43 research outputs found
Choroidal thickness and morphology analysed by optical coherence tomography as a method to approach diabetic ocular disease prognosis and progression
TÍTULO
ESPESOR COROIDEO Y MORFOLOGÍA ANALIZADO POR TOMOGRAFÍA DE COHERENCIA ÓPTICA COMO MÉTODO PARA ABORDAR LA PROGNOSIS Y LA PROGRESIÓN DE LA ENFERMEDAD OCULAR DIABÉTICA
INTRODUCCIÓN
La evidencia clínica in vivo de coroidopatía diabética (DC) ha sido difícil de demostrar clínicamente debido a la falta de medios para visualizar la coroides. Los avances de la tecnología de la tomografía de coherencia óptica (OCT) permitieron la visualización in vivo de la coroides. Los resultados controvertidos en la Diabetes para el grosor coroideo (CT) y la falta de identificación de los cambios morfológicos hacen que la DC identificada con OCT aún no se conozca.
PROPÓSITO
Evaluar si la medición por CT sola es un parámetro confiable para caracterizar la DC, para caracterizar los hallazgos morfológicos coroidales usando la OCT y la correlación con la CT y la retinopatía diabética (DR).
MÉTODOS
Estudio cohorte, prospectivo, longitudinal y observacional, donde se siguieron los controles diabéticos y sanos en visitas consecutivas. Los criterios de inclusión fueron: pacientes sanos y diabéticos sin o con cualquier estadio de RD, de 18 años o más, firmados voluntariamente con consentimiento informado. Los criterios de exclusión fueron: tratamiento previo de cualquier tipo para DR; enfermedad ocular previa o en curso o antecedentes de cirugía ocular; opacidades de medios relevantes; errores de refracción mayores que ± 6 dioptrías; medicamentos séricos crónicos o inmunosupresores sistémicos; cualquier condición sistémica grave e incontrolada. Se realizaron estudios previos para identificar los hallazgos morfológicos de la coroides en OCT que se utilizarán como método de clasificación. Evaluación cuantitativa del grosor de la coroides retiniana y subfoveal (SFCT), evaluación cualitativa de los hallazgos morfológicos coroidales y correlación con el estado de la enfermedad diabética retiniana. Evaluación de progresión y relevancia predictiva.
RESULTADOS
Se incluyeron 96 ojos diabéticos y setenta y ocho ojos sanos. A partir del análisis morfológico de la coroides, encontramos que el 78% de los sanos eran normales y las anormalidades encontradas siempre en las capas de grandes vasos con capas preservadas de coriocapilar / Sattler (ChS). La mayoría de los ojos diabéticos sin anomalías no tenían y las etapas iniciales de DR. Los cambios vasculares coroidales focales se correlacionaron con la enfermedad retiniana subyacente. La atrofia de la capa de ChS o la capa de grandes vasos estaba bien correlacionada con etapas más avanzadas de DR y maculopatía. La progresión de los cambios morfológicos coroidales se evidenció y se correlacionó con la progresión de la enfermedad retiniana. A partir del análisis estadístico: SFCT mostró una gran variabilidad con la dependencia multifactorial. La significación estadística de la correlación con SFCT se encontró solo para la edad para ambos grupos y las anomalías de las capas coroideas para los diabéticos y la presión arterial sistólica para la salud.
CONCLUSIÓN
SFCT mostró ser dependiente de variables multifactoriales con una amplia gama de valores que muestran que no es un parámetro confiable solo para la evaluación de DC. Con las imágenes de OCT podemos identificar y clasificar como hallazgos morfológicos coroidales normales o anormales. Los hallazgos anormales de la coroides están bien correlacionados con la enfermedad diabética retiniana suprayacente y pueden ser un marcador de evolución o progresión de la enfermedad del efecto del tratamiento.INTRODUCTION
Clinical evidence of diabetic choroidopathy (DC) in-vivo has been difficult to demonstrate clinically due to the lack of means to visualize the choroid. Advances of Optical Coherence Tomography (OCT) technology allowed in-vivo visualization of the choroid. Controversial results in Diabetes for choroidal thickness (CT) and lack in the identification of morphologic changes makes DC identified with OCT still to be understood.
PURPOSE
To evaluate whether CT measurement alone is a reliable parameter to characterize DC, to characterize choroidal morphological findings using the OCT and correlation with CT and the diabetic retinopathy (DR).
