Glaucoma is a chronic eye disease characterized by thinning of the retina, death of ganglion cells, and progressive loss of vision, eventually leading to blindness. The prevalence of glaucoma is estimated at 1-3% of those over 40 years old. With a constantly aging population, this number is expected to increase significantly over the next 10 years. Even with treatment, about 15% of people with glaucoma currently develop residual vision or tunnel vision and eventually become blind or partially sighted. The mechanisms behind ganglion cell death are poorly understood. Elevated eye pressure is the main risk factor for glaucoma, but treatment in the form of medication, laser, or surgery can only slow the decline, not stop it. In addition, high intraocular pressure is neither necessary nor sufficient for the development of glaucoma, indicating the existence of other unknown risk factors. It has been established that the death of ganglion cells results in a decreased oxygen demand and a concomitant decrease in blood flow. However, there is also a hypothesis that reduced or unstable blood supply is not only a consequence, but also a cause of glaucoma. This is known as the ‘chicken-egg’ dilemma in glaucoma. It is supported by the observation that the risk of developing glaucoma is higher in people with very low blood pressure (sometimes even as a result of overtreatment of high blood pressure). This dissertation is an attempt to methodically examine whether blood pressure can be linked to changes in the retina that could suggest susceptibility to glaucoma. For this purpose, we analyze epidemiological data from the Groningen Longitudinal Glaucoma Study, we use advanced imaging techniques to model the microcirculation, and we describe its relationship with the neural structure and oxygen consumption of the retina. We provide evidence leaning towards the existence of a vascular component, likely pertinent to glaucoma.
Purpose: To compare retinal oxygen delivery (DO2) and oxygen extraction (VO2) in ophthalmologically healthy subjects with different blood pressure (BP) status. Methods: In this case-control study, we prospectively included 93 eyes of 93 subjects (aged 50-65 years) from a Dutch cohort (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We estimated vascular calibers from fundus images and fractal dimension from optical coherence tomography angiography scans. We combined calibers, fractal dimension, BP, and intraocular pressure measurements in a proxy of retinal blood flow (RBF), using a Poiseuille-based model. We measured arterial and venous oxygen saturations (SaO2, SvO2) with a scanning laser ophthalmoscope. We calculated the DO2 and VO2 from the RBF, SaO2, and SvO2. We compared the DO2 and VO2 between groups and investigated the DO2-VO2 association. Results: DO2 and VO2 were different between groups (P = 0.009, P = 0.036, respectively). In a post hoc analysis, the low BP group had lower DO2 than the untreated AHT group (P = 4.9 × 10-4). The low BP group and the treated AHT group had a lower VO2 than the untreated AHT group (P = 0.021 and P = 0.034, respectively). There was a significant DO2-VO2 correlation (Robs = 0.65, bobs = 0.51, P = 2.4 × 10-12). After correcting for shared measurement error, the slope was not significant. Conclusions: The DO2 and VO2 were altered in ophthalmologically healthy subjects with different BP status. Future studies could elucidate whether these changes can explain the increased risk of ophthalmic pathologies in those subjects. Translational relevance: Understanding the baseline interplay between BP, retinal perfusion, and oxygenation allows for improved evaluation of retinal disease manifestation.
Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG. Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs. Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) 0.64; p 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR 0.75; p 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p 1.2 × 10 −05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7-13.1). Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.
Purpose: We wanted to investigate the association of blood pressure (BP) status with the ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thickness of nonglaucomatous eyes and to elucidate whether this effect is related to vascular metrics proxying retinal perfusion. Methods: For this case-control study, we prospectively included 96 eyes of 96 healthy subjects (age 50-65) from a large-scale population-based cohort in the northern Netherlands (n = 167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We measured macular GCIPL and RNFL (mRNFL) and peripapillary RNFL (pRNFL) thicknesses with optical coherence tomography (OCT). We estimated retinal blood flow (RBF), retinal vascular resistance (RVR), and autoregulatory reserve (AR) from quantitative OCT-angiography, fundus imaging, BP, and intraocular pressure. We compared structural and vascular metrics across groups and performed mediation analysis. Results: Compared to controls, GCIPL was thinner in the low BP group (P = 0.013), treated hypertensives (P = 0.007), and untreated hypertensives (P = 0.007). Treated hypertensives exhibited the thinnest mRNFL (P = 0.001), temporal pRNFL (P = 0.045), and inferior pRNFL (P = 0.034). The association of GCIPL thickness with BP was mediated by RBF within the combined low BP group and controls (P = 0.003), by RVR and AR within the combined treated hypertensives and controls (P = 0.001, P = 0.032), and by RVR within the combined untreated antihypertensives and controls (P = 0.022). Conclusions: Inner retinal thinning was associated with both tails of the BP distribution and with ineffective autoregulation. Longitudinal studies could clarify whether these defects can explain the reported glaucomatous predisposition of these population groups.
Purpose: Primary open-angle glaucoma (POAG) has been reported to occur more frequently inAfricans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe. Methods: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA). Results: The biogeographic ancestry analysis showed that the median proportion of GAA was97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: meanage: 63, 57, 66, 70 years (p < 0.001); visual acuity in the worse eye: 1.78, 1.78, 0.3, 0.3 LogMAR(p < 0.001); maximum intraocular pressure of both eyes: 36, 34, 29, 29 mmHg (pANOVA< 0.001);maximum vertical cup to disc ratio (VCDR) of both eyes: 0.90, 0.90, 0.84, 0.83 (p < 0.001); meancentral corneal thickness: 506, 487, 511, 528 lm(p < 0.001). Fourteen percent of Tanzanian patients presented with blindness (<3/60 Snellen) in the better eye in contrast to only 1% in the Dutch. Conclusion: In this multi-ethnic comparative study, Sub-Saharan Africans present at a younger age with lower visual acuity, higher IOP, larger VCDR, than SAC and Dutch participants. This indicates the more progressive and destructive course in Sub-Saharan Africans.
