Retinal Functional and Structural Neural Indices: Potential Biomarkers for the Monitoring of Cerebral Neurodegeneration: The Maastricht Study.

BACKGROUND: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. OBJECTIVE: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. METHODS: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). RESULTS: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. CONCLUSION: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

Alcohol consumption and microvascular dysfunction: a J-shaped association: The Maastricht Study.

BACKGROUND: Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. OBJECTIVE: Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. DESIGN: We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. RESULTS: The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction < 0.001), and glucose metabolism status (Pinteraction = 0.02). CONCLUSIONS: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions.

(Pre)diabetes, glycemia, and daily glucose variability are associated with retinal nerve fiber layer thickness in The Maastricht Study.

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively - 0.16 [- 0.25; - 0.08]; - 0.05 [- 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively - 0.05 [- 0.08; - 0.01]; - 0.06 [- 0.09; - 0.02]; - 0.05 [- 0.08; - 0.02]; - 0.04 [- 0.07; - 0.01]; - 0.06 [- 0.12; - 0.01]; and - 0.07 [- 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.

Economic evaluation of prevention of cystoid macular edema after cataract surgery in diabetic patients: ESCRS PREMED study report 6.

PURPOSE: To investigate the cost-effectiveness of prophylactic treatments against cystoid macular edema after cataract surgery in diabetic patients. SETTING: 7 ophthalmology clinics in the Netherlands and Belgium. DESIGN: Prospective trial-based cost-effectiveness analysis using data from a European multicenter randomized clinical trial. METHODS: Diabetic patients (n = 163) undergoing uneventful cataract surgery were randomized to perioperative subconjunctival triamcinolone acetonide (n = 36), perioperative intravitreal bevacizumab (n = 36), combination treatment (n = 45), or no additional treatment (control group, n = 46). The cost analysis was performed from a healthcare perspective within a 12-week postoperative time horizon. The main effectiveness outcome was quality-adjusted life years (QALYs). The main cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER; cost per QALY). RESULTS: The mean total healthcare costs and QALYs were as follows: triamcinolone group €1827 (U.S. dollars [$] 2295)/0.166; bevacizumab group €2050 ($2575)/0.144; combination group €2027 ($2546)/0.166; and control group €2041 ($2564)/0.156. Bevacizumab and control treatment were most costly and least effective. The ICER was €321 984 ($404 503) per QALY for the combination group compared with that of the triamcinolone group. Assuming the willingness-to-pay as €20 000 ($25 126) per QALY, the cost-effectiveness probability was 70% and 23% in the triamcinolone and combination groups, respectively. No patient who received triamcinolone developed clinically significant macular edema (CSME). A secondary cost-effectiveness analysis based on this outcome showed a clear preference for triamcinolone. CONCLUSIONS: In diabetic patients, subconjunctival triamcinolone was effective in preventing CSME after cataract surgery. The cost-effectiveness analysis showed that triamcinolone is also cost-effective.

Effect of combined water drinking test and dark room provocative testing in Caucasian eyes with narrow angles.

PURPOSE: To assess the usefulness of water drinking test and dark room provocative testing (WDT + DRPT) in current clinical practice by evaluating input parameters from Swept-source Optical Coherence Tomography (SS-OCT) images, and to determine if clinical factors like axial length, central endothelial cell count (CECC) and retinal nerve fibre layer thickness (RNFL) thickness are associated with a positive WDT + DRPT. METHODS: SS-OCT examination was performed in consecutive subjects presenting as new patients in the outpatient clinic aged > 40 years. If at least one eye met the inclusion criteria (anterior chamber angles <20° and anterior chamber depth < 2.5 mm on SS-OCT), subjects were included in this study and WDT + DRPT was carried out. The eye with the smallest angle was analysed. The difference in parameters between eyes with a positive (≥8 mmHg) and negative (<8 mmHg) increase in intraocular pressure (IOP) after WDT + DRPT were statistically analysed. Second, the correlation between IOP increase after WDT + DRPT and anterior chamber angle parameters (RNFL thickness, CECC and axial length) was studied. RESULTS: A total of 95 subjects with a mean age of 64 years were included. There was an association between IOP increase after WDT + DRPT and anterior chamber angle characteristics, however this was not of clinical significance. No positive results after WDT + DRPT were found in patients with anterior chamber angles ≥ 20°. CONCLUSIONS: The present findings indicate that this combined provocative test has no definite correlative or predictive value in angle closure disease. Further, the test is not useful in predicting early diagnosis or possible CECC or RNFL loss.