METHODS
A cohort, prospective, longitudinal and observational study, where diabetic and healthy controls were followed in consecutive visits. Inclusion criteria were: healthy and Diabetic patients without or with any stage of DR, aged 18 or more, signed voluntarily informed consent. Exclusion criteria were: previous treatment of any kind for DR; previous or ongoing ocular disease or history of ocular surgery; relevant media opacities; refractive errors greater than ± 6 Diopters; systemic chronic steroid or immunosuppressive medication; any serious and uncontrolled systemic condition. Previous studies were performed to identify choroidal morphological findings on OCT to be used as classification method. Quantitative assessment of retinal and subfoveal choroidal thickness (SFCT), qualitative assessment of choroidal morphological findings, and correlation with the retinal diabetic disease state. Evaluation of progression and predictive relevancy.
RESULTS
One hundred and ninety-six diabetic eyes and seventy-eight healthy eyes were included. From choroidal morphologic analysis we found: on healthy 78% were normal, and abnormalities found were always on the great vessels layers with preserved choriocapillaris/Sattler (ChS) layers. Most of diabetic eyes with no abnormalities had no and initial stages of DR. Focal choroidal vascular changes were correlated with the subjacent retinal disease. Atrophy of the ChS layer or the great vessels layer was well corelated with more advanced stages of DR and maculopathy. Progression of choroidal morphologic changes was well evidenced and correlated with progression of retinal disease. From statistical analysis: SFCT showed huge variability with multifactorial dependence. Statistical significance of correlation with SFCT was found only for age for both groups and choroidal layers abnormalities for diabetics and systolic blood pressure for healthy.
CONCLUSION
SFCT showed to be dependent on multifactorial variables with a wide range of values showing not to be a reliable parameter alone for DC evaluation. With OCT images we can identify and classify as normal or abnormal choroidal morphologic findings. Abnormal choroidal findings are well correlated with suprajacent retinal diabetic disease and can be a marker of evolution or progression of the disease of treatment effect
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Automatic Choroidal Layer Segmentation Using Markov Random Field And Level Set Method
The choroid is an important vascular layer that supplies oxygen and nourishment to the retina. The changes in thickness of the choroid have been hypothesised to relate to a number of retinal diseases in the pathophysiology. In this work, an automatic method is proposed for segmenting the choroidal layer from macular images by using the level set framework. The 3D nonlinear anisotropic diffusion filter is used to remove all the OCT imaging artifacts including the speckle noise and to enhance the contrast. The distance regularisation and edge constraint terms are embedded into the level set method to avoid the irregular and small regions and keep information about the boundary between the choroid and sclera. Besides, the Markov Random Field method models the region term into the framework by correlating the single pixel likelihood function with neighbour-hood information to compensate for the inhomogeneous texture and avoid the leakage due to the shadows cast by the blood vessels during imaging process. The effectiveness of this method is demonstrated by comparing against other segmentation methods on a dataset with manually labelled ground truth. The results show that our method can successfully and accurately estimate the posterior choroidal boundary
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Level set segmentation of retinal structures
This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University London.Changes in retinal structure are related to different eye diseases. Various retinal imaging techniques, such as fundus imaging and optical coherence tomography (OCT) imaging modalities, have been developed for non-intrusive ophthalmology diagnoses according to the vasculature changes. However, it is time consuming or even impossible for ophthalmologists to manually label all the retinal structures from fundus images and OCT images. Therefore, computer aided diagnosis system for retinal imaging plays an important role in the assessment of ophthalmologic diseases and cardiovascular disorders. The aim of this PhD thesis is to develop segmentation methods to extract clinically useful information from these retinal images, which are acquired from different imaging modalities. In other words, we built the segmentation methods to extract important structures from both 2D fundus images and 3D OCT images. In the first part of my PhD project, two novel level set based methods were proposed for detecting the blood vessels and optic discs from fundus images. The first one integrates Chan-Vese's energy minimizing active contour method with the edge constraint term and Gaussian Mixture Model based term for blood vessels segmentation, while the second method combines the edge constraint term, the distance regularisation term and the shape-prior term for locating the optic disc. Both methods include the pre-processing stage, used for removing noise and enhancing the contrast between the
