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Uveal melanoma is the most common intraocular tumor in adults. Our group has previously developed a human uveal melanoma animal model; however, adverse effects caused by the immunosuppressive agent, cyclosporine A, prevented animals from surviving more than 12 weeks. In this study, we tested multiple cyclosporine A doses over an extended disease course up to 20 weeks, providing complete clinical imaging of intraocular tumors, histopathological analysis and liquid biopsy biomarker analysis. Twenty albino rabbits were divided into four groups with different daily cyclosporine A schedules (0-10â mg/kg) and inoculated with human uveal melanoma cell lines, 92.1 or MP41, into the suprachoroidal space. Rabbits were monitored with fundoscopy, ultrasound and optical coherence tomography. Intraocular tumors (macroscopic or microscopic) were detected in all study animals. Tumor size and growth were correlated to cyclosporine A dose, with tumors regressing when cyclosporine A was arrested. All tumors expressed HMB-45 and MelanA; however, tumor size, pigmentation and cell morphology differed in 92.1 vs. MP41 tumors. Finally, across all groups, circulating tumor DNA from plasma and aqueous humor was detected earlier than tumor detection by imaging and correlated to tumor growth. In conclusion, using three clinically relevant imaging modalities (fundoscopy, ultrasonography and optical coherence tomography) and liquid biopsy, we were successfully able to monitor tumor progression in our rabbit xenograft model of human uveal melanoma.
Assuntos
Melanoma , Neoplasias Uveais , Animais , Neoplasias Uveais/patologia , Coelhos , Melanoma/patologia , Humanos , Biópsia Líquida/métodos , Modelos Animais de Doenças , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular TumoralRESUMO
Immune recovery uveitis (IRU) is an intraocular inflammation that typically occurs as part of immune reconstitution inflammatory syndrome (IRIS) in the eye. Typically, it affects human immunodeficiency virus (HIV)-infected patients with recognized or unrecognized cytomegalovirus (CMV) retinitis who are receiving highly active antiretroviral therapy (HAART). IRU is a common cause of new vision loss in these patients, and it manifests with a wide range of symptoms and an increased risk of inflammatory complications, such as macular edema. Recently, similar IRU-like responses have been observed in non-HIV individuals with immune reconstitution following immunosuppression of diverse etiologies, posing challenges in diagnosis and treatment. This review provides an updated overview of the current literature on the epidemiology, pathophysiology, biomarkers, clinical manifestations, diagnosis, differential diagnosis, and treatment strategies for IRU.
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Infecções por HIV , Síndrome Inflamatória da Reconstituição Imune , Uveíte , Humanos , Uveíte/diagnóstico , Uveíte/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/imunologia , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Síndrome Inflamatória da Reconstituição Imune/imunologia , Diagnóstico DiferencialRESUMO
AIM: To develop the first Ophthalmology joint guidelines with Paediatric Rheumatology with recommendations on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis (JIA-U), endorsed by the Portuguese Society of Ophthalmology (SPO). METHODS: A systematic literature review was conducted to include publications up to July 14th 2020, with no language restrictions, in order to include all the international position papers/guidelines concerning the medical management of JIA-U and randomised clinical trials assessing the efficacy and safety of medical treatment in this field. We searched through MEDLINE (PubMed), Scopus, Web of Science and Cochrane Library. The Delphi modified technique to generate consensus was used. Preliminary evidence statements were subject to an anonymous agreement assessment and discussion process using an online survey, followed by further discussion and update at a national meeting. A draft of the manuscript with all recommendations was then circulated among all participants and suggestions were incorporated. The final version was again circulated before publication. RESULTS: Twenty-six recommendations were developed focusing on the following topics: general management (3), screening and follow-up of uveitis (4), treatment (17) and health education in JIA-U among patients and families (2). CONCLUSION: These guidelines were designed to support the shared medical management of patients with JIA-U and emphasize the need for a multidisciplinary approach between Ophthalmology and Paediatric Rheumatology regarding the comprehensive care of JIA-U. We acknowledge that updating these recommendations will be warranted in the future, as more evidence becomes available. KEY-WORDS: juvenile idiopathic arthritis, uveitis, biological treatment, conventional immunosuppressive treatment, multidisciplinary management, guidelines, consensus, review, Delphi Technique.
