Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study).

PURPOSE: To compare the efficacy of ranibizumab 0.5-mg and 2.0-mg intravitreal injections for persistent diabetic macular edema (DME) previously treated with bevacizumab. METHODS: In all, 43 patients with residual center-involved DME following intravitreal bevacizumab were included in this 12-month prospective, nonrandomized, multicenter study. Enrolled patients received three monthly ranibizumab 0.5-mg injections. At month 3, patients with residual macular edema switched to three monthly injections of ranibizumab 2.0-mg. Assessments included monthly visual acuity and spectral-domain optical coherence tomography. RESULTS: Mean visual acuity improved by +6.4 letters at month 3 and +8.8 letters at month 6. Mean central subfield thickness (CST) decreased by -113 µm at month 3 and -165 µm at month 6. Before enrollment, 29/43 (67.4%) patients showed <10% CST reduction following monthly bevacizumab treatment. After three monthly ranibizumab 0.5-mg injections, 22/29 (75.9%) patients showed >10% reduction in CST, whereas 6 showed <10% reduction. Of these six, three (50%) showed >10% reduction in CST after switching to three monthly ranibizumab 2.0-mg doses. No serious adverse events were observed to month 6. CONCLUSION: Ranibizumab 0.5-mg or 2.0-mg may improve visual and anatomic outcomes in patients with DME who demonstrated minimal or no response to bevacizumab therapy. Moreover, increased dosage of ranibizumab (2.0-mg) may provide additional benefit over ranibizumab 0.5-mg in some patients. However, 2.0-mg ranibizumab is not currently commercially licensed or available.

Epiretinal membrane removal in diabetic eyes: comparison of viscodissection with conventional methods of membrane peeling.

AIMS: To compare conventional methods of epiretinal membrane peeling with viscodissection. METHODS: 154 eyes with proliferative diabetic retinopathy (PDR) that underwent pars plana vitrectomy with membrane dissection (89 traditional, 65 viscodissection) were studied retrospectively. Incidence of retinal breaks (RBs), length of time under anaesthesia, postoperative intraocular pressure, retinal reattachment rate, and final visual acuity (VA) were measured. RESULTS: To compare cases of similar complexity, a "complexity score" was defined. The average complexity score for cases done with and without viscodissection was 4.7 and 3.2, respectively. The mean frequency of RBs in eyes undergoing viscodissection was 0.43 (SD 0.5) v 0.14 (0.35) RBs/eye without viscodissection. In complex cases, the frequency of posterior/peripheral RBs was 0.31 (0.47)/0.13 (0.34) RBs/eye, respectively, with viscodissection v 0.12 (0.33)/0.23 (0.43) RBs/eye without viscodissection. None of these differences were statistically significant. The average preoperative/postoperative VA (logMAR) in the viscodissection cohort was 1.7/1.3 (range 0.3 to >1.9/0.1 to >1.9) v 1.4/1 (range 0.48 to >1.9/0.1 to >1.9) in the non-viscodissection cohort, among eyes with 6 months of follow up. Anaesthesia duration was significantly shorter for cases done without viscodissection (p=0.03), but cases done with viscodissection were significantly more complex than cases done without viscodissection (p<0.0001). CONCLUSION: Viscodissection appears to be a safe and effective alternative technique in eyes with PDR. Owing to the retrospective nature of the study, additional studies are warranted.

Vitrectomy with silicone oil infusion in severe diabetic retinopathy.

AIMS: To determine the results of pars plana vitrectomy (PPV) and silicone oil infusion (SOI) in severe proliferative diabetic retinopathy (PDR). METHODS: The records of 23 eyes (21 patients: 12 males, nine females) with PDR who had undergone PPV and SOI were reviewed retrospectively. RESULTS: Average follow up was 5.4 months (range 1-25). Surgical indications were tractional retinal detachment (TRD) (17.4%), traction-rhegmatogenous retinal detachment (TRRD) (8.7%), TRD with vitreous haemorrhage (VH) (48%), TRD with neovascular glaucoma (NVG) (8.6%), TRD with fibrinoid syndrome (FS) (17.3%). With one operation, the retinal reattachment rate was 17/23 (74%). Among these 23 eyes, 11 (48%) had previously failed vitrectomy, and the retina was attached in 8/11 (73%) with a single procedure. With additional surgery employing PPV and SOI, the final reattachment rate was 20/23 (87%). The only cases with intraocular pressure <5 mm Hg had retinal detachment. Postoperative visual acuity (VA) improved in 10 eyes (44%), was unchanged in three (12%), and decreased in 10 eyes (44%). CONCLUSION: SO tamponade is useful in severely diseased eyes with PDR, even in the presence of rubeosis iridis (RI) and NVG, FS, or in cases with previously failed vitrectomy, especially in the presence of RI.

