Clinical outcome using a modified treat-and-extend protocol for neovascular age-related macular degeneration.

AIM: To compare outcome between patients treated using a modified treat-and-extend (mT&E) protocol and patients treated using a conventional T&E protocol. METHODS: A retrospective cohort study of two groups of treatment-naïve neovascular age-related macular degeneration patients within a single centre were evaluated. One group treated using the conventional T&E protocol, with visual acuity, dilated fundus examination (DFE) and optical coherence tomography (OCT) performed at each visit. The second group treated using the mT&E protocol in which visual acuity and DFE were performed only every three visits. The main outcome measures were time spent per clinical visit, visual and anatomical outcomes measured for 36 months. RESULTS: The T&E and mT&E groups included 135 eyes in 116 patients and 119 eyes in 94 patients, respectively, with similar baseline characteristics. At 36 months, the number of injections administered (7.9±2.9 vs 8.1±2.3 injections, respectively; p=0.55), the percentage of eyes that gained ≥15 Early Treatment for Diabetic Retinopathy Study (ETDRS) letters (23% vs 25.2%, respectively; p=0.39) and the percentage of eyes that lost ≥15 ETDRS letters (21.5% vs 17.7%; p=0.43, respectively) were similar between the T&E and mT&E groups. However, waiting and contact time were reduced during the OCT-only visits compared with the full visits, with an average of 41 min saved per patient encounter. CONCLUSIONS: Both protocols yielded similar visual and anatomical outcomes. However, the mT&E protocol reduced the number of full visits, with considerably less time spent at the clinic.

Aflibercept as a Second Line Therapy for Neovascular Age Related Macular Degeneration in Israel (ASLI) study.

PurposeThe purpose of this study is to evaluate an early switch to aflibecept in eyes with neovascular age-related macular degeneration (nvAMD) showing partial or lack of response for initial therapy with bevacizumab.MethodsThe Aflibercept as a Second Line Therapy for Neovascular Age Related Macular Degeneration in Israel (ASLI) was a prospective, multicenter, single-arm clinical trial. Eyes with nvAMD having incomplete response to 3-9 prior bevacizumab injections were recruited. Three monthly intravitreal aflibercept (2 mg) injections were administered, followed by two bi-monthly injections and a final examination at week 28. An optional injection was allowed at week 20.ResultsForty-seven eyes of 46 patients (mean±SD age 76±8 years) were recruited. The mean number of prior bevacizumab injections was 5.5±2.9. The mean visual acuity improved from 60.3±10 ETDRS letters at baseline to 63.1±15 letters at week 28 (P=0.02, paired t-test). The central subfield thickness (CST) reduced from 409±127 micron at baseline to 330±110 microns at week 4 (P=0.0002; paired t-test), and 277±70 microns at week 28 (P=0.00002; paired t-test). Twenty-two eyes had three to five prior bevacizumab injections (mean 5.1±0.7), and 25 eyes had six to nine prior injections (7.32±1.2). Both groups had reduced CST from baseline to week 28 (P=0.0004 and P=0.0007; paired t-test, respectively). Thirty-five (75%) eyes required the optional additional aflibercept injection at week 20.ConclusionsThe ASLI study demonstrated improved BCVA and reduced CST following an early switch to aflibercept therapy in eyes with prior incomplete response to initial therapy with three to nine bevacizumab injections.

Fellow eye effect of unilateral intravitreal bevacizumab injection in eyes with diabetic macular edema.

