Misa Suzuki

Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration

Background/aims To study the initial characteristics and response to intravitreal ranibizumab (IVR) treatment of age-related macular degeneration (AMD). Methods We reviewed the clinical records of 141 eyes in 141 AMD patients who received monthly IVR for 3u2005months and thereafter pro re nata (PRN) injections for 9u2005months as the first treatment for AMD. Patients whose best corrected visual acuity (BCVA) worsened at month 12, and those with increased exudative fundus findings after IVR or an increased central retinal thickness of more than 100 μm at month 12, were considered to be non-responders as judged by BCVA and fundus findings, respectively. Non-responders’ initial characteristics were analysed using logistic regression models. Results 14.9% of eyes were non-responders as judged by BCVA, and 17.0% were non-responders as judged by fundus findings. Initial fibrovascular pigment epithelial detachment (PED) (OR 22.9, 95% CI 2.61 to 201) and serous PED (OR 4.12, 95% CI 1.08 to 15.8) were associated with non-response as judged by BCVA. Initial fibrovascular PED (OR 33.5, 95% CI 2.95 to 381) and type 1 choroidal neovascularization (OR 6.46, 95% CI 1.39 to 30.0) were associated with non-response, as judged by fundus findings. Conclusions Although most AMD responded to IVR, non-responders had initial clinical characteristics that might be informative for managing their treatment.

Non-responsiveness to intravitreal aflibercept treatment in neovascular age-related macular degeneration: implications of serous pigment epithelial detachment

The prognosis of neovascular age-related macular degeneration (AMD) has been improved by anti-vascular endothelial growth factor treatments, including intravitreal aflibercept (IVA) treatment. However, many patients remain incurable. In this study, we retrospectively evaluated non-responsiveness to IVA monotherapy at 12 months in 133 eyes of 133 AMD patients. Sixty-two patients were initially treatment-naive, and 71 had received other treatments before IVA (the treatment-switched group). Mean best-corrected visual acuity (BCVA) was improved in the treatment-naive group but not in the treatment-switched group, although mean central retinal thickness (CRT) decreased in both groups. The respective percentages of non-responders as determined by worsened BCVA in the treatment-naive and treatment-switched groups were 8.1% and 15.5%, and via fundus findings, they were 12.9% and 8.5%. Multivariate analyses adjusted for age, gender, CRT, and greatest linear dimension showed that serous pigment epithelial detachment (PED) at baseline was associated with non-responsiveness in both groups as determined by BCVA and by fundus findings, and fibrovascular PED measurements indicated no response as determined by fundus findings in the treatment-switched group. The results reported herein may assist the formulation of appropriate treatment protocols for AMD patients.

Neuroprotective response after photodynamic therapy : Role of vascular endothelial growth factor

BackgroundAnti-vascular endothelial growth factor (VEGF) drugs and/or photodynamic therapy (PDT) constitute current treatments targeting pathological vascular tissues in tumors and age-related macular degeneration. Concern that PDT might induce VEGF and exacerbate the disease has led us to current practice of using anti-VEGF drugs with PDT simultaneously. However, the underlying molecular mechanisms of these therapies are not well understood.MethodsWe assessed VEGF levels after PDT of normal mouse retinal tissue, using a laser duration that did not cause obvious tissue damage. To determine the role of PDT-induced VEGF and its downstream signaling, we intravitreally injected a VEGF inhibitor, VEGFR1 Fc, or a PI3K/Akt inhibitor, LY294002, immediately after PDT. Then, histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses, respectively.ResultsAt both the mRNA and protein levels, VEGF was upregulated immediately and transiently after PDT. VEGF suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT. Under these conditions, activation of the anti-apoptotic molecule Akt was suppressed in the irradiated area, and levels of the pro-apoptotic protein BAX were increased. Intravitreal injection of a PI3K/Akt inhibitor immediately after PDT increased BAX levels and photoreceptor cell apoptosis.ConclusionCytotoxic stress caused by PDT, at levels that do not cause overt tissue damage, induces VEGF and activates Akt to rescue the neural tissue, suppressing BAX. Thus, the immediate and transient induction of VEGF after PDT is neuroprotective.

