INTRODUÇÃO: A degeneração macular relacionada à idade (DMRI) é a principal causa de perda de visão irreversível e cegueira mundialmente. A perda da visão central interfere nas atividades de vida diária, como o reconhecimento facial, leitura e escrita, direção de veículos automotores e em atividades funcionais e de lazer. Esta perda de visão relaciona-se também com o desencadeamento de quadros de ansiedade e depressão. Este estudo avaliou a qualidade de vida visual em pacientes com degeneração macular relacionada à idade neovascular por meio do questionário de função visual 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). MÉTODOS: Estudo clínico observacional de 87 pacientes de ambos os sexos, com idade >= 50 anos e com o diagnóstico de DMRI neovascular unilateral ou bilateral. Todos os pacientes responderam ao questionário de função visual NEI VFQ- 25 no final do tratamento em regime Tratar e Estender ou PrONTO, com as drogas antiangiogênicas ranibizumabe ou aflibercepte. RESULTADOS: A idade dos pacientes foi a variável que menos influenciou a qualidade de vida visual dos pacientes. O gênero teve uma influência um pouco maior que a idade, no entanto, a lateralidade da doença demonstrou maior influência na qualidade de vida visual, comparada ao gênero e idade dos pacientes e foi significante para oito dos 12 domínios do questionário de função visual NEI VFQ-25. Os pacientes com acometimento bilateral tiveram pontuações mais baixas que os com doença unilateral em todos os domínios do questionário. A acuidade visual corrigida (AVc) foi a variável que apresentou o maior número de domínios com valores significantes e, portanto, foi a variável que mais se correlacionou com a qualidade de vida visual. A AVc do melhor olho (MO) foi significante para a maioria dos domínios relacionados com a visão, ao contrário do pior olho (PO) que não foi significante para nenhum domínio do questionário. CONCLUSÃO: Todas as variáveis testadas afetaram a qualidade de vida visual dos pacientes, onde a lateralidade teve uma maior influência, seguida pela idade e sexo dos pacientes. Na tomada de decisão para o tratamento de pacientes com DMRI neovascular, pelo menos para esta população, a manutenção da AVc do MO >= 0,5 (escala decimal de Snellen) foi essencial para a manutenção de boa qualidade de vida visual, independente da AVc do PO, que não teve efeito significante em nenhum domínio do questionário de função visual NEI VFQ-25 / INTRODUCTION: The neovascular age-related macular degeneration (AMD) is the main cause of irreversible loss of vision and blindness woldwide. The loss of the central visual field interferes on daily activities such as facial recognition, reading and writing, driving as well as functional and leasure activities. This loss of vision may also increases anxiety and depression for this age group. To evaluate the impact of neovascular AMD on the visual quality of life of patients using the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25). METHODS: This was an observational clinical, with 87 patients of both genders, with age >= 50 years and a clinical diagnosis of unilateral or bilateral neovascular age related macular degeneration. All patients answered the visual functioning questionaire NEI VFQ-25 at the end of the treatment with the Treat and Extend or PrONTO regimen using antiangiogenic drugs ranibizumab or aflibercept. RESULTS: The age of patients was the variable with the lower influence on the quality of life of the patients. Gender had an influence slightly higher then the age, however, the laterality of the disease had the highest influence on the quality of life, compared with age and gender, and was significant for 8 of the 12 domains of the visual functioning questionaire NEI VFQ-25. The patients with bilateral age-related macular degeneration had lower scores than patients with unilateral disease for all domains of the questionaire. Visual acuity was the variable with the higher number of domains with significant values, and therefore the variable with the higher correlation with the quality of life. The visual acuity of the best eye (BE) was