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Artrite Juvenil , Oftalmologia , Reumatologia , Uveíte , Artrite Juvenil/complicações , Criança , Humanos , Portugal , Uveíte/diagnósticoRESUMO
BACKGROUND: Uveal melanoma (UM) is the most common intraocular tumor in adults. Despite good primary tumor control, up to 50% of patients develop metastasis, which is lethal. UM often presents asymptomatically and is usually diagnosed by clinical examination and imaging, making it one of the few cancer types diagnosed without a biopsy. Hence, alternative diagnostic tools are needed. Circulating tumor DNA (ctDNA) has shown potential as a liquid biopsy target for cancer screening and monitoring. The aim of this study was to evaluate the feasibility and clinical utility of ctDNA detection in UM using specific UM gene mutations. METHODS: We used the highly sensitive digital droplet PCR (ddPCR) assay to quantify UM driver mutations (GNAQ, GNA11, PLCß4 and CYSTLR2) in cell-free DNA (cfDNA). cfDNA was analyzed in six well established human UM cell lines with known mutational status. cfDNA was analyzed in the blood and aqueous humor of an UM rabbit model and in the blood of patients. Rabbits were inoculated with human UM cells into the suprachoroidal space, and mutated ctDNA was quantified from longitudinal peripheral blood and aqueous humor draws. Blood clinical specimens were obtained from primary UM patients (n = 14), patients presenting with choroidal nevi (n = 16) and healthy individuals (n = 15). RESULTS: The in vitro model validated the specificity and accuracy of ddPCR to detect mutated cfDNA from UM cell supernatant. In the rabbit model, plasma and aqueous humor levels of ctDNA correlated with tumor growth. Notably, the detection of ctDNA preceded clinical detection of the intraocular tumor. In human specimens, while we did not detect any trace of ctDNA in healthy controls, we detected ctDNA in all UM patients. We observed that UM patients had significantly higher levels of ctDNA than patients with nevi, with a strong correlation between ctDNA levels and malignancy. Noteworthy, in patients with nevi, the levels of ctDNA highly correlated with the presence of clinical risk factors. CONCLUSIONS: We report, for the first time, compelling evidence from in vitro assays, and in vivo animal model and clinical specimens for the potential of mutated ctDNA as a biomarker of UM progression. These findings pave the way towards the implementation of a liquid biopsy to detect and monitor UM tumors.
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Biomarcadores Tumorais/metabolismo , DNA Tumoral Circulante/sangue , Biópsia Líquida/métodos , Melanoma/diagnóstico , Melanoma/genética , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/genética , Animais , Feminino , Humanos , Mutação , CoelhosRESUMO
Tumor biopsies in uveal melanoma (UM) serve mainly the purpose of prognostication and assessment of individual metastatic risk, but can be used for diagnosis in selected cases. The importance of precise information is paramount for selecting adequate surveillance protocols, patient counseling, and optimization of treatment strategies. However, intratumoral heterogeneity and sample representativity are major concerns and can interfere with the correct prediction of the patient's prognosis. We report a series of cases of UM with distinct morphologically identifiable areas, highlighting the differences in clinical behavior, as well as histopathological and genetic features.
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Internal carotid artery dissection (ICAD) is caused by the disruption of the tunica intima, with the formation of an intramural haematoma that can cause stenosis or occlusion of the artery's lumen, leading to reduced blood flow and secondary thrombus formation. Up to two-thirds of patients with ICAD show ophthalmological symptoms or signs, which are, frequently, the first manifestations of this clinical condition, often preceding for weeks the neurological signs of cerebral infarction. Central retinal artery occlusion (CRAO) is a rare complication of ICAD, secondary either to haemodynamic compromise, with ocular hypoperfusion and reverse flow within the ophthalmic artery, or to thromboembolic events, in rarer cases. We report a case of CRAO secondary to a spontaneous ICAD, in an otherwise healthy middle-aged patient.
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Dissecação da Artéria Carótida Interna/diagnóstico , Pressão Intraocular/fisiologia , Isquemia/diagnóstico , Oclusão da Artéria Retiniana/diagnóstico , Dissecação da Artéria Carótida Interna/fisiopatologia , Dissecação da Artéria Carótida Interna/terapia , Angiografia Cerebral , Embolização Terapêutica , Feminino , Cefaleia , Humanos , Isquemia/fisiopatologia , Isquemia/terapia , Pessoa de Meia-Idade , Oclusão da Artéria Retiniana/fisiopatologia , Oclusão da Artéria Retiniana/terapia , Trombectomia , Resultado do TratamentoRESUMO
Leber's hereditary optic neuropathy (LHON) is an optic neuropathy of mitochondrial inheritance, characterised by incomplete penetrance and variable expressivity. Typically, young male patients present with sequential, severe, rapidly progressive loss of central vision, with characteristic funduscopic findings. However, LHON may present at any age, in both genders, and fundus examination may be normal. Evidence has emerged to support the role of environmental factors in triggering LHON, by disrupting the normal mechanisms of mitochondrial function. We present two clinical cases of LHON of late onset, and provide a literature review on atypical cases of LHON and the role of environmental triggers.
