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PURPOSE: Perimetry is a both demanding and strenuous examination method that is often accompanied by signs of fatigue, leading to false responses and thus incorrect results. Therefore, it is essential to monitor the response quality. The purpose of this study was to evaluate the response time (RT) and its variability (RTV) as quality indicators during static automated perimetry. METHODS: Size III Goldmann stimuli (25.7') were shown with the OCTOPUS 900 perimeter in four visual field locations with 13 different stimulus luminance levels (0.04-160 cd/m2). An increased rate of false-positive and false-negative catch trials (25% each) served to monitor the response quality simultaneously together with response time recording. Data evaluation was divided into global and individual analysis. For global analysis, the agreement indices (AI, agreement between time periods with an increased number of false responses to catch trials and time periods with pathological response to time-based values set into relation to time periods in which only one of the two criteria was considered pathological) and for individual analysis, the Spearman correlation coefficients were calculated. Ophthalmologically normal subjects with a visual acuity ≥ 0.8, and a maximum spherical/cylindrical ametropia of ± 8.00/2.50 dpt were included. RESULTS: Forty-eight subjects (18 males, 30 females, age 22-78 years) were examined. The total number of false responses to catch trials was (median/maximum): 6/82. RT and RTV were compared to the occurrence of incorrect responses to catch trials. The resulting individual Spearman correlation coefficients (median/maximum) were for RT: ρRT = 0.05/0.35 and for RTV: ρRTV = 0.27/0.61. The global analysis of the RTV showed agreement indices (median/maximum) of AIRTV = 0.14/0.47. CONCLUSIONS: According to this study, an increased portion of catch trials is suitable as a verification tool for possible response quality indicators. The RTV is a promising parameter for indicating the response quality.
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Testes de Campo Visual , Campos Visuais , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação , Reprodutibilidade dos Testes , Acuidade Visual , Testes de Campo Visual/métodos , Adulto JovemRESUMO
BACKGROUND: The purpose of this study is to introduce a method for benchmarking intraocular lenses during driving activities under highly standardized conditions, specifically with regard to visual acuity (VA) and contrast sensitivity (CS). Therefore, patients with intraocular lens (IOL) implants ICB00 (Tecnis Eyhance, Johnson & Johnson, Santa Ana, CA, USA) vs. CNA0T0 (Clareon, Alcon Laboratories Inc., Fort Worth, TX, USA) were examined clinically and in a nighttime driving simulator. PATIENTS AND METHODS: Clinical tests for high (HCVA), low contrast (LCVA) distant VA, and mesopic CS were conducted in subjects at least 2 months after binocular IOL surgery (inclusion criteria: VA > 20/25, ophthalmologically normal, except cataract surgery). All patients completed a straight driving simulator route. VA, CS, and halo size were assessed binocularly during nighttime driving using eight-position Landolt Cs in four different locations and two (far and intermediate) distances. RESULTS: Results are presented as median/interquartile range: ICB00 data (corresponding CNA0T0 data are shown in brackets): 5 (6) subjects, aged 69.6/8.3 (71.1/13.0) years were enrolled. Clinical tests: logMAR HCVA 0.11/0.39 (0.00/0.51), logMAR LCVA 0.78/0.52 (0.80/0.54); logCS without glare 0.50/0.31 (0.30/0.65), logCS with glare 0.20/0.15 (0.20/0.5). Nighttime driving simulator: logMAR VA thresholds for right roadside, dashboard, navigation screen, and interior rear-view mirror were 0.50/0.06 (0.57/0.22), 0.81/0.07 (0.91/0.14), 0.80/0.17 (0.92/0.27), 0.50/0.11 (0.63/0.26); logCS thresholds were1.53/0.67 (1.00/0.81), 0.82/0.11 (0.61/0.19), 0.71/0.14 (0.50/0.15), 0.87/0.07 (0.81/0.11). Halo size: 5.40°/0.89° (5.88°/2.00°). CONCLUSIONS: Within a nighttime driving simulator environment, ICB00 exceeded CNA0T0 in median logMAR (VA) and logCS by 0.1 log unit at intermediate distances (dashboard, navigation screen). The clinical test for far and remote distances did not show a difference. These results confirm benefits of monofocal IOLs with enhanced optical properties for intermediate distances compared to conventional monofocal lenses within the target medium distance ranges.