significant for most of the vision related domains, in opposition the the visual acuity of the worst eye (WE) which was not significant for any domain of the questionaire. CONCLUSION: All variables tested affected the visual quality of life, where the laterality of the disease had the highest influence, followed by the age and gender of the patients. The decision process for the treatment of patients with neovascular AMD, at least for this population, keeping the visual acuity of the BE >= 0,5 (Snellen\'s decimal scale) was essential to maintain a long term quality of life, despite the visual acuity of the worst eye, that had no significant effect on any domain of the visual functioning quaestionaire NEI VFQ-25

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Localisé entre l'Epithélium Pigmentaire Rétinien (EPR) et les segments externes des photorécepteurs, l'espace sous-rétinien est une zone immunosuppressive ; régulée par des signaux comme la thrombospondine-1 (TSP-1) ou Fas Ligand (FasL), qui empêchent l'accumulation des phagocytes mononucléés (PMs), en particulier des monocytes inflammatoires. La Dégénérescence Maculaire Liée à l'Age (DMLA) est associée à une rupture de l'immunosuppression de cet espace, et s'accompagne d'une accumulation de PMs ; causant la mort des photorécepteurs, la dédifférenciation de l'EPR et une néovascularisation pathologique. Des études d'associations génétiques ont établi un lien entre la DMLA et un haplotype qui affecte le locus 10q26, qui contient trois gènes : PLEKHA1, ARMS2 et HTRA1. L'haplotype est associé à une augmentation de la transcription de HTRA1 dans les lymphocytes ou les cellules de l'EPR. HTRA1 code pour une sérine protéase qui a une multitude de substrats ; mais le mécanisme par lequel elle pourrait être impliquée dans la pathogenèse de la DMLA reste inconnu. TSP-1 est une glycoprotéine exprimée par l'EPR, les macrophages résidents et inflammatoires. Le domaine C-terminal de TSP-1 contient deux séquences VVM qui peuvent chacune interagir avec un récepteur CD47. Dans cette étude, nous montrons que HTRA1 clive TSP-1 et inhibe l'élimination des PMs régulée par l'interaction entre TSP-1 et CD47 à l'état physiologique, in vitro et in vivo. L'activation pharmacologique de CD47 nous a permis d'annuler les effets pro-inflammatoires de HTRA1 et pourrait représenter un espoir thérapeutique pour le contrôle de la progression de la DMLA chez les patients porteurs de l'haplotype à risque. / Localized between the Retinal Pigment Epithelium (RPE) and the photoreceptors outer segments, the subretinal space is an immunosuppressive zone, mediated by signals such as Thrombospondin-1 (TSP-1), Fas Ligand (FasL) that prevent the accumulation of Mononuclear Phagocytes (MPs) and in particular pathogenic inflammatory monocytes. Age related Macular Degeneration (AMD) is associated with a breakdown of this immunosuppressivity and an accumulation of MPs, which causes photoreceptor degeneration, RPE dedifferentiation and pathological neovascularization. Genome association studies showed a strong link between AMD and a relatively common haplotype of 10q26 locus that contains the PLEKHA1, ARMS2 and HTRA1 genes. The disease haplotype is associated with increased HTRA1 transcription in cell types such as lymphocytes and RPE cells. HTRA1 is a serine protease with a number of substrates, but the mechanism by which it might be involved in AMD pathogenesis is unknown. TSP-1 is a glycoprotein expressed by RPE, resident macrophages and inflammatory macrophages. The C-terminal domain of TSP-1 contains two VVM sequences that can each interact with a CD47 receptor. We show that HTRA1 induced subretinal MP accumulation is dependent on TSP-1 deactivation in an RPE/Mo co-culture model and in a laser induced inflammation model in vivo. This pathogenic effect of HTRA1 was reversible by synthetic CD47 agonists. Our study reveals a comprehensive mechanism how the risk-allele 10q26 participates in the pathogenesis of AMD and opens new therapeutic avenues to restore subretinal immunosuppressivity and inhibit the inflammation-dependent neurodegeneration.

