Norbert Pfeiffer

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

Endophthalmitis in cataract surgery: Results of a german survey

OBJECTIVE To document perioperative prophylactic treatment and to evaluate the risk factors for endophthalmitis after cataract surgery. DESIGN Cross-sectional study via anonymous survey. PARTICIPANTS Four hundred sixty-nine centers in Germany were queried. RESULTS A total of 311 (67%) questionnaires were received, with each center reporting an average of 900 cataract surgeries per year (total, 340,633 surgeries in 1996). Respondents reported a total of 267 cases of endophthalmitis, which resulted in a mean responder-specific endophthalmitis rate of 0.148% versus a median rate of 0%. Statistical analysis via Poisson regression suggested that sclerocorneal incisions were associated with a reduced incidence of endophthalmitis (odds ratio, 0.35; 95% confidence interval, 0.24-0.51). Antibiotics used intraocularly (odds ratio, 0.65; 95% confidence interval, 0.43-0.98) and the preoperative application of diluted povidone-iodine on the conjunctiva (odds ratio, 0.59; 95% confidence interval, 0.36-0.99) were associated with a reduced risk of postoperative infection. Immune deficiencies (66%), diabetes mellitus (62%), occlusion of the lacrimal system (40%), and skin diseases (33%) were regarded as risk factors for endophthalmitis by the respondents. When cataract surgery is performed solely under inpatient conditions, the use of systemic antibiotics as well as the periocular injection of antibiotics at the end of the operation were associated (although not significantly) with a trend toward reducing the incidence of postoperative infection. Conversely, flushing the lacrimal drainage system, using eye shields, and cutting the eyelashes had no demonstrable effect in preventing endophthalmitis. The use of preoperative topical antibiotics (odds ratio, 2.38; 95% confidence interval, 1.21-4.68) and the performance of more than 20% of the surgeries in an outpatient center (odds ratio, 2.0; 95% confidence interval, 1.24-3.21) were associated with a detrimental effect on the development of endophthalmitis. CONCLUSIONS Although the appropriate antibiotic agent and dosage are not yet established, the administration of intracameral antibiotics and the application of povidone-iodine on the conjunctiva significantly reduced the relative risk of postoperative endophthalmitis in this survey. Because the study was not individual based but rather on aggregate questionnaire, the results have to be interpreted with care.

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe

Background: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. Methods: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. Results: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated €86 for each incremental step ranging from €455 per person year for stage 0 to €969 per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. Conclusions: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Diagnostic ability of retinal ganglion cell complex, retinal nerve fiber layer, and optic nerve head measurements by Fourier-domain optical coherence tomography

PurposeTo evaluate the diagnostic ability of Fourier-domain optical coherence tomography (FD-OCT) measurements in glaucoma patients, patients with ocular hypertension, and normal subjects.MethodsNinety-three participants with open-angle glaucoma (OAG), 58 patients with ocular hypertension (OHT), and 60 healthy control subjects were included in the study. All study participants underwent FD-OCT imaging. Retinal ganglion cell complex (GCC), macular thickness, peripapillary retinal nerve fiber layer thickness (RFNL), and optic nerve head parameters (ONH) were measured in each participant. The diagnostic ability was evaluated using area under the receiver operating characteristics curves (AUROC).ResultsGlaucoma patients showed a significant reduction in GCC and macular retinal thickness compared to patients with OHT and normal subjects. No differences in GCC were found between the patients with OHT and normal subjects. The best diagnostic ability in the comparison between glaucoma and normal subjects after adjusting for age was found for cup-to-disc ratio (AUROC = 0.848), RNFL average thickness (AUROC = 0.828), and GCC global loss volume (AUROC = 0.805). The diagnostic power of the best GCC, RNFL, and ONH parameter did not show differences beyond random variation (p > 0.05).ConclusionsImaging of the GCC using FD-OCT (RTVue-100) has a comparable diagnostic ability to RNFL and ONH measurements in distinguishing between glaucoma patients and healthy subjects. No differences were found between patients with OHT and normal subjects with regard to ONH, RNFL, and GCC parameters.

Switching from a preserved to a preservative‐free prostaglandin preparation in topical glaucoma medication

Purpose:  The purpose of this study was to investigate the tolerability and intraocular pressure (IOP) reducing effect of the first preservative‐free prostaglandin tafluprost (Taflotan®) in patients exhibiting ocular surface side‐effects during latanoprost (Xalatan®) treatment.