object and the background. Three automated layer segmentation methods were built for segmenting intra-retinal layers from 3D OCT macular and optic nerve head images in the second part of my PhD project. The first two methods combine different methods according to the data characteristics. First, eight boundaries of the intra-retinal layers were detected from the 3D OCT macular images and the thickness maps of the seven layers were produced. Second, four boundaries of the intra-retinal layers were located from 3D optic nerve head images and the thickness maps of the Retinal Nerve Fiber Layer (RNFL) were plotted. Finally, the choroidal layer segmentation method based on the Level Set framework was designed, which embedded with the distance regularisation term, edge constraint term and Markov Random Field modelled region term. The thickness map of the choroidal layer was calculated and shown.Department of Computer Science, Brunel University London
DEVELOPMENT AND UTILIZATION OF NOVEL IMAGE PROCESSING TECHNIQUES TO CHARACTERIZE THE CHOROID IN ASIANS
Ph.DDOCTOR OF PHILOSOPH
IMAGING AND BIOLOGICAL MARKERS IN RETINAL DISORDERS TO ASSESS GENE THERAPY SAFETY AND INVESTIGATE VASCULAR DISEASE MECHANISMS
The retina is the neurosensory tissue responsible for the acquisition of visual stimuli. It is biologically separated from the systemic circulation by blood-retinal barriers, limiting the possibility for circulating markers to reflect retinal changes due to disease or therapeutic intervention. However, due to the transparency of ocular media, the retina is highly accessible to high-resolution imaging, and image processing provides access to physiological parameters quantitatively. In addition, the analysis of ocular media sampled during surgical procedures provides access to biological data regarding disease processes. In this work, imaging and biological markers were developed for several experimental and clinical situations: a gene therapy preclinical safety study (Project 1); the analysis of disease mechanisms in the choroical choroidal vascular disorder central serous chorioretinopathy (CSCR) (Project 2), and a similar translational approach in retinal vascular telangiectatic disorders (Project 3). Specific image processing algorithms were designed.
In Project 1, the preclinical safety of a lentiviral subretinal gene therapy for RPE65 replacement in Leber congenital amaurosis, LV-RPE65, was assessed on healthy non-human primates by conventional methods (in vivo electrophysiology, ex vivo immunohistochemistry, systemic biodistribution study) combined to in vivo analysis of the retinal structure by optical coherence tomography (OCT) at different timepoints, including early follow-up within 7 days. Imaging techniques revealed a transient and pronounced inflammatory process linked to LV-RPE65 injection that delayed retinal reattachment. Partial and transient photoreceptor loss was observed in the macular region, that was to a lesser extent also observed in control eyes injected with the vehicle. This work highlights the need to improve the surgical procedure for subretinal gene therapy delivery, and to consider using anti-inflammatory agents to prevent damaging processes occurring rapidly after subretinal injection.
In Project 2, mechanisms of CSCR, a retinal disease caused by choroidal vessel dilation leading to subretinal fluid accumulation, were explored. We analyzed predictive multimodal imaging factors of episode duration (2a) and recurrence (2b), evidencing in particular choroidal thickness as prognosis factor. Non-invasive OCT angiography images of the choriocapillaris, the innermost layer of the choroid beneath the retinal pigment epithelium, were processed to detect flow voids and investigate their distribution (2c). Finally, the molecular composition of subretinal fluid from a unique case of CSCR requiring subretinal surgery, was explored using a multi-omics approach (2d).
In Project 3, mechanisms of retinal vasculopathy were investigated in two pure phenotypes represented by telangiectatic disorders: type 1 macular telangiectasia (Mactel 1) (3a and 3b), and radiation maculopathy (3c). For the investigation of Mactel 1, image processing tools were used to compute global and local capillary density on OCT angiography images, showing that non-perfusion is a critical feature in Mactel 1, related to visual outcome and telangiectasia formation. This approach was combined to the biological investigation of aqueous humor from Mactel 1 cases. Intraocular levels of angiogenic factors demonstrated the involvement of placental growth factor in the pathophysiology of MacTel 1, that was correlated with multimodal imaging findings (3b). Finally, an image processing algorithm was designed and applied to radiation maculopathy, to compute automatically the fractal dimension of OCT angiography images. This parameter was relevant in assessing capillary network disruption, and demonstrated that alterations of the deep plexus influence independently visual function.
The strategies developed throughout these three projects demonstrate the interest of quantitative image analysis for the investigation of retinal disorders, and the possibility of coupling imaging and biological data. This approach contributed to identify potential imaging or biological markers for diagnosis, prognosis, therapeutic response and toxicity in several biomedical situations.
