Huibert J. Simonsz

GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness

Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG b-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision.

Electronically measured compliance with occlusion therapy for amblyopia is related to visual acuity increase

Abstract Purpose. We set out to determine whether the children who have low compliance (measured electronically) with occlusion therapy for amblyopia are those with insufficient increase of visual acuity. Methods. In 14 newly identified amblyopic children (mean age 4.3±1.9 years), compliance was measured electronically over a period of 1 week, 6 months after the start of occlusion therapy. Compliance was measured with an Occlusion Dose Monitor (ODM). The measurements took place during planned domiciliary visits. The children were diagnosed with anisometropia (n=5), strabismus (n=4) and anisometropia and strabismus (n=5). Compliance was expressed in percentages of the electronically registered time compared with the prescribed occlusion time. Satisfactory acuity increase following 6 months of occlusion therapy was defined on reaching any of the following criteria: acuity increase expressed as a ratio between acuity of the amblyopic eye and acuity of the good eye of more than 0.75, acuity of the amblyopic eye exceeding 0.5 as measured on the E-Chart or Landolt-C, or three LogMAR lines of increase in acuity. Results. Measured compliance averaged 80% in the eight children who had a satisfactory acuity increase and 34% in the six children who had an unsatisfactory visual acuity increase. Children with low acuity increase had statistically significantly lower compliance (P=0.038). Conclusion. The general assumption among orthoptists, that compliance with occlusion therapy for amblyopia is low in children with insufficient acuity increase, has been validated by electronic, objective means.

Amblyopia & Strabismus Questionnaire: design and initial validation

Literature on the benefits of screening and treatment of amblyopia emphasizes the costs of insufficiently treated amblyopic patients who lose their better eye. However, patients with insufficiently treated amblyopia and strabismus who do not lose their better eye only experience a slight decrease in their quality of life, and such patients occur more frequently. We designed and validated a questionnaire for amblyopia and strabismus in order to assess the decrease in quality of life of such patients. Complaints were collected from outpatients and reduced to five domains, pertaining to distance estimation, visual disorientation, problems with social contacts and cosmetic problems, diplopia, and fear of losing the better eye. For these domains 26 questions were formulated that constitute the Amblyopia & Strabismus Questionnaire (A&SQ). The A&SQ, the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) and the Short Form-12 Health Survey (SF-12) were presented to 53 healthy controls, 68 outpatients and a cohort of 174 outpatients born between 1962 and 1972 and treated between 1968 and 1974 for amblyopia and strabismus. The quality of life was best in healthy controls and worst in current outpatients, not only on the SF-12 and the VFQ-25 but also on the A&SQ, demonstrating an acceptable construct validity of the A&SQ. The decrease in the quality of life as measured by the A&SQ was most outspoken in our outpatient group of amblyopia and strabismus patients, less in the cohort that had been treated 30 years previously and least in the healthy controls, demonstrating an acceptable discriminatory validity of the A&SQ.

Rotterdam AMblyopia screening effectiveness study: detection and causes of amblyopia in a large birth cohort.

PURPOSE. The Dutch population-based child health monitoring program includes regular preverbal (age range, 1-24 months) and preschool (age range, 36-72 months) vision screening. This study is on the contribution of an organized vision screening program to the detection of amblyopia. METHODS. A 7-year birth cohort study of 4624 children was started in 1996/1997 in Rotterdam. Vision screening data were obtained from the child screening centers. Treating orthoptists working at the regional ophthalmology departments provided information about diagnosis and treatment. The diagnosis was reviewed by two experts. The parents provided additional information on their childs eye history through written questionnaires and telephone interviews. At age 7 years, the children underwent a final examination by the study orthoptists. RESULTS. Of the 3897 children still living in Rotterdam by 2004, 2964 (76.1%) underwent the final examination. Amblyopia was diagnosed in 100 (3.4%) of these (95% CI, 2.7-4.0). At age 7, 23% had visual acuity >0.3 logMAR. Amblyopia was caused by refractive error (n = 42), strabismus (n = 19), combined-mechanism (n = 30), deprivation (n = 7), or unknown (n = 2). Eighty-three amblyopia cases had been detected before age 7. Amblyopia detection followed positive results in vision screening in 56 children, either preverbal (n = 15) or preschool (n = 41). Twenty-six other amblyopes were self-referred (n = 12, before a first positive screening test), especially strabismic or combined-mechanism amblyopia; data were uncertain for one other positively screened amblyopic child. Amblyopia remained undetected until age 7 due to unsuccessful referral (n = 4, three with visual acuity >0.3 logMAR at age 7) or false-negative screening (n = 13). CONCLUSIONS. Most cases of amblyopia were detected by vision screening with visual acuity measurement. Preverbal screening contributed little to the detection of refractive amblyopia.