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Lentes Intraoculares , Facoemulsificação , Benchmarking , Sensibilidades de Contraste , Humanos , Implante de Lente Intraocular , Desenho de Prótese , Acuidade VisualRESUMO
PURPOSE: On-road testing is considered the standard for assessment of driving performance; however, it lacks standardization. In contrast, driving simulators provide controlled experimental settings in a virtual reality environment. This study compares both testing conditions in patients with binocular visual field defects due to bilateral glaucomatous optic neuropathy or due to retro-chiasmal visual pathway lesions. METHODS: Ten glaucoma patients (PG), ten patients with homonymous visual field defects (PH), and 20 age- and gender-matched ophthalmologically normal control subjects (CG and CH, respectively) participated in a 40-min on-road driving task using a dual brake vehicle. A subset of this sample (8 PG, 8 PH, 8 CG, and 7 CH) underwent a subsequent driving simulator test of similar duration. For both settings, pass/fail rates were assessed by a masked driving instructor. RESULTS: For on-road driving, hemianopia patients (PH) and glaucoma patients (PG) showed worse performance than their controls (CH and CG groups): PH 40%, CH 30%, PG 60%, CG 0%, failure rate. Similar results were obtained for the driving simulator test: PH 50%, CH 29%, PG 38%, CG 0%, failure rate. Twenty-four out of 31 participants (77%) showed concordant results with regard to pass/fail under both test conditions (p > 0.05; McNemar test). CONCLUSIONS: Driving simulator testing leads to results comparable to on-road driving, in terms of pass/fail rates in subjects with binocular (glaucomatous or retro-chiasmal lesion-induced) visual field defects. Driving simulator testing seems to be a well-standardized method, appropriate for assessment of driving performance in individuals with binocular visual field loss.
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Condução de Veículo , Simulação por Computador , Hemianopsia/reabilitação , Visão Ocular , Campos Visuais/fisiologia , Adulto , Idoso , Feminino , Hemianopsia/diagnóstico , Hemianopsia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Testes de Campo VisualRESUMO
The assessment of visual field findings is fundamental in neuro-ophthalmological functional diagnostics: By means of perimetry, functional and topodiagnostic considerations in case of unexplained visual loss or suspected lesions of the visual pathway are possible in a non-invasive manner. Repeated examinations allow for functional follow-up of a disease and judgement on the efficacy of a therapeutic procedure. This paper is intended to convey the basics of visual field examination and diagnostics. The focus is on the value of perimetry in neuro-ophthalmological functional diagnostics. Both kinetic and static perimetric methods are addressed. In addition, common examination grids and strategies, as well as interpretation of perimetric recordings and indices for the evaluation of progression analysis, are compared. Scotoma classification and the topodiagnostical relevance of visual field defects are discussed, taking into account quality parameters and plausibility controls.
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Oftalmologia , Transtornos da Visão/diagnóstico , Testes de Campo Visual , Humanos , Escotoma , Campos VisuaisRESUMO
BACKGROUND AND OBJECTIVE: Erythropoietin (EPO) is a candidate neuroprotective drug. We assessed its long-term safety and efficacy as an adjunct to methylprednisolone in patients with optic neuritis and focused on conversions to multiple sclerosis (MS). METHODS: The TONE trial randomized 108 patients with acute optic neuritis but without previously known MS to either 33,000 IU EPO or placebo in conjunction with 1,000 mg methylprednisolone daily for 3 days. After reaching the primary end point at 6 months, we conducted an open-label follow-up 2 years after randomization. RESULTS: The follow-up was attended by 83 of 103 initially analyzed patients (81%). There were no previously unreported adverse events. The adjusted treatment difference of peripapillary retinal nerve fiber layer atrophy in relation to the fellow eye at baseline was 1.27 µm (95% CI -6.45 to 8.98, p = 0.74). The adjusted treatment difference in low-contrast letter acuity was 2.87 on the 2.5% Sloan chart score (95% CI -7.92 to 13.65). Vision-related quality of life was similar in both treatment arms (National Eye Institute Visual Functioning Questionnaire median score [IQR]: 94.0 [88.0 to 96.9] in the EPO and 93.4 [89.5 to 97.4] in the placebo group). The rate of multiple sclerosis-free survival was 38% in the placebo and 53% in the EPO group (hazard ratio: 1.67, 95% CI 0.96 to 2.88, p = 0.068). DISCUSSION: In line with the results at 6 months, we found neither structural nor functional benefits in the visual system of patients with optic neuritis as a clinically isolated syndrome, 2 years after EPO administration. Although there were fewer early conversions to MS in the EPO group, the difference across the 2-year window was not statistically significant. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute optic neuritis, EPO as an adjunct to methylprednisolone is well tolerated and does not improve long-term visual outcomes. TRIAL REGISTRATION INFORMATION: The trial was preregistered before commencement at clinicaltrials.gov (NCT01962571).