Association of Retinal Nerve Fiber Layer Thickness, an Index of Neurodegeneration, With Depressive Symptoms Over Time.

Importance: Whether neurodegeneration contributes to the early pathobiology of late-life depression remains incompletely understood. Objective: To investigate whether lower retinal nerve fiber layer (RNFL) thickness, a marker of neurodegeneration, is associated with the incidence of clinically relevant depressive symptoms and depressive symptoms over time. Design, Setting, and Participants: This is a population-based cohort study from the Netherlands (The Maastricht Study) with baseline examination between 2010 and 2020 and median (IQR) follow-up of 5.0 (3.0-6.0) years. Participants were recruited from the general population. Individuals with type 2 diabetes were oversampled by design. Data analysis was performed from September 2020 to January 2021. Exposures: RNFL, an index of neurodegeneration, assessed with optical coherence tomography. Main Outcomes and Measures: Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ)-9 (continuous score, 0-27) at baseline and over time via annual assessments. The presence of clinically relevant depressive symptoms was defined as a PHQ-9 score of 10 or higher. Results: We used data from 4934 participants with depressive symptoms over time (mean [SD] age, 59.7 [8.4] years; 2159 women [50.8%]; 870 had type 2 diabetes [20.5%]). Lower RNFL thickness was associated with higher incidence of clinically relevant depressive symptoms (per 1 SD, hazard ratio 1.11; 95% CI, 1.01-1.23) and more depressive symptoms over time (per 1 SD, rate ratio, 1.04; 95% CI, 1.01-1.06), after adjustment for demographic, cardiovascular, and lifestyle factors. Conclusions and Relevance: The findings of this study suggest that lower RNFL thickness is associated with higher incidence of clinically relevant depressive symptoms and more depressive symptoms over time. Hence, neurodegeneration may be associated with the early pathobiology of late-life depression.

Carotid stiffness is associated with retinal microvascular dysfunction-The Maastricht study.

OBJECTIVE: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy. RESEARCH DESIGN AND METHODS: This study used cross-sectional data from the Maastricht Study, a type 2 diabetes-enriched population-based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid-femoral pulse wave velocity with retinal microvascular diameters and flicker light-induced dilation and adjusted for cardiovascular and lifestyle risk factors. RESULTS: The retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light-induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non-significantly, but directionally similarly, associated with greater retinal venular flicker light-induced dilation (0.04 [-0.02; 0.10]). Carotid-femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light-induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light-induced dilation were two- to threefold stronger in individuals with type 2 diabetes than in those without. CONCLUSION: In this population-based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light-induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction.

Contributing ocular comorbidity to end-of-life visual acuity in medically treated glaucoma patients, ocular hypertension and glaucoma suspect patients.