Background To investigate whether copy number variations (CNVs) are implicated in molecular mechanisms underlying primary open-angle glaucoma (POAG), we used genotype data of POAG individuals and healthy controls from two case-control studies, AGS ( n = 278) and GLGS-UGLI ( n = 1292). PennCNV, QuantiSNP, and cnvPartition programs were used to detect CNV. Stringent quality controls at both sample and marker levels were applied. The identified CNVs were intersected in CNV region (CNVR). After, we performed burden analysis, CNV-genome-wide association analysis, gene set overrepresentation and pathway analysis. In addition, in human eye tissues we assessed the expression of the genes lying within significant CNVRs. Results We reported a statistically significant greater burden of CNVs in POAG cases compared to controls ( p -value = 0,007). In common between the two cohorts, CNV-association analysis identified statistically significant CNVRs associated with POAG that span 11 genes ( APC , BRCA2, COL3A1, HLA-DRB1, HLA-DRB5, HLA-DRB6, MFSD8 , NIPBL, SCN1A, SDHB , and ZDHHC11 ). Functional annotation and pathway analysis suggested the involvement of cadherin, Wnt signalling, and p53 pathways. Conclusions Our data suggest that CNVs may have a role in the susceptibility of POAG and they can reveal more information on the mechanism behind this disease. Additional genetic and functional studies are warranted to ascertain the contribution of CNVs in POAG.
Purpose Axenfeld‐Rieger syndrome (ARS) is a rare autosomal dominant disorder that affects the anterior segment of the eye. The aim of this study was to examine the PITX2 gene to identify possible novel mutations in Pakistani and Mexican families affected by the ARS phenotype. Methods Three unrelated probands with a diagnosis of ARS were recruited for this study. Genomic DNA was isolated from the peripheral blood of the probands and their family members. Polymerase chain reaction and Sanger sequencing were used for the analysis of coding exons and the flanking intronic regions of the PITX2 gene. Bioinformatics tools and database (VarSome, Provean, and MutationTaster, SIFT, PolyPhen‐2, and HOPE) were evaluated to explore missense variants. Results We identified novel heterozygous variations in the PITX2 gene that segregated with the ARS phenotype within the families. The variant NM_153426.2(PITX2):c.226G > T or p.(Ala76Ser) and the mutation NM_153426.2(PITX2):c.455G > A or p.(Cys152Tyr) were identified in two Pakistani pedigrees, and the mutation NM_153426.2(PITX2):c.242_265del or p.(Lys81_Gln88del), segregated in a Mexican family. Conclusion Our study extends the spectrum of PITX2 mutations in individuals with ARS, enabling an improved diagnosis of this rare but serious syndrome.
Purpose: This study explores the effect of glaucomatous visual field defects on several neuropsychological tests that are often used in research and in clinical settings. Methods: Nineteen glaucoma patients and nineteen healthy participants, which are current drivers and older than 65 years old were included. All participants completed the Montreal Cognitive Assessment (MoCA), the Trail Making Test (TMT), the Benton Visual Retention Test (BVRT), the Snellgrove Maze Task (SMT) and the Digit Span Test (DST). All participants were also tested on contrast sensitivity and near and far visual acuity. For the glaucoma patients, visual field tests were downloaded from hospital servers. Results: On the MoCA test, glaucoma patients scored lower than the healthy group, but not significantly. On the MoCA-Blind, the difference was statistically significant. Glaucoma patients also had lower percentile scores on the TMT, with a significant difference in the TMT-A, but this difference largely disappeared in the calculated TMT B-A index, which isolates the cognitive component. The BVRT and SMT showed no significant differences between both groups. In the only non-visual test, the DST, glaucoma patients outperformed the healthy group. Glaucoma severity did not influence results, except for the BVRT on which the moderate/severe group has better scores. Conclusion: Using visual items might lead to conclusions about cognition when it should be one about vision. Therefore, careful selection of tests is needed when examining cognition in glaucoma patients.
Early in vivo embryonic retinal development is a well-documented and evolutionary conserved process. The specification towards eye development is temporally controlled by consecutive activation or inhibition of multiple key signaling pathways, such as the Wnt and hedgehog signaling pathways. Recently, with the use of retinal organoids, researchers aim to manipulate these pathways to achieve better human representative models for retinal development and disease. To achieve this, a plethora of different small molecules and signaling factors have been used at various time points and concentrations in retinal organoid differentiations, with varying success. Additions differ from protocol to protocol, but their usefulness or efficiency has not yet been systematically reviewed. Interestingly, many of these small molecules affect the same and/or multiple pathways, leading to reduced reproducibility and high variability between studies. In this review, we make an inventory of the key signaling pathways involved in early retinogenesis and their effect on the development of the early retina in vitro. Further, we provide a comprehensive overview of the small molecules and signaling factors that are added to retinal organoid differentiation protocols, documenting the molecular and functional effects of these additions. Lastly, we comparatively evaluate several of these factors using our established retinal organoid methodology.
Purpose: To explore the effect of gaze direction and eyelid closure on intraocular pressure (IOP). Methods: Eleven patients with primary open-angle glaucoma previously implanted with a telemetric IOP sensor were instructed to view eight equally-spaced fixation targets each at three eccentricities (10°, 20°, and 25°). Nine patients also performed eyelid closure. IOP was recorded via an external antenna placed around the study eye. Differences of mean IOP between consecutive gaze positions were calculated. Furthermore, the effect of eyelid closure on gaze-dependent IOP was assessed. Results: The maximum IOP increase was observed at 25° superior gaze (mean ± SD: 4.4 ± 4.9 mm Hg) and maximum decrease at 25° inferonasal gaze (-1.6 ± 0.8 mm Hg). There was a significant interaction between gaze direction and eccentricity (P = 0.003). Post-hoc tests confirmed significant decreases inferonasally for all eccentricities (mean ± SEM: 10°: -0.7 ± 0.2, P = 0.007; 20°: -1.1 ± 0.2, P = 0.006; and 25°: -1.6 ± 0.2, P = 0.006). Eight of 11 eyes showed significant IOP differences between superior and inferonasal gaze at 25°. IOP decreased during eyelid closure, which was significantly lower than downgaze at 25° (mean ± SEM: -2.1 ± 0.3 mm Hg vs. -0.7 ± 0.2 mm Hg, P = 0.014). Conclusions: Our data suggest that IOP varies reproducibly with gaze direction, albeit with patient variability. IOP generally increased in upgaze but decreased in inferonasal gaze and on eyelid closure. Future studies should investigate the patient variability and IOP dynamics.