The extent to which cortical maps may reorganize in adult humans is a significant and topical debate in visual neuroscience. Though there are conflicting findings, evidence from humans and animals indicates that the topography of the visual cortex may change after retinal deafferentation. Remarkably, this reorganization seems to be possible in adults, whose brains are less amenable to plastic change. If adult visual reorganization is legitimate, an understanding of its causes and consequences could be profound considering the millions suffering from age-related visual disorders. This dissertation explores whether visual training may yield a reorganization of sensory maps in the adult visual cortex. It describes research in which patients, diagnosed with age-related macular degeneration (AMD), underwent visual rehabilitation therapy. Functional brain scans and behavioral tests were conducted pre and post training. These interventions generated valuable knowledge regarding whether "reorganized" activity is a true rewiring of feed forward cortical processes or an artifact of attentional feedback. The rehabilitation training produced demonstrable differences in activation patterns along the primary visual cortex (V1), but sparse improvement in the behavioral tests. In contrast, there was significant improvement in fixation tests which assessed oculomotor control. These results suggest that the nature of reorganized activity has more to do with attentional mechanisms than feed forward reorganization. Future investigations could benefit from examining the brain sites that govern visual attention in the frontal and parietal cortices. These areas may have more to do with visual adaptation in AMD patients than V1.

Age related macular degeneration (AMD) is a public health concern in an aging society. The retinal pigment epithelium (RPE) layer of the eye is a principal site of pathogenesis for AMD. Morphological characteristics of the cells in the RPE layer can be used to discriminate age and disease status of individuals. In this thesis three genotypes of mice of various ages are used to study the predictive abilities of these characteristics. The disease state is represented by two mutant genotypes and the healthy state by the wild-type. Classification analysis is applied to the RPE morphology from the different spatial regions of the RPE layer. Variable reduction is accomplished by principal component analysis (PCA) and classification analysis by the k-nearest neighbor (k-NN) algorithm. In this way the differential ability of the spatial regions to predict age and disease status by cellular variables is explored.

Darbo uždaviniai: 1. Nustatyti pradinės AGDD paplitimą vidutinio amžiaus (40 – 64 metų) pacientų, sergančių IŠL grupėje bei atsitiktinėje to paties amžiaus Kauno miesto gyventojų imtyje. 2. Palyginti pacientų, sergančių tik IŠL ir IŠL bei pradinės AGDD klinikinius duomenis. 3. Nustatyti MMP-2 (-735 C/T), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T) genotipų dažnį bei genotipų derinių įtaką AGDD susiformavimui. 4. Nustatyti MMP-2 (-735 C/T), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T) genotipų dažnį esant minkštoms ir kietoms drūzoms, sergant AGDD. 5. Nustatyti MMP-2 (-735 C/T), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T) genotipų dažnį bei genotipų derinių įtaką AGDD ir IŠL drauge bei tik IŠL pasireiškimui. 6. Nustatyti funkcinio kontrastinio jautrumo tyrimo rodmenis pacientams, sergantiems pradine lengva ir pradine vidutine AGDD bei spalvų juslės pokyčius sergantiems pradine AGDD, ir oftalmologiškai sveikiems pacientams. / The goals were as follows: 1. To determine the prevalence of AMD in patients with IHD and compare with the prevalence in a random sample of Kaunas population (at 40-64 yrs old). 2. To compare the main clinical characteristics of the patients exhibiting early AMD and IHD together with the patients with IHD alone. 3. To determine the frequency of the genotypes of the matrix metalloproteinases (MMP-2 (-735 C/T), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T)), and genotype combinations that have an influence on the development of early AMD. 4. To determine the frequency of the genotypes of the matrix metallo¬proteinases (MMP-2 (-735 C/T), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T)), in early AMD patients with soft or hard drusen. 5. To determine the frequency of the genotypes of the matrix metallo¬proteinases (MMP-2 (-735 C/T), MMP-2 (-1306 C/T), MMP-3 (-1171 5A/6A), MMP-9 (-1562 C/T)), and the influence of genotype combi¬na¬tions on the development of AMD and IHD together, and only on IHD development. 6. To determine the results of functional acuity contrast sensitivity test in patients with early mild and early intermediate AMD, and color contrast sensitivity in patients with AMD, and in ophthalmologically healthy patients.