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Eritropoetina , Esclerose Múltipla , Neurite Óptica , Humanos , Seguimentos , Qualidade de Vida , Acuidade Visual , Eritropoetina/uso terapêutico , Metilprednisolona/uso terapêutico , Esclerose Múltipla/tratamento farmacológicoRESUMO
Purpose: (i) To assess how well contrast sensitivity (CS) predicts night-time hazard detection distance (a key component of night driving ability), in normally sighted older drivers, relative to a conventional measure of high contrast visual acuity (VA); (ii) To evaluate whether CS can be accurately quantified within a night driving simulator. Materials and Methods: Participants were 15 (five female) ophthalmologically healthy adults, aged 55-81 years. CS was measured in a driving simulator using Landolt Cs, presented under static or dynamic driving conditions, and with or without glare. In the dynamic driving conditions, the participant was asked to simultaneously maintain a (virtual) speed of 60 km/h on a country road. In the with glare conditions, two calibrated LED arrays, moved by cable robots, simulated the trajectories and luminance characteristics of the (low beam) headlights of an approaching car. For comparison, CS was also measured clinically (with and without glare) using a Optovist I instrument (Vistec Inc., Olching, Germany). Visual acuity (VA) thresholds were also assessed at high and low contrast using the Freiburg Visual Acuity Test (FrACT) under photopic conditions. As a measure of driving performance, median hazard detection distance (MHDD) was computed, in meters, across three kinds of simulated obstacles of varying contrast. Results: Contrast sensitivity and low contrast VA were both significantly associated with driving performance (both P < 0.01), whereas conventional high contrast acuity was not (P = 0.10). There was good correlation (P < 0.01) between CS measured in the driving simulator and a conventional clinical instrument (Optovist I). As expected, CS was shown to decrease in the presence of glare, in dynamic driving conditions, and as a function of age (all P < 0.01). Conclusion: Contrast sensitivity and low contrast VA predict night-time hazard detection ability in a manner that conventional high contrast VA does not. Either may therefore provide a useful metric for assessing fitness to drive at night, particularly in older individuals. CS measurements can be made within a driving simulator, and the data are in good agreement with conventional clinical methods (Optovist I).
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Purpose: To evaluate the relationship between intraocular straylight perception and: (i) contrast sensitivity (CS), (ii) halo size, and (iii) hazard recognition distance, in the presence and absence of glare. Subjects and methods: Participants were 15 (5 female) ophthalmologically healthy adults, aged 54.6-80.6 (median: 67.2) years. Intraocular straylight (log s) was measured using a straylight meter (C-Quant; Oculus GmbH, Wetzlar, Germany). CS with glare was measured clinically using the Optovist I device (Vistec Inc., Olching, Germany) and also within a driving simulator using Landolt Cs. These were presented under both static or dynamic viewing conditions, and either with or without glare. Hazard detection distance was measured for simulated obstacles of varying contrast. For this, the participant was required to maintain a speed of 60 km/h within a custom-built nighttime driving simulator. Glare was simulated by LED arrays, moved by cable robots to mimic an oncoming car's headlights. Halo size ("halometry") was measured by moving Landolt Cs outward originating from the center of a static glare source. The outcome measure from "halometry" was the radius of the halo (angular extent, in degrees visual angle). Results: The correlation between intraocular straylight perception, log s, and hazard recognition distance under glare was poor for the low contrast obstacles (leading/subdominant eye: r = 0.27/r = 0.34). Conversely, log CS measured with glare strongly predicted hazard recognition distances under glare. This was true both when log CS was measured using a clinical device (Optovist I: r = 0.93) and within the driving simulator, under static (r = 0.69) and dynamic (r = 0.61) conditions, and also with "halometry" (r = 0.70). Glare reduced log CS and hazard recognition distance for almost all visual function parameters. Conclusion: Intraocular straylight was a poor predictor of visual function and driving performance within this experiment. Conversely, CS was a strong predictor of both hazard recognition and halo extent. The presence of glare and motion lead to a degradation of CS in a driving simulator. Future studies are necessary to evaluate the effectiveness of all above-mentioned vision-related parameters for predicting fitness to drive under real-life conditions.