Purpose: Assessing the presence of visual field defects (VFD) through procedures such as perimetry is an essential aspect of the management and diagnosis of ocular disorders. However, even the latest perimetric methods have shortcomings-a high cognitive demand and requiring prolonged stable fixation and feedback through a button response. Consequently, an approach using eye movements (EM)-as a natural response-has been proposed as an alternate way to evaluate the presence of VFD. This approach has given good results for computer-simulated VFD. However, its use in patients is not well documented yet. Here we use this new approach to quantify the spatiotemporal properties (STP) of EM of various patients suffering from glaucoma and neuro-ophthalmological VFD and controls. Methods: In total, 15 glaucoma patients, 37 patients with a neuro-ophthalmological disorder, and 21 controls performed a visual tracking task while their EM were being recorded. Subsequently, the STP of EM were quantified using a cross-correlogram analysis. Decision trees were used to identify the relevant STP and classify the populations. Results: We achieved a classification accuracy of 94.5% (TPR/sensitivity = 96%, TNR/specificity = 90%) between patients and controls. Individually, the algorithm achieved an accuracy of 86.3% (TPR for neuro-ophthalmology [97%], glaucoma [60%], and controls [86%]). The STP of EM were highly similar across two different control cohorts. Conclusions: In an ocular tracking task, patients with VFD due to different underlying pathology make EM with distinctive STP. These properties are interpretable based on different clinical characteristics of patients and can be used for patient classification. Translational relevance: Our EM-based screening tool may complement existing perimetric techniques in clinical practice.
Genetically complex ocular neuropathies, such as glaucoma, are a major cause of visual impairment worldwide. There is a growing need to generate suitable human representative in vitro and in vivo models, as there is no effective treatment available once damage has occured. Retinal organoids are increasingly being used for experimental gene therapy, stem cell replacement therapy and small molecule therapy. There are multiple protocols for the development of retinal organoids available, however, one potential drawback of the current methods is that the organoids can take between 6 weeks and 12 months on average to develop and mature, depending on the specific cell type wanted. Here, we describe and characterise a protocol focused on the generation of retinal ganglion cells within an accelerated four week timeframe without any external small molecules or growth factors. Subsequent long term cultures yield fully differentiated organoids displaying all major retinal cell types. RPE, Horizontal, Amacrine and Photoreceptors cells were generated using external factors to maintain lamination.
Purpose: To compare the diagnostic performance and to evaluate the interrelationship of electroretinographical and structural and vascular measures in glaucoma. Methods: For 14 eyes of 14 healthy controls and 15 eyes of 12 patients with glaucoma ranging from preperimetric to advanced stages optical coherence tomography (OCT), OCT-angiography (OCT-A), and electrophysiological measures (multifocal photopic negative response ratio [mfPhNR] and steady-state pattern electroretinography [ssPERG]) were applied to assess changes in retinal structure, microvasculature, and function, respectively. The diagnostic performance was assessed via area-under-curve (AUC) measures obtained from receiver operating characteristics analyses. The interrelation of the different measures was assessed with correlation analyses. Results: The mfPhNR, ssPERG amplitude, parafoveal (pfVD) and peripapillary vessel density (pVD), macular ganglion cell inner plexiform layer thickness (mGCIPL) and peripapillary retinal nerve fiber layer thickness (pRNFL) were significantly reduced in glaucoma. The AUC for mfPhNR was highest among diagnostic modalities (AUC: 0.88, 95% confidence interval: 0.75-1.0, P < 0.001), albeit not statistically different from that for macular (mGCIPL: 0.76, 0.58-0.94, P < 0.05; pfVD: 0.81, 0.65-0.97, P < 0.01) or peripapillary imaging (pRNFL: 0.85, 0.70-1.0, P < 0.01; pVD: 0.82, 0.68-0.97, P < 0.01). Combined functional/vascular measures yielded the highest AUC (mfPhNR-pfVD: 0.94, 0.85-1.0, P < 0.001). The functional/structural measure correlation (mfPhNR-mGCIPL correlation coefficient [rs]: 0.58, P = 0.001; mfPhNR-pRNFL rs: 0.66, P < 0.001) was stronger than the functional-vascular correlation (mfPhNR-pfVD rs: 0.29, P = 0.13; mfPhNR-pVD rs: 0.54, P = 0.003). Conclusions: The combination of ERG measures and OCT-A improved diagnostic performance and enhanced understanding of pathophysiology in glaucoma. Translational relevance: Multimodal assessment of glaucoma damage improves diagnostics and monitoring of disease progression.
