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Significance: Glaucoma patients treated with topical hypotensive eye drops often experience changes in the ocular surface, including the lid margin and the meibomian glands. In this study, the clinical parameters of the ocular surface have been analyzed to detect the presence of meibomian gland dysfunction-related dry eye disease., Purpose: This study aimed to evaluate the meibomian gland dysfunction in glaucoma patients secondary to topical antiglaucomatous treatment., Methods: A total of 131 eyes from different patients with open-angle glaucoma treated with topical medication and 92 eyes from different patients with untreated ocular hypertension were consecutively and prospectively enrolled. The structure of the meibomian glands was assessed using noncontact meibography (Keratograph 5M; Oculus, Wetzlar, Germany), and their function was evaluated by measurement of meibomian glands expressibility, the duct appearance, and the Marx line location. Moreover, tear osmolarity measurement, corneal staining score (Oxford scale), and ocular symptom assessment (Ocular Surface Disease Index questionnaire) were performed. We also compared these variables in the glaucoma group according to the presence (or not) of preservative in topical treatment., Results: Meibomian gland depletion was higher in glaucoma patients with topical medication (P < .001). Furthermore, the quantity of meibomian glands and expressibility of meibum in these patients were altered compared with the control group (P < .001 in both cases). In addition, the glaucoma group presented a higher degree of corneal staining as measured with the Oxford scale (P < .001). The Marx line location score was higher (P < .001 in central Marx line and P < .003 in temporal Marx line) in patients using drugs containing preservative than in those having preservative-free treatment. Logistical regression found that Marx line central, Marx line temporal, quantity of meibum expression, and quality of meibum expression have predictive ability to detect meibomian gland dysfunction-related dry eye disease., Conclusions: Glaucoma topical treatments produce meibomian gland dysfunction altering their structure and function, and this condition can be worsened using topical treatments containing preservative., Competing Interests: Conflict of Interest Disclosure: None of the authors have reported a financial conflict of interest., (Copyright © 2021 American Academy of Optometry.)

Background: Multiple sclerosis (MS) is a neurodegenerative disease that affects the central nervous system, especially the brain, spinal cord, and optic nerve. Diagnosis of this disease is a very complex process and generally requires a lot of time. In addition, treatments are applied without any information on the disability course in each MS patient. For these two reasons, the objective of this study was to improve the MS diagnosis and predict the long-term course of disability in MS patients based on clinical data and retinal nerve fiber layer (RNFL) thickness, measured by optical coherence tomography (OCT)., Material and Methods: A total of 104 healthy controls and 108 MS patients, 82 of whom had a 10-year follow-up, were enrolled. Classification algorithms such as multiple linear regression (MLR), support vector machines (SVM), decision tree (DT), k-nearest neighbours (k-NN), Naïve Bayes (NB), ensemble classifier (EC) and long short-term memory (LSTM) recurrent neural network were tested to develop two predictive models: MS diagnosis model and MS disability course prediction model., Results: For MS diagnosis, the best result was obtained using EC (accuracy: 87.7%; sensitivity: 87.0%; specificity: 88.5%; precision: 88.7%; AUC: 0.8775). In line with this good performance, the accuracy was 85.4% using k-NN and 84.4% using SVM. And, for long-term prediction of MS disability course, LSTM recurrent neural network was the most appropriate classifier (accuracy: 81.7%; sensitivity: 81.1%; specificity: 82.2%; precision: 78.9%; AUC: 0.8165). The use of MLR, SVM and k-NN also showed a good performance (AUC ≥ 0.8)., Conclusions: This study demonstrated that machine learning techniques, using clinical and OCT data, can help establish an early diagnosis and predict the course of MS. This advance could help clinicians select more specific treatments for each MS patient. Therefore, our findings underscore the potential of RNFL thickness as a reliable MS biomarker., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This paper presents a novel nanoformulation for sustained-release delivery of dexamethasone (DEX) to the ocular posterior segment using a Laponite (LAP) carrier-DEX/LAP 1:10 w w -1 formulation; 10 mg ml -1 . In vivo ocular feasibility and pharmacokinetics after intravitreal (IV) and suprachoroidal (SC) administration in rabbit eyes are compared against IV administration of a DEX solution (1 mg ml -1 ). Thirty rabbit eyes were injected with the DEX/LAP formulation (15 suprachoroid/15 intravitreous). Ophthalmological signs were monitored at day 1 and at weeks 1-4-12-24 post-administration. Three eyes per sample time point were used to quantify DEX concentration using high-performance liquid chromatography-mass spectrometry. The ocular tissues' pharmacokinetic parameters (lens, vitreous humour, choroid-retina unit and sclera) were studied. DEX/LAP was well tolerated under both administration methods. Peak intraocular DEX levels from the DEX/LAP were detected in the vitreous humour after both deliveries soon after administration. The vitreous area under the curve was significantly greater after both DEX/LAP deliveries (IV: 205 968.47; SC: 11 442.22 ng g -1 d -1 ) than after IV administration of the DEX solution (317.17 ng g -1 d -1 ). Intravitreal DEX/LAP delivery extended higher vitreous DEX levels up to week 24 (466.32 ± 311.15 ng g -1 ). With SC delivery, DEX levels were detectable in the choroid-retina unit (12.04 ± 20.85 ng g -1 ) and sclera (25.46 ± 44.09 ng g -1 ) up to week 24. This study demonstrated the intraocular feasibility of both SC and IV administration of the DEX/LAP formulation. The LAP increased the intraocular retention time of DEX when compared with conventional solutions. DEX/LAP could be considered a biocompatible and useful sustained-release formulation for treating posterior-pole eye diseases.