Distinct Responsiveness to Intravitreal Ranibizumab Therapy in Polypoidal Choroidal Vasculopathy With Single or Multiple Polyps.

PURPOSEnTo understand the prognosis of polypoidal choroidal vasculopathy (PCV) by evaluating the responsiveness to intravitreal ranibizumab (IVR) monotherapy according to the presence of a single or multiple polyps.nnnDESIGNnRetrospective case series.nnnMETHODSnWe included 48 treatment-naïve eyes of 48 patients who received IVR monotherapy at the Medical Retina Division Clinic, Keio University Hospital between March 2009 and January 2013 and attended the clinic for at least 12xa0months. All patients received 3xa0monthly IVR injections followed by pro re nata injections and were divided into single polyp and multiple polyps groups according to indocyanine green angiography and optical coherence tomography (OCT) findings. The outcome measures included changes in best-corrected visual acuity (BCVA) and OCT findings over 2 years after initial IVR.nnnRESULTSnAt baseline, the multiple polyps group exhibited a poorer BCVA, larger greatest linear dimension, and higher prevalence of fibrovascular pigment epithelial detachment compared with the single polyp group. Over 2 years, the multiple polyps group showed no improvement in BCVA, although the central retinal thickness (CRT) decreased in both groups. The multiple polyps group exhibited a significantly greater CRT at 1 year and required more injections in the first year compared with the single polyp group; furthermore, it included a higher number of nonresponders judged either by BCVA or fundus findings at 1 year and fundus findings at 2 years.nnnCONCLUSIONSnWe propose that the stratification of PCV lesions according to the presence of single or multiple polyps may be valuable to understand the prognosis.

Association of macular pigment optical density with serum concentration of oxidized low-density lipoprotein in healthy adults

Purpose: To analyze the association between macular pigment optical density (MPOD), which reflects lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) in the macula, and background characteristics. Methods: Fifty-five healthy adult volunteers were analyzed. Macular pigment optical density was measured using a heterochromatic flicker photometry technique, and serum concentrations of carotenoids and lipoproteins were by high-performance liquid chromatography and enzyme-linked immunosorbent assay, respectively. Dietary intake of nutrient was determined by a validated self-administered questionnaire on ingestion frequency. Results: Macular pigment optical density was positively correlated with serum concentrations of L and Z and dietary L intake and inversely correlated with serum oxidized low-density lipoprotein (LDL). Although MPOD decreased with age (95% confidence interval, −0.011 to −0.002; correlation coefficient, −0.269; P = 0.007), serum L/Z and dietary L intake did not. In contrast, serum oxidized LDL was positively correlated with age (95% confidence interval, 0.69–2.34; correlation coefficient, 0.333; P = 0.0004). After adjusting for age, sex, and oxidized LDL, serum L was positively correlated with MPOD (95% confidence interval, 0.88–1.69; P = 0.000001). After adjusting for age, sex, and serum L, serum oxidized LDL was inversely correlated with MPOD (95% confidence interval, −0.002 to −0.0004; P = 0.006). Conclusion: Macular pigment optical density was inversely correlated with serum oxidized LDL. Further study to know the impact of oxidized LDL on MPOD may be warranted.

Functional Visual Acuity in Age-Related Macular Degeneration.