AIMS: Anti-vascular endothelial growth factor compounds are routinely used for the treatment of diabetic macular edema (DME). We aim to evaluate for the existence and magnitude of treatment effect on fellow un-injected eyes. METHODS: A consecutive group of patients with bilateral DME who received unilateral bevacizumab injections was retrospectively evaluated. Data collected included demographics, ophthalmic and systemic findings, and optical coherence tomography (OCT) measurements of macular thickness. RESULTS: Thirty-five patients were evaluated. Mean follow-up was 245 days (range: 30-800), and the mean number of bevacizumab injections was 3.6 (range: 1-11). At end of follow-up, the mean (SD) OCT central subfield thickness reduced by 72 ± 112 micron in the injected eye (from 469 ± 139 to 397 ± 120 micron; P=0.001), while in the non-injected eye it reduced by 49 ± 75 micron (from 380 ± 130 to 331 ± 106 micron; P<0.001). Sixteen injected eyes (45.7%) showed central subfield thickness reduction of ≥50 micron while 10 (28.6%) non-injected eyes showed such thickness reduction. Improved VA following treatment was detected in 14 (40%) injected eyes and in 15 (43%) non-injected eyes. CONCLUSIONS: Unilateral bevacizumab injections in patients with bilateral DME are often associated with bilateral response. SUMMARY STATEMENT: Anti-vascular endothelial growth factor compounds are routinely used for the treatment of diabetic macular edema (DME). In this retrospective study, we show that unilateral bevacizumab injections often result in reduction of the macular thickness in the fellow un-injected eye.

Intravitreal bevacizumab therapy for neovascular age-related macular degeneration associated with poor initial visual acuity.

AIM: The aim of the study was to assess the efficacy of intravitreal bevacizumab injections for eyes with neovascular age-related macular degeneration (NVAMD) and poor initial visual acuity (VA). METHODS: A retrospective study of 44 consecutive treatment-naïve eyes with NVAMD who had initial VA of 0.1 decimal or worse, and that were treated with intravitreal bevacizumab injections, was undertaken. Charts, optical coherence tomography (OCT) and fluorescein angiograms (FAs) were reviewed for the purpose of the study. RESULTS: Mean lesion size was 3375 (SD 2116) microm, all lesions showed sub- or intra-retinal fluid in OCT, and active neovascularisation comprised 41.6 (SD 17.7)% (range 10-90%) of the lesion area according to FA. The mean follow-up time was 3.9 (SD 5.8) (range 1-21) months. Patients received a mean of 2.6 (SD 2.4) bevacizumab injections (range 1-14), and mean VA improved from 1.85 (SD 0.64) to 1.52 (SD 0.77) LogMAR (p = 0.002). At final examination, nine eyes (20%) had reduced VA, ten eyes (23%) had stable VA and 25 eyes (57%) had improved VA compared with baseline. Following treatment, mean macular thickness was reduced from 332 (SD 98) to 248 (SD 79) microm (p<0.0001). CONCLUSIONS: Poor initial VA should not prevent use of bevacizumab in eyes with NVAMD. Selection of patients with signs of active neovascularisation based on ophthalmoscopy, OCT and FA may increase the likelihood of a favourable response to treatment.

Prevalence of clinical asymptomatic retinal detachment in myopic population.

AIM: To evaluate the prevalence of clinical asymptomatic retinal detachment (ARD) in myopic population. METHODS: A retrospective study including all myopic individuals who underwent ophthalmic evaluation prior to excimer laser procedures at the Hadassah Center for Refractive Surgery between March 2002 and March 2006. Medical records were reviewed to extract demographics and refraction, and to identify patients who were diagnosed as having asymptomatic retinal detachment. RESULTS: Data were collected on 6547 myopic individuals (12 815 eyes); of these, 2907 (44.4%) were males, and 3640 (55.6%) were females. The mean age was 31.5 (SD 10) years (range 18-64 years). The mean preoperative spheric equivalence was -4.42 (2.07) (range -0.75 to -16.00). The mean best spectacle-corrected visual acuity was 20/20 (range 20/32 to 20/12.5). Five eyes (0.039% or one of approximately 2563 eyes) of four patients had clinical ARD which was diagnosed during the routine preoperative examination. Three eyes underwent successful scleral buckling procedure while two patients were lost to follow-up. CONCLUSIONS: Clinical asymptomatic retinal detachment is uncommon, accounting for a minority of retinal detachments in myopes, and may be diagnosed during routine ophthalmoscopy prior to a refractive procedure.

Maculopathy in patients with primary CNS lymphoma treated with chemotherapy in conjunction with blood-brain barrier disruption.