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Atrofia Óptica Hereditária de Leber/diagnóstico , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Fumar Cigarros/efeitos adversos , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Atrofia Óptica Hereditária de Leber/complicações , Atrofia Óptica Hereditária de Leber/etiologia , Disco Óptico/diagnóstico por imagem , Disco Óptico/patologia , Tomografia de Coerência ÓpticaRESUMO
The Rho kinase (ROCK) signaling pathway is involved in several cellular events that include cell proliferation and cytoskeleton modulation leading to cell adhesion. The ROCK pathway in the human eye has been hypothesized to play important roles in corneal endothelial cell physiology and pathologic states. In addition, ROCK signaling has been identified as an important regulator of trabecular meshwork (TM) outflow, which is altered in glaucomatous eyes. These roles in corneal and glaucomatous disease states have led to the growing interest in the development of drugs selectively targeting this pathway (ROCK inhibitors). The authors provide a review of the literature on the pathobiology of the ROCK signaling in corneal endothelial disease, glaucoma, and vitreoretinal disease, as well as the clinical usefulness of ROCK inhibitors in Ophthalmology.
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Doenças da Córnea/tratamento farmacológico , Glaucoma/tratamento farmacológico , Oftalmologia/métodos , Doenças Retinianas/tratamento farmacológico , Quinases Associadas a rho/antagonistas & inibidores , Animais , Humor Aquoso/metabolismo , Células Cultivadas , Doenças da Córnea/metabolismo , Doenças da Córnea/patologia , Glaucoma/metabolismo , Glaucoma/patologia , Humanos , Pressão Intraocular , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Transdução de Sinais , Malha Trabecular/metabolismo , Malha Trabecular/patologiaRESUMO
The authors report a case of an orbital metastasis from an occult breast carcinoma. A 66-year-old woman presented with a growing left orbital tumour. Orbital CT scan was consistent with lymphoma. However, ocular pathology revealed small neoplastic cells showing an 'indian file pattern' suggestive of metastatic carcinoma and immunohistochemistry was positive for CK7, CK CAM5.2 and oestrogen receptor. A systemic evaluation was then performed with mammogram, breast ultrasound and MRI considered normal. An exhaustive systemic evaluation revealed multiple bone lesions, a right axillary lymph node lesion, which presented the same pattern on pathology and immunohistochemistry, with no evidence of a primary tumour. A diagnosis of a metastatic lobular carcinoma of the breast (T0, N1, M1) was made and the patient was started on chemotherapy and adjuvant hormonal therapy.
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Neoplasias da Mama/patologia , Carcinoma Lobular/secundário , Neoplasias Oculares/secundário , Neoplasias Primárias Desconhecidas/patologia , Idoso , Biomarcadores Tumorais , Biópsia , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Lobular/diagnóstico por imagem , Terapia Combinada , Neoplasias Oculares/diagnóstico por imagem , Neoplasias Oculares/patologia , Neoplasias Oculares/terapia , Feminino , Humanos , Queratina-7/análise , Imageamento por Ressonância Magnética , Mamografia , Neoplasias Primárias Desconhecidas/diagnóstico por imagem , Neoplasias Primárias Desconhecidas/terapia , Tomografia Computadorizada por Raios X , Ultrassonografia , Imagem Corporal TotalRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder that can involve any organ system. Central nervous system involvement can be a severe life threatening complication, ultimately resulting in severe neurodegenerative changes. Magnetic resonance imaging suggests that neurodegeneration, which may have deleterious effects on brain function, may occur early in SLE and experimental models suggest that neuroprotection may be feasible and beneficial. The retina is an extension of the brain. Recent ophthalmic imaging technologies are capable of identifying early changes in retinal and choroidal morphology and circulation that may reflect CNS degeneration. However, their utility in monitoring CNS involvement in SLE has been poorly studied as these have only been performed in small cohorts, in a cross-sectional design, non-quantitatively and without correlation to disease activity. The authors aim to review the current understanding of neurodegeneration associated with SLE, with particular focus on the visual pathway. We describe the neuropathology of the visual system in SLE and the evidence for retinal and choroidal neurodegenerative and microvascular changes using optical coherence tomography technology. We aim to describe the potential role of optical imaging modalities in NPSLE diagnosis and their likely impact on the study of neuronal function.
