data and prospective collaborative studies in this field.

Clinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosis.

The mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans in several tissues and organs. This accumulation results in an array of clinical manifestations and premature death in severe cases. Ocular problems are very common in children with MPS and may involve the cornea, sclera, trabecular meshwork, retina, optic nerve and also the posterior visual pathways. The aims of this study are to give an overview of ocular problems in MPS and to provide clinical guidelines for paediatric ophthalmologists for early diagnosis and management of ocular manifestations in children with MPS. Diagnostic problems may arise in children with severe corneal clouding, hampering visualization of the fundus. Intraocular pressures may be falsely high, even leading to suspicion and unnecessary pressure-lowering treatment. Simple interventions such as the use of prescription glasses or photochromatic glasses can considerably improve quality of life in children with MPS.

Diagnosis and management of ophthalmological features in patients with mucopolysaccharidosis.

Ocular pathology is common in patients with mucopolysaccharidosis (MPS), a hereditary lysosomal storage disorder, where the eye as well as other tissues accumulate excessive amounts of glycosaminoglycans. Despite genetic and phenotypic heterogeneity within and between different types of MPS, the disease symptoms and clinical signs often manifest during the first 6 months of life with increasing head size, recurrent infections, umbilical hernia, growth retardation and skeletal problems. Typical ocular features include corneal clouding, ocular hypertension/glaucoma, retinal degeneration and optic nerve atrophy. Visual deterioration and sensitivity to light may substantially reduce the quality of life in MPS patients, particularly when left untreated. As an early intervention, haematopoietic stem cell transplantation and/or enzyme replacement therapy are likely to improve patients' symptoms and survival, as well as visual outcome. Thus, it is of utmost importance to ensure proper detection and accurate diagnosis of MPS at an early age. It is of fundamental value to increase awareness and knowledge among ophthalmologists of the ocular problems affecting MPS patients and to highlight potential diagnostic pitfalls and difficulties in patient care. This review provides insight into the prevalence and severity of ocular features in patients with MPS and gives guidance for early diagnosis and follow-up of MPS patients. MPS poses therapeutic challenges in ocular management, which places ophthalmologists next to paediatricians at the forefront of interventions to prevent long-term sequelae of this rare but serious disease.

Ocular manifestations as key features for diagnosing mucopolysaccharidoses.

Diagnosis of mucopolysaccharidosis (MPS) requires awareness of the multisystem disease manifestations and their diverse presentation in terms of time of onset and severity. Many patients with MPS remain undiagnosed for years and progressively develop irreversible pathologies, which ultimately lead to premature death. To foster timely treatment and ensure a better outcome, it is of utmost importance to recognize and evaluate the typical ocular features that present fairly early in the course of the disease in many children with MPS. These include corneal clouding, ocular hypertension/glaucoma, retinal degeneration, optic disc swelling and optic nerve atrophy. Other associations include pseudo-exophthalmos, amblyopia, strabismus and large refractive errors requiring spectacle correction. While some ocular manifestations require specialized equipment for detecting abnormalities, light sensitivity, pseudo-exophthalmos and strabismus are often apparent on a routine physical examination. In addition, patients may be symptomatic from vision impairment, photosensitivity, night blindness and visual field constriction. Combined with the skeletal/joint complications and other manifestations, these ocular features are key in the differential diagnosis of children with joint abnormalities. Rheumatologists should have a high index of suspicion for MPS to facilitate early diagnosis. Referral to a geneticist, a metabolic specialist or physician who specializes in MPS can confirm the diagnosis and provide disease management. Consultation with an ophthalmologist who has expertise in MPS is also needed for thorough examination of the eyes and regular follow-up care.

Mucopolysaccharidoses and the eye.

The mucopolysaccharidoses (MPSs) are a group of disorders caused by inherited defects in lysosomal enzymes resulting in widespread intra- and extra-cellular accumulation of glycosaminoglycans. They have been subdivided according to enzyme defect and systemic manifestations and include MPS IH (Hurler), MPS IS (Scheie), MPS IH/S (Hurler/Sheie), MPS II (Hunter), MPS III (Sanfilippo), MPS IV (Morquio), MPS VI (Maroteaux-Lamy), MPS VII (Sly) and MPS IX (Natowicz). The mucopolysaccharidoses have a spectrum of systemic manifestations, including airway and respiratory compromise, skeletal deformities, intellectual and neurological impairment, cardiac abnormalities, and gastrointestinal problems. Ocular manifestations are common in the mucopolysaccharidoses and may result in significant visual impairment. Corneal opacification of varying severity is frequently seen, as well as retinopathy, optic nerve swelling and atrophy, ocular hypertension, and glaucoma. New treatment modalities for the systemic manifestations of the mucopolysaccharidoses include bone marrow transplant and enzyme replacement therapy, and have resulted in an improved prognosis in many cases. This article reviews the systemic and ocular manifestations of the mucopolysaccharidoses, as well as new treatment options, and discusses the ophthalmic management of mucopolysaccharidosis patients.

Fibrillin: from microfibril assembly to biomechanical function.

Fibrillins form the structural framework of a unique and essential class of extracellular microfibrils that endow dynamic connective tissues with long-range elasticity. Their biological importance is emphasized by the linkage of fibrillin mutations to Marfan syndrome and related connective tissue disorders, which are associated with severe cardiovascular, ocular and skeletal defects. These microfibrils have a complex ultrastructure and it has proved a major challenge both to define their structural organization and to relate it to their biological function. However, new approaches have at last begun to reveal important insights into their molecular assembly, structural organization and biomechanical properties. This paper describes the current understanding of the molecular assembly of fibrillin molecules, the alignment of fibrillin molecules within microfibrils and the unique elastomeric properties of microfibrils.

Fibrillin-rich microfibrils: elastic biopolymers of the extracellular matrix.

Fibrillin-rich microfibrils are evolutionarily ancient macromolecular assemblies of the extracellular matrix. They have unique extensible properties that endow vascular and other tissues with long-range elasticity. Microfibril extensibility supports the low pressure closed circulations of lower organisms such as crustaceans. In higher vertebrates, microfibrils act as a template for elastin deposition and are components of mature elastic fibres. In man, the importance of microfibrils is highlighted by the linkage of mutations in their principal structural component, fibrillin-1, to the heritable disease Marfan syndrome which is characterised by severe cardiovascular, skeletal and ocular defects. When isolated from tissues, fibrillin-rich microfibrils have a complex ultrastructural organisation with a characteristic 'beads-on-a-strong' appearance. X-ray fibre diffraction studies and biomechanical testing have shown that microfibrils are reversibly extensible at tissue extensions of 100%. Ultrastructural analysis and 3D reconstructions of isolated microfibrils using automated electron tomography have revealed new details of how fibrillin molecules are aligned within microfibrils in untensioned and extended states, and delineated the role of calcium in regulating microfibril beaded periodicity, rest length and molecular organisation. The molecular basis of how fibrillin molecules assemble into microfibrils, the central role of cells in regulating this process, and the identity of other molecules that may coassemble into microfibrils are now being elucidated. This information will enhance our understanding of the elastic mechanism of these unique extracellular matrix polymers, and may lead to new microfibril-based strategies for repairing elastic tissues in ageing and disease.