Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.

PURPOSE: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. METHODS: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. RESULTS: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. CONCLUSION: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.

Periosteal muscle anchoring for large angle incomitant squint.

PURPOSE: To describe a surgical technique for correcting very large angle exodeviations and determine long term outcomes leading to the evolution of surgical technique. METHODS: A consecutive series of seven patients with large angle, incomitant squint were operated on at Moorfields Eye Hospital over a five-year period using periosteal anchoring by a joint Strabismus/Adnexal team. All patients underwent anchoring of the insertion of the medial rectus (MR) muscle to the periosteum of the medial orbital wall via a retrocaruncular approach, with or without lateral rectus (LR) disinsertion and suturing to the lateral orbital rim connective tissue. Retrospective analysis of notes assessed previous procedures, prism dioptre (PD) deviations and complications. RESULTS: Included were seven eyes (five right, two left) of seven patients (two female, five male). Median age at first anchoring procedure was 25 years (range 4-57). Mean follow up was 34 months (range 8-66). Six patients had long-standing third nerve palsy, one patient had Moebius syndrome. Pre-operative exotropia ranged from 45 to 115 PDs (mean 76, median 75). At the final follow up, all patients had reduced horizontal deviations ranging from 0 to 80 PDs (mean 34, median 30). Further surgery was required in three patients all of whom did not undergo release of the LR muscle at the first procedure. CONCLUSION: Large angle incomitant divergent squints present a particularly difficult surgical challenge. We advocate a combined bi-rectus fixation approach to hold the globe in the primary position.

Paediatric endophthalmitis: a UK retrospective study.

INTRODUCTION: Paediatric endophthalmitis is a severe but rare complication of intraocular surgery, penetrating trauma and far less commonly extra-ocular surgery or endogenous origin. We set out to establish the incidence and risk factors of exogenous endophthalmitis in children, and to develop an evidence-based protocol that can be used for treatment of suspected exogenous endophthalmitis in children. METHODS: Microbiology reports and operation numbers were obtained from two large tertiary referral hospitals sharing 24-h paediatric ophthalmology cover for the period January 2009-December 2016. All cases of aqueous and/or vitreous tap performed on children aged ≤18 years were identified and case notes reviewed for complete information on each case. RESULTS: Sixteen cases were eligible for inclusion as 'postoperative endophthalmitis': complete data was found on 13 cases. The incidence of postoperative endophthalmitis was 0.17% over 7 years. The mean age of presentation was 5.5 years (range from 7 months to 16 years and 9 months), from 3 days-78 months post operatively. In all, 11/13 had at least one glaucoma procedure. Microbiology results showed growth in 8/13. Most isolates were Gram-positive bacteria but Gram-negatives were also isolated and in one case Candida from a conjunctival swab. The antibiotic regime varied depending on age, organism identified and sensitivities. In all, 9/13 had hand movement or worse vision after treatment. CONCLUSION: Paediatric endophthalmitis may present to any paediatric/general ophthalmologist. It is a rare but devastating condition with poor visual prognosis, requiring prompt recognition and aggressive management. Previous glaucoma surgery is a long-term risk factor in our local paediatric population. Based on our study, an evidence-based protocol for management is proposed in order to improve outcomes.

Quality of life and functional vision in children treated for cataract-a cross-sectional study.

PurposeChildren with cataract and their families face intensive medical and surgical management, with numerous hospital attendances, topical medications, and surgical procedures, as well as uncertainty about the child's future visual ability, education, and independence. Little is known about the impact on functional visual ability, vision-, and health-related quality of life (VR-, HR-QoL).Patients and methodsSeventy two children aged 2-16 years (mean 8.45, SD 4.1) treated for developmental or secondary cataract and their parents/carers completed three validated instruments measuring functional visual ability, VR-, and HR-QoL: the Cardiff Visual Ability Questionnaire for Children (CVAQC), Impact of Vision Impairment for Children (IVI-C), and PedsQL V 4.0.ResultsAll scores are markedly reduced: median (interquartile range (IQR)) CVAQC score -1.42 (-2.28 to -0.03), mean (SD) IVI-C score 65.67 (16.91), median (IQR) PedsQL family impact score 75 (56.94-88.19), parent report 71.74 (51.98-88.5), self-report 76.09 (61.96-89.13). Psychosocial PedsQL subscores are lower than physical subscores. Parent-completed tools (PedsQL family and parent report) state greater impact on HR-QoL than tools completed by children/young people, particularly in teenagers. Older children/young people have higher functional visual ability scores than younger children.ConclusionsCataract has a marked a long-term impact on functional visual ability and quality of life of children and young people, with HR-QoL affected to degrees reported in children with severe congenital cardiac defects or liver transplants.

Batten disease: features to facilitate early diagnosis.