AIM: To determine the incidence and characteristics of maculopathy associated with blood-brain barrier disruption (BBBD) which is used in treating primary central nervous system lymphoma (PCNSL). METHODS: Files of all 56 patients with PCNSL, with or without intraocular lymphoma (IOL), treated at Hadassah University Hospital during the years 1997-2007 were reviewed. Data on 46 patients for whom we had documentation of ocular examination were studied. Those who were alive at the time of the data collection were invited for further evaluation of the presence or absence of maculopathy. The patients were divided into four groups according to treatment protocol. Group 1: systemic intravenous chemotherapy; Group 2: systemic intravenous chemotherapy and intravitreal methotrexate (MTX); Group 3: systemic intra-arterial (IA) chemotherapy and BBBD; Group 4: systemic IA chemotherapy, BBBD, and intravitreal MTX. RESULTS: Of the 23 patients of Groups 1 and 2 who were not treated by BBBD, none developed maculopathy. Of those 23 patients who were treated by BBBD, 12 of 17 (70.5%) in Group 3 and three of six (50%) in Group 4, for a total of 15 of 23 (65.2%) developed maculopathy. The maculopathy did not significantly affect visual acuity in any of them. CONCLUSIONS: BBBD may cause maculopathy in almost two-thirds of patients treated for PCNSL, without affecting significantly the visual acuity. Intravitreal injection of MTX, according to the protocol which we apply, is not associated with maculopathy.

Lack of benefit of early awareness to age-related macular degeneration.

AIMS: To assess the rate of early awareness to the presence of age-related macular degeneration (AMD) and whether it enables early detection of transition to neovascular AMD (NVAMD) as compared with patients whose first presentation to an ophthalmologist is already at the neovascular stage of disease. METHODS: A retrospective analysis of 268 eyes of 268 consecutive patients with newly diagnosed NVAMD that were treated in a tertiary referral centre was performed. Patients were classified into those who were unaware (Group 1), or aware (Group 2), of the fact that they had AMD before diagnosis of NVAMD. Visual acuity, lesion size and composition, and demographics were compared between both groups. RESULTS: In all, 185 patients (69%) and 83 patients (31%) were classified to Groups 1 and 2, respectively. Patients in Groups 1 and 2 had similar demographic characteristics, presenting visual acuity and lesion size, and lesion compositions. Group 1 patients were more likely to have a positive history for smoking (41 vs26% in Group 2, P=0.03), whereas Group 2 patients were more likely to have positive family history for AMD (20 vs10%, P=0.02). CONCLUSIONS: These data suggest that current screening methods fail to identify the majority of patients with AMD before the development of NVAMD. The findings also demonstrate that in the routine clinical setting, prior awareness of AMD may not facilitate early detection of treatable choroidal neovascularization lesions.

Post-brachytherapy initial tumour regression rate correlates with metastatic spread in posterior uveal melanoma.

AIM: To confirm the prognostic value of post-brachytherapy initial tumour regression rate in posterior uveal melanoma. METHODS: A prospective, comparative, observational cohort study was carried out on 147 eyes (147 patients) with choroidal melanoma (mean age 61 years) treated with Ru-106 brachytherapy. OBSERVATION PROCEDURE: Patients were followed clinically and ultrasonically every 6.7 (SD 0.3) months (1001 examinations). On average each patient was examined 5.8 times (mean follow up 9.6 (3.7) years). The echographic parameters included tumour base size, height, internal reflectivity, regularity, vascularity, and extrascleral extension. The clinical follow up included ocular examination and periodic metastatic screening (liver function tests and liver imaging). Main outcome measures were risk of liver metastasis in correlation with the post-brachytherapy initial tumour regression rate. RESULTS: At brachytherapy the mean tumour height was 5.2 mm (range 2.2-11.8 mm). After brachytherapy 142 tumours (96.6%) responded by a decrease in height. The initial height regression rate was 6.1% (0.8%) per month in patients who later developed metastasis v 4.3% (0.4%) per month in those who did not. Tumours higher than 6 mm, tumours with an internal reflectivity smaller than 50%, and tumours with an initial rate of height regression larger than 0.7 mm/month (10% per month) had higher 5 year melanoma related mortality. Kaplan-Meier survival analysis and the multivariate Cox proportional hazards model showed a significant role for tumour height and initial tumour regression rate on patients' survival. CONCLUSION: This study confirms that post-brachytherapy initial tumour regression rate has a prognostic value.