Background: Bruch membrane opening-minimum rim width (BMO-MRW) assessment offers a new diagnostic use in glaucoma patients of the Glaucoma Module Premium Edition (GMPE) available for the Spectralis optical coherence tomography (OCT) system. The objective of our research was to evaluate the diagnostic benefits of examining BMO-MRW and peripapillary retinal nerve fibre layer (pRNFL) readings acquired with Spectralis OCT to distinguish between healthy and mild glaucoma patients, comparing those readings with the standard pRNFL application. Moreover, we investigated whether using a particular combination of BMO-MRW and pRNFL parameters with a linear discriminant function (LDF) could further enhance glaucoma diagnosis., Methods: One hundred thirty-six eyes from 136 individuals were incorporated into this observational, prospective cross-sectional study: 68 mild primary open-angle glaucoma (POAG) patients according to the Hodapp-Parrish-Anderson criteria (mean deviation between 0 and - 6 dB) and 68 healthy control subjects selected by Propensity Score Matching. MRW and pRNFL thickness around the disc (diameters: 3.5 mm, 4.1 mm, and 4.7 mm) were obtained using the BMO-MRW protocol, and pRNFL thickness at 3.5 mm was obtained with the standard glaucoma application. The group data were contrasted. One sample was chosen at random to develop the LDF (teaching set: 34 healthy subjects and 34 POAG patients) using a combination of MRW and pRNFL parameters (acquired with the BMO-MRW protocol); the other sample provided a test of how the LDF performed on an independent group (validating set: 34 healthy subjects and 34 POAG patients). The receiver operating curves (ROCs) were plotted for every measurement and contrasted with the proposed LDF. The OCT parameters with the best area under the receiver operating characteristic curve (AUC) were determined., Results: Global MRW and pRNFL thicknesses were significantly thinner in the POAG group (p <  0.001). The BMO-MRW parameters showed good diagnostic accuracy; the largest AUCs reached 0.875 for the LDF and 0.879 for global RNFL thickness using the standard glaucoma application. There were no statistical differences between the AUCs calculated., Conclusions: BMO-MRW parameters show a strong capability to differentiate between mild glaucoma and control eyes. Our LDF based on the new BMO-MRW OCT protocol did not perform better than isolated parameters.