Didėjant vyresnių žmonių populiacijai amžinė geltonosios dėmės degeneracija (AGDD) yra vis dažnesnė vyresnio nei 50 metų amžiaus žmonių negrįžtamo regos netekimo priežastis. AGDD prevencinės priemonės bei gydymo galimybės ribotos, nes ligos etiopatogenezė iki šiol nėra visiškai aiški. Disertacinio darbo metu įvertintos AGDD ir išeminės širdies ligos (IŠL) sąsajos, atsižvelgiant į vainikinių arterijų aterosklerozinius pažeidimus. Pirmą kartą analizuota SCARB1 rs5888 C/T genotipų įtaka AGDD ir IŠL pasireiškimui. Tyrimo rezultatai parodė, kad AGDD ir IŠL, kai vainikinėse arterijose yra aterosklerozinių pažeidimų (IŠLath+), sieja bendri, šių ligų pasireiškimo galimybę didinantys, klinikiniai veiksniai ir oksidacinis stresas. Nustatytas „apsauginis“ SCARB1 rs5888 T/T genotipas, mažinantis AGDD ir IŠLath+, bei „rizikingas“ SCARB1 rs5888 C/T genotipas, didinantis AGDD+IŠLath+ galimybę. Pritaikius matematinės morfologijos metodus, nustatyta, jog sergantiems vėlyvąja AGDD SCARB1 rs5888 „rizikingas“ genetinis variantas susijęs su didesniu centrinės tinklainės dalies pažeidimo plotu. Bendrų AGDD ir IŠL patogenezinių grandžių tyrimas suteikia naujos informacijos apie AGDD etiologiją, patogenezę ir galbūt pasitarnaus efektyvaus gydymo bei prevencijos krypčių kūrimui. Tyrimo metu taikyti morfometriniai geltonosios dėmės pažaidos ploto matavimai gali būti naudojami gydytojų-oftalmologų klinikinėje praktikoje, siekiant tiksliau įvertinti centrinės tinklainės dalies pokyčius dinamikoje... [toliau žr. visą tekstą] / Age-related macular degeneration (ARMD) is the commonest cause of blindness among persons over the age of 50 and its prevalence is likely to increase as a consequence of population ageing. ARMD is a disorder of unknown cause and pathogenesis, therefore current options for ARMD prevention and treatment are limited. In the recent study the associations between ARMD and CAD, according the angiographic findings of atherosclerosis in the coronary arteries, were analyzed. The oxidative stress impact and clinical factors determining susceptibility to ARMD and CADath+, separately and common susceptibility factors for both diseases prediction were ascertained. Analysis of novel genetic biomarker, the rs5888 variant of SCARB1 gene, identified the „protective“ SCARB1 rs5888 TT genotype, associated with the lower risk of ARMD and CADath+, and a „risk-determining“ CT genotype, determining higher ARMD+CADath+ risk. The evaluation of macular lesion area by using the methods of mathematical morphology revealed that in late stage ARMD subjects carriers of SCARB1 rs5888 CT genotype the area of macular lesion was larger than in TT genotype carriers. New information about ARMD and CAD discovered additional knowledge about ARMD etiopathogenesis and might be helpfull in search of new treatments or strategies for ARMD prevention. Evaluation of macular lesion area by mathematical morphology methods used in this study may be useful in ophthalmological practice to monitor the dynamics of ARMD.