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La rétine est un tissu neurosensoriel responsable de l'acquisition des signaux visuels. Elle se trouve biologiquement séparée de la circulation systémique par les barrières hémato-rétiniennes, limitant la possibilité pour des marqueurs circulants de refléter des altérations du tissu rétinien, dus à des maladies ou secondaires à des interventions thérapeutiques. Cependant, en raison de la transparence des milieux oculaires, la rétine est accessible à l'imagerie haute résolution, et l’analyse d'images permet d’extraire des paramètres physiologiques quantitatifs. En outre, l'analyse des milieux oculaires prélevés au cours d’interventions chirurgicales permet d'accéder à des données biologiques concernant les processus physiopathologiques. Dans ce travail, des marqueurs biologiques et d'imagerie ont été développés pour plusieurs situations expérimentales et cliniques : une étude de sécurité préclinique en thérapie génique (Projet 1), l'analyse de mécanismes pathologiques dans la choriorétinopathie séreuse centrale (CRSC) (Projet 2), et dans les pathologies télangiectatiques vasculaires rétiniennes (Projet 3). Des algorithmes de traitement d'image spécifiques ont été conçus.
Dans le Projet 1, la tolérance préclinique d'une thérapie génique sous-rétinienne lentivirale pour remplacement du gène RPE65 dans l'amaurose congénitale de Leber, LV-RPE65, a été évaluée sur des primates non humains sains par des méthodes conventionnelles (électrophysiologie in vivo, immunohistochimie ex vivo, étude de biodistribution systémique), et par analyse in vivo de la structure rétinienne par tomographie par cohérence optique (OCT) à différents points, y compris un suivi précoce dans les 7 jours. Les techniques d'imagerie ont révélé un processus inflammatoire transitoire lié à l'injection de LV-RPE65 qui a retardé le réattachement rétinien. Une perte partielle et transitoire des photorécepteurs a été observée dans la région maculaire, détécté également, et dans une moindre mesure dans les yeux témoins, injectés avec la solution véhicule. Ce travail souligne la nécessité d'améliorer la procédure chirurgicale pour l’administration de thérapies géniques sous- rétiniennes, et d'envisager l’usage d’agents anti-inflammatoires pour limiter ces altérations.
Dans le projet 2, les mécanismes de la CRSC, une maladie rétinienne causée par la dilatation des vaisseaux choroïdiens menant à l'accumulation de liquide sous-rétinien, ont été explorés. Nous avons analysé les facteurs d'imagerie multimodaux prédictifs de la durée des épisodes (2a) et de récurrence (2b), mettant en évidence notamment l'épaisseur choroïdienne comme facteur pronostic. Des images en OCT angiographie, non invasive, de la choriocapillaire, la couche la plus interne de la choroïde sous l'épithélium pigmentaire rétinien, ont été traitées pour détecter des lacunes dans le flux sanguin, et étudier leur distribution (2c). Enfin, la composition moléculaire du liquide sous-rétinien d'un cas rare de CRSC nécessitant une chirurgie sous-rétinienne, a été explorée en utilisant une approche multi- omique collaborative (2d).
Dans le projet 3, les mécanismes de vasculopathie rétinienne ont été étudiés dans deux phénotypes purs représentés par les troubles télangiectasiques : télangiectasie maculaire de type 1 (Mactel 1) (3a et 3b), et maculopathie radique (3c). Pour l'étude de Mactel 1, des outils de traitement d'images ont été utilisés pour calculer la densité capillaire globale et locale sur des images d’OCT angiographie, montrant que la non-perfusion est un paramètre critique dans les Mactel 1, corrélé à la fonction visuelle et à la formation des télangiectasies. Cette approche a été combinée à l'étude biologique de l'humeur aqueuse dans des cas de Mactel 1. Des niveaux intraoculaires de facteurs angiogéniques ont démontré l'implication du facteur de croissance placentaire dans la physiopathologie de MacTel1. De plus, ce facteur était corrélé avec la densité capillaire en OCT angiographie (3b). Enfin, un algorithme de traitement d'images a été conçu et appliqué à la maculopathie radique pour calculer automatiquement la dimension fractale des images d’OCT angiographie. Ce paramètre était pertinent dans l'évaluation de la perturbation du réseau capillaire, et a démontré que les altérations du plexus profond influencent indépendamment la fonction visuelle.