Purpose We evaluated whether a functional visual acuity (FVA) system can detect subtle changes in central visual acuity that reflect pathological findings associated with age-related macular degeneration (AMD). Methods Twenty-eight patients with unilateral AMD and logMAR monocular best corrected VA better than 0 in both eyes, as measured by conventional chart examination, were analyzed between November 2012 and April 2013. After measuring conventional VA, FVA, and contrast VA with best correction, routine eye examinations including spectral domain–optical coherence tomography were performed. Standard Schirmer test was performed, and corneal and lens densities were measured. Results The FVA score (p < 0.001) and visual maintenance ratio (p < 0.001) measured by the FVA system, contrast VA (p < 0. 01), and conventional VA (p < 0.01) were significantly worse in the AMD-affected eyes than in the fellow eyes. No significant differences were observed in the anterior segment conditions. Forward stepwise regression analysis demonstrated that the length of interdigitation zone disruption, as visualized by optical coherence tomography imaging, correlated with the FVA score (p < 0.01) but not with any other parameters investigated. Conclusions The FVA system detects subtle changes in best corrected VA in AMD-affected eyes and reflects interdigitation zone disruption, an anatomical change in the retina recorded by optical coherence tomography. Further studies are required to understand the value of the FVA system in detecting subtle changes in AMD.

Predictive factors of better outcomes by monotherapy of an antivascular endothelial growth factor drug, ranibizumab, for diabetic macular edema in clinical practice

Abstract Intravitreal ranibizumab (IVR) has been approved for treating diabetic macular edema (DME), and is used in daily clinical practice. However, the treatment efficacies of IVR monotherapy in real-world clinical settings are not well known. The medical records of 56 eyes from 38 patients who received their first IVR for DME between April 2014 and March 2015, and were retreated with IVR monotherapy as needed with no rescue treatment, such as laser photocoagulation, were retrospectively reviewed. The clinical course, best-corrected visual acuity (BCVA), and fundus findings at baseline, before the initial IVR injection, and at 12 months, were evaluated. Twenty-five eyes from 25 patients (16 men; mean age 68.7u200a±u200a9.8 years) who received IVR in the first eye, or unilaterally, without any other treatments during follow-up were included. After 12 months, mean central retinal thickness (CRT), which includes edema, was reduced (Pu200a=u200a.003), although mean BCVA remained unchanged. There was a negative correlation between individual changes in BCVA (ru200a=u200a−0.57; Pu200a=u200a.003) and CRT (ru200a=u200a−0.60; Pu200a=u200a.002) at 12 months compared with baseline values. BCVA changes were greater in individuals with a history of pan-retinal photocoagulation at baseline (Pu200a=u200a.026). After adjusting for age and sex, CRT improvement >100u200a&mgr;m at 12 months was associated with a greater CRT at baseline (OR 0.87 per 10u200a&mgr;m [95% CI 0.72–0.97]; Pu200a=u200a.018) according to logistic regression analyses; however, better BCVA and CRT at 12 months were associated with a better BCVA (ru200a=u200a0.77; Pu200a<u200a.001) and lower CRT (ru200a=u200a0.41; Pu200a=u200a.039) at baseline, respectively, according to linear regression analyses. IVR monotherapy suppressed DME, and the effects varied according to baseline conditions. Eyes that had poorer BCVA or greater CRT, or a history of pan-retinal photocoagulation at baseline, demonstrated greater improvement with IVR monotherapy. In contrast, to achieve better outcome values, DME eyes should be treated before the BCVA and CRT deteriorate. These findings advance our understanding of the optimal use of IVR for DME in daily clinical practice, although further study is warranted.

Benefits of aflibercept treatment for age-related macular degeneration patients with good best-corrected visual acuity at baseline

Currently, age-related macular degeneration (AMD) is treated while patients exhibit good best-corrected visual acuity (BCVA). However, previous clinical trials only include patients with poor BCVA. We prospectively analyzed the benefits of intravitreal aflibercept (IVA) treatment for AMD patients exhibiting good BCVA at baseline. Twenty-nine treatment-naive AMD patients (29 eyes) with BCVA better than 0.6 (74 letters in ETDRS chart) were treated with IVA once a month for 3 months and every 2 months thereafter with no additional treatments. Improvement in mean BCVA, measured using the conventional Landolt C chart, contrast VA chart, and functional VA (FVA) system, and reductions in mean central retinal thickness (CRT), central choroidal thickness, macular volume (MV), and choroidal area on optical coherence tomography images were observed at 6 and 12 months. Improvements in contrast VA and FVA scores, in contrast to conventional BCVA, correlated with MV reduction; no VA scores correlated with a reduced CRT. The MV correlated with choroidal area after IVA. No severe adverse events occurred. IVA improved visual function, retinal condition, and quality of life evaluated by Visual Function Questionnaire, and was beneficial in these patients. The contrast VA and FVA scores and MVs, which detect subtle changes, helped demonstrate the benefits.