This research was designed to address important issues for the effective prescription of, and training in the use of, magnifiers for reading patients with visual impairment. The emphasis was on the development of simple methods of assessment and training that could be easily implemented, at no great cost, by low vision practitioners in clinical practice. To ensure that the results would be widely applicable, the research focused on subjects with age-related macular degeneration (AMD) using stand magnifiers (being the most common cause of low vision and the most commonly prescribed magnifiers respectively). From this research, modifications to the current methods of reading rehabilitation are suggested to more effectively improve low vision reading for the millions of people with low vision around the world. The magnification and reading performance achieved with the magnifier determined by the fixed acuity reserve method was as valid as that achieved with the magnifier determined by the individual acuity reserve method. The fixed acuity reserve is a simpler method to calculate the required magnification, as it requires only near visual acuity and the patient's goal reading task. This method was primarily used to select the appropriate illuminated stand magnifiers for the subjects participating in the subsequent studies and is recommended for use as the starting point in clinical low vision practice. The main study of this thesis was a longitudinal investigation of the benefit of large print reading practice on reading performance with stand magnifiers. Instead of the intensive training programs on magnifier use which have been suggested by previous studies, this study aimed to investigate the effect of simple large print reading practice, under either full or restricted field of view (the latter simulated by a practice stand), on reading rate with stand magnifiers for subjects with AMD. The experimental hypothesis was that reading practice prior to the prescription of stand magnifiers would improve reading performance with the stand magnifiers for subjects with AMD. As previous studies have shown, reading rate reduced when a stand magnifier was first introduced. One week of reading practice on large print, with or without a reduced field of view, gave an improvement in reading rate with the stand magnifier for passages of text (such that the reading rates with and without magnifiers were not significantly different). There was a suggestion that this practice may give a more rapid improvement in reading rate than that achieved by the control subjects who did not do any large print reading practice, but this did not reach statistical significance. Even very brief reading with the stand magnifiers by the control subjects gave some improvement in reading rate. Therefore, home or in-office reading practice on large print or with magnifiers is recommended for patients with AMD before magnifiers are prescribed. Subjects who had neither reading practice nor exposure to the magnifier prior to its prescription required two weeks practice using their stand magnifiers to achieve their maximum reading rate. This suggests that home practice in using stand magnifiers is beneficial and a follow up visit is recommended two weeks after the provision of a magnifier to assess any change in reading rate. If no improvement in the magnifier reading rate is found or the rate is less than the reading rate on large print without a magnifier, further investigations of the patients' vision and/or their magnifier manipulation strategy are necessary. In the last study, a simple method aimed at alleviating difficulties with magnifier manipulation and navigation, the attachment of a line guide to the base of the stand magnifier, was investigated using both objective methods (recording magnifier movements and reading rate measures) and subjective methods (simple questionnaire). Although there was no improvement in the objective measures of reading or navigation performance with the line guide, more than half of the subjects with low vision preferred to have the line guide on their stand magnifiers. This suggests that the objective measures might not be sensitive enough to predict the subjective response, or that other factors that were not measured in this study influenced subjects' preferences in selecting the line guide (e.g., psychological support provided by the line guide in reading orientation). Clinically, the subjective response of patients to the use of low vision aids as well as their motivation are important criteria for success in low vision rehabilitation. There was a tendency for less experienced users to prefer the line guide to assist their use of the stand magnifier for reading. Therefore, a line guide could be offered as a preliminary training aid when stand magnifiers are first prescribed for AMD patients. Possible improvements to the design of the line guide were identified. Further research is required to assess the benefits of this or similar devices for new magnifier users and to understand the difficulties that people with visual impairment have with page navigation in order to determine improved methods of training navigation strategies. The unique contribution of this study to the field of low vision rehabilitation is that the benefit of short-term reading practice, on large print or with magnifiers, as simple, cheap methods of enhancing reading performance with stand magnifiers was demonstrated. The results of this study have led to the development of recommendations for assessing and training AMD patients who are prescribed stand magnifiers.