Les stratégies développées dans ce travail démontrent l'intérêt de l'analyse d'image quantitative pour l'étude des pathologies rétiniennes, et la possibilité de coupler l'imagerie et les données biologiques. Cette approche a permis d'identifier des marqueurs biologiques ou d'imagerie potentiels pour le diagnostic, le pronostic, la réponse thérapeutique et la toxicité dans les différentes situations étudiées
Deep learning in ophthalmology: The technical and clinical considerations
The advent of computer graphic processing units, improvement in mathematical models and availability of big data has allowed artificial intelligence (AI) using machine learning (ML) and deep learning (DL) techniques to achieve robust performance for broad applications in social-media, the internet of things, the automotive industry and healthcare. DL systems in particular provide improved capability in image, speech and motion recognition as well as in natural language processing. In medicine, significant progress of AI and DL systems has been demonstrated in image-centric specialties such as radiology, dermatology, pathology and ophthalmology. New studies, including pre-registered prospective clinical trials, have shown DL systems are accurate and effective in detecting diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), retinopathy of prematurity, refractive error and in identifying cardiovascular risk factors and diseases, from digital fundus photographs. There is also increasing attention on the use of AI and DL systems in identifying disease features, progression and treatment response for retinal diseases such as neovascular AMD and diabetic macular edema using optical coherence tomography (OCT). Additionally, the application of ML to visual fields may be useful in detecting glaucoma progression. There are limited studies that incorporate clinical data including electronic health records, in AL and DL algorithms, and no prospective studies to demonstrate that AI and DL algorithms can predict the development of clinical eye disease. This article describes global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable. Technical and clinical aspects to build a DL system to address those needs, and the potential challenges for clinical adoption are discussed. AI, ML and DL will likely play a crucial role in clinical ophthalmology practice, with implications for screening, diagnosis and follow up of the major causes of vision impairment in the setting of ageing populations globally
Quantifying ocular inflammation in uveitis using optical coherence tomography
Inflammation is the key underlying physiological process in uveitis. It drives the onset of acute flares, causes permanent structural damage and can result in sight-threatening complications. Being able to accurately detect and measure changes in inflammatory activity is crucial for managing uveitic flares and rationalising therapeutic decisions. Unfortunately, many of the current methods for quantifying inflammation are imperfect, due to the fact that they are based on subjective and unreliable clinician estimates.
In this thesis, I evaluated the potential for imaging-based technologies such as optical coherence tomography (OCT) to measure key markers of intraocular inflammation in uveitis. Whilst several key markers of inflammation are recognised, this thesis focuses on those with an existing clinical standard, which can be used as a comparator or reference test (anterior chamber cells, anterior chamber flare and vitreous haze).
I conducted a series of systematic reviews evaluating potential instrument-based techniques for measuring anterior chamber cells, anterior chamber flare and vitreous inflammation, respectively. These identified OCT and laser flare photometry as potential instruments for measuring anterior chamber cell and flare, and OCT and retinal photography for measuring vitreous inflammation. However, the interpretation of results in each review was limited by relatively few studies and the inclusion of highly heterogenous uveitic patient populations, varying severities of disease, and lack of a standardised image acquisition protocol.
Second, in the prospective study, OCTAVE (OCT-assisted vitreous evaluation), I found that our custom OCT-based vitreous analysis technique (EQUIP) demonstrated good repeatability in healthy and uveitic eyes, was able to detect vitreous inflammation and was associated with the current clinical vitreous haze grading. The EQUIP measurement was able to predict visual acuity whereas the current standard method (clinician grading 3 using the National Eye Institutevitreous haze scale) could not. Whilst these results were encouraging, there remains substantial overlap in the OCT measurement between NEI vitreous haze grades. It is not clear whether this is due to poor signal-to-noise ratio of the OCT technique, or a sign of poor reliability of the comparator (clinician-based grading using the NEI vitreous haze scale). Further investigation through longitudinal studies may be able to answer this question.