Purpose: To assess the reproducibility of retinal and choroidal measurements in the macular and peripapillary areas using swept-source optical coherence tomography in patients with Parkinson's disease., Methods: A total of 63 eyes of 63 patients with idiopathic Parkinson's disease were evaluated using a three-dimensional protocol of swept-source optical coherence tomography. The following layers were analyzed: full retinal thickness, retinal nerve fiber layer, ganglion cell layer, and choroid. The coefficient of variation was calculated for every measurement., Results: In the macular area, the mean coefficients of variation of retinal thickness, ganglion cell layer + thickness, and choroidal thickness were 0.40%, 0.84%, and 2.09%, respectively. Regarding the peripapillary area, the mean coefficient of variation of the retinal nerve fiber layer thickness was 2.78. The inferior quadrant showed the highest reproducibility (coefficient of variation= 1.62%), whereas the superonasal sector showed the lowest reproducibility (coefficient of variation= 8.76%)., Conclusions: Swept-source optical coherence tomography provides highly reproducible measurements of retinal and choroidal thickness in both the macular and peripapillary areas. The reproducibility is higher in measurements of retinal thickness versus choroidal thickness.

As multiple sclerosis (MS) usually affects the visual pathway, visual electrophysiological tests can be used to diagnose it. The objective of this paper is to research methods for processing multifocal electroretinogram (mfERG) recordings to improve the capacity to diagnose MS. MfERG recordings from 15 early-stage MS patients without a history of optic neuritis and from 6 control subjects were examined. A normative database was built from the control subject signals. The mfERG recordings were filtered using empirical mode decomposition (EMD). The correlation with the signals in a normative database was used as the classification feature. Using EMD-based filtering and performance correlation, the mean area under the curve (AUC) value was 0.90. The greatest discriminant capacity was obtained in ring 4 and in the inferior nasal quadrant (AUC values of 0.96 and 0.94, respectively). Our results suggest that the combination of filtering mfERG recordings using EMD and calculating the correlation with a normative database would make mfERG waveform analysis applicable to assessment of multiple sclerosis in early-stage patients., Competing Interests: The authors declare no conflict of interest.

Purpose: To evaluate visual and retinal changes in patients with bipolar disorder. To analyze the correlation between structural changes and visual function parameters., Methods: Thirty patients with bipolar disorder and 80 healthy controls underwent visual function evaluation with Early Treatment Diabetic Retinopathy Study charts at 100%, 2.50%, and 1.25% contrast, Pelli-Robson chart, and color vision Farnsworth and Lanthony tests. Analysis of the different retinal layers was performed using Spectralis optical coherence tomography with automated segmentation software. Correlation analysis between structural and functional parameters was conducted., Results: Patients with bipolar disorder presented worse color vision compared with controls (Lanthony's index, P = 0.002). Full macular thickness, the retinal nerve fiber layer (RNFL), ganglion cell layer, and inner plexiform layer were reduced in patients compared with healthy individuals (P < 0.005). The inner nuclear layer was significantly thickened in patients (P < 0.005). Peripapillary RNFL thickness was reduced in all temporal sectors (P < 0.005). Significant correlations were found between visual acuity and the RNFL thickness, the Pelli-Robson score and the inner plexiform layer, and between the Lanthony's color index and the ganglion cell layer thickness., Conclusion: Patients with bipolar disorder present quantifiable thinning of the macular RNFL, ganglion cell layer, and inner plexiform layer, as well as in the peripapillary RNFL thickness, and increasing thinning in the inner nuclear layer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the leading cause of hypersensitivity drug reactions. The different chemical structures, cyclooxygenase 1 (COX-1) and/or COX-2 inhibitors, are taken at all ages and some can be easily obtained over the counter. Vasoactive inflammatory mediators like histamine and leukotriene metabolites can produce local/systemic effects. Responders can be selective (SR), IgE or T-cell mediated, or cross-intolerant (CI). Inhibition of the COX pathway is the common mechanism in CI, with the skin being the most frequent organ involved, followed by the lung and/or the nose. An important number of cases have skin and respiratory involvement, with systemic manifestations ranging from mild to severe anaphylaxis. Among SR, this is the most frequent entity, often being severe. Recent years have seen an increase in reactions involving the skin, with many cases having urticaria and/or angioedema in the absence of chronic urticaria. Aspirin, the classical drug involved, has now been replaced by other NSAIDs, with ibuprofen being the universal culprit. For CI, no in vivo/in vitro diagnostic methods exist and controlled administration is the only option unless the cases evaluated report repetitive and consistent episodes with different NSAIDs. In SR, skin testing (patch and intradermal) with 24-48 reading can be useful, mainly for delayed T-cell responses. Acetyl salicylic acid (ASA) is the test drug to establish the diagnosis and confirm/exclude CI by controlled administration. Desensitization to ASA has been extensively used in respiratory cases though it can also be applied in those cases where it is required., Competing Interests: The authors report no conflicts of interest in this work.