Use of viscodissection and silicone oil in vitrectomy for severe diabetic retinopathy.

Improvement in surgical techniques has led to improved anatomic and functional success rates following surgery for severe complications of proliferative diabetic retinopathy (PDR). We compared the anatomic and functional outcomes of surgery in a non-randomized, consecutive case series of patients with severe PDR. We found that viscodissection using Healon provides outcomes comparable to conventional pick and scissors dissection. We also found that adjunctive use of silicone oil can salvage selected cases with particularly severe manifestations of PDR (e.g., the fibrinoid syndrome). With proper selection of patients and techniques, the anatomic success rate can exceed 80% even in the most severe cases. The goal of this paper is to show the applicability of using viscodissection and silicone oil infusion during vitrectomy in eyes with severe PDR.

[Catch-up growth and final height in celiac disease].

BACKGROUND: Growth retardation resulting from celiac disease diagnosed in infancy or in early childhood is remediable after introduction of a gluten-free diet. The aim of this study was to evaluate long-term growth, catch-up growth and final height in a group of treated patients with celiac disease. METHODS: The study population consisted of 35 patients (13 M, 22 F) with typical celiac disease. Age at diagnosis was 1.17 (+/- 0.69) years. For each patient, the standard deviation score (SDS) and centile of height at diagnosis, target height and final height were elaborated, and linear regression and correlations between SDS of final height and age at diagnosis, SDS of height at diagnosis and SDS of target height, respectively, were calculated. RESULTS: At diagnosis patients had a general tendency to short stature: mean height was 81.8 cm +/- 22.9 cm (SDS -0.75 +/- 1.61), while target height was 164.3 cm +/- 13.5 cm (SDS -0.14 +/- 1.04) and final height 169.2 cm +/- 7.7 cm (SDS 0.41 +/- 1.04). Linear regression and correlations between SDS of final height and age at diagnosis, SDS of height at diagnosis and SDS of target height, respectively, proved nonsignificant. CONCLUSIONS: Irrespective of age and height at diagnosis, catch-up growth was complete in this group of patients, with satisfactory achievement of final height. Only one patient (age at diagnosis 13 years) failed to reach the target height.

Early attachment of uncultured retinal pigment epithelium from aged donors onto Bruch's membrane explants.

Retinal pigment epithelium (RPE) transplantation might replace cells lost as a consequence of choroidal neovascular membrane excision in patients with age-related macular degeneration (AMD). Autologous transplantation of RPE cells harvested from a peripheral biopsy may overcome problems of immune rejection. To study the feasibility of autologous RPE cell transplantation, the authors examined the attachment of freshly harvested RPE cells from aged donors onto Bruch's membrane explants, debrided to (1) remove or (2) preserve the RPE basement membrane. Human retinal pigment epithelial sheets were harvested from adult donor eyes (N = 12, mean age 79.00 +/- 9.40 years) and, following incubation in collagenase, were mechanically fragmented into microaggregates. Microaggregates (approximately 120 000 cells) were seeded onto the paired explants (7 mm diameter) and incubated for 20 min, 1, 4, or 24 hr at 37 degrees C. The percent coverage of the debrided surface by microaggregates was determined by sampling the center of the explants with scanning electron microscopy. RPE microaggregate attachment to Bruch's membrane was significantly greater at all time points analysed in samples with intact basement membrane versus those with an exposed inner collagenous layer. Coverage of debridements retaining intact RPE basement membrane was 1.83 +/- 1.10% at 20 min, 3.54 +/- 2.14% at 1 hr, and 8.68 +/- 2.63% at 4 hr. Coverage of debridements lacking basement membrane was 0.10 +/- 0.04% at 20 min, 0.39 +/- 0.25% at 1 hr, and 0.63 +/- 0.42% at 4 hr. Based on their morphologic appearance, many cells were dying as early as 1 hr following seeding. To increase surface coverage, the authors seeded four times the above number of cells and incubated the specimens for 1 hr. Coverage on explants lacking RPE basement membrane showed no increase in the number of cells attached to the inner collagenous layer. There was a significant approximately three-fold increase in the number of cells attached in the presence of basement membrane. These results indicate that if RPE cells from aged human donors are used for transplantation, some modification of the Bruch's membrane surface or the cells must be considered for cell attachment and eventual cell survival.