In summary, OCT has demonstrated potential for quantifying inflammation for multiple key measures in uveitis. However, a key limitation for the validation of all instrument-based measures has been the lack of a reliable reference test
Visual function in aging and age-related macular degeneration including subretinal drusenoid deposits
Age-related macular degeneration (AMD) is the leading cause of visual impairment in the developed world among people over 50 years of age. Although AMD is clinically characterised by the presence of drusen, subretinal drusenoid deposits (SDD) have also been recognized as a distinct morphological feature that confers increased risk of developing advanced AMD. To date, there has been a lack of validated biomarkers that can capture early changes in visual function that strongly correlate to the anatomical alterations which also include SDD phenotype. This thesis aimed to explore functional and structural markers to differentiate between healthy eyes (n=11) and intermediate AMD (iAMD) with SDD (n=11) and without SDD (n=17) and non-foveal atrophic AMD (n=11). Firstly, I assessed scotopic thresholds using a novel dark-adapted chromatic (DAC) perimeter, in healthy aging and in varying AMD disease. Individuals with SDD had depressed retinal sensitivity centrally, particularly inferiorly and nasally. Functionally, eyes with SDD were comparable to eyes with non-foveal atrophy, but structurally differed in outer nuclear layer (ONL) and total retinal volumes and thicknesses. Importantly, only rod-mediated tests were able to distinguish iAMD with and without SDD. Another aim of this thesis was to explore the efficacy of 670nm light on aging and AMD. Although an improvement in scotopic thresholds was observed in healthy aged eyes (n=4) compared to younger eyes (n=5), a pilot study conducted in 40 participants over the age 55 years (12 control, 28 with intermediate AMD) refuted any clinical benefit. In conclusion, this thesis supports the need to re-classify the AMD severity scale by incorporating eyes with SDD as a separate group. This phenotype should be sub-analysed in clinical trials evaluating potential prophylactic agents to delay the progression. Scotopic sensitivity offers diagnostic value, but rod intercept time offers both prognostic and diagnostic value as candidate biomarkers
Manifestações oftalmológicas no lúpus eritematoso sistémico: epidemiologia e neurodegeneração
Introdução: O lupus eritematoso sistémico (LES) é uma doença autoimune crónica do tecido
conjuntivo, de etiologia desconhecida, que afeta preferencialmente mulheres jovens. Ao longo
dos últimos anos, tem-se verificado um aumento quer da prevalência quer da incidência de LES a
nível global. Estudos europeus apontam para uma prevalência de 37 a 123,4 casos por 100.000
pessoas, com uma incidência de 1,4 a 8,6 casos por 100.000 pessoas por ano. Apesar dos
notáveis avanços que se têm verificado na monitorização e tratamento, o LES mantém-se uma
doença com um impacto significativo na qualidade de vida, capacidade produtiva e na esperança
média de vida.
Cerca de um terço dos doentes apresenta envolvimento oftalmológico, o qual pode preceder
outras manifestações sistémicas, podendo afetar potencialmente qualquer estrutura do globo
ocular, anexos e órbita. O envolvimento das estruturas do segmento posterior, particularmente
da retina e coroideia, destaca-se quer pela sua potencial gravidade em termos de prognóstico da
função visual quer pela sua relação com a atividade sistémica da doença. Para além das
manifestações oftalmológicas relacionadas com a atividade inflamatória da doença, salientam-se
ainda as resultantes de efeitos secundários da terapêutica, nomeadamente da corticoterapia e
dos antimaláricos.
O envolvimento do sistema nervoso, designado LES neuropsiquiátrico (LES-NP), é frequente e
com graus de gravidade muito distintos. Trata-se de uma entidade complexa, de etiologia
multifatorial, que se associa a um significativo aumento da morbilidade e mortalidade. No
entanto, vários estudos com exames de imagem estruturais e funcionais do sistema nervoso
central, bem como estudos envolvendo testes cognitivos demonstraram uma proporção
anormalmente elevada de alterações em indivíduos com LES assintomático, sem critérios de LESNP.
Estudos populacionais revelam igualmente uma incidência aumentada de demência em
doentes com LES, comparativamente a indivíduos saudáveis da mesma idade e sexo.
A tomografia de coerência ótica (OCT) é um exame não invasivo que permite a obtenção de
imagens de alta resolução da retina, coroideia e nervo ótico. Nos últimos anos, a evolução desta
tecnologia permitiu a criação de softwares capazes de identificar e medir as várias camadas da
retina e coroideia com elevada precisão e fiabilidade.
