Alfredo García-Layana

Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS

Objectives: To assess the association between the thickness of the retinal nerve fiber layer (RNFL), assessed by optical coherence tomography (OCT), retinal periphlebitis (RP), and multiple sclerosis (MS) disease activity. Methods: We studied a prospective cohort of 61 patients and 29 matched controls for 2 years, performing a neurologic assessment every 3 months and an ophthalmologic evaluation, including OCT scans, every 6 months. Baseline MRI studies were also carried out from which brain volume and lesion load were assessed. Results: We found that the RNFL thickness in patients with MS was thinner than in controls, particularly in the temporal quadrant (p = 0.004). Although RNFL atrophy was greater in patients who also had optic neuritis (p = 0.002), it also augmented in MS patients who did not have optic neuritis compared with controls (p = 0.014). RNFL atrophy was correlated with greater disability (r = −0.348, p = 0.001) and longer disease duration (r = −0.301, p = 0.003). Furthermore, baseline temporal quadrant RNFL atrophy was associated with the presence of new relapses and changes in the Expanded Disability Status Scale by the end of the study (p < 0.05 in all cases). Indeed, RNFL thickness was correlated with white matter volume (r = 0.291, p = 0.005) and gray matter volume (r = 0.239, p = 0.021). The presence of RP was a risk factor for having new relapses in the next 2 years (odds ratio = 1.52, p = 0.02), and patients with RP had larger gadolinium-enhancing lesions volume (p = 0.003). Conclusion: Retinal nerve fiber layer atrophy and the presence of retinal periphlebitis are associated with disease activity, suggesting that retinal evaluation can be used as biomarkers of multiple sclerosis activity.

Optical coherence tomography evaluation of the corneal cap and stromal bed features after laser in situ keratomileusis for high myopia and astigmatism

OBJECTIVE To study the corneal microstructure by optical coherence tomography (OCT) after laser in situ keratomileusis (LASIK) for high myopia with and without astigmatism. DESIGN Nonrandomized self-controlled comparative trial. PARTICIPANTS Sixty-three consecutive LASIK eyes with spherical equivalent refraction between -6.0 and -17.0 diopters (D) and astigmatism between 0.0 and -5.0 D were prospectively recruited for examination. INTERVENTION LASIK was performed with the Chiron Hansatome microkeratome (160-microm fixed plate) and Summit Apex Plus excimer laser using a 5.5/6.0/6.5-mm multizone pattern. Proper preoperative calculations were performed to ensure stromal beds thicker than 250 microm. MAIN OUTCOME MEASURES OCT imaging and measurement of corneal thickness was performed preoperatively. In addition, corneal cap and stromal bed thickness measurements were performed 1 day, 1 month, and 3 months postoperatively. RESULTS The average central corneal pachymetry was 538.9 +/- 26.2 microm preoperatively. Mean corneal cap thickness measured 124.8 +/- 18.5 microm 1-day postoperatively. Mean stromal bed thickness was 295.2 +/- 37.1 microm on the first postoperative day. Compared with the 1-day postoperative examination, the average stromal bed thickness increased significantly by 5.9 microm (P = 0.001) and 7.2 microm (P = 0.001) at the 1-month and 3-month postoperative examinations, respectively. Mean difference between actual (118.7 +/- 27.8 microm) and predicted (104.1 +/- 20.8 microm) central ablation depths was 14.6 +/- 16.7 microm (P = 0.0001). A weak but statistically significant positive association was found between preoperative refraction and the difference between expected and real ablation depth values (R = 0.26; P = 0.042). Posterior stromal beds were more than 250-microm thick in 58 eyes (89.9%) 1 day postoperatively. This safety requirement improved at the 1-month postoperative examination, when the partial regression accounted for slightly thicker stromal beds and only two cases (3.2%) exhibited posterior stromal tissue thinner than 250 microm. These two cases were seen only for corrections exceeding 12 D (P = 0.04). CONCLUSIONS OCT appears to be a useful tool for the evaluation of both the qualitative and quantitative anatomic outcome of LASIK. Corrections of higher degrees of ametropia run a higher risk of producing a thinner than expected central cornea. Particularly, corrections greater than 12 D may lead eventually to stromal beds thinner than 250 microm, despite proper preoperative calculations. Because corneal flaps are usually thinner than expected with the microkeratome used herein, adequate posterior corneal stroma is preserved in most instances.