Psychological causes of non-compliance with electronically monitored occlusion therapy for amblyopia

Aim: To analyse psychological causes for low compliance with occlusion therapy for amblyopia. Method: In a randomised trial, the effect of an educational programme on electronically measured compliance had been assessed. 149 families who participated in this trial completed a questionnaire based on the Protection Motivation Theory after 8 months of treatment. Families with compliance less than 20% of prescribed occlusion hours were interviewed to better understand their cause for non-compliance. Results: Poor compliance was most strongly associated with a high degree of distress (p<0.001), followed by low perception of vulnerability (p = 0.014), increased stigma (p = 0.017) and logistical problems with treatment (p = 0.044). Of 44 families with electronically measured compliance less than 20%, 28 could be interviewed. The interviews confirmed that lack of knowledge, distress and logistical problems resulted in non-compliance. Conclusion: Poor parental knowledge, distress and difficulties implementing treatment seemed to be associated with non-compliance. For the same domains, the scores were more favourable for families who had received the educational programme than for those who had not.

Electronic recording of occlusion treatment for amblyopia: potential of the new technology

BackgroundApproximately one third of all amblyopic eyes do not reach visual acuity of 20/40 in spite of occlusion therapy. One of the reasons is a lack of adherence to therapy, which, however, could not be quantified in the past. Experience with new devices (occlusion dose monitors, ODMs) for electronic recording of occlusion has recently been reported. The aim of the present study was to evaluate the potential of the ODMs developed in the Netherlands. Various features were tested, including the reliability of the ODM recordings compared to diaries, two ODMs used simultaneously on one patch, the influence of the ambient temperature, and the specificity of the recording pattern for measurements on the eye.MethodsThe ODMs were taped to the outside of the standard occlusion patch and measured the temperature difference between their front and back surfaces. Members of the research group and the families of two patients kept occlusion diaries while using the ODMs. Recorded and written occlusion periods were compared. Measurements were carried out under various conditions: patch with one ODM tightly on the eye or detached (allowing peeping); ODMs taped to various parts of the body; two ODMs simultaneously on one patch; variation of room temperature.ResultsThere was good correspondence between the occlusion times recorded by the ODMs and those from the diaries, as well as between the recordings of two ODMs used simultaneously on one patch. High ambient temperatures (33°C to 37°C) prevented reliable ODM measurements. Measurements on other parts of the body were misclassified with probabilities between P=0.099 and P=0.325 as measurements with the patch tightly on the eye.ConclusionsIn spite of some technical limitations, the ODMs provide a chance for reliable assessment of compliance and therefore objective information on dose–response function for occlusion therapy. This will lead to a more evidence-based treatment for amblyopia.

The history of the treatment of amblyopia.

The Greek word amblyopia means dimness or dullness of vision ( ambly αμβλυσ = dull and ops ωψ = vision) and the condition has been defined in a variety of ways in the literature. Amblyopia is a decrease in visual acuity, usually in one eye. It persists after the correction of the refractive error (i.e., acuity is not improved by glasses) or removal of any pathological obstacle to vision (i.e. cataract) and no organic cause can normally be found. 1 , 2 The general estimate of the prevalence of amblyopia hovers around 3.5%. The reported prevalence in the literature varies considerably, however (0.5–5.3%), due to differences in study design, population and the examination methods used. 2 − 9 In addition, the criteria used to diagnose amblyopia differ at the start of treatment, the end of the treatment and later in life

Quantitative visual fields under binocular viewing conditions in primary and consecutive divergent strabismus.