Cell proliferation activity in posterior uveal melanoma after Ru-106 brachytherapy: an EORTC ocular oncology group study.

AIM: To evaluate the cell proliferation activity in posterior uveal melanomas after Ru-106 brachytherapy. METHODS: Eyes containing choroidal or ciliary body melanoma from seven ocular oncology centres, which were enucleated after first being treated by Ru-106 brachytherapy and which had enough melanoma tissue to enable histological assessment, were included. The 57 eligible specimens were divided into a group of 44 eyes that were enucleated because of tumour regrowth, and a non-recurrent group of 13 eyes that were enucleated because of complications such as neovascular glaucoma. 46 non-irradiated eyes harbouring uveal melanoma served as a control group. All specimens underwent routine processing. They were cut into 5 microm sections, and were stained with two main cell proliferation markers: PC-10 for PCNA and MIB-1 for Ki-67. The stained sections were assessed, and the cells that were positive in the immunostaining were counted in each section. The results were evaluated by various statistical methods. RESULTS: The PC-10 score showed a statistically significant difference across the three groups (p = 0.002). The control group showed the highest PC-10 score (median 31.0 PCC/HPF) followed by the tumour regrowth group (median 4.9 PCC/HPF). The lowest PC-10 scores were found in the non-recurrent tumours (median 0.05 PCC/HPF). The MIB-1 score in the control group (median 5.77 PCC/HPF) was similar to the regrowth group (median 5.4 PCC/HPF). In contrast, the MIB-1 score in the non-recurrent tumours was statistically significantly lower (median 0.42 PCC/HPF). The PC-10 and MIB-1 scores were similar in tumours composed of either spindle cells or epithelioid cells in all groups. CONCLUSIONS: The non-recurrent melanomas demonstrate significantly lower cellular proliferation activity than melanomas that showed regrowth or that were not irradiated at all. In our hands, PCNA gave more meaningful information than Ki-67. Our findings strongly support the need for treating regrowing posterior uveal melanoma either by enucleation or re-treatment by brachytherapy. On the other hand, also in the non-recurrent uveal melanomas there are viable cells with potential for proliferation, although fewer in number, with unknown capacity for metastatic spread. Therefore, the irradiated tumours should be followed for many years, probably for life.

Traumatic wound dehiscence after cataract extraction.

PURPOSE: To study the visual outcome and factors associated with it in patients with traumatic dehiscence of a cataract surgery wound. SETTING: Department of Ophthalmology and the Brown School of Public Health and Community Medicine, The Hebrew University-Hadassah Medical School, Jerusalem, Israel. METHODS: A retrospective observational study of 37 eyes of 37 consecutive patients with traumatic wound dehiscence of a cataract surgery wound was conducted. A complete ophthalmic evaluation was performed in all patients. Statistical analysis was done to identify factors associated with the best corrected visual acuity at the end of follow-up. RESULTS: Patients had extracapsular cataract extraction (n = 29), intracapsular cataract extraction (n = 4), or lensectomy (n = 4). No patient had phacoemulsification via a small incision. A univariate analysis showed that factors associated with a worse visual outcome included the presence at presentation of hyphema (P = .05), intraocular lens dislocation or loss (P = .006), vitreous hemorrhage (P = .0002), scleral rupture (P = .001), a long interval from surgery to trauma (P < .0001), and fall as the cause of trauma (P < .0001). In a multivariate model, only a surgery-to-trauma interval longer than 8 weeks was associated with a worse visual outcome (P < .0001). Visual acuity immediately after trauma was a poor predictor of final visual acuity. CONCLUSIONS: Visual outcome after traumatic wound dehiscence of a cataract surgery wound was strongly associated with the interval from surgery to trauma. Other factors were less reliable predictors of visual outcome. Traumatic wound dehiscence only moderately affected visual outcome after cataract surgery in most cases.