In this study, 1) we mathematically predict Retinal Vascular Resistance (RVR) and Retinal Blood Flow (RBF), 2) we test predictions using Laser Speckle Flowgraphy (LSFG), 3) we estimate the range of vascular autoregulation, and 4) we examine the relationship of RBF with the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). Fundus, OCT, and OCT-angiography images, systolic/diastolic blood pressure (SBP/DBP), and intraocular pressure (IOP) measurements were obtained from 36 human subjects. We modeled two circulation markers (RVR and RBF) and estimated individualized lower/higher autoregulation limits (LARL/HARL), using retinal vessel calibers, fractal dimension, perfusion pressure, and population-based hematocrit values. Quantitative LSFG waveforms were extracted from vessels of the same eyes, before and during IOP elevation. LSFG metrics explained most variance in RVR (R2=0.77/P=6.9·10-9) and RBF (R2=0.65/P=1.0·10-6), suggesting that the markers strongly reflect blood flow physiology. Higher RBF was associated with thicker RNFL (P=4.0·10-4) and GCC (P=0.003), thus also verifying agreement with structural measurements. LARL was at SBP/DBP of 105/65 mmHg for the average subject without arterial hypertension, and at 115/75 mmHg for the average hypertensive subject. Moreover, during IOP elevation, changes in RBF were more pronounced than changes in RVR. These observations physiologically imply that healthy subjects are already close to LARL, thus prone to hypoperfusion. In conclusion, we modeled two clinical markers and described a novel method to predict individualized autoregulation limits. These findings could improve understanding of retinal perfusion and pave the way for personalized intervention decisions, when treating patients with coexisting ophthalmic and cardiovascular pathologies.
fMRI studies in macular degeneration (MD) and retinitis pigmentosa (RP) demonstrated that responses in the lesion projection zones (LPZ) of V1 are task related, indicating significant limits of bottom-up visual system plasticity in MD and RP. In advanced glaucoma (GL), a prevalent eye disease and leading cause of blindness, the scope of visual system plasticity is currently unknown. We performed 3T fMRI in patients with extensive visual field defects due to GL (n=5), RP (n=2) and healthy controls (n=7; with simulated defects). Participants viewed contrast patterns drifting in 8 directions alternating with uniform gray and performed 3 tasks: (1) passive viewing (PV), (2) one-back task (OBT) and (3) fixation-dot task (FDT). During PV, they passively viewed the stimulus with central fixation, during OBT they reported the succession of the same two motion directions, and during FDT a change in the fixation color. In GL, LPZ responses of the early visual cortex (V1, V2 and V3) shifted from negative during PV to positive for OBT [p (corrected): V1(0.006); V2(0.04); V3(0.008)], while they were negative in the controls’ simulated LPZ for all stimulation conditions. For RP a similar pattern as for GL was observed. Consequently, activity in the de-afferented visual cortex in glaucoma is, similar to MD and RP, task-related. In conclusion, the lack of bottom-up plasticity appears to be a general feature of the human visual system. These insights are of importance for the development of treatment and rehabilitation schemes in glaucoma. Highlights Functional dynamics of early visual cortex LPZ depend on task demands in glaucoma Brain activity in deprived visual cortex suggests absence of large-scale remapping Limited scope of bottom-up plasticity is a general feature of human visual system Visual system stability and plasticity is of relevance for therapeutic advances
Purpose: To explore the feasibility of using various easy-to-obtain biomarkers to monitor non-compliance (measurement error) during visual field assessments. Methods: Forty-two healthy adults (42 eyes) and seven glaucoma patients (14 eyes) underwent two same-day visual field assessments. An ordinary webcam was used to compute seven potential biomarkers of task compliance, based primarily on eye gaze, head pose, and facial expression. We quantified the association between each biomarker and measurement error, as defined by (1) test-retest differences in overall test scores (mean sensitivity), and (2) failures to respond to visible stimuli on individual trials (stimuli -3 dB or more brighter than threshold). Results: In healthy eyes, three of the seven biomarkers were significantly associated with overall (test-retest) measurement error (P = 0.003-0.007), and at least two others exhibited possible trends (P = 0.052-0.060). The weighted linear sum of all seven biomarkers was associated with overall measurement error, in both healthy eyes (r = 0.51, P < 0.001) and patients (r = 0.65, P < 0.001). Five biomarkers were each associated with failures to respond to visible stimuli on individual trials (all P < 0.001). Conclusions: Inexpensive, autonomous measures of task compliance are associated with measurement error in visual field assessments, in terms of both the overall reliability of a test and failures to respond on particular trials ("lapses"). This could be helpful for identifying low-quality assessments and for improving assessment techniques (e.g., by discounting suspect responses or by automatically triggering comfort breaks or encouragement). Translational relevance: This study explores a potential way of improving the reliability of visual field assessments, a crucial but notoriously unreliable clinical measure.
Purpose: The aim of this study was to investigate the safety and performance of the second generation of an implantable intraocular pressure (IOP) sensor in patients with primary open angle glaucoma (POAG). Design: prospective, non-comparative, open-label, multicenter clinical investigation METHODS: In this study patients with POAG, regularly scheduled for cataract surgery, were implanted with a ring-shaped, sulcus placed, foldable IOP sensor in a single procedure after intraocular lens implantation. Surgical complications as well as adverse events (AEs) during 12 months of follow-up were recorded. At each follow-up visit, a complete ophthalmic examination, including visual acuity, IOP, slit lamp examination, and dilated funduscopy as well as comparative measurements between Goldmann applanation tonometry and the EYEMATE-IO implant were performed. Results: The EYEMATE-IO implant was successfully implanted in 22 patients with few surgical complications and no unexpected device-related AEs. All ocular AEs resolved quickly under appropriate treatment. Comparative measurements showed good agreement between EYEMATE-IO and Goldmann applanation tonometry (GAT) with an intraclass correlation coefficient (ICC(3,k)) of 0.783 (95%CI: 0.743 - 0.817). EYEMATE-IO measurements were higher than GAT with a mean difference of 3.2 mmHg (95%CI: 2.8 - 3.5 mmHg). Conclusions: The EYEMATE-IO sensor was safely implanted in 22 patients and performed reliably until the end of follow-up. This device allows for continual and long-term measurements of IOP.