Increasing Prevalence of Myopia in Europe and the Impact of Education

Purpose To investigate whether myopia is becoming more common across Europe and explore whether increasing education levels, an important environmental risk factor for myopia, might explain any temporal trend. Design Meta-analysis of population-based, cross-sectional studies from the European Eye Epidemiology (E3) Consortium. Participants The E3 Consortium is a collaborative network of epidemiological studies of common eye diseases in adults across Europe. Refractive data were available for 61 946 participants from 15 population-based studies performed between 1990 and 2013; participants had a range of median ages from 44 to 78 years. Methods Noncycloplegic refraction, year of birth, and highest educational level achieved were obtained for all participants. Myopia was defined as a mean spherical equivalent ≤−0.75 diopters. A random-effects meta-analysis of age-specific myopia prevalence was performed, with sequential analyses stratified by year of birth and highest level of educational attainment. Main Outcome Measures Variation in age-specific myopia prevalence for differing years of birth and educational level. Results There was a significant cohort effect for increasing myopia prevalence across more recent birth decades; age-standardized myopia prevalence increased from 17.8% (95% confidence interval [CI], 17.6–18.1) to 23.5% (95% CI, 23.2–23.7) in those born between 1910 and 1939 compared with 1940 and 1979 (P = 0.03). Education was significantly associated with myopia; for those completing primary, secondary, and higher education, the age-standardized prevalences were 25.4% (CI, 25.0–25.8), 29.1% (CI, 28.8–29.5), and 36.6% (CI, 36.1–37.2), respectively. Although more recent birth cohorts were more educated, this did not fully explain the cohort effect. Compared with the reference risk of participants born in the 1920s with only primary education, higher education or being born in the 1960s doubled the myopia prevalence ratio–2.43 (CI, 1.26–4.17) and 2.62 (CI, 1.31–5.00), respectively—whereas individuals born in the 1960s and completing higher education had approximately 4 times the reference risk: a prevalence ratio of 3.76 (CI, 2.21–6.57). Conclusions Myopia is becoming more common in Europe; although education levels have increased and are associated with myopia, higher education seems to be an additive rather than explanatory factor. Increasing levels of myopia carry significant clinical and economic implications, with more people at risk of the sight-threatening complications associated with high myopia.

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10−8 for rs6445055), two on chromosome 9 (P = 2.80 × 10−11 for rs2472493 near ABCA1 and P = 6.39 × 10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10−11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Retinal vascular occlusion and deficiencies in the protein C pathway

PURPOSE To report abnormalities in the protein C pathway and other vascular occlusion risk factors in patients with retinal vascular occlusion. METHODS In a study, we investigated 76 consecutive patients who had in-patient evaluation of venous or arterial retinal vascular occlusion. All patients underwent comprehensive tests for coagulation disorders including determinations of protein C, protein S, lupus anticoagulants, and resistance to activated protein C and were screened for vascular disease risk factors. Resistance to activated protein C was confirmed by a polymerase chain reaction method to detect the specific factor V R506Q mutation. For comparative purposes, we also screened 209 consecutive inpatients with deep vein thrombosis from the same geographic region for resistance to activated protein C as well as protein C and protein S deficiencies. RESULTS Ten (29%) of 35 patients with central retinal vein occlusion (CRVO) had factor V R506Q mutation. The factor V R506Q mutation was detected in four (19%) of 21 patients with branch retinal vein occlusion. The higher frequency in factor V R506Q mutation compared with the expected 9% mutation prevalence in a white population was highly significant for the central retinal vein occlusion group but not for the branch retinal vein occlusion group. In all patients with resistance to activated protein C, the factor V R506Q mutation was detected; 16 were heterozygous, one homozygous. No cases of lupus anticoagulants, protein C, or protein S deficiencies were detected. Forty (19%) of 209 patients with deep vein thrombosis were carriers of the factor V R506Q mutation. CONCLUSIONS The prevalence of the factor V R506Q mutation is similar in patients with central retinal vein occlusion and patients with deep vein thrombosis and represents a relevant risk factor. Screening for this mutation is therefore recommended in all patients with central retinal vein occlusion.

Proinflammatory cytokine profiling of tears from dry eye patients by means of antibody microarrays.

PURPOSE In the pathogenesis of keratoconjunctivitis sicca, immune processes are thought to play an important role. However, the exact details of the pathomechanisms are still unknown. In this study, the expression patterns of proinflammatory cytokines in the tears of patients with different subtypes of dry eye were analyzed. METHODS One hundred forty-three subjects subdivided into healthy controls (CTRL, n = 38), patients with aqueous-deficient dry eye (DRYaq, n = 35), patients with changes of the lipid layer (DRYlip, n = 36), and patients with a combination of both (DRYaplip, n = 34) were examined. Expression patterns of proteins (e.g., IL-1β, IL-6, ITNF-α, and IFN-γ) were examined using an advanced antibody microarray approach. RESULTS Several highly significant differences in the cytokine levels of dry eye patients compared with healthy controls were detected. Patients with DRYaq or those with DRYaplip showed elevated levels for most of the tested proteins. For example, IL-1β was found to be elevated 2.4-fold in DRYaq patients and 2.75-fold in DRYaqlip patients (both P < 8.00E-6). The detected amounts of protein in DRYlip patients and in healthy controls showed only minimal differences (fold increase/decrease for all proteins >1.2; P > 5.00E-1). CONCLUSIONS The similarity between the profiles of healthy controls and DRYlip patients justifies the assumption that the pathomechanism of this dry eye subtype is based on mechanisms other than inflammation, whereas it seems to be the case for DRYaq patients.

Dorzolamide: Development and clinical application of a topical carbonic anhydrase inhibitor

Systemic carbonic anhydrase inhibitors are among the most powerful agents to lower intraocular pressure. Unfortunately, their use is frequently accompanied by undesired side effects. Some are due to the relatively large amounts of drug that have to be systemically administered to inhibit the carbonic anhydrase in the ciliary processes. Recently, dorzolamide, a topical carbonic anhydrase inhibitor, has become commercially available for clinical use. This article reviews the development of topical carbonic anhydrase inhibitors with special reference to dorzolamide. When administered three-times daily, dorzolamide lowers intraocular pressure in a clinically useful manner. Ocular side-effects include frequent stinging and burning and allergy can develop. Systemic side effects have not been observed that could definitively be related to inhibition of extraocular carbonic anhydrase. Blood dyscrasias have not yet been observed. Absence of cardiovascular and pulmonary side effects, as can occur with beta adrenergic antagonists, and lack of pupillary and accommodative stimulation, as occur with cholinergic agonists, might make dorzolamide first-line medical treatment for elevated intraocular pressure.