AIM: To assess the visual acuity at the end of life in glaucoma suspect patients, ocular hypertension, and patients treated for glaucoma and to find factors contributing to a reduced visual acuity in this cohort of deceased patients. METHODS: In a cohort of 3883 medically treated glaucoma patients, glaucoma suspect, or patients with ocular hypertension assembled in 2001-2004, 1639 were deceased. Patient data were collected from electronic and paper patient files. The files of 1378 patients were studied and the last measured visual acuity and ocular comorbidities influencing the visual acuity were extracted. RESULTS: Our results show that only 37.2% of patients had no visual impairment in either eye, 30.5% was visually impaired or blind in both eyes and 4.1% was blind in both eyes, all based on VA. The most common contributing factors for severe visual impairment or blindness (prevalence ≥ 1%) were: glaucoma, retinal vein occlusion, dry and exudative age-related macular degeneration, past retinal detachment, amblyopia, diabetic retinopathy, anterior ischemic optic neuropathy, trauma, decompensated cornea, past keratitis, enucleation, corneal transplantation, and macular hole. CONCLUSIONS: Despite the current advanced treatment modalities for glaucoma, 30.5% of patients had a VA < 0.5 in both eyes and 4.1% was blind in both eyes. However, this disability cannot be confidently attributed only to glaucoma. Besides glaucoma, most common contributing factors were among others retinal and macular diseases. Patient management in glaucoma should be based on more than lowering the intraocular pressure to prevent blindness at the end of life.

Vascular risk factors for optical coherence tomography-detected macular cysts: The Maastricht Study.

PURPOSE: To investigate whether higher blood pressure and greater arterial stiffness are associated with the presence of macular cysts and whether this association is already present in the absence of micro-aneurysms in individuals with and without type 2 diabetes. METHODS: Using spectral domain optical coherence tomography (OCT), we performed a macular volume scan in 2647 individuals (mean age 60 ± 8 years, 50% men, 27% type 2 diabetes). The association between macular cysts and 24-hour systolic and diastolic blood pressure, pulse pressure, mean arterial blood pressure, carotid-femoral pulse wave velocity and carotid distensibility was assessed by use of logistic regression. RESULTS: Twenty-four hours systolic blood pressure was associated with the presence of macular cysts [OR = 1.03 (95% CI 1.00-1.05) per 1 mmHg, p = 0.03]. 24 hr pulse pressure [OR = 1.61 (95% CI 1.11-2.34) per 10 mmHg, p = 0.01] and carotid-femoral pulse wave velocity [OR = 1.16 (95% CI 1.02-1.32) per 1 m/s, p = 0.02] were associated with macular cysts, while carotid distensibility was not [OR = 1.03 (95% CI 0.96-1.11) per 1.0*10-3 /kPa, p = 0.45]. Associations were similar in individuals with and without type 2 diabetes and were already present in the absence of micro-aneurysms. CONCLUSION: Twenty-four hours systolic blood pressure, 24 hr pulse pressure and carotid-femoral pulse wave velocity are associated with the presence of OCT-detected macular cysts in individuals with and without type 2 diabetes, even in the absence of micro-aneurysms. Therefore, blood pressure and aortic stiffness are potential factors contributing to macular cysts.

Economic evaluation of prevention of cystoid macular edema after cataract surgery in patients without diabetes: ESCRS PREMED study report 4.

PURPOSE: To investigate the cost-effectiveness of prophylactic treatments against cystoid macular edema (CME) after cataract surgery in patients without diabetes. SETTING: Seven ophthalmology clinics in the Netherlands and Belgium. DESIGN: Prospective cost-effectiveness analysis using data from a European multicenter randomized clinical trial (ESCRS PREMED). METHODS: Patients without diabetes planned for expected uneventful cataract surgery were randomized to topical bromfenac (Yellox, n = 242), topical dexamethasone (n = 242), or a combination treatment (n = 238). All relevant resources from a healthcare perspective were included in the cost analysis within a time horizon of 12 weeks postoperatively. The main effectiveness outcome was quality-adjusted life years (QALYs). The main cost-effectiveness outcome was the incremental cost-effectiveness ratio (ICER) based on the cost per QALY. RESULTS: The study comprised 722 patients without diabetes. Total healthcare costs and QALYs were € 447 (US $562) and 0.174 in the bromfenac group, €421 (US $529) and 0.179 in the dexamethasone group, and €442 (US $565) and 0.182 in the combination group. Bromfenac was most costly and least effective (ie, strongly dominated). The ICER was €6544 (US $8221) per QALY for the combination group compared with the dexamethasone group. Assuming that the willingness to pay is € 20 000 (US $25 126) per QALY, the cost-effectiveness probability was 3%, 32%, and 65% in the bromfenac, dexamethasone, and combination groups, respectively. CONCLUSIONS: In patients without diabetes, combination treatment with topical bromfenac and dexamethasone was effective and cost-effective in preventing CME after cataract surgery compared with treatment with either drug alone.