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Técnicas de Diagnóstico Oftalmológico , Olho/diagnóstico por imagem , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Degeneração Neural/diagnóstico , Degeneração Neural/etiologia , Encéfalo/patologia , Estudos Transversais , Olho/patologia , Humanos , Lúpus Eritematoso Sistêmico/patologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/etiologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Imageamento por Ressonância MagnéticaRESUMO
PURPOSE: Conjunctival melanoma is a rare but potentially lethal tumor. Its biologic profile is still largely unknown, with recent studies aiming at establishing histopathological and genetic tumor profiles. The aim of this study was to analyze the association between clinicopathological characteristics and tumor expression of cyclooxygenase-2 (COX-2) to prognosis, assessing its usefulness as a possible prognostic marker. METHODS: Case series of 50 patients from 1991 to 2008 with pathologically proven conjunctival melanoma. Demographic, clinical, and pathological characteristics were evaluated by reviewing clinical files and pathology. Expression of COX-2 was studied by immunohistochemistry of formalin-fixed paraffin-embedded tissue samples of 20 melanomas. Samples were classified in a score which included intensity of staining and percentage of cells with positive reactivity. RESULTS: Clinicopathological features significantly associated (p < .05) with a poor prognosis (death) included involvement of fornix and tarsal conjunctiva, tumor thickness exceeding 2 mm, local tumor recurrence, lymph node, and systemic metastasis. In the immunohistochemistry study (n = 20), 18 cases expressed COX-2 although with different scores. However, only cases with a high score were associated with a poor outcome. Multivariate association analysis revealed that recurrence rate, metastasis, corneal invasion, and tumor thickness were associated with high score cases and, therefore, with a clinical profile with a higher risk of death. CONCLUSIONS: Results suggest that higher COX-2 expression may be a negative prognostic factor in conjunctival melanoma. Further studies can address the potential use of anti-COX-2 drugs as adjuvant therapy of this disease.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Túnica Conjuntiva/enzimologia , Ciclo-Oxigenase 2/metabolismo , Melanoma/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Túnica Conjuntiva/patologia , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: To compare choroidal thickness (CT) between diabetic patients without diabetic retinopathy and a nondiabetic group. To explore how CT relates to disease duration, mean arterial pressure, glycemia, glycosylated hemoglobin, intraocular pressure, and ocular pulse amplitude. METHODS: Choroidal thickness was assessed using a spectral-domain optical coherence tomography and enhanced depth mode at 13 locations (subfoveal and 3 measurements 500 µm apart in 4 directions-nasal, temporal, superior, and inferior). Linear regression models were used. RESULTS: One hundred seventy-five patients were recruited (125 diabetic patients without diabetic retinopathy and 50 nondiabetic patients). In diabetic patients, although without statistical significance, CT showed a trend to be thicker in all locations (6.16-24.27 µm). Choroidal thickness was negatively associated with age (P < 0.001) in both groups, but only in the diabetic group, it was positively associated to ocular pulse amplitude (with a mean increase between 8.5 µm and 11.6 µm for each millimeter of mercury increase in ocular pulse amplitude). Diabetic patients' CT seems to stabilize after 150 months of diabetes, increase with higher glycemia levels (>160 mg/dL) while showing no fluctuation with glycosylated hemoglobin and mean arterial pressure. CONCLUSION: There seems to be a thickening of the choroid in diabetic patients without diabetic retinopathy. Moreover, this tissue may be functionally different in diabetes, as the pattern of associations seems to differ between groups.