AIMS: To ascertain the clinical and electrophysiological features in patients with juvenile neuronal ceroid lipofuscinosis (jNCL/Batten disease) and to identify those features that facilitate early diagnosis. METHODS: Nine patients with jNCL were identified retrospectively and their case notes reviewed. All had undergone an extensive clinical examination, including electrophysiology. Blood and molecular genetic testing confirmed the diagnosis. RESULTS: Age at onset ranged from 4-8 years. At presentation, two of nine patients had normal fundi; only two of nine patients had a bull's eye maculopathy. The electroretinogram (ERG) findings in this series included undetectable rod specific ERGs, an electronegative maximal response, reduced and delayed cone flicker ERGs, reduction in the b:a ratio in the photopic single flash ERG, and an undetectable pattern ERG. Vacuolated lymphocytes on peripheral blood film testing were present in eight of nine patients. Five of eight patients were homozygous for the 1.02 kb deletion on the CLN3 gene on molecular genetic testing; two of eight patients were heterozygous for that deletion. CONCLUSION: jNCL should be considered in children of 10 years and under presenting with visual loss and fundal changes ranging from normal through to pigmentary/atrophic changes or a bull's eye maculopathy. Electrophysiology may suggest jNCL. Although currently untreatable, early diagnosis is important to institute appropriate counselling and support.

Does strabismus surgery improve quality and mood, and what factors influence this?

AimsTo establish the impact of adult strabismus surgery on clinical and psychosocial well-being and determine who experiences the greatest benefit from surgery and how one could intervene to improve quality of life post-surgery.MethodsA longitudinal study, with measurements taken pre-surgery and at 3 and 6 months post-surgery. All participants completed the AS-20 a disease specific quality of life scale, along with measures of mood, strabismus and appearance-related beliefs and cognitions and perceived social support. Participants also underwent a full orthoptic assessment at their preoperative visit and again 3 months postoperatively. Clinical outcomes of surgery were classified as success, partial success or failure, using the largest angle of deviation, diplopia and requirement for further therapy.Results210 participants took part in the study. Strabismus surgery led to statistically significant improvements in psychosocial and functional quality of life. Those whose surgery was deemed a partial success did however experience a deterioration in quality of life. A combination of clinical variables, high expectations, and negative beliefs about the illness and appearance pre-surgery were significant predictors of change in quality of life from pre- to post-surgery.ConclusionsStrabismus surgery leads to significant improvements in quality of life up to 6 months postoperatively. There are however a group of patients who do not experience these benefits. A series of clinical and psychosocial factors have now been identified, which will enable clinicians to identify patients who may be vulnerable to poorer outcomes post-surgery and allow for the development of interventions to improve quality of life after surgery.

Retinal dysfunction and refractive errors: an electrophysiological study of children.

AIMS: To evaluate the relation between refractive error and electrophysiological retinal abnormalities in children referred for investigation of reduced vision. METHODS: The study group comprised 123 consecutive patients referred over a 14 month period from the paediatric service of Moorfields Eye Hospital for electrophysiological investigation of reduced vision. Subjects were divided into five refractive categories according to their spectacle correction: high myopia (< or = -6D), low myopia (>-6D and < or = -0.75D), emmetropia (>-0.75 and <1.5D), low hyperopia (> or = 1.5 and <6D), and high hyperopia (> or = 6D). Patients with a specific diagnosis at the time of electrophysiological testing were excluded. Only the first member of any one family was included if more than one sibling had been tested. All tests were performed to incorporate ISCEV standards, using gold foil corneal electrodes where possible. In younger patients skin electrodes and an abbreviated protocol were employed. RESULTS: The mean age of patients was 7.1 years with an overall incidence of abnormal electrophysiological findings of 29.3%. The incidence of abnormality was higher in high ametropes (13/25, 52%) compared to the other groups (23/98, 23.5%). This difference was statistically significant (chi2 test, p = 0.005). There was also a significant association between high astigmatism (>1.5D) and ERG abnormalities (18/35 with high astigmatism v 20/88 without, chi2 test, p = 0.002). There was no significant variation in frequency of abnormalities between low myopes, emmetropes, and low hyperopes. The rate of abnormalities was very similar in both high myopes (8/15) and high hyperopes (5/10). CONCLUSIONS: High ametropia and astigmatism in children being investigated for poor vision are associated with a higher rate of retinal electrophysiological abnormalities. An increased rate of refractive errors in the presence of retinal pathology is consistent with the hypothesis that the retina is involved in the process of emmetropisation. Electrophysiological testing should be considered in cases of high ametropia in childhood to rule out associated retinal pathology.

Pilot study of the systemic effects of three different screening methods used for retinopathy of prematurity.