Measurement of Factor H Variants in Plasma Using Variant-Specific Monoclonal Antibodies: Application to Assessing Risk of Age-Related Macular Degeneration

PURPOSE The Y402H polymorphism in the complement regulator factor H (fH) is strongly associated with age-related macular degeneration (AMD) across diverse populations. Persons homozygous for histidine at this position have up to 12-fold greater risk for AMD than those homozygous for tyrosine. Knowledge of fH-Y402H status is, therefore, valuable in predicting risk and focusing preventive measures in the elderly. This knowledge requires genetic analysis, which is unavailable in most laboratories and which provides no information about the levels of fH protein, a putative linked determinant of disease risk. METHODS The authors describe novel monoclonal antibodies that distinguish the two fH allelic variants in plasma. ELISA with these antibodies not only reliably identifies the fH-Y402H status, confirmed by genotyping, but also quantifies the concentration of total fH and the fH-Y402 and fH-H402 variants. RESULTS In young adult control subjects, mean fH concentration was 233 mg/L. In elderly control subjects, mean fH concentration was 269 mg/L, whereas in a matching AMD cohort, mean fH concentration was 288 mg/L. Total fH concentration was similar in each subgroup of young and elderly control subjects; however, in the AMD group, fH concentration was significantly higher in the heterozygous subgroup. Measurement of the two variants in this subgroup showed that both were elevated to a similar degree. CONCLUSIONS The novel monoclonal antibody MBI-7 was used to develop a robust assay for measurement of fH and the variants in plasma. The simplicity of the assay means that it may be used by any clinical laboratory to identify polymorphic status and to quantify plasma levels in persons at risk for AMD.

Cost-effectiveness of ranibizumab compared with pegaptanib in neovascular age-related macular degeneration.

ObjectiveTo assess the cost-effectiveness of ranibizumab compared with pegaptanib in the treatment of patients with minimally classic/occult neovascular age-related macular degeneration (AMD), from a societal perspective in Spain.MethodsWe constructed a Markov model with five states defined by visual acuity (VA) in the better-seeing eye (Snellen scale): VA >20/40, ≤20/40 to >20/80, ≤20/80 to >20/200, ≤20/200 to >20/400, ≤20/400, and an additional death state. Two cohorts of patients were distributed along the VA states, and treated with either ranibizumab or pegaptanib. Transition probabilities assigned for movement between these states with both drugs were obtained from published randomized clinical trials. Medical costs related to AMD treatment and follow-up, medical costs related to AMD comorbidities, and non-medical-related costs were taken into account. Costs (2008 Euro), health outcomes (Quality-adjusted life years—QALYs), both discounted at a 3.5% annual rate, and incremental cost-effectiveness ratios (ICER: €/QALY), were determined for a lifetime horizon in the base case analysis. Sensitivity analyses were conducted to explore different scenarios and assumptions in the model.ResultsTreating patients with varying degrees of visual impairment with monthly ranibizumab instead of pegaptanib was €71,206 more costly and provided 2.437 additional QALYs (€29,224/QALY). When administered on an as-needed basis, as in the Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Ranibizumab (PrONTO) trial, the cost per QALY gained with ranibizumab was reduced to €4,623.ConclusionsThe cost per QALY gained with monthly ranibizumab compared with pegaptanib in the minimally classic/occult neovascular AMD population is just below the €30,000 threshold below which new drugs are sometimes regarded as cost-effective strategies in Spain. In this model, the key variables with greater impact on the cost-effectiveness results were the selected time horizon and the chosen extrapolation method, the source for data on pegaptanib efficacy and the number of ranibizumab injections. When administered on an as-needed basis, ranibizumab was a cost-effective strategy compared to pegaptanib in this population.