Este projeto teve como objetivos principais a realização de um estudo epidemiológico das
manifestações oftalmológicas associadas ao LES e a identificação de alterações estruturais na
camada de fibras nervosas retiniana peripapilar (pRNFL), nas diferentes camadas celulares
maculares e na coroideia em doentes com LES sem envolvimento oftalmológico, em comparação
com indivíduos sem doença autoimune. Os doentes com LES foram posteriormente seguidos ao
longo de pelo menos um ano, de forma a estudar a evolução das referidas alterações com o
tempo. Pretendeu-se, igualmente, avaliar a relação das alterações estruturais retinianas e
coroideias com fatores demográficos, oculares e sistémicos.
Métodos: Esta investigação decorreu entre agosto de 2017 e agosto de 2019, no Centro
Hospitalar Universitário de Lisboa Central e incluiu um estudo transversal, um estudo de casocontrolo
e um estudo de coorte prospetivo. Numa primeira visita (V0), foram observados 161
doentes com LES, provenientes da Consulta de Doenças Autoimunes. Documentaram-se as
características demográficas e clínicas e procedeu-se ao recrutamento dos participantes para
comparecerem na visita V1 a fim de integrarem os estudos de caso-controlo e de coorte
prospetivo. Recrutaram-se, igualmente, 50 indivíduos sem doença autoimune para o grupo
controlo, provenientes da Consulta Geral de Oftalmologia. Todos os participantes foram
submetidos a uma avaliação oftalmológica completa, que incluiu a realização de OCT de domínio
espectral (SD-OCT) com e sem o software Enhanced Depth Imaging (EDI). Os doentes com LES
atualmente ou previamente medicados com hidroxicloroquina (HCQ) realizaram também
perimetria estática computorizada 10-2 e autofluorescência fundoscópica, para excluir
toxicidade macular. Após segmentação automática da imagem de SD-OCT, registou-se a
espessura da pRNFL, a nível global e nos seis setores peripapilares. A espessura macular total e
das várias camadas celulares foi também determinada nas nove áreas Early Treatment Diabetic
Retinopathy Study (ETDRS). A espessura coroideia foi medida manualmente em treze
localizações: subfoveal e outros três pontos, com intervalos de 500 μm, nas direções superior,
inferior, nasal e temporal relativamente à fóvea. No final do período de seguimento, os doentes
com LES que integraram o estudo de coorte prospetivo repetiram a referida avaliação – visita
V2. Apenas um olho de cada indivíduo foi aleatoriamente selecionado para análise nos estudos
de caso-controlo e de coorte prospetivo. Na análise estatística foi considerado um nível de
significância α=0,05.
Resultados: A avaliação dos doentes em V0 revelou que 31,1% apresentavam pelo menos uma
manifestação oftalmológica potencialmente atribuível ao LES. A manifestação mais frequente foi
a síndroma de olho seco (12,4%), seguida da catarata (11,2%) e toxicidade macular por HCQ
(11,2%). Entre os doentes com maculopatia por HCQ, dois apresentaram um padrão de SD-OCT
atípico. Cinco doentes tinham glaucoma (3,1%), dois doentes (1,2%) apresentavam retinopatia
lúpica e apenas um apresentava coroidopatia lúpica (0,6%).
Para a visita V1, foram recrutados 68 doentes com LES e 50 indivíduos sem doença autoimune
(grupo controlo). Verificou-se que a pRNFL era significativamente mais fina nos doentes com LES
a nível global (p=0,026) e nos setores temporal superior (p=0,007) e temporal (p=0,037),
comparativamente ao grupo controlo. Considerando apenas os doentes com LES, verificou-se
que aqueles cronicamente medicados para a hipercolesterolémia, hipertensão arterial ou com
anticoagulantes apresentavam uma redução significativa da pRNFL.
Comparativamente aos controlos, os doentes com LES apresentaram uma redução significativa
da espessura da camada de fotorrecetores em cinco áreas ETDRS (p<0,05). Por outro lado,
doentes com menor duração da doença apresentaram uma maior redução da espessura desta
camada em todas as áreas estudadas. Considerando apenas o grupo de doentes com LES,
verificou-se uma associação negativa significativa entre a espessura desta camada e o
diagnóstico de LES-NP, índice de atividade sistémica, medicação crónica para
hipercolesterolémia e para a hipertensão arterial. Não se verificaram diferenças com significado
estatístico entre os grupos de estudo na espessura retiniana total bem como nas restantes
camadas maculares.