Absolute and estimated values of macular pigment optical density in young and aged Asian participants with or without age-related macular degeneration

BackgroundLutein and zeaxanthin are suggested micronutrient supplements to prevent the progression of age-related macular degeneration (AMD), a leading cause of blindness worldwide. To monitor the levels of lutein/zeaxanthin in the macula, macular pigment optical density (MPOD) is measured. A commercially available device (MPSII®, Elektron Technology, Switzerland), using technology based on heterochromatic flicker photometry, can measure both absolute and estimated values of MPOD. However, whether the estimated value is applicable to Asian individuals and/or AMD patients remains to be determined.MethodsThe absolute and estimated values of MPOD were measured using the MPSII® device in 77 participants with a best-corrected visual acuity (BCVA)xa0>xa00.099 (logMAR score).ResultsThe studied eyes included 17 young (20–29xa0years) healthy, 26 aged (>50xa0years) healthy, 18 aged and AMD-fellow, and 16 aged AMD eyes. The mean BCVA among the groups were not significantly different. Both absolute and estimated values were measurable in all eyes of young healthy group. However, absolute values were measurable in only 57.7%, 66.7%, and 43.8%, of the aged healthy, AMD-fellow, and AMD groups, respectively, and 56.7% of the eyes included in the 3 aged groups. In contrast, the estimated value was measurable in 84.6%, 88.9% and 93.8% of the groups, respectively, and 88.3% of eyes in the pooled aged group. The estimated value was correlated with absolute value in individuals from all groups by Spearman’s correlation coefficient analyses (young healthy: R2xa0=xa00.885, Pxa0=xa00.0001; aged healthy: R2xa0=xa00.765, Pxa0=xa00.001; AMD-fellow: R2xa0=xa00.851, Pxa0=xa00.0001; and AMD: R2xa0=xa00.860, Pxa0=xa00.013). Using the estimated value, significantly lower MPOD values were found in aged AMD-related eyes, which included both AMD-fellow and AMD eyes, compared with aged healthy eyes by Student’s t-test (Pxa0=xa00.02).ConclusionsAbsolute, in contrast to estimated, value was measurable in a limited number of aged participants; however, it was correlated with estimated value both in young and aged Asian populations with or without AMD. These results may inform future clinical studies investigating the measurement of MPOD in understanding the role of macular pigments in the pathogenesis of AMD.

Cyclooxygenase inhibitor improved an exudative lesion of choroidal neovascularization in age-related macular degeneration.

Purpose To report a case in which a nonselective cyclooxygenase (COX) inhibitor improved an exudative lesion in age-related macular degeneration. Methods/Results A 64-year-old man had a complaint of metamorphopsia in the left eye. Visual acuity was 0.5 in the left eye. Fluorescein angiography and indocyanine angiography showed juxtafoveal occult choroidal neovascularization (CNV) in the left eye, and pegaptanib sodium 0.3 mg was administered once every 6 weeks. After 4 months, visual acuity improved to 0.8. After 8 months follow-up, optical coherence tomography (OCT) showed subretinal fluid (SRF) and retinal pigment epithelium (RPE) irregularity. Visual acuity was 0.4. We recommended further pegaptanib sodium injections, but the patient did not consent to the treatment. Onset of cellulitis of the left toe occurred 1 week before the scheduled visit after 9 months. The patient was treated with loxoprofen sodium (nonselective COX inhibitor) and cefdinir for 7 days. At 2 weeks after onset of cellulitis, SRF had disappeared and OCT showed improvement of RPE irregularity. Conclusions A COX inhibitor had an effect on vascular permeability in CNV and may have improved exudative changes.