Blood pressure variability and microvascular dysfunction: the Maastricht Study.

BACKGROUND: Microvascular dysfunction (MVD) contributes to stroke, dementia, depression, retinopathy and chronic kidney disease. However, the determinants of MVD are incompletely understood. Greater blood pressure variability (BPV) may be one such determinant. METHODS AND RESULTS: We used cross-sectional data of The Maastricht Study (n = 2773, age 59.9 years; 51.9% men) to investigate whether greater very short- to mid-term BPV is associated with various MVD measures. We standardized and averaged within-visit, 24-h and 7-day BPV into a systolic and a diastolic BPV composite score. MVD measures included a composite score of MRI cerebral small vessel disease (CSVD) features (total brain parenchymal volume, white matter hyperintensity volume, lacunar infarcts and cerebral microbleeds), a composite score of flicker light-induced retinal arteriolar and venular dilation response, albuminuria, heat-induced skin hyperemia and a composite score of plasma biomarkers of MVD (sICAM-1, sVCAM-1, sE-selectin and von Willebrand Factor). We used linear regression adjusted for age, sex, glucose metabolism status, mean 24-h systolic or DBP, cardiovascular risk factors and antihypertensive medication. We found that higher systolic and diastolic BPV composite scores (per SD) were associated with higher albuminuria [higher ratio, 1.04 (95% CI 1.00-1.08) and 1.07 (1.03-1.11), respectively], but not with other measures of MVD tested. CONCLUSION: Greater systolic and diastolic BPV was associated with higher albuminuria, but not with CSVD features, flicker light-induced retinal arteriolar and venular dilation response, heat-induced skin hyperemia and plasma biomarkers of MVD. This suggests that the microvasculature of the kidneys is most vulnerable to the detrimental effects of greater BPV.

Reduced corneal nerve fibre length in prediabetes and type 2 diabetes: The Maastricht Study.

PURPOSE: In individuals with diabetes, injury to the corneal nerve fibres predisposes to delayed corneal epithelial healing, reduced corneal sensitivity and corneal erosion. We investigated to what extent a reduction in corneal nerve fibre length (CNFL) is present in individuals with prediabetes or type 2 diabetes (DM2) compared with individuals with normal glucose metabolism (NGM). METHODS: Using composite images acquired by corneal confocal microscopy, we assessed total CNFL per mm2 in the subbasal nerve plexus of the cornea in 134 participants (mean age 59 ± 8 years, 49% men, 87 NGM, 20 prediabetes, 27 DM2). Multivariable linear regression was used to assess the association between CNFL and glucose metabolism status, adjusted for age and sex. RESULTS: In individuals with type 2 diabetes, the mean CNFL was significantly reduced [ß = -1.86 mm/mm2 (95% CI -3.64 to -0.08), p = 0.04], as compared with individuals with normal glucose metabolism after adjustment for age and sex. Part of the reduction was present in individuals with prediabetes [ß = -0.96 mm/mm2 (95% CI -2.91 to 0.99), p = 0.34], with a linear trend of corneal nerve fibre reduction with severity of glucose metabolism status (p trend = 0.04). CONCLUSIONS: A significant reduction in CNFL was found in individuals with DM2 compared with individuals with NGM. A trend of reduction in CNFL was observed between individuals with NGM and prediabetes. The reduction in corneal nerve fibre length could contribute to a delayed corneal healing and an increased risk for corneal complications after surgery.