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The video retinoscope presented here makes it possible for the first time to interactively demonstrate, discuss, evaluate and document optical phenomena with the aid of an integrated touch display. The precision in relation to the objective refraction results between the conventional retinoscope (CS) and video retinoscope (VS) is comparable (pâ¯= 0.093, Wilcoxon test). On the basis of questionnaires using visual analogue scales (0â¯= very unfavorable/10â¯= very favorable; subsequently the median/interquartile range is given) during a pilot study, 12 test persons rated the CS (VS) with respect to the feasibility of continuous light band movements with 6.9/1.3 (6.0/4.2) and the ease of use with 8.1/2.1 (8.9/1.6) out of a maximum of 10 points each and thus both retinoscopes as equivalent. In terms of weight, the subjects favored the conventional retinoscope with a rating of 8.7/2.2 (4.0/4.8).
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Retinoscópios , Humanos , Projetos PilotoRESUMO
SIGNIFICANCE: Horizontal visual field extension was assessed for red and white stimuli in subjects with protanopia using semi-automated kinetic perimetry. In contrast to a conventional anomaloscope, the "red/white dissociation ratio" (RWR) allows to describe protanopia numerically. For the majority of subjects with protanopia a restriction for faint red stimuli was found. PURPOSE: Comparing the horizontal visual field extensions for red and white stimuli in subjects with protanopia and those with normal trichromacy and assessing the related intra-subject intra-session repeatability. METHODS: The subjects were divided into groups with protanopia and with normal trichromacy, based on color vision testing (HMC anomaloscope, Oculus, Wetzlar/FRG). Two stimulus characteristics, III4e and III1e, according to the Goldmann-classification, were presented with semi-automated kinetic perimetry (Octopus 900 perimeter, Haag-Streit, Köniz/CH). They moved along the horizontal meridian, with an angular velocity of 3°/s towards the visual field center, starting from either the temporal or nasal periphery. If necessary, a 20° nasal fixation point offset was chosen to capture the temporal periphery of the visual field. For each condition the red/white dissociation ratio (RWR); Pat Appl. DPMA DRN 43200082D) between the extent of the isopter for red (RG610, Schott, Mainz/ FRG) and white stimuli along the horizontal meridian was determined. RESULTS: All data are listed as median/interquartile range: Five males with protanopia (age 22.1/4.5 years) and six males with normal trichromacy (control group, age 30.5/15.2 years) were enrolled. The RWR is listed for the right eye, as no clinically relevant difference between right and left eye occurred. Protanopes' RWR for mark III4e (in brackets: control group) was 0.941/0.013 (0.977/0.019) and for mark III1e 0.496/0.062 (0.805/0.051), respectively. CONCLUSIONS: In this exploratory "proof-of-concept study" red/white dissociation ratio perimetry is introduced as a novel technique aiming at assessing and quantifying the severity of protanopia. Further effort is needed to understand the magnitude of the observed red-/white dissociation and to extend this methodology to a wider age range of the sample and to anomalous trichromacies (protanomalia) with varying magnitude.
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Percepção de Cores/fisiologia , Defeitos da Visão Cromática/diagnóstico , Adolescente , Adulto , Humanos , Masculino , Estimulação Luminosa , Tempo de Reação , Testes de Campo Visual , Adulto JovemRESUMO
BACKGROUND: The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial. METHODS: This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33â000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571. FINDINGS: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 µm (SD 14·91) in the erythropoietin group and 14·65 µm (15·60) in the placebo group (adjusted mean treatment difference 1·02 µm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae. INTERPRETATION: Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis. FUNDING: German Federal Ministry of Education and Research (BMBF).
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Eritropoetina , Neurite Óptica , Animais , Método Duplo-Cego , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Humanos , Neurite Óptica/tratamento farmacológico , Estudos Prospectivos , Resultado do TratamentoRESUMO
The auditory system consists of the ear located in the periphery, in which a conversion of the sound into an electrical signal takes place, and neurons, which perform central processing based on action potentials. The most important anatomical and functional features of the auditory system are explained. For this purpose, a selective literature search was carried out in the databases PubMed (also in the Europe PubMed Central), Psychline, Google Scholar, Cochrane Library and Web of Science. Additional information was obtained from relevant books or websites in the fields of (neuro)anatomy, (neuro)physiology, (neuro)ophthalmology and (neuro)otology, among others with the keywords Hörbahn, auditory system, auditory pathway, receptors, spatial hearing and auditory cognition.
