Pascale Massin

The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema.

OBJECTIVE To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic macular edema (DME). DESIGN A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study. PARTICIPANTS We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME. METHODS Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits). MAIN OUTCOME MEASURES Mean average change in BCVA from baseline to month 1 through 12 and safety. RESULTS Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study. CONCLUSIONS Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.

A contribution of image processing to the diagnosis of diabetic retinopathy-detection of exudates in color fundus images of the human retina

In the framework of computer assisted diagnosis of diabetic retinopathy, a new algorithm for detection of exudates is presented and discussed. The presence of exudates within the macular region is a main hallmark of diabetic macular edema and allows its detection with a high sensitivity. Hence, detection of exudates is an important diagnostic task, in which computer assistance may play a major role. Exudates are found using their high grey level variation, and their contours are determined by means of morphological reconstruction techniques. The detection of the optic disc is indispensable for this approach. We detect the optic disc by means of morphological filtering techniques and the watershed transformation. The algorithm has been tested on a small image data base and compared with the performance of a human grader. As a result, we obtain a mean sensitivity of 92.8% and a mean predictive value of 92.4%. Robustness with respect to changes of the parameters of the algorithm has been evaluated.

Safety and Efficacy of Ranibizumab in Diabetic Macular Edema (RESOLVE Study) A 12-month, randomized, controlled, double-masked, multicenter phase II study

OBJECTIVE The expression of vascular endothelial growth factor (VEGF) is elevated in diabetic macular edema (DME). Ranibizumab binds to and inhibits multiple VEGF variants. We investigated the safety and efficacy of ranibizumab in DME involving the foveal center. RESEARCH DESIGN AND METHODS This was a 12-month, multicenter, sham-controlled, double-masked study with eyes (age >18 years, type 1 or 2 diabetes, central retinal thickness [CRT] ≥300 μm, and best corrected visual acuity [BCVA] of 73–39 ETDRS letters [Early Treatment Diabetic Retinopathy Study]) randomly assigned to intravitreal ranibizumab (0.3 or 0.5 mg; n = 51 each) or sham (n = 49). The treatment schedule comprised three monthly injections, after which treatment could be stopped/reinitiated with an opportunity for rescue laser photocoagulation (protocol-defined criteria). After month 1, dose-doubling was permitted (protocol-defined criteria, injection volume increased from 0.05 to 0.1 ml and remained at 0.1 ml thereafter). Efficacy (BCVA and CRT) and safety were compared between pooled ranibizumab and sham arms using the full analysis set (n = 151, patients receiving ≥1 injection). RESULTS At month 12, mean ± SD BCVA improved from baseline by 10.3 ± 9.1 letters with ranibizumab and declined by 1.4 ± 14.2 letters with sham (P < 0.0001). Mean CRT reduction was 194.2 ± 135.1 μm with ranibizumab and 48.4 ± 153.4 μm with sham (P < 0.0001). Gain of ≥10 letters BCVA from baseline occurred in 60.8% of ranibizumab and 18.4% of sham eyes (P < 0.0001). Safety data were consistent with previous studies of intravitreal ranibizumab. CONCLUSIONS Ranibizumab is effective in improving BCVA and is well tolerated in DME. Future clinical trials are required to confirm its long-term efficacy and safety.

OPTICAL COHERENCE TOMOGRAPHY FOR EVALUATING DIABETIC MACULAR EDEMA BEFORE AND AFTER VITRECTOMY

PURPOSE To report the use of optical coherence tomography (OCT) for evaluation of diffuse diabetic macular edema (DME) before and after vitrectomy. DESIGN Interventional case series. METHODS A retrospective study was made of 15 consecutive eyes of 13 patients that had vitrectomy for diffuse DME and OCT preoperatively and postoperatively. In seven eyes of six patients (group 1), vitrectomy was performed because of vitreomacular traction observed on biomicroscopy or OCT. In the other eight eyes of seven patients (group 2), vitrectomy was performed for DME not responsive to laser photocoagulation, with no vitreomacular traction on biomicroscopy or OCT. RESULTS Mean +/- standard deviation (SD) follow-up after vitrectomy was 18 +/- 10 months (range, 6 to 33 months). In group 1, mean +/- SD retinal thickness decreased significantly from 661 +/- 181 microm preoperatively to 210 +/- 32 microm at the end of follow-up (P =.018). Median best-corrected visual acuity (BCVA) improved from 20/100 before surgery (range, 20/250 to 20/50) to 20/80 at the end of follow-up (range, 20/250 to 20/25; P =.046). In one eye in group 1, vitreomacular traction was only observed on OCT and not on biomicroscopy. In group 2, mean +/- SD retinal thickness decreased from 522 +/- 103 microm preoperatively to 428 +/- 121 microm at the end of follow-up (P =.2). Median BCVA was 20/100 before vitrectomy (range, 20/320 to 20/63) and 20/200 at the end of follow-up (range, 20/250 to 20/63; P =.78). CONCLUSIONS Vitrectomy was beneficial in eyes with diffuse DME combined with vitreomacular traction but not in eyes without traction. Optical coherence tomography allowed diagnosis of subtle vitreomacular traction and provided precise preoperative and postoperative assessments of macular thickness.