Childhood obesity: different definition criteria, different prevalence rate.

BACKGROUND: Evaluate the influence of reference growth curves on determination of prevalence of obesity in children and particularly compare two indicators most commonly used, overweight (OW%) and body mass index (BMI centile), measured in the same population. DESIGN: cross-sectional study. SUBJECTS: 40,068 children (19,892 males, 20,176 females) aged from 3 to 17 years. RESULTS: The results obtained in this study show different prevalence rates according to the indicators used to define childhood obesity and according to the reference curves adopted. When Tanner-Whitehouse curves were used, prevalence peaked at age 9-13 years in males and age 8-14 years in females, with rates of up to 18%. When using our own curves to calculate ideal weight, the peak prevalence of obesity was at 12 years in males and 10 years in females, with prevalence rates of 11.8 and 13.7%, respectively. The prevalence of obesity, calculated using the BMI 90th percentile as the cut-off, ranged from 8 to 12%, with rates similar to those observed with OW% in children aged from 8 to 17 years, whereas the differences were greater in children aged from 3 to 8 (2.1% with OW% and 10.24% with BMI centile at 3 years). CONCLUSIONS: Prevalence rates are influenced by the reference curves used and the obesity indicator adopted. It would be desirable for epidemiological studies to use the same indicator, the same cut-off and, whenever possible, recent reference curves suitable for the particular population surveyed.

BMI centile as an indicator of degree of obesity in childhood.

OBJECTIVE: To evaluate body mass index (BMI centile) as an indicator of degree of obesity in childhood. DESIGN: Random. SETTING: Obese and nonobese healthy children were recruited in the Verona University Department of Pediatrics and Division of Pediatrics of the Verona City Hospital. SUBJECTS AND METHODS: 70 males aged 9.7 +/- 2.75 years and 55 females aged 9.9 +/- 3 years. Percentage fat mass was estimated by bioelectrical impedance analysis using Kushner's equation, and Italian BMI charts (A. Luciano et al. 1997) were used to calculate the BMI centile (BMI > 90 degrees in 76 subjects and BMI < 90 degrees in 59 subjects). RESULTS: Linear regression analysis and correlations between percentage fat mass and BMI centile were significant in males (P = 0.000, r = 0.6) and females (P = 0.000, r = 0.7) in both obese and nonobese subjects. CONCLUSIONS: BMI is a reliable, easy-to-use indicator of degree of obesity in childhood. Pediatricians should be encouraged to use BMI centiles to assess childhood obesity and particularly the onset of overweight, its evolution and its response to different types of management.

Short-term study of allogeneic retinal pigment epithelium transplants onto debrided Bruch's membrane.

PURPOSE: To investigate the survival and behavior of retinal pigment epithelium (RPE) microaggregates transplanted onto hydraulically debrided Bruch's membrane and to compare results of using three different vehicles for cell delivery. METHODS: RPE microaggregates obtained from male cats were transplanted onto the tapetal area of female cats after native RPE was debrided. For the control, one of three vehicles was introduced into the debridements. Each transplant or control specimen was analyzed histologically and immunohistochemically. Transplanted male RPE cells were identified by in situ labeling of the cat Y chromosome. RESULTS: Histologically, significant numbers of condensed, darkly stained RPE nuclei were observed in all transplants compared with few TUNEL-positive RPE cells. Cellular retinaldehyde-binding protein was present up to day 7 in all RPE cells in transplants. In both transplant and control specimens, the antibody against the Ki-67 nuclear antigen labeled some RPE cells at day 3. TUNEL-positive outer nuclear layer nuclei were most frequently observed at day 1, but were much less frequent at 7 days in both transplant and control specimens. CONCLUSIONS: Transplanted RPE appeared to retain at least some markers of differentiation up to 7 days after surgery. Some proliferation of transplanted RPE cells was also seen. Apoptotic cell death of transplanted RPE, as judged by TUNEL staining was observed rarely. RPE transplants imposed no adverse effect on the overlying retina. RPE survival appeared to be similar with each of the three vehicles for cell delivery.