Purpose (1) To mathematically predict retinal vascular resistance and blood flow from minimal input; (2) to validate the model predictions in a healthy population using Laser Speckle Flowgraphy (LSF). Methods Fundus photographs, OCT and OCT‐angiography scans, and systolic/diastolic blood pressure (SBP/DBP) and intraocular pressure (IOP) measurements were performed in 32 healthy subjects. Predicted vascular resistance (PVR) was determined from the central retinal artery and vein equivalents, the fractal dimension of the vasculature, and population‐based hematocrit values, according to the Poiseuille law and an adapted version of the fractal model proposed by Takahashi et al. (2009). Predicted blood flow (PBF) was calculated as OPP/PVR, where OPP is the ocular perfusion pressure. For validation, the mean blur rate (MBR; measure of velocity) of large vessels inside the optic disc and waveform parameters (heart rate [HR], flow acceleration index [FAI], skew, acceleration time index, blowout score and time, fluctuation, rising rate, falling rate [FR]) were recorded by means of LSF. Linear models reduced by the Akaike Information Criterion were used to assess the relationship of PVR and PBF with the LSF parameters. Results In the reduced multivariable model, PVR was higher with higher DBP (p < 0.001), FAI (p < 0.001), and FR (p = 0.042), as well as with lower skew (p < 0.001), MBR (p = 0.001), and fluctuation (p = 0.103). PBF was higher with higher skew (p < 0.001) and MBR (p = 0.040), as well as with lower FAI (p < 0.001) and HR (p = 0.055). The R² of the models was 0.83 and 0.58, respectively. PVR correlated with retinal nerve fiber layer thickness (RNFLT), but not with macular volume (r = −0.53, p = 0.002; r = −0.218, p = 0.23). PBF correlated with macular volume, but not with RNFLT (r = 0.382, p = 0.031; r = 0.326, p = 0.068). Conclusions PVR can be used as a surrogate of vascular resistance. PBF provided a lesser fit with the LSF parameters and partially describes retinal blood flow. Reference Takahashi T, Nagaoka T, Yanagida H, et al. (2009). A mathematical model for the distribution of hemodynamic parameters in the human retinal microvascular network. J Biorheol 23:77‐86
Assessing the presence of visual field defects (VFD) is essential in the diagnosis and management of ocular disorders. Grillini et al.,  recently proposed an alternative approach to Standard Automated Perimetry to assess the consequences of simulated visual field defects. The goal of the present exploratory study was to evaluate this approach in a clinical context. During the test, a patient performs a visual tracking task while their eye movements (EM) are recorded. EM are intuitive to make and allow for continuous response monitoring. The test has two conditions in which the dot either moves in a continuous random walk (“smooth”) or additionally moves with sudden positional displacements (“displaced”). Subsequently, the spatio-temporal parameters of the eye movements are computed for both conditions. We assessed 34 Indian patients (23 male, age range: 17-66 yrs, mean age: 37.7 yrs) who were diagnosed with various ocular disorders (Primary Open Angle Glaucoma (POAG), patients who were either suspected/at risk to have glaucoma, optic atrophy, advanced glaucomatous neuropathy and hemianopia) and 15 controls (9 male, age range: 23-45 yrs, mean age: 26.6 yrs). The test compares a patient’s performance to that of a normative control population (previously assessed in the Netherlands (age range: 30--80, 8 observers per decade, 4 male). To illustrate its outcome parameters, we highlight the case of patient P08 (male, 40 yrs) who was suspected of glaucoma. Our method confirms that while his performance on the “smooth” condition was preserved (Figs. G, I & J), his “displaced” performance clearly deviated from the norm (Figs. H, K & L). This result suggests that, under the absence of other underlying neurological pathologies, the peripheral vision is impaired as compared to the central vision, which would align with a typical glaucomatous VFD. We conclude that the new test has clear potential as a screening tool in clinical practice and that eye movements can reveal the perceptual consequences of ophthalmic disorders.
Perimetry---assessment of visual field defects (VFD)---requires patients to be able to maintain a prolonged stable fixation, as well as to provide feedback through motor response. These aspects limit the testable population and often lead to inaccurate results. We hypothesized that different VFD would alter the eye-movements in systematic ways, thus making it possible to infer the presence of VFD by quantifying the spatio-temporal properties of eye movements. We developed a tracking test to record participant's eye-movements while we simulated different gaze-contingent VFD. We tested 50 visually healthy participants and simulated three common scotomas: peripheral loss, central loss and hemifield loss. We quantified spatio-temporal features using cross-correlogram analysis, then applied cross-validation to train a decision tree algorithm to classify the conditions. Our test is faster and more comfortable than standard perimetry and can achieve a classifying accuracy of ∼90% (True Positive Rate = ∼98%) with data acquired in less than 2 minutes.
Purpose To compare rates of visual field (VF) loss in uveitis patients with glaucoma against patients with primary open angle glaucoma (POAG) and explores the association between intraocular pressures (IOP) and rate of VF loss. Methods: Anonymized VFs and IOP measurements extracted from the EMR of 5 regionally different glaucoma clinics in England. A total of 205 eyes with diagnosis of “uveitis” plus “glaucoma” were compared with 4600 eyes with “POAG” only. Minimum inclusion criteria was ≥4 visits within a 4-year window. Relative risk (RR) of being a “rapid progressor” (mean deviation (MD) loss ≥1.5 dB/year) was calculated. A mixed-effects model (MEM) and a pointwise VF progression analysis of pattern deviation was used to confirm differences between the groups. Longitudinal IOP mean, range and variability were compared with rate of VF progression. Results: Median (IQR) baseline MD in the uveitis and POAG groups was –3.8 (-8.7, -1.5) dB and –3.1 (-6.6, -1.2) dB respectively. The uveitis and POAG groups had 23/205 (11%) and 331/4600 (7%) “rapidly progressing” eyes respectively. Age-adjusted RR for “rapid progression” in uveitic versus POAG eyes was 1.9 (95% CI:1.8-2.0). The MEM confirmed that uveitic eyes (-0.49 dB/year) showed higher rates of VF progression than the POAG group (-0.37 dB/year; p<0.01). IOP range and variability were higher in the “rapidly progressing” uveitic eyes. Conclusions: Our analysis suggests that VF loss occurs faster in glaucoma patients with uveitis than those without uveitis. The risk of progressing rapidly in glaucoma with uveitis is almost double than in those without uveitis. Early identification of “rapid progressors” may enable targeted intervention to preserve visual function in this high-risk group.