Relevance of Complement Factor H–Related 1 (CFHR1) Genotypes in Age-Related Macular Degeneration

PURPOSE Age-related macular degeneration (AMD) has a strong genetic component with a major locus at 1q31, including the complement factor H (CFH) gene. Detailed analyses of this locus have demonstrated the existence of one SNP haplotype block, carrying the CFH 402His allele, which confers increased risk for AMD, and two protective SNP haplotypes, one of them carrying a deletion of the CFHR1 and CFHR3 genes (ΔCFHR3-CFHR1). The purpose of these studies was to evaluate the contribution of newly described CFHR1 alleles to the association of the 1q31 locus with AMD. METHODS Two hundred fifty-nine patients and 191 age-matched controls of Spanish origin were included in a transversal case-control study using multivariate logistic regression analysis and ROC (receiver operating characteristic) statistics to generate and test models predictive of the development of AMD. RESULTS This study showed for the first time that a particular CFHR1 allotype, CFHR1*A, is strongly associated with AMD (odds ratio, 2.08; 95% confidence interval, 1.59-2.73; P<0.0001) and illustrate a peculiar genotype-phenotype correlation between the CFHR1 alleles and different diseases that may have important implications for understanding the pathophysiology of AMD. It also shows that CFHR1*A is in strong linkage disequilibrium with the CFH 402His allele, which provides additional candidate variants within the major risk haplotype at 1q31, promoting its association with AMD. Further, using the Spanish population as a model, the results showed that analysis of the CFHR1 genotypes provide sufficient information to delineate the individual risk of developing AMD. CONCLUSIONS The results support a relevant role of CFHR1 in the pathogenesis of AMD.

Smoking and Age-Related Macular Degeneration: Review and Update

Age-related macular degeneration (AMD) is one of the main socioeconomical health issues worldwide. AMD has a multifactorial etiology with a variety of risk factors. Smoking is the most important modifiable risk factor for AMD development and progression. The present review summarizes the epidemiological studies evaluating the association between smoking and AMD, the mechanisms through which smoking induces damage to the chorioretinal tissues, and the relevance of advising patients to quit smoking for their visual health.

Rebound tonometer compared with goldmann tonometer in normal and pathologic corneas.

Purpose: To compare the intraocular pressure (IOP) measurements obtained with the rebound tonometer (RT) and the Goldmann handheld tonometer (GT) in normal and altered corneas. Methods: A total of 208 normal corneas and 50 corneas with pathologies were included in this prospective study. All measurements were randomly obtained by 1 observer. The medians and interquartile range (IR) for both tonometers were compared. The median differences were assessed in IOP groups. Agreement between the tonometers was calculated using the Bland-Altman method. Results: The median IOP in all eyes was 17 mm Hg (IR, 13-22 mm Hg) with the RT and 16 mm Hg (IR, 13-21 mm Hg) with the GT (P < 0.001). The correlation was excellent between tonometers (r2 = 0.86; P < 0.001). The minimal differences between the two were obtained from 10 to 20 mm Hg (GT). The Bland-Altman scatterplot obtained good agreement between the instruments. In normal corneas, the median difference was ≤2 mm Hg in 77.4% of cases. In the altered corneas, the median difference was ≤2 mm Hg in 73% of cases (P = 0.21 compared with the normal group). In 10% and 2% of cases, the IOP could not be measured using the GT and RT, respectively. Conclusions: The results were similar for both tonometers. In the altered corneas, the IOP could be difficult to obtain with the GT because of distorted half-circles. The 1-mm-diameter disposable RT tip facilitated obtaining measurements without anesthetic drops, which avoids infections. The RT could be useful in routine clinical settings when measuring IOP in corneas with pathologies.