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Made available in DSpace on 2014-07-29T15:29:14Z (GMT). No. of bitstreams: 1 Dissertacao Livia C de S N Bianchi - Oftalmologia.pdf: 3291987 bytes, checksum: bf690044678ae1c1ecf40768b3ef062a (MD5) Previous issue date: 2012-03-27 / Purpose: To evaluate the efficacy and safety of strontium-90 epimacular brachytherapy combined with intravitreal bevacizumab for treating subfoveal choroidal neovascularization secondary to exudative age-related macular degeneration. Its effects on visual acuity and macular thickness at 36 months of follow up were also studied. Methods: Sixteen patients with predominantly classic, minimally classic and occult choroidal neovascularization were treated with a single 24 Gy dose of radiation during pars plana vitrectomy, associated to two injections of bevacizumab at baseline and one injection at the one-month visit. The patients underwent a complete ophthalmologic examination, which included fluorescein angiography and optical coherence tomography, at the initial visit, every three months during the first year, and every six months during the second and third years of follow up. Results: Of the 16 cases, 2 patients (12.5%) lost more than 15 letters at the end of 36 months, and 3 (18.75%) lost fewer than 15 letters. Among the patients with improved visual acuity, 3 (18.75%) gained less than 15 letters and 8 (50%) gained more than 15 letters at the end of treatment. The mean best corrected visual acuity showed a gain of 16.0 letters at 12 months. After 36 months (n = 16), the mean best corrected visual acuity showed a gain of 10.4 letters. Of the 16 eyes included in the study, six required further therapy. The evaluation of macular thickness showed decreased thickness in 10, among the 16 patients (62.5%). Three eyes (18.75%) had similar values at the beginning and the end of 36 months, and 3 eyes (18.75%) showed increased macular thickness. Conclusion: Epimacular brachytherapy combined with bevacizumab may be considered a possible therapeutic option for choroidal neovascularization in age-related macular degeneration. The procedure was thought to be safe and was well tolerated by the patients. The treatment resulted in anatomical and functional improvements, compatible with currently available therapies. / Objetivo: Avaliar a eficácia e segurança da braquiterapia epimacular com estrôncio 90 e bevacizumabe intravítreo para tratamento da neovascularização coróidea subfoveal secundária à degeneração macular relacionada à idade exsudativa, e observar seus efeitos na acuidade visual e espessura macular, em 36 meses de seguimento. Metodologia: Foram estudados 16 pacientes portadores de neovascularização coróidea, (predominantemente clássicas, minimamente clássicas e ocultas) tratados com dose única de radiação de 24Gray, durante vitrectomia via pars plana, associada a duas injeções de bevacizumabe uma no início do tratamento e a outra um mês após. Foram realizados exame oftalmológico completo, angiofluoresceinografia e tomografia de coerência óptica na visita inicial, a cada três meses durante o primeiro ano e a cada seis meses durante o segundo e o terceiro anos de seguimento. Resultados: Dos 16 casos, 2 (12,5%) perderam mais de 15 letras ao final de 36 meses, e 3 pacientes (18,75%) perderam menos de 15 letras. Dentre os pacientes que melhoraram a acuidade visual, 3 (18,75%) ganharam menos de 15 letras e 8 (50%) ganharam mais de 15 letras ao final do tratamento. A média da melhor acuidade visual corrigida demonstrou ganho de 16,0 letras ao final de 12 meses. Após 36 meses (n = 16), a média da melhor acuidade visual corrigida apresentou um ganho de 10,4 letras pela tabela ETDRS. Dos 16 olhos observados, 6 necessitaram de tratamento adicional. Na avaliação da espessura macular, 10 (62,5%) dos 16 pacientes apresentaram diminuição da espessura, 3 olhos (18,75%) mantiveram valores semelhantes no início e ao final de 36 meses, e 3 olhos (18,75%) apresentaram aumento da espessura macular. Conclusão: A braquiterapia epimacular combinada ao uso de bevacizumabe se mostra como uma possível opção terapêutica para a neovascularização de coróide na degeneração macular relacionada à idade. O procedimento foi considerado seguro e bem tolerado, com melhora antômica-funcional compatível aos tratamentos atualmente disponíveis.