Background: There are more than one million National Health Service visits in England and Wales each year for patients with glaucoma or ocular hypertension (OHT). With the ageing population and an increase in optometric testing, the economic burden of glaucoma-related visits is predicted to increase. We examined the conversion rates of OHT to primary open-angle glaucoma (POAG) in England and assessed factors associated with risk of conversion. Methods: Electronic medical records of 45 309 patients from five regionally different glaucoma clinics in England were retrospectively examined. Conversion to POAG from OHT was defined by deterioration in visual field (two consecutive tests classified as stage 1 or worse as per the glaucoma staging system 2). Cox proportional hazards models were used to examine factors (age, sex, treatment status and baseline intraocular pressure (IOP)) associated with conversion. Results: The cumulative risk of conversion to POAG was 17.5% (95% CI 15.4% to 19.6%) at 5 years. Older age (HR 1.35 per decade, 95% CI 1.22 to 1.50, p<0.001) was associated with a higher risk of conversion. IOP-lowering therapy (HR 0.45, 95% CI 0.35 to 0.57, p<0.001) was associated with a lower risk of conversion. Predicted 5-year conversion rates for treated and untreated groups were 14.0% and 26.9%, respectively. Conclusion: Less than one-fifth of OHT patients managed in glaucoma clinics in the UK converted to POAG over a 5-year period, suggesting many patients may require less intensive follow-up. Our study provides real-world evidence for the efficacy of current management (including IOP-lowering treatment) at reducing risk of conversion.
Objective This study aimed to demonstrate that large-scale visual field (VF) data can be extracted from electronic medical records (EMRs) and to assess the feasibility of calculating metrics from these data that could be used to audit aspects of service delivery of glaucoma care. Method and analysis Humphrey visual field analyser (HFA) data were extracted from Medisoft EMRs from five regionally different clinics in England in November 2015, resulting in 602 439 records from 73 994 people. Target patients were defined as people in glaucoma clinics with measurable and sustained VF loss in at least one eye (HFA mean deviation (MD) outside normal limits ≥2 VFs). Metrics for VF reliability, stage of VF loss at presentation, speed of MD loss, predicted loss of sight years (bilateral VF impairment) and frequency of VFs were calculated. Results One-third of people (34.8%) in the EMRs had measurable and repeatable VF loss and were subject to analyses (n=25 760 patients). Median (IQR) age and presenting MD in these patients were 71 (61, 78) years and −6 (–10, –4) dB, respectively. In 19 264 patients with >4 years follow-up, median (IQR) MD loss was −0.2 (−0.8, 0.3) dB/year and median (IQR) intervals between VF examinations was 11 (8, 16) months. Metrics predicting loss of sight years and reliability of examinations varied between centres (p<0.001). Conclusion This study illustrates the feasibility of assessing aspects of health service delivery in glaucoma clinics through analysis of VF databases. Proposed metrics could be useful for blindness prevention from glaucoma in secondary care centres.
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Objectives: To optimize stimulation parameters for electroretionographic recordings of the multifocal photopic negative response (mfPhNR) for the detection of glaucoma and to compare the diagnostic accuracy of electrophysiological, structural and functional measures of glaucoma. Methods: In 24 healthy controls, 10 glaucoma suspects (GLAS) and 16 glaucoma participants (GLAG), mfPhNR for 6 different stimulation rates were assessed to compare their discrimination performance. Subsequently, a cross-modal comparison of the mfPhNR/b-wave ratio was performed with pattern electroretinogram (PERG), and peripapillary retinal nerve fiber layer (pRNFL) thickness. These analyses were based on area under curves (AUC) obtained from receiver-operating-characteristics (ROC) analyses and step-wise regression analyses. Results: Compared to the other mfPhNR-conditions, the PhNR/b-wave ratio for the fastest stimulation condition had the highest AUC for GLAS (0.84, P = 0.008, 95%CI: 0.71- 0.98); the other modalities, i.e., PERG-amplitude and pRNFL had AUCs of 0.77, and 0.74 respectively. pRNFL was the significant predictor for mfPhNR/b-wave ratio [t (48) = 4, P 0.0002]. Conclusions: Fast mfPhNR protocols outperform other mf-protocols in the identification of glaucomatous damage especially for GLAS and thus aid the early detection of glaucoma. Significance. mfPhNR recordings might serve as surrogate marker of ganglion cell dysfunction especially in glaucoma suspects.