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Vias Auditivas , Audição , PubMedRESUMO
Humans receive information from their environment via the visual and auditory systems. This information protects us from dangers and guarantees vital actions, such as social interaction, locomotion, work processes and nutrition. The most important anatomical and functional features of these two sensory systems are compared and elucidated with respect to their interaction/functional complementarity. For this purpose, a selective literature search was carried out in the databases PubMed (also in the Europe PubMed Central), Psychline, Google Scholar, Cochrane Library and Web of Science. Additional information was obtained from relevant books and websites in the fields of (neuro)anatomy, (neuro)physiology, (neuro)ophthalmology and (neuro)otology. Search terms were Hörbahn, Sehbahn, visual system, auditory system, visual pathway, auditory pathway, receptors, spatial hearing, spatial cognition, auditory cognition and visual cognition.
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Vias Auditivas , Bases de Dados Factuais , Humanos , PubMedRESUMO
Humans receive information from their environment mainly via the visual system. Signals from the photoreceptors of the retina via bipolar and ganglion cells are projected onto specific neuronal subpopulations in the lateral geniculate body and from there are forwarded to appropriate layers of the primary visual cortex. The most important anatomical and functional features of the visual system are explained. For this purpose, a selective literature search was carried out in the databases PubMed (also in Europe PubMed Central), Psychline, Google Scholar, Cochrane Library and Web of Science as well as additional information in relevant books or websites in the fields of (neuro)anatomy, (neuro)physiology, (neuro)ophthalmology and (neuro)otology, among others with the search terms Sehbahn, visual system, visual pathway, receptors, spatial cognition and visual cognition.
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Córtex Visual , Vias Visuais , Corpos Geniculados , Humanos , Células Fotorreceptoras , RetinaRESUMO
BACKGROUND: The purpose of this project is to apply and optimize a conventional streak retinoscope connected to a smartphone in order to demonstrate and record retinoscopic techniques, related phenomena, typical examination errors in a standardized environment and to use this set-up to produce instructional video clips. The videos enhance and improve the trainer-trainee interaction by instantly visualizing the optical phenomena on the integrated monitor of the retinoscope. METHODS: A smartphone (iPhone 6, Apple, Cupertino, CA, USA) is reversibly connected to a Beta 200 streak retinoscope (HEINE, Herrsching, Germany) via a coupling plate. This allows visualization of the optical phenomena on the screen of a smartphone, which can also be used for recording. To stabilize the recording conditions, the battery handle of the retinoscope is connected to a 3-axis gimbal (Zhiyun Crane Plus, Zhiyun, Guilin, China). In this way the examination unit can be rotated around all axes without any relevant changes in distance. A software-based post-processing (Adobe Premiere Pro CC 2017, Adobe Systems Software Ireland Limited, Dublin. Ireland) of the video sequences almost completely eliminates motion artefacts. RESULTS: With the aforementioned experimental set-up, the following optical phenomena have so far been documented as videos, which are available online: flashing point, with-movement and against-movement, scissors phenomenon, cataract, astigmatic ametropia and refraction scotoma. CONCLUSION: For the first time smartphone video retinoscopy allows optical phenomena to be presented to the examiner (trainee) and trainer at the same time and to produce realistic instructional videos of high quality with comparatively little effort.
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Retinoscópios , Smartphone , Artefatos , Alemanha , Retinoscopia , Gravação em VídeoRESUMO
BACKGROUND: All over the world, refractive errors are among the most frequently occuring treatable distur - bances of visual function. Ametropias have a prevalence of nearly 70% among adults in Germany and are thus of great epidemiologic and socio-economic relevance. METHODS: In the light of their own clinical experience, the authors review pertinent articles retrieved by a selective literature search employing the terms "ametropia, "anisometropia," "refraction," "visual acuity," and epidemiology." RESULTS: In 2011, only 31% of persons over age 16 in Germany did not use any kind of visual aid; 63.4% wore eyeglasses and 5.3% wore contact lenses. Refractive errors were the most common reason for consulting an ophthalmologist, accounting for 21.1% of all outpatient visits. A pinhole aperture (stenopeic slit) is a suitable instrument for the basic diagnostic evaluation of impaired visual function due to optical factors. Spherical refractive errors (myopia and hyperopia), cylindrical refractive errors (astigmatism), unequal refractive errors in the two eyes (anisometropia), and the typical optical disturbance of old age (presbyopia) cause specific functional limitations and can be detected by a physician who does not need to be an ophthalmologist. CONCLUSION: Simple functional tests can be used in everyday clinical practice to determine quickly, easily, and safely whether the patient is suffering from a benign and easily correctable type of visual impairment, or whether there are other, more serious underlying causes.