Purpose: To evaluate neurodegeneration in patients with type 2 diabetes mellitus (DM2) without diabetic retinopathy and to assess the possible role of systemic vascular complications in retinal changes., Methods: Sixty eyes of 60 patients with DM2 and without any signs of diabetic retinopathy and 60 eyes of 60 healthy controls underwent retinal evaluation using Spectralis optical coherence tomography. Macular ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) were evaluated. Peripapillary RNFL thickness was assessed using Glaucoma and Axonal Analytics applications. Comparison between patients with the presence/absence of systemic vascular complications and different disease duration was made., Results: Macular GCL was reduced in patients compared to controls ( p < 0.001). Differences in the macular RNFL thickness were only observed in the outer inferior sector ( p =0.033). A reduction in the peripapillary RNFL (average, inferior, and inferotemporal thickness, p < 0.05 for all three) was observed in patients using both applications. Patients with chronic systemic vascular complications presented a reduction in the temporal RNFL ( p =0.019) compared to patients without complications. The superotemporal RNFL thickness was thinner in patients with longer disease duration., Conclusions: Patients with type 2 DM without diabetic retinopathy and good metabolic control present neurodegeneration affecting neurons in the macular area and axons in different sectors of the optic disc. Systemic vascular complications contributed to further axonal damage in these patients, suggesting a possible role of subclinical ischaemia to retinal neurodegeneration in type 2 DM., Competing Interests: The authors declare that they have no conflicts of interest.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Many studies of MS patients have described axonal loss in the optic nerve of the retina, and specifically progressive thinning of the retinal nerve fiber layer (RNFL). We hypothesize that RNFL thinning involves the participation of 2 processes that cause CNS damage: autoimmune inflammation and axonal degeneration. To test this hypothesis, we developed a mathematical model based on ordinary differential equations to relate the evolution of RNFL thickness (measured by optical coherence tomography [OCT]) with that of the Expanded Disability Status Scale (EDSS) score in MS patients. Data were obtained from a longitudinal study of 114 MS patients who were followed-up for 10 years. After adjusting the parameters using a genetic algorithm, the model's prediction of the evolution of RNFL thickness accurately reflected the progression revealed by the 10-year clinical data. Our findings suggest that differences in the relative contributions of autoimmune inflammation and axonal degeneration can account for the complex dynamics of MS, which vary from one patient to the next. Moreover, our results show that CNS damage occurs cumulatively from the onset of MS and that most RNFL thinning occurs before the appearance of significant disability. RNFL thickness could therefore serve as a reliable biomarker of MS disease course. Our proposed methodology would enable the use of OCT data from new MS patients to predict the evolution of RNFL thinning and hence the progression of MS in individual patients, and to facilitate the selection of patient-specific therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the ability of swept source optical coherence tomography (SS-OCT) to detect retinal changes in patients with bipolar disorder (BD)., Methods: Twenty-three patients with BD and 23 controls underwent retinal evaluation using SS deep range imaging (DRI) Triton OCT. Full retinal thickness, the ganglion cell layer (GCL), the retinal nerve fiber layer (RNFL), and choroidal thickness were evaluated with automated segmentation software., Results: Patients with BD were shown to have significant thinning of the macular full retinal thickness in the center (p = 0.049), inner temporal (p = 0.045), inner nasal (p = 0.016), and inner inferior (p = 0.016) of the ETDRS areas. The macular GCL layer was reduced in patients compared with controls (average, p = 0.002; superior, p = 0.009; superonasal, p = 0.009; inferonasal, p = 0.003; and inferior, p = 0.009). Peripapillary reduction of full retinal thickness (average, p < 0.001; superotemporal, p < 0.001; superonasal, p = 0.003; nasal, p = 0.005; and inferotemporal, p = 0.033), GCL (nasal, p = 0.025), and RNFL thickness (average, p = 0.002; superotemporal, p < 0.001; and superonasal, p = 0.045) was observed in patients compared with controls. No significant differences were observed in choroidal thickness measurements., Conclusions: BD patients were shown to have quantifiable thinning of full retinal thickness and the GCL in the macular area, as well as a peripapillary reduction of the RNFL and GCL thickness. The analysis of the retinal sublayers with SS-OCT may be a useful indicator to show degeneration and monitor disease progression in bipolar disorder.