PURPOSE: This pilot study compared the physiological and behavioural changes in premature infants undergoing three different methods of screening for retinopathy of prematurity (ROP). STUDY DESIGN: Prospective randomized cross-over pilot study. SUBJECTS AND METHODS: Fifteen premature infants requiring screening for ROP were recruited, and physiological and behavioural responses produced by three different methods of screening were compared. The screening methods employed a RetCam 120 and an indirect ophthalmoscope with and without an eyelid speculum. Physiological indices (change in pulse, mean blood pressure and oxygen saturation) and facial responses to pain (brow bulge, eye squeeze, nasolabial fold, mouth opening and the presence of cry) were recorded at five points: before, during and immediately after screening and 10 and 30 min after examination. RESULTS: Screening with the RetCam 120 and the indirect ophthalmoscope with a speculum both caused a greater change in pulse and mean blood pressure and an increase in facial responses to pain during and immediately after screening as compared to the indirect ophthalmoscope without the speculum. RetCam 120 screening caused greater desaturation than the other methods. CONCLUSIONS: Although this was a small sample which limits absolute conclusions, the study showed that screening using a RetCam or a speculum and indirect ophthalmoscope caused more stress to the infant, as indicated by physiological and behavioural changes, than simply screening using an indirect ophthalmoscope without a speculum. These effects should be considered when deciding on the appropriate screening method for examining particularly sick infants.

Postmortem monocular indirect ophthalmoscopy.

Postmortem monocular indirect ophthalmoscopy permits examination of the posterior fundus and peripheral retina even if there is less than perfect anterior segment media such as postmortem corneal clouding. Light directed through the decedent's pupil from a bright focal light source illuminates the fundus and reflected light from the retina is then projected out of the eye. An aspheric condensing lens positioned in front of the eye focuses the retinal image at the focal plane of the lens. The real inverted, laterally reversed image comprises a wide field of view permitting evaluation of the decedent's fundus for retinal hemorrhages and other lesions.

Appearance and location of retinal haemorrhages in critically ill children.

BACKGROUND: There are few high-quality studies describing the appearance and location of retinal haemorrhages in critically ill children not due to birth or abusive head trauma. METHODS: Prospective study from February 2008 to December 2009 of emergency admissions to a paediatric intensive care unit aged over 6 weeks. Children with a penetrating eye injury or suspected or proven abusive head injury were excluded. The children underwent either dilated funduscopy performed by a paediatric ophthalmologist or RetCam imaging. RESULTS: Retinal haemorrhages were identified in 24/159 (15%) patients. 50% of the haemorrhages were bilateral. The severity was mild (<5 retinal haemorrhages) or moderate (5-20 retinal haemorrhages) in 75%. The location was in zone 1 in 45.8%, zones 1 and 2 in 33.3%, zone 2 alone in 8.3% and not described in 8.3%. Schisis cavities and perimacular folds were identified in two patients with one having a pseudohypopyon appearance; a further one patient had bilateral haemorrhagic retinal detachments. Three patients had exudates or scarring consistent with cytomegalovirus infection. CONCLUSIONS: Retinal haemorrhages are seen in a proportion of critically ill children, however most retinal bleeding is not extensive as indicated by location within the retina or layer of bleeding. Higher numbers and extent of retinal haemorrhages were only observed in the presence of severe coagulopathy, leukaemia, one victim of a road traffic accident, and one child who sustained a fatal witnessed fall down the stairs; all circumstances that would be readily distinguished by history and laboratory testing from abusive head injury.

Spontaneous subluxation of iris-claw aphakic intraocular lens causing complications in two children.

Many surgeons consider implantation of iris-claw intraocular lenses a favorable option for pediatric aphakic eyes with poor capsular support. The authors present two children who had spontaneous subluxation of such lenses resulting in complications that required explantation. These cases highlight the potential sight-threatening complications of such intraocular lenses.

Mediators involved in retinopathy of prematurity and emerging therapeutic targets.

Retinopathy of prematurity (ROP) is a potentially blinding disease of premature infants and despite timely treatment some infants develop retinal detachment and sight loss. Current treatment utilises laser therapy which causes destruction of treated retinal tissue resulting in field loss. There is considerable research work ongoing on neovascular eye disease which is likely to result in antiangiogenic approaches that will arrest the development of ROP by specifically targeting the involved molecular mediators. Some of these new therapeutic interventions have entered clinical trials. This article reviews new information available on the molecular pathogenesis of ROP which may result in novel treatments for ROP; it does not discuss the well-known role of oxygen in the development of ROP.

The management of patients with thyroid eye disease after bilateral orbital 3 wall decompression.

INTRODUCTION: Thyroid eye disease is the most common cause of unilateral and bilateral proptosis in adults. Orbital decompression surgery may cause and/or worsen a pre-existing ocular motility disorder. METHODS: A retrospective review was carried out of all bilateral 3 wall orbital decompressions for severe thyroid eye disease performed between January 2002 and December 2004 by one surgeon. Subsequent surgeries were recorded. RESULTS: Seventy-four patients were identified, 59 (80%) females and 15 (20%) males. Mean age at the time of decompression was 46 years. Fifteen (20%) patients complained of diplopia due to strabismus prior to decompression surgery and 20 (27%) developed new diplopia postsurgery. Twenty patients (27%) required no further intervention following decompression surgery; the remainder underwent an average of 2.5 procedures. Strabismus surgery was performed in 32 (43%) patients. The mean time from the decompression to first strabismus surgery was 12 months. Forty-three (58%) patients underwent lid surgery. The mean time from decompression to first lid surgery was 16 months. CONCLUSION: This study demonstrates how this group of complex patients required multiple surgical procedures within an extended timescale, therefore requiring several in- and outpatient visits.