Previous studies demonstrated that alterations in functional MRI derived receptive field (pRF) properties in cortical projection zones of retinal lesions can erroneously be mistaken for cortical large-scale reorganization in response to visual system pathologies. We tested, whether such confounds are also evident in the normal cortical projection zone of the fovea for simulated peripheral visual field defects. We applied fMRI-based visual field mapping of the central visual field at 3 Tesla in eight controls to compare the pRF properties of the central visual field of a reference condition (stimulus radius: 14°) and two conditions with simulated peripheral visual field defect, i.e., with a peripheral gray mask, stimulating only the central 7° or 4° radius. We quantified, for the cortical representation of the actually stimulated visual field, the changes in the position and size of the pRFs associated with reduced peripheral stimulation using conventional and advanced pRF modeling. We found foveal pRF-positions (≤3°) to be significantly shifted towards the periphery (p<0.05, corrected). These pRF-shifts were largest for the 4° condition [visual area (mean eccentricity shift): V1 (0.9°), V2 (0.9°), V3 (1.0°)], but also evident for the 7° condition [V1 (0.5°), V2 (0.5°), V3 (0.9°)]. Further, an overall enlargement of pRF-sizes was observed. These findings indicate the dependence of foveal pRF parameters on the spatial extent of the stimulated visual field. Consequently, our results imply that, previously reported similar findings in patients with actual peripheral scotomas need to be interpreted with caution and indicate the need for adequate control conditions in investigations of visual cortex reorganization. Keywords: Visual cortex, human, fMRI, visual field defect, fovea, retinotopy
Il n'existe pas de méthode non invasive validée pour déterminer la valeur absolue de la pression intracrânienne (PIC). Le liquide céphalorachidien (LCS) et le liquide cochléaire sont reliés par l'aqueduc cochléaire. Le but de ce projet est d'utiliser l'absorbance de l'oreille, optimale lorsque les structures vibrantes sont en position de repos, de sorte que les étriers lorsque la pression à l'extérieur de l'oreille (dans le conduit auditif externe -P_cae ) contrarie la PIC par les osselets de l'oreille moyenne. Les sujets ont été testés dans différentes positions d'inclinaison du corps, ce qui augmente la PIC, à l'aide d'un tympanomètre à large bande. 78 oreilles (sujets témoins entre 20 et 30 ans) ont montré que l'absorbance est maximale à toutes les fréquences à P_cae = 0 mmH2O en position début, elle diminue de façon complexe à P_cae zéro, mais à nouveau identique l'absorbance maximale à P_cae = 13 mm H2O ± 7 en position allongée, et 23 mm H2O ± 14 en position Trendelenburg (-30°), en 68 oreilles sur 78. Les 10 oreilles restantes présentaient un dysfonctionnement anatomique. Un modèle physique a été établi à partir d'un modèle d'oreille électromécanique classique, qui reproduit le comportement observé en attribuant à la PIC la cause des changements d'absorbance et en prédisant la capacité du P_cae pour compenser les changements d'absorbance dus à la PIC. De plus, 3 patients traités par un test de perfusion ont été testés, ainsi que 2 patients traités par ponction lombaire. Ces patients ont montré l'effet de la pression positive et négative dans les courbes d'absorbance. La littérature permet d'établir une corrélation entre la PIC absolue (dans chaque position du corps) et l'absorbance, nous pouvons conclure qu'en raison de la géométrie de l'oreille moyenne, la relation d'équilibre entre les valeurs absolues est PIC = 15 x P_cae , où 15 est le rapport des surfaces entre la MT et la platine de l’étrier. Des sujets suivis par une mesure invasive de la PIC seront nécessaires pour la continuation de cette étude.
Purpose: Eyemate is a system for the continual monitoring of intraocular pressure (IOP), comprised of an intraocular sensor, and a hand-held reader device. The eyemate-IO sensor is surgically implanted in the eye during cataract surgery. Once implanted, the sensor communicates telemetrically with the hand-held device to activate and record IOP measurements. The aim of this study was to assess the possible influence of electromagnetic radiation emitted by daily-use electronic devices on the eyemate IOP measurements. Methods: The eyemate-IO sensor was placed in a plastic bag, immersed in a sterile sodium chloride solution at 0.9% and placed in a water bath at 37 C. The antenna, connected to a laptop for recording the data, was positioned at a fixed distance of 1 cm from the sensor. Approximately two hours of quasi-continuous measurements was recorded for the baseline and for cordless phone, smart-phone and laptop. Repeated measures ANOVA was used to compare any possible differences between the baseline and the tested devices. Results: For baseline measurements, the sensor maintained a steady-state. The same behavior was observed with the devices measurements during active and inactive states. Conclusion: We found no evidence of signal drifts or fluctuations associated with the tested devices, thus showing a lack of electromagnetic interference with data transmission. Patients who already have the eyemate-IO sensor implanted, or those considering it, can be informed that the electromagnetic radiation emitted by their daily-use electronic devices does not interfere with IOP measurements made by the eyemate-IO sensor.
Purpose: White matter (WM) degeneration of the visual pathways in primary open-angle glaucoma (POAG) is well documented, but its exact pathophysiology remains unclear. To date, glaucomatous WM degeneration has been exclusively studied using diffusion tensor imaging (DTI) only. However, DTI measures lack direct biological interpretation, and the approach itself suffers from multiple technical limitations. Fixel-based analysis (FBA) is a novel framework for studying WM degeneration, overcoming DTI's technical limitations and providing biologically meaningful metrics. FBA measures fiber density (FD), representing early microstructural changes, and fiber-bundle cross section (FC), representing late macrostructural changes. In this study, we use FBA to study glaucomatous degeneration of the pregeniculate optic tracts (OTs) and postgeniculate optic radiation (ORs) in POAG. Methods: This was a cross-sectional case-control study with 12 POAG patients and 16 controls. Multi-shell diffusion-weighted images were acquired. FBA was used to produce a population template, and probabilistic tractography was used to track the OTs and ORs in template space. Finally, FD and FC of the tracts of interest were compared between the two groups. Results: Compared with the controls, the OTs of the patients exhibited a significant (familywise error corrected P < 0.05) decrease in FD and FC, whereas their ORs exhibited a significant decrease in FD but not in FC. Conclusions: FBA provides sensitive measures to assess WM changes in glaucoma. Our findings suggest that the OTs of glaucoma patients exhibit signs of more advanced WM degeneration compared with the ORs. This potentially implicates anterograde trans-synaptic propagation as the primary cause of glaucomatous spread along the visual pathways.
Purpose To test the feasibility of simultaneous steady-state pattern electroretinogram (PERG) and intraocular pressure (IOP) measurements with an IOP sensor and to test a model for IOP manipulation during lateral decubitus positioning (LDP) and its impact on the PERG. Design A prospective, observational study. Methods 15 healthy controls and 15 treated glaucoma patients participated in the study. 8 patients had an intraocular IOP sensor (eyemate-IO ® , Implandata Ophthalmic Products GmbH) in the right eye (GLA IMP ) and 7 had no sensor and with glaucoma in the left eye. (1) We tested the feasibility of simultaneous IOP and PERG recordings by comparing PERGs with and without simultaneous IOP-read out in GLA IMP . (2) All participants were positioned in the following order: sitting1 (S1), right LDP (LD R ), sitting2 (S2), left LDP (LD L ) and sitting3 (S3). For each position, PERG amplitudes and IOP were determined with rebound tonometry (Icare® TA01i) in all participants without the IOP sensor. Results Electromagnetic intrusions of IOP sensor readout onto steady-state PERG-recordings had, due to different frequency ranges, no relevant effect on PERG amplitudes. IOP and PERG measures were affected by LDP, e.g., IOP was increased during LD R vs S1 in the lower eyes of GLA IMP and controls (P < 0.001 and P < 0.05, respectively) and PERG amplitude was decreased (P < 0.05 and P < 0.01, respectively). Conclusions During LDP, IOP and PERG measurements changed more in the lower eye. IOP changes induced by LDP may be a model for studying the interaction of IOP and ganglion cell function.