Aims: To evaluate and compare peripapillary choroidal thickness (PPCT) in a wide area around the optic disk and various choroidal established zones in healthy controls and primary open-angle glaucoma (POAG) patients using a new swept-source (SS) optical coherence tomography (OCT) device., Methods: A total of 246 eyes were finally included in this observational, prospective, cross-sectional study: 111 healthy controls and 135 POAG patients. The healthy subjects were divided into 2 populations: the teaching population (25 used to establish choroidal zones) and the validating population (86 used for comparing choroidal thickness with POAG patients). A 26 × 26 cube grid centered on the optic disk was generated using an SS-OCT to automatically measure choroidal thickness. Four choroidal zones were established and used to compare PPCT between healthy controls and POAG patients., Results: PPCT was significantly thinner in zones 3 and 4 of the POAG group. The choroid exhibited a similar pattern in controls and patients with POAG; it was thickest in the superior region, followed in order by the temporal, nasal, and inferior regions., Conclusions: Peripapillary choroidal tissue shows a concentric pattern in both groups, and glaucoma patients present with peripapillary choroidal thinning compared with healthy subjects, especially in areas further away from the optic disk., (© 2017 S. Karger AG, Basel.)

Purpose: To evaluate the thickness of the 10 retinal layers in the paramacular area of Parkinson disease patients using a new segmentation technology of optical coherence tomography (OCT) to examine whether the thickness of specific layers predicts neurodegeneration or Parkinson disease severity., Design: Observational prospective study., Methods: Parkinson disease patients (n = 129) and age-matched healthy subjects (n = 129) were enrolled. The Spectralis OCT system was used to automatically segment all retinal layers in a parafoveal scan using the new segmentation application prototype. Mean thickness of each layer was calculated and compared between Parkinson disease patients and healthy subjects, and between Parkinson disease patients with disease durations of less than or at least 10 years. A correlation analysis was performed to evaluate the association between retinal layer thickness, duration of disease, and Parkinson disease severity. Logistic regression analysis was performed to determine the most sensitive layer for predicting axonal atrophy., Results: Parkinson disease patients showed statistically significant reduced thickness in the retinal nerve fiber, ganglion cell, inner plexiform, and outer plexiform layers and increased thickness in the inner nuclear layer compared with healthy subjects (P < .05). The inner retinal layers were more affected in Parkinson disease patients with long disease duration. The ganglion cell layer thickness was inversely correlated with disease duration and Parkinson disease severity, and was predictive of axonal damage in Parkinson disease patients., Conclusions: The segmentation application of the Spectralis OCT revealed retinal layer atrophy in Parkinson disease patients, especially in the inner layers of patients with long disease duration. Ganglion cell layer reduction was associated with increased axonal damage., (Copyright © 2014 Elsevier Inc. All rights reserved.)

N-Acetyltransferase 2 (NAT2) is the key enzyme in aromatic amine metabolism. NAT2 genotyping requires a subsequent determination of the haplotype pairs (formerly: alleles) to derive the acetylation status. The chromosomal phase of the single nucleotide polymorphisms (SNPs) is unclear for about 2/3 of the genotypes. We investigated NAT2 genotypes of 1,234 bladder cancer cases and 2,207 controls from Germany, Hungary, Pakistan and Venezuela plus 696 further German cancer cases. We reconstructed NAT2 haplotypes using PHASE v2.1.1. We analysed if the variability of the NAT2 haplotypes affected the haplotype reconstruction. Furthermore, we compared population haplotype frequencies in three Caucasian control cohorts (German, Hungarian, Spanish), in Pakistanis and Venezuelans and the impact on bladder cancer. We conclude that a common haplotype reconstruction is feasible, enhances precision and reliability. Hungarian controls showed the largest intra-ethnic variability whereas the Pakistanis showed a haplotype distribution typical for Caucasians. The main differences could be observed for the slow haplotypes *5B, *6A and *7B. The association of slow NAT2 genotypes with bladder cancer risk was most prominent in the Venezuelan study group.