A systematic approach to evaluate practice-based process- and outcome data applied to the treatment of neovascular age-related macular degeneration.

BACKGROUND: Following the principles of value-based health care, outcomes and processes of daily-practice eye care need to be systematically evaluated. We illustrate an approach that can be used to support data-driven quality improvements. We used patient data regarding the treatment of neovascular age-related macular degeneration (nAMD). METHODS: In a cohort study, we reviewed medical records of patients with nAMD confirmed on fluorescein angiography (FA). Patients were treated with intravitreal injections with bevacizumab; ranibizumab; or photodynamic therapy (PDT). Visual acuity (VA), ophthalmic exam results and treatments were recorded. VA was compared between treatments by linear mixed model. Diagnosis was re-evaluated on the original FAs. Outcome analysis was performed by 1) selecting VA as the relevant outcome parameter; 2) Preventing selection by comparing treatments with historical untreated cohort and cohorts from the literature, 3) correcting for confounding due to lesion type, and 4) identifying relevant process variables that affect the outcome. These were severity of disease at presentation, and doctor- and patient dependent process variables. RESULTS: In total, 473 eyes were included. At 12 months, change in VA was 0.54, 0.48, 0.09, and 0.07 LogMAR in the no-treatment, photodynamic therapy (PDT), bevacizumab, and ranibizumab groups, respectively. Lesion type on FA differed between groups. Diagnosis of nAMD could not be confirmed in 104 patients. Patient delay, inaccurate diagnosis and treatment intervals may have impacted outcomes. CONCLUSIONS: The effect of PDT was small to absent. Anti-VEGFs were effective and appeared as effective as in RCTs. Correct selection of a comparator cohort and addressing confounding, including confounding by indication and effect modification, are needed to achieve valid results and interpretation. Patient delay, diagnosis accuracy, indication for and application of treatment can potentially be improved to improve treatment outcomes. In a value-based care perspective, systematic evaluation of diagnostic accuracy, treatment indication, protocols, and outcomes of new interventions is needed at an early stage to improve outcomes.

Early Phacoemulsification After Acute Angle Closure in Patients With Coexisting Cataract.

PURPOSE: The purpose of this study is to evaluate the effect of early phacoemulsification on the management of acute angle closure glaucoma in patients with coexisting cataract after initial treatment with medical therapy and laser peripheral iridotomy. PATIENTS AND METHODS: This study involved a retrospective analysis of patients presenting to the Maastricht University Medical Center+ with acute angle closure and coexisting cataract between 2005 and 2015. Patients were included after initial treatment with a standard protocol comprising topical and systemic medical therapy and laser peripheral iridotomy. Patients underwent small-incision phacoemulsification with intraocular lens implantation into the capsular bag by experienced surgeons within 3 months of the acute angle closure episode. The effect on intraocular pressure, number of glaucoma medications, visual acuity, and complications was assessed. RESULTS: A total 35 patients were included in the study (mean age, 71±10 y; 20% male; mean refractive error, +1.6±1.8 diopters). The mean duration between acute angle closure episode and phacoemulsification was 37±22 days. There were no complications. Intraocular pressure decreased in all patients from 17.0±8.2 mm Hg to 13.2±3.9 mm Hg after 3 months (P=0.008), whereas the mean number of glaucoma medications decreased from 2.9±1.1 to 0.7±0.9 (P<0.001), with 56% of patients discontinuing all medications. Visual acuity improved from 0.9±0.9 logMAR to 0.2±0.3 logMAR (P<0.001). CONCLUSIONS: Early phacoemulsification with intraocular lens implantation results in a reduced intraocular pressure and number of glaucoma medications after an acute angle closure glaucoma crisis in patients with coexisting cataract. Although surgery may be challenging, the results are promising, with significant improvement in visual acuity in most patients.