Endophthalmitis.

Endophthalmitis is an inflammatory reaction of intraocular fluids or tissues. Infectious endophthalmitis is one of the most serious complications of ophthalmic surgery. Occasionally, infectious endophthalmitis is the presenting feature of an underlying systemic infection. Successful management of infectious endophthalmitis depends on timely diagnosis and institution of appropriate therapy. Recognition of the different clinical settings in which endophthalmitis occurs and awareness of the highly variable presentation it may have facilitate timely diagnosis. Biopsy of intraocular fluid/tissue is the only method that permits reliable diagnosis and treatment. The different presenting clinical settings, a rational approach to diagnosis (i.e., when, what, and how to biopsy), and the treatment of infectious endophthalmitis are reviewed.

Clinicopathological correlation of primary and recurrent choroidal neovascularisation following surgical excision in age related macular degeneration.

AIMS/BACKGROUND: Fluorescein angiography and histopathological findings were correlated in two patients with recurrent choroidal neovascular membranes (CNVs) in an attempt to gain insight into the possible causes of recurrent CNVs and into the healing response after CNV excision. METHODS: Two patients with recurrent CNVs underwent repeat excision, and the excised tissue was studied with light and electron microscopy. RESULTS: Incomplete CNV excision probably led to the recurrences. The portion initially excised appears to have been anterior to the RPE in case 1. In both cases, recurrent CNVs contained RPE-like like cells suggesting that native RPE can repopulate the dissection bed. The tissue excised at the second operation contained areas with hyperplastic RPE and fragments of Bruch's membrane (external to the RPE basement membrane) in a matrix of fibrillar collagen and fibrocytes, suggesting that initial removal of the CNV can be followed by an abnormal anatomical arrangement of RPE and scarring of Bruch's membrane. CONCLUSIONS: Abnormal resurfacing of the dissection bed by RPE and fibroblasts may underlie, in part, the limited visual outcome often seen after surgical excision of CNVs in age related macular degeneration.

Progressive presumed choriocapillaris atrophy after surgery for age-related macular degeneration.

PURPOSE: The authors sought to evaluate the progression of presumed choriocapillaris atrophy after surgical excision of a subfoveal choroidal neovascular membrane (CNV) in an 80-year-old man with age-related macular degeneration. METHODS: The CNV was excised using a conventional three-port vitrectomy with subretinal dissection. The excised tissue was studied with light and electron microscopy. Preoperative and serial postoperative fluorescein angiograms (FA) and fundus photographs were obtained to study the dissection bed. RESULTS: Seven days after surgery, the FA showed hyperfluorescence in the area previously occupied by the CNV. Six weeks after surgery, this area showed retinal pigment epithelium (RPE) depigmentation, atrophy, or both on clinical examination, and the FA showed presumed choriocapillaris nonperfusion. Seven months after surgery, the area of the RPE depigmentation or atrophy and the corresponding area of presumed choriocapillaris nonperfusion had enlarged. The area of depigmentation or atrophy continued to enlarge for 1 year after surgery. Histologically, the excised CNV specimen disclosed RPE cells but no choriocapillaris. CONCLUSIONS: Presumed choriocapillaris nonperfusion after CNV excision may be due to RPE removal at surgery and may progress postoperatively.

In vitro transplantation of fetal human retinal pigment epithelial cells onto human cadaver Bruch's membrane.