Relativamente à espessura coroideia, não se verificaram diferenças estatisticamente
significativas entre doentes com LES e controlos. Contrariamente aos indivíduos do grupo
controlo, nos doentes com LES verificou-se uma alteração do normal padrão de distribuição
topográfica da espessura coroideia no polo posterior. Por outro lado, apenas neste grupo a
espessura coroideia não apresentou variações significativas com os valores de pressão arterial
média. A análise de regressão linear multivariável considerando apenas o grupo de doentes com
LES revelou uma associação negativa entre a espessura coroideia e a medicação crónica com
anticoagulantes, bem como com o diagnóstico de nefrite lúpica, em várias localizações.
Dos 68 doentes avaliados na visita V1, 65 compareceram na visita V2 (attrition rate de 4,6%). O
tempo mediano de seguimento foi 12 meses. Comparativamente a V1, a análise da pRNFL
revelou uma redução da espessura a nível global (p=0,006) e no setor temporal inferior
(p=0,017). Doentes medicados à partida com anticoagulante ou anti-hipertensor apresentaram
uma redução da espessura desta camada em algumas localizações. Não se verificaram
diferenças estatisticamente significativas na espessura das diversas camadas maculares ou
coroideia no final do período de seguimento.
Conclusões: A avaliação clínica dos doentes com LES demonstrou que aproximadamente um
terço apresenta envolvimento oftalmológico, o que está em linha com os dados da literatura
existente. Porém, no nosso estudo verificou-se uma redução das manifestações relacionadas
com a atividade sistémica da doença, particularmente da retinopatia e coroidopatia lúpicas,
comparativamente a estudos anteriores. Em contrapartida, observou-se um aumento da
prevalência de catarata e glaucoma, bem como de maculopatia por HCQ. Estes resultados
sugerem uma mudança de paradigma das manifestações oftalmológicas associadas ao LES. Esta
tendência deve-se provavelmente a uma combinação de fatores que incluem um melhor
controlo sistémico da doença e consequente aumento da sobrevida, fruto dos avanços
terapêuticos observados ao longo dos últimos anos. A monitorização mais regular e a
extraordinária melhoria dos métodos de diagnóstico oftalmológicos também contribuíram para
estes resultados.
Os doentes com LES sem manifestações oftalmológicas apresentaram uma redução da pRNFL
global e nos setores temporal superior e temporal, comparativamente aos indivíduos sem
doença autoimune. A redução da espessura desta camada, particularmente nos setores
temporais, poderá constituir um sinal indireto de neurodegeneração, tal como descrito para
outras patologias. A análise de regressão linear multivariável nos doentes com LES sugere que os
fatores de risco cardiovascular têm um efeito potenciador das referidas alterações
neurodegenerativas. Os doentes com LES apresentaram, igualmente, uma redução da camada
de fotorrecetores macular, comparativamente ao grupo controlo. Alterações subclínicas da
circulação coroideia ou a produção de autoanticorpos específicos poderão justificar a redução
seletiva desta camada. A análise sugere também que a lesão dos fotorrecetores será mais
marcada em doentes com LES que apresentem envolvimento neuropsiquiátrico, pior controlo
sistémico e fatores de risco cardiovascular. Parece, por outro lado, existir uma recuperação
parcial da espessura desta camada com o tempo de diagnóstico, a qual poderá dever-se a um
processo de remodelação retiniana.
Relativamente à espessura coroideia, as alterações encontradas nos doentes com LES
comparativamente aos controlos apontam para a existência de alterações subtis de espessura,
que poderão estar associadas a uma deficiência dos mecanismos de autorregulação vascular. A
redução da espessura coroideia observada nos doentes medicados com anticoagulantes e com
antecedentes de nefrite lúpica sugere a existência de um maior dano microvascular coroideu
nestes subgrupos, que poderá refletir um estado mais avançado de lesão noutros territórios
microvasculares sistémicos.
O estudo longitudinal confirmou o caráter progressivo da redução de espessura da pRNFL nos
doentes com LES. Uma vez mais se verificou uma associação negativa entre a espessura desta
camada e a medicação crónica, quer com anti-hipertensores, quer com anticoagulantes,
enaltecendo a importância dos fatores de risco cardiovascular. Este estudo vem reforçar a
hipótese da existência de um processo de neurodegeneração retiniana progressivo em doentes
com LES