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Corioide/patologia , Diabetes Mellitus Tipo 2/patologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Pressão Intraocular/fisiologia , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Tomografia de Coerência Óptica/métodos , Acuidade Visual/fisiologiaRESUMO
BACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) and internal macular layer thinning have been demonstrated in Alzheimer's disease (AD) with optical coherence tomography (OCT) studies. The purpose of this study is to compare the pRNFL thickness and overall retinal thickness (RT) in AD patients with non-AD patients, using spectral domain optical coherence tomography (SD-OCT) and determine the sectors most characteristically affected in AD. METHODS: A cross-sectional study was performed to determine the pRNFL and overall macular RT thicknesses in AD and non-AD patients, attending a tertiary hospital center. For pRNFL, the global and six peripapillary quadrants were calculated, and for overall RT values, the nine Early Treatment Diabetic Retinopathy Study (ETDRS) areas were used. A multiple regression analysis was applied to assess the effects of disease, age, gender, spherical equivalent, visual acuity, intraocular pressure, axial length and blood pressure on pRNFL and overall macular RT. RESULTS: A total of 202 subjects, including 50 eyes of 50 patients with mild AD (mean age 73.10; SD = 5.36 years) and 152 eyes of 152 patients without AD (mean age 71.03; SD = 4.62 years). After Bonferroni correction, the pRNFL was significantly thinner for the AD group globally and in the temporal superior quadrant (10.76 µm and 20.09 µm mean decrease, respectively). The RT thickness was also decreased in superior sectors S3 and S6 (mean thinning of 9.92 µm and 11.65 µm, respectively). Spearman's correlation coefficient showed a direct association between pRNFL in the temporal superior quadrant and RT in superior S6 and S3 sectors (rS = 0.41; p < 0.001 and rS = 0.28; p < 0.001, respectively). CONCLUSIONS: Patients with AD showed a significant thickness reduction in global and temporal superior quadrants in pRNFL and in superior pericentral and peripheral sectors of RT. These findings may reflect a peripapillary and retinal changes characteristic of AD, suggesting the importance of SD-OCT as a potential adjuvant in early diagnosis of AD. Further studies are needed to understand which retinal layers and macular sectors are more useful as potential ocular biomarker over time in AD.
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Doença de Alzheimer/diagnóstico , Macula Lutea/patologia , Fibras Nervosas/patologia , Doenças Retinianas/diagnóstico , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Pressão Sanguínea/fisiologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Disco Óptico , Doenças Retinianas/etiologia , Doenças Retinianas/fisiopatologia , Estudos RetrospectivosRESUMO
INTRODUCTION: The purpose of this study was to measure and to compare macular choroidal thickness (CT) between patients with mild Alzheimer's disease (AD), patients without AD, and elderly patients. METHODS: CT was measured manually in 13 locations at 500-µm intervals of a horizontal and a vertical section from the fovea. Linear regression models were used to analyze the data. RESULTS: Fifty patients with a diagnosis of mild AD (73.1 years), 152 patients without AD (71.03 years), and 50 elderly without AD (82.14 years) were included. In the AD patients, CT was significantly thinner in all 13 locations (P < .001-comparing with age-match group), and comparing with the elderly group, a more pronounced difference was found in two locations temporal to the fovea. DISCUSSION: Patients with AD showed a significant choroidal thinning even when compared with elderly subjects. The reduction of CT may aid in the diagnoses of AD, probably reflecting the importance of vascular factors in their pathogenesis.
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PURPOSE: To identify changes in choroidal thickness (CT) and all retinal layers of diabetic patients without diabetic retinopathy (DR) after 1 year of follow-up. DESIGN: Prospective observational cohort study. METHODS: Overall, 125 diabetic patients without DR were included. Two visits were scheduled: the first visit (V1) and a second visit after 12 months (V2). At both visits, patients received a complete ophthalmologic evaluation that included OCT. Each retinal layer thickness was calculated for 9 ETDRS sectors, and CT was measured at 13 locations. Generalized linear mixed-effects models were used. RESULTS: Of the 125 patients, 103 completed the study, and 9 of the 103 developed DR (8.7%). CT was significantly higher at V2 than at V1, with an average value of 10-17 µm at almost half the locations (500, 1000, and 1500 µm temporal; 500 and 1000 µm nasal; and 1000 µm superior to the fovea) (P < .001-.003). The thicknesses of the ganglion cell layer (I3 and N6 sectors), inner plexiform layer (S6 and N6 sectors), inner nuclear layer (T6 and N6 sectors), and outer plexiform layer (S6 sector), as well as the overall retinal thickness (RT) (S3, N3, I3, S6, and T6 sectors), were decreased at V2 (P < .001). Visible retinopathy was negatively associated with overall RT (central, S3, T3, I3, and N3 sectors, P = .004-.024) and the thickness of the ONL (T6 and I6 sectors, P = .007 and P = .009) and photoreceptor layer (N6 sector, P = .038). The presence of DR decreased the overall RT by 13.04-16.63 µm. CONCLUSIONS: Diabetic patients without DR showed a thicker choroid and a thinner retina, particularly in inner layers, after 1 year of follow-up. These structural changes may correspond to the early neurodegenerative phase of DR.