Retinal pigment epithelium transplantation has been proposed as adjunctive treatment for age-related macular degeneration following surgical excision of choroidal neovascular membranes. The goal of this study was to develop a model to evaluate retinal pigment epithelium transplantation onto human Bruch's membrane in vitro. We investigated the ability of cultured fetal human retinal pigment epithelium to colonize human cadaver Bruch's membrane, determined the incubation time needed to form a monolayer and to exhibit apical microvilli and tight junctions, and assessed the production of basement membrane. Freshly enucleated (less than 48 hours old) human eyes were cut through the pars plana, and the anterior segment, vitreous, and retina were removed. The native retinal pigment epithelium was debrided with a surgical sponge. Bruch's membrane and choroid at the macula were trephined with a 7.0 mm diameter trephine and then incubated with 1/2 ml of Dulbecco's modified Eagle's medium +15% fetal calf serum+basic fibroblast growth factor (1 ng ml-1), and fetal human retinal pigment epithelium at a concentration of 242,000 cells ml-1. Specimens were incubated for 1, 4, 6, 8, 12, or 24 hours. The specimens were fixed in half strength Karnovsky's fixative, processed, and analysed with scanning and transmission electron microscopy. The retinal pigment epithelium covered the debrided macular specimens to different degrees at different incubation times. After 1 hour, the cells started to attach and flatten (median percent coverage: 78%). The extent of Bruch's membrane coverage by fetal retinal pigment epithelium varied greatly between specimens. After 4-6 hours, the cells covered the entire debrided surface in a monolayer (median percent coverage: 97.2% at 4 hours, 99.8% at 6 hours). Tight junctions were observed, and the cells had few apical microvilli. The lateral cell borders were obliquely oriented with respect to Bruch's membrane, and the nuclei were elongated, exhibited prominent nucleoli, and were oriented parallel to Bruch's membrane. After 6-8 hours, cells started to become hexagonal (median percent coverage at 8 hours: 99.97%). Cells attached to the inner collagenous layer tended to be flatter than cells attached to residual native basement membrane. At 12 and 24 hours, expression of hexagonal shape, tight junctions, and apical microvilli were observed more frequently (median percent coverage: 99.87% at 12 and 100% at 24 hours). No newly formed basement membrane was observed at these time points. In separate experiments comparing attachment in the presence and absence of native RPE basement membrane, the presence of native retinal pigment epithelial basement membrane promoted the early attachment of the cells and more rapid expression of normal morphology. This in vitro system provides a reproducible way to study the adherence of retinal pigment epithelium to normal and diseased human Bruch's membrane.

Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus.

BACKGROUND: Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes. METHODS: As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20-59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative). FINDINGS: The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p = 0.2). Patients on lisinopril had significantly lower HbA1c at baseline than those on placebo (6.9% vs 7.3 p = 0.05). Retinopathy progressed by at least one level in 21 (13.2%) of 159 patients on lisinopril and 39 (23.4%) of 166 patients on placebo (odds ratio 0.50 [95% CI 0.28-0.89], p = 0.02). This 50% reduction was the same when adjusted for centre and glycaemic control (0.55 [0.30-1.03], p = 0.06). Lisinopril also decreased progression by two or more grades (0.27 [0.07-1.00], p = 0.05), and progression to proliferative retinopathy (0.18 [0.04-0.82], p = 0.03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0.69 [0.30-1.59], p = 0.4). INTERPRETATION: Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated.

Clinicopathological correlation of an excised choroidal neovascular membrane in pseudotumour cerebri.

AIMS/BACKGROUND: To correlate the histopathology of an excised choroidal neovascular membrane (CNV) with the clinical and angiographic findings in a 32-year-old woman with pseudotumour cerebri and a peripapillary CNV with subfoveal extension. METHODS: The patient's visual acuity was assessed by individuals experienced in low vision refraction and who were not members of the surgical team. The CNV was excised via a conventional three port vitrectomy with subretinal dissection. The excised tissue was studied with light and electron microscopy. Preoperative and serial postoperative fluorescein angiograms (FAs) and fundus photographs were obtained to study the dissection bed. RESULTS: One week after surgery, the FA showed mottled subfoveal choriocapillaris perfusion. Three weeks after surgery, this area showed retinal pigment epithelium (RPE) atrophy clinically, and the FA showed choriocapillaris non-perfusion. Six months after surgery, the area of RPE atrophy and the corresponding area of choriocapillaris non-perfusion had expanded. Histologically, the excised CNV disclosed hyperplastic RPE, fibrovascular tissue, and no choriocapillaris. Fragments of RPE basement were present along the external edge of the specimen. The patient's visual acuity did not improve significantly after surgery. CONCLUSIONS: Choriocapillaris non-perfusion can develop even in young patients following CNV excision. In this particular case, it is believed that choriocapillaris atrophy was caused by incomplete ingrowth of RPE into the dissection bed following RPE removal with CNV excision. As far as is known, this is the first report describing the results of surgery for CNV secondary to papilloedema associated with pseudotumour cerebri.