Gene transfer by viral vectors into blood vessels in a rat model of retinopathy of prematurity.

AIMS: To test the feasibility of gene transfer into hyaloid blood vessels and into preretinal neovascularisation in a rat model of retinopathy of prematurity (ROP), using different viral vectors. METHODS: Newborn rats were exposed to alternating hypoxic and hyperoxic conditions in order to induce ocular neovascularisation (ROP rats). Adenovirus, herpes simplex, vaccinia, and retroviral (MuLV based) vectors, all carrying the beta galactosidase (beta-gal) gene, were injected intravitreally on postnatal day 18 (P18). Two sets of controls were also examined: P18 ROP rats injected with saline and P18 rats that were raised in room air before the viral vectors or saline were injected. Two days after injection, the rats were killed, eyes enucleated, and beta-gal expression was examined by X-gal staining in whole mounts and in histological sections. RESULTS: Intravitreal injection of the adenovirus and vaccinia vectors yielded marked beta-gal expression in hyaloid blood vessels in the rat ROP model. Retinal expression of beta-gal with these vectors was limited almost exclusively to the vicinity of the injection site. Injection of herpes simplex yielded a punctuate pattern of beta-gal expression in the retina but not in blood vessels. No significant beta-gal expression occurred in rat eyes injected with the retroviral vector. CONCLUSIONS: Adenovirus is an efficient vector for gene transfer into blood vessels in an animal model of ROP. This may be a first step towards utilising gene transfer as a tool for modulating ocular neovascularisation for experimental and therapeutic purposes.

Proliferative activity and p53 expression in primary and recurrent pterygia.

PURPOSE: To assess p53 expression and proliferative activity in primary and recurrent pterygia from the same eyes. DESIGN: Retrospective comparative human tissue study. PARTICIPANTS: Tissue from excised primary pterygia that did not recur (group A, n = 10) was compared with tissue from primary pterygia that recurred (group B, n = 10) and to the recurrent pterygia tissue that was excised from subjects in group B (group C, n = 10). Ten normal conjunctivas served as controls (group D). METHODS: Sections from each pterygium were immunostained with the MIB-1 and bp53. 12 monoclonal antibodies that react with Ki-67 and p53 antigens, respectively. MAIN OUTCOME MEASURES: Proliferative activity was calculated as the mean of the MIB-1 positive cell count per eyepiece grid in high magnification (x40) (positive cell count/grid). Percentage of positive cells of all cells in the grid area was evaluated in the p53-stained sections. RESULTS: Proliferative activity was found in the epithelium overlying the pterygia and normal conjunctiva. The mean MIB-1 positive cell count/grid +/- standard error was 2.84 +/- 1.07, 1.74 +/- 0.82, 3.83 +/- 1.35, and 0.86 +/- 0.33 in groups A, B, C, and D, respectively (P = 0.17, Kruskal-Wallis). P53 staining was found in 50% of pterygia in groups A, B, and C; none of the normal conjunctival tissues showed p53 immunoreactivity. Four of five p53-positive tissues in group B were p53-negative in group C. In the p53-positive pterygia, less than 10% of cells were p53 positive. However, p53-positive pterygia had higher mean MIB-1 positive cell count/grid +/- standard error as compared with the p53-negative lesions, 4.56 +/- 0.94 vs 1.39 +/- 0.59 (P = 0.021, Mann-Whitney). CONCLUSIONS: p53 immunoreactivity and high proliferative activity in the epithelium overlying the pterygium are not associated with recurrence of pterygium.

Comparison of microcirculation patterns and MIB-1 immunoreactivity in iris and posterior uveal melanoma.