Optical coherence tomography to monitor photodynamic therapy in pathological myopia

Aim: To evaluate the role of optical coherence tomography (OCT) in determining choroidal neovascularisation (CNV) activity before and after photodynamic therapy (PDT) in patients with pathological myopia. Methods: 33 patients (33 eyes) with pathological myopia and being treated with PDT were included. Every 3 months all patients were evaluated and presence or absence of leakage on fluorescein angiography, presence of intraretinal or subretinal fluid on OCT, and macular and choroidal neovascular complex thickness on OCT, were determined at each examination. Results: The macular thickness decreased significantly after PDT at 6 months (p = 0.001) and at 12 months follow up (p = 0.01). However, no significant changes in CNV thickness were measured after PDT at 6 months of follow up (p = 0.418) and at 12 months of follow up (p = 0.521). Once the diagnosis of CNV associated with pathological myopia was established, before treatment, OCT had a sensitivity of 96.96% for detecting CNV activity. After treatment, OCT had a good sensitivity (95.23%) and a moderate specificity (69,69%) in determining CNV activity, which resulted in a diagnostic efficiency (proportion of correct results) of 79.62%. Conclusions: OCT appears to be useful for indicating CNV activity. Therefore, it may serve as a complementary technique for deciding the need for PDT and re-treatment in patients with pathological myopia.

Current Treatment Limitations in Age-Related Macular Degeneration and Future Approaches Based on Cell Therapy and Tissue Engineering

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. With an ageing population, it is anticipated that the number of AMD cases will increase dramatically, making a solution to this debilitating disease an urgent requirement for the socioeconomic future of the European Union and worldwide. The present paper reviews the limitations of the current therapies as well as the socioeconomic impact of the AMD. There is currently no cure available for AMD, and even palliative treatments are rare. Treatment options show several side effects, are of high cost, and only treat the consequence, not the cause of the pathology. For that reason, many options involving cell therapy mainly based on retinal and iris pigment epithelium cells as well as stem cells are being tested. Moreover, tissue engineering strategies to design and manufacture scaffolds to mimic Bruchs membrane are very diverse and under investigation. Both alternative therapies are aimed to prevent and/or cure AMD and are reviewed herein.

Effect of Zeaxanthin and Antioxidant Supplementation on Vascular Endothelial Growth Factor (VEGF) Expression in Apolipoprotein-E Deficient Mice

Purpose: Apolipoprotein E-/- deficient (apoE-/-) mice develop hypercholesterolemia, atherosclerosis, and retinal alterations. We studied the oxidative status and vascular endothelial growth factor (VEGF) expression in murine retinal pigment epithelium-choroid (RPE) and Bruchs membrane (BM) ultrastructure and the effect of zeaxanthin. Methods: Ten 6-month-old C57BL/6 and 40 apoE-/- mice were divided into four groups (n = 10 each) and fed different diets for 12 weeks based on body weight: wild type (WT) and apoE-/- (AE-Con) mice standard rodent chow; apoE-/- mice (AES) standard rodent chow with ascorbate (800 mg/kg), tocopherol (1053 mg/kg), and zinc (135 mg/kg); and apoE-/- mice the last diet plus zeaxanthin with either 0.4 g/kg (AES-Z04) or 4 g/kg feed (AES-Z4). Results: Plasma total cholesterol (TC) and triglycerides (TG) and urine lipid peroxidation (isoprostanes) were measured. VEGF expression was determined in RPE-choroid homogenates. Zeaxanthin uptake was assessed in liver and retina by high-performance liquid chromatography; the retinal ultrastructure was analyzed by electron microscopy. AE-Con mice had higher plasma TC (p < 0.001) and TG (p < 0.001) values than WT mice. AE-Con mice had higher RPE-choroid-VEGF levels than WT mice (p < 0.05), BM thickness (p < 0.001) and presence of basal laminar deposits (BLamD). AES-Z4 resulted in lower urinary isoprostanes (p = 0.054) and lower VEGF expression in the RPE-choroid (p < 0.01). BM in the AES-Z4 animals had less confluent BLamD than AE-Con, AES, or AES-Z04 animals. Conclusions: We have reported that supplementation with zeaxanthin and antioxidants may delay or reverse alterations in the RPE and deposits in BM, and reduced VEGF expression observed in apoE-/- mice.