Purpose: To describe, refine, evaluate, and provide normative control data for two freely available tablet-based tests of real-world visual function, using a cohort of young, normally-sighted adults. Methods: Fifty young (18-40 years), normally-sighted adults completed tablet-based assessments of (1) face discrimination and (2) visual search. Each test was performed twice, to assess test-retest repeatability. Post-hoc analyses were performed to determine the number of trials required to obtain stable estimates of performance. Distributions were fitted to the normative data to determine the 99% population-boundary for normally sighted observers. Participants were also asked to rate their comprehension of each test. Results: Both tests provided stable estimates in around 20 trials (~1-4 min), with only a further reduction of 14%-17% in the 95% Coefficient of Repeatability (CoR95 ) when an additional 40 trials were included. When using only ~20 trials: median durations for the first run of each test were 191 s (Faces) and 51 s (Search); test-retest CoR95 were 0.27 d (Faces) and 0.84 s (Search); and normative 99% population-limits were 3.50 d (Faces) and 3.1 s (Search). No participants exhibited any difficulties completing either test (100% completion rate), and ratings of task-understanding were high (Faces: 9.6 out of 10; Search: 9.7 out of 10). Conclusions: This preliminary assessment indicated that both tablet-based tests are able to provide simple, quick, and easy-to-administer measures of real-world visual function in normally-sighted young adults. Further work is required to assess their accuracy and utility in older people and individuals with visual impairment. Potential applications are discussed, including their use in clinic waiting rooms, and as an objective complement to Patient Reported Outcome Measures (PROMs).
Purpose: To determine the association of statins, five classes of antihypertensive medications, and proton pump inhibitors with (1) primary open-angle glaucoma (POAG) progression and (2) conversion of POAG suspects to POAG. Methods: We retrospectively investigated the records of a cohort with POAG cases and suspects from the Groningen Longitudinal Glaucoma Study. To quantify visual field (VF) deterioration in cases, we used the rate of progression of the mean deviation (MD). Suspects were considered to have converted at the time point after which two consecutive VF tests for at least one eye were abnormal (glaucoma hemifield test outside normal limits). Progression and conversion were analyzed with quantile and logistic regression, respectively, with the systemic medications as predictors, controlling for age, sex, body mass index, pretreatment IOP, corneal thickness, and baseline MD. The multivariable models were built with and without IOP intervention. Results: No systemic medications were associated with POAG progression in the final IOP/treatment-adjusted or unadjusted model. However, angiotensin II receptor blockers (ARBs) appeared to slow progression in older patients (b = 0.014, P = 0.0001). Angiotensin-converting enzyme inhibitors (ACEIs) were significantly associated with a decrease in POAG suspect conversion in both the IOP/treatment-adjusted and -unadjusted model (odds ratio [OR] 0.23, 95% confidence interval [CI] 0.07-0.79, P = 0.012; OR=0.24, 95% CI 0.07-0.78, P = 0.021, respectively), as were ARBs (OR 0.12, 95% CI 0.01-0.98, P = 0.014; OR 0.11, 95% CI 0.01-0.87, P = 0.005, respectively). Conclusions: No overall association of VF progression with systemic medication was found; ARBs delayed progression in older patients. ACEIs and ARBs were associated with lower risk of suspect conversion. The pathophysiology of this relationship is to be disentangled.
Purpose: To determine the intrasession repeatability (test-retest variability) of parafoveal and peripapillary perfused capillary density (PCD) and normalized flux index (NFI) as assessed with Canon OCT-HS100 angiography. Methods: Pairs of optical coherence tomography angiography (OCT-A) images were obtained from the parafoveal and peripapillary region of 30 eyes of 30 healthy subjects. PCD and NFI were calculated using generic image-processing software. Macular ganglion-cell complex thickness (GCC) and peripapillary retinal nerve fiber layer thickness (RNFLT) were also recorded. Bland-Altman analysis was performed and the coefficient of repeatability (CoR) and intraclass correlation coefficient (ICC) were calculated. Correlations of parafoveal PCD/NFI with GCC and of peripapillary PCD/NFI with RNFLT were also computed. Results: Mean (standard deviation) parafoveal and peripapillary PCD were 40.0% (1.8%) and 44.5% (1.3%), respectively. Corresponding values for NFI were 151.2 (6.8) and 164.2 (3.9). For PCD, ICC was 0.76 for parafoveal and 0.79 for peripapillary measurements; corresponding CoRs were 2.7% and 1.8%. Corresponding values for NFI were 0.62 and 0.67 for ICC and 13.3 and 7.0 for CoR. Average measures ICC was 0.87/0.88 and 0.76/0.80 for the parafoveal/peripapillary PCD and NFI, respectively. PCD and NFI were weakly correlated with GCC (r = 0.39, P = 0.035; r = 0.33, P = 0.077) and moderately correlated with RNFLT (r = 0.43, P = 0.017; r = 0.55, P = 0.002). Conclusions: Repeatability of a commercially available OCT-A with generic image-processing software was good (NFI) to excellent (PCD). Our results indicate that changes surpassing the variability in healthy subjects should be easily detectable in a clinical setting. Translational relevance: Repeatability estimates provide information regarding the relevance of changes in retinal perfusion.