Abstract · Background: Although there have been a number of studies on the size of the suppression scotoma in divergent strabismus, there have been no reports on the full extent (i.e. size as well as depth) of this scotoma. · Methods: Binocular static perimetry was used to measure suppression scotomas in five patients with primary divergent strabismus and ten patients with consecutive divergent strabismus. Four control subjects were also included in the study. With two modified Friedmann visual field analysers, we measured the visual field of both eyes under monocular and binocular viewing conditions. The objective angle of squint ranged from 3° to 25°. Best corrected visual acuity was at least 0.4, but mostly 1.0 in both eyes. · Results: All subjects had normal visual fields for each eye under monocular viewing conditions. In 12 of the 15 subjects, we found a large area of suppression encompassing the projection of the fixation point as well as that of the fovea in the non-fixating eye under binocular viewing conditions. In 2 of these 12 patients, one with primary and one with consecutive divergent strabismus, the area of suppression was located nasally to the postion of the fovea in the field of the non-fixating eye (nasal hemisuppression). In another two patients with divergent squint combined with vertical deviation, a small fixation-point suppression scotoma was found. The depth of suppression ranged from 3 dB to 16 dB. In one subject only, no suppression was found. · Conclusions: Our findings indicate that the shape of the suppression scotoma is not related to the origin of divergent strabismus or to the angle of squint. Our results also indicate that the critical age for the development of suppression in divergent squint might be up to 14 years.

Mechanical properties and functional importance of pulley bands or faisseaux tendineux

INTRODUCTION Connective tissue bands connect the horizontal rectus muscles at the level of the posterior pole to the orbital wall. These bands, referred to as pulley bands or faisseaux tendineux, purportedly act like springs to keep the rectus muscle bellies in place during eye movement out of the plane of the muscle. We examined the mechanical properties of these bands in human specimens obtained during surgery. In addition, we examined eye motility and stability of rectus muscles in a patient who had no functional pulley bands. METHODS Exenterations were carried out on two patients with sebaceous gland carcinoma. Pulley bands were identified and force-elongation behavior was examined with a forceps and a force gauge. Stability of rectus muscles was examined in a patient with severe Crouzons syndrome by orbital CT scans and during surgery under local, eye drop, anesthesia. RESULTS The pulley bands showed leash-like mechanical behavior: they were slack over approximately 10mm and became taut when stretched further. In the patient with Crouzons syndrome, both CT and observation of the muscle during surgery showed little sideways displacement of the muscle bellies in eye movement out of the plane of the muscle, despite the lack of functional pulley bands. DISCUSSION The leash-like mechanical behavior of the pulley bands seems unsuited for stabilization of the muscle bellies. The patient with Crouzons syndrome had relatively good eye motility and stable rectus muscle paths despite the lack of functional pulley bands.

Inventory of current EU paediatric vision and hearing screening programmes

Objective To examine the diversity in paediatric vision and hearing screening programmes in Europe. Methods Themes for comparison of screening programmes derived from literature were used to compile three questionnaires on vision, hearing, and public health screening. Tests used, professions involved, age, and frequency of testing seem to influence sensitivity, specificity, and costs most. Questionnaires were sent to ophthalmologists, orthoptists, otolaryngologists, and audiologists involved in paediatric screening in all EU full-member, candidate, and associate states. Answers were cross-checked. Results Thirty-nine countries participated; 35 have a vision screening programme, 33 a nation-wide neonatal hearing screening programme. Visual acuity (VA) is measured in 35 countries, in 71% of these more than once. First measurement of VA varies from three to seven years of age, but is usually before age five. At age three and four, picture charts, including Lea Hyvarinen, are used most; in children over four, Tumbling-E and Snellen. As first hearing screening test, otoacoustic emission is used most in healthy neonates, and auditory brainstem response in premature newborns. The majority of hearing testing programmes are staged; children are referred after 1–4 abnormal tests. Vision screening is performed mostly by paediatricians, ophthalmologists, or nurses. Funding is mostly by health insurance or state. Coverage was reported as >95% in half of countries, but reporting was often not first-hand. Conclusion Largest differences were found in VA charts used (12), professions involved in vision screening (10), number of hearing screening tests before referral (1–4), and funding sources (8).