Background and Purpose: Two siblings diagnosed with Okihiro Syndrome (also named Duane Radial Ray Syndrome) associated with ophthalmic manifestation including Duane Syndrome and retinal nerve fiber layer (RNFL) hypoplasia were presented., Methods: The first patient (15-years old female) was diagnosed of Duane Syndrome presenting reduction of visual acuity and pale optic discs. She showed a diffuse decrease in the RNFL thickness, mainly in her left eye, retaining the typical RNFL morphology as double hump, demonstrated by OCT and scanning laser polarimetry. Neurophysiology evaluation found a decrease in visual evoked potentials and pattern electroretinogram amplitudes, and an increase of the latency of P100 component. The second patient (12 year-old female) presented with Duane malformation. Both patients underwent a complete ophthalmic evaluation with best corrected visual acuity, visual field examination, optical coherence tomography (OCT), scanning laser polarimetry, visual evoked potentials, pattern electroretinogram, and genetic study., Results: The neuro-ophthalmic evaluation showed a subclinical reduction of RNFL average thickness provided by OCT and an increase of P50 and N95 latency by pattern electroretinogram. RNFL average thickness presented a score reduction in both patients, without typical glaucomatous morphology., Conclusions: Our analyses suggest that Okihiro Syndrome may affect retinal nerve fiber layer development and visual acuity.

Purpose: To present full ophthalmologic examination and retinal nerve fiber layer (RNFL) photographs of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) patients showing significant increases in RNFL thickness compared to healthy subjects, but without myelinated retinal fibers., Methods: The study design was observational case series. Ten eyes of five patients with molecular confirmation of ARSACS underwent a full ophthalmologic examination that included clinical history, visual acuity, biomicroscopy of the anterior segment, gonioscopy, Goldmann applanation tonometry, central corneal ultrasonic pachymetry, ophthalmoscopy of the posterior segment, standard automatic perimetry (Humphrey field), simultaneous stereophotographs of the optic disc after mydriasis, a series of five red-free digital fundus photographs for RNFL evaluation, topographic analysis of the optic disc using the Heidelberg retina tomography, and measurement of peripapillary RNFL thickness with Cirrus optical coherence tomography., Results: All patients showed abnormal visual fields, normal optic discs with a mild to strikingly increased visibility of RNFL in color stereophotographs, normal Heidelberg tomography, and moderate to markedly increased RNFL thickness in Cirrus tomography (average thickness ranging from 119 μm to 220 μm)., Conclusions: We found evidence of RNFL hypertrophy in ARSACS patients that may have been interpreted as hypermyelinated retinal fibers in previous reports. A revision of ARSACS diagnostic criteria, particularly with regard to retinal alterations, is necessary.

Purpose: To quantify changes in the retinal nerve fiber layer (RNFL) of patients with multiple sclerosis (MS) over a 1-year time period and to compare the ability of noninvasive diagnostic imaging devices and visual evoked potentials (VEP) to detect axonal loss in these patients., Methods: Eighty-one patients with MS underwent a complete ophthalmic examination that included assessment of visual acuity and color vision, refractive evaluation, visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (GDx), and measurement of VEP. All the patients were re-evaluated after a period of 12 months in order to quantify any change in the RNFL. Only one randomly chosen eye from each patient was included in the study., Results: Statistically significant differences between the 2 examinations were recorded for the overall mean and inferior RNFL thickness and the macular volume, as assessed by OCT, as well as for the temporal-superior-nasal-inferior-temporal average standard deviation provided by GDx. The greatest differences were obtained for the mean RNFL thickness (90.46 microm vs 85.96 microm). Changes in the optic nerve were detected by structural measurements but not by functional assessments., Conclusions: Axonal loss in the optic nerve of patients with MS is greater than that expected in healthy subjects, regardless of the presence of a previous optic neuritis.