PURPOSE: To compare melanomas confined to the iris and those involving either the ciliary body or choroid for the histologic features of microcirculation patterns and tumor cell proliferation indices. DESIGN: Retrospective comparative human tissue study. PARTICIPANTS: Ninety-eight uveal melanomas were studied, including 18 tumors confined to the iris, 30 tumors involving the ciliary body, and 50 tumors confined to the choroid. METHODS: Formalin-fixed, paraffin-embedded sections from each tumor were stained with hematoxylin-eosin and with periodic acid-Schiff. Adjacent histologic sections were stained with the MIB-1 antibody that reacts with the Ki-67 antigen. MAIN OUTCOME MEASURES: Microcirculation patterns were assessed in the periodic acid-Schiff-stained sections. Proliferative activity was assessed in the MIB-1-stained sections. The mean MIB-1 positive cell count per high-power field (HPF) was calculated in 10 HPF (x 40) in the area of maximal immunoreactivity. Two observers evaluated each MIB-1-stained section, and the interobserver reproducibility was assessed. RESULTS: Histologic microcirculation patterns associated with death from metastatic disease in ciliary body and choroidal melanomas (parallel vessels with cross-linking and networks of back-to-back loops) were not found in any of the iris melanomas. By contrast, 34% and 63% of the choroidal and ciliary body melanomas, respectively, showed at least one of these patterns. The mean positive cell count per HPF +/- standard error was 19.9 +/- 3.5, 27 +/- 5.3, and 1.9 +/- 0.4 in choroidal, ciliary body, and iris melanoma, respectively (P: = 0.003, Kruskal-Wallis test). CONCLUSIONS: Melanoma confined to the iris is characterized by a low rate of proliferation and the histologic absence of microcirculation patterns associated with metastatic posterior uveal melanoma. Both features are consistent with the relatively benign nature of iris lesions compared with melanomas involving the ciliary body or choroid.

Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients.

PURPOSE: To assess the long-term efficacy of combined vitamin A and E treatment in preventing retinal degeneration in patients with abetalipoproteinaemia (ABL) or homozygous hypobetalipoproteinaemia (HBL). METHODS: Ten patients with ABL and 3 with homozygous HBL who were treated with oral supplements of vitamins A and E were studied. Systemic, ophthalmological and electroretinographic follow-up for a mean of 11.7 years (range 4-20 years) after onset of treatment was evaluated. RESULTS: Despite vitamin A and E treatment, 7 of 10 patients who began treatment prior to 2 years of age and all 3 patients who began treatment later in life manifested unusual fundoscopic pigmentary changes over time. At the end of follow-up, 11 of 13 patients had subnormal mixed cone-rod electroretinogram amplitudes. Seven of 10 patients for whom perimetry was available had mild to severe constriction of the visual fields. CONCLUSIONS: Combined oral vitamin A and E supplementation that is initiated prior to 2 years of age can markedly attenuate the severe retinal degeneration that is associated with untreated ABL or homozygous HBL. Yet, fundoscopic and functional retinal changes do occur despite early initiation of vitamin treatment. Therefore, the adequacy of the present treatment protocol for ABL and homozygous HBL should be re-evaluated.

Retinitis pigmentosa associated with Fuchs' heterochromic uveitis.

OBJECTIVE: To investigate whether the combination of Fuchs' heterochromic uveitis (FHU) and retinitis pigmentosa (RP) in the same patient is coincidental or represents a true association. METHODS: We have examined the frequency of FHU in 338 patients with RP and in 1984 patients who were seen in our primary care ophthalmic clinic because of reasons other than RP. RESULTS: Of 338 patients with RP, 4 (1.2%) had the typical findings of FHU. Three of them had Usher syndrome type II, and 1 had RP simplex. By contrast, only 1 patient in the control group had FHU (5%), and the difference in the frequency of FHU between the 2 groups was significant (P=.002, Fisher exact test). CONCLUSIONS: Fuchs' heterochromic uveitis is associated with RP. Since autoimmune phenomena have been previously described in patients with RP, it is conceivable that RP predisposes to the development of FHU. Arch Ophthalmol. 2000;118:800-802