Maternally Inherited Diabetes and Deafness: A Multicenter Study

Mitochondrial (mt) gene abnormalities cause disease due to defects in oxidative production of energy (1). In 1990, Goto and colleagues (2) described the co-segregation of a syndrome called mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (which is sometimes associated with diabetes) and an A to G transition at position 3243 of mtDNA, encoding transfer RNA leucine (tRNALeu [UUR]). In 1992, a subtype of diabetes called maternally inherited diabetes and deafness (MIDD) was reported to co-segregate with the same point mutation (3, 4). Maternally inherited diabetes and deafness was initially characterized by matrilineal transmission, associated hearing loss, or both, without major neurologic defects. In MIDD, diabetes seems to be due primarily to a defect in insulin secretion (4-9), while insulin sensitivity is unaltered (8, 10). An estimated 0.5% to 2.8% of diabetic patients have MIDD (9, 11-16). Because most reported series have been small, the clinical description of MIDD and its course, particularly the occurrence of diabetic complications, remains incomplete. The aims of our study were to delineate the clinical presentation of MIDD, including involvement of other organs, in a large series of patients and to assess the prevalence of diabetic microvascular and macrovascular complications. Methods Patients We conducted this prospective multicenter descriptive study between September 1995 and December 1999. A questionnaire was sent to all members of the French Association for the Study of Diabetes (ALFEDIAM) in order to assess the clinical presentation of MIDD in a large series of patients. A total of 52 patients were included as a result of the questionnaire, and 19 patients were recruited directly from Lariboisire Hospital. The 3243 mtDNA mutation was identified in 40 probands who were selected primarily because they had both diabetes and deafness. Family screening identified 31 additional carriers of the mutation. All patients were white and European, except one who was of Caribbean origin. Three patients had mitochondrial encephalopathy, lactic acidosis, and strokelike episodes associated with diabetes. Among the 68 remaining patients, 54 had overt diabetes, 2 had impaired glucose tolerance, and 12 were healthy carriers. The study conformed to the principles of the Declaration of Helsinki, and all patients gave informed consent. Measurements We used a structured interview and a standardized examination of the patients and of their relatives to ascertain a family history of diabetes and hearing loss and to determine glucose tolerance disorders, treatment, diabetic complications, and associated manifestations. Abnormalities in glucose tolerance were diagnosed on the basis of the 1997 criteria outlined by the American Diabetes Association (17). Accordingly, diabetes was defined as a fasting plasma glucose level of 7 mmol/L (126 mg/dL) or greater on two occasions, a plasma glucose level of 11 mmol/L (200 mg/dL) or greater 2 hours after a 75-g oral glucose load, or both. In our study, we report only on the 54 patients with overt diabetes. Obesity was defined as a body mass index (BMI) of 30 kg/m2 or greater, body weight excess was defined as a BMI of 25 kg/m2 or greater, and low body weight was defined as a BMI less than 18.5 kg/m2 (18). Hemoglobin A1c level was assayed by using high-performance liquid chromatography. Islet-cell antibodies, antibodies to glutamic acid decarboxylase 65, or IA2 antibodies were determined in 32 cases. Hypertension was defined as a blood pressure exceeding 140/85 mm Hg on two occasions after 10 minutes in the resting position or as the use of antihypertensive treatment (19). Diagnosis of macrovascular complications (coronary heart disease, lower-limb arteriopathy, cerebrovascular disease) and diagnosis of cardiomyopathy were based on medical records, clinical examination, and appropriate tests (echocardiography, ultrasonography). We determined 24-hour urinary albumin excretion, proteinuria, and plasma creatinine concentration. A standardized ophthalmologic examination was performed in 49 patients, including ophthalmoscopy after pupillary dilation, color photographs, and fluorescein angiography, all of which were read by the same investigator. The retinal epithelium alterations were graded according to published criteria (20, 21). Molecular Studies The A to G 3243 mtDNA mutation was identified in peripheral blood leukocytes in 70 patients and from a buccal smear in 1 patient. Total DNA was extracted from the peripheral blood by using the conventional salting-out procedures. The 3243 mutation was detected by using 2% agarose electrophoresis after polymerase chain reaction amplification of a 294base pair fragment and enzymatic digestion with Apa I, as described elsewhere (2, 22). Statistical Analysis Data were stored and analyzed by using SPSS for Windows (SPSS Inc., Chicago, Illinois). Data are expressed as the mean (SD), with ranges indicated in parentheses. Differences in BMI and hemoglobin A1c levels among patient groups were assessed by using KruskalWallis analysis of variance. Correlations were analyzed by using the Spearman nonparametric rank correlation coefficient. Results Diabetes All 54 patients with overt diabetes (21 men, 33 women) had a fasting plasma glucose level greater than 7 mmol/L (126 mg/dL) when diabetes was diagnosed. Diabetes was diagnosed by systematic screening in 32 patients (59%). In the 22 remaining patients (41%), diabetes was revealed by the occurrence of polyuria, which was associated with ketoacidosis in 4 patients (7%). Age at diagnosis of diabetes was 38.8 9.6 years (range, 12 to 67 years); in 25 patients, diabetes was diagnosed before age 35. At the time of the study, the mean patient age was 50.0 10.3 years (range, 31 to 71 years), and diabetes duration was 11.8 8.7 years (range, 0 to 37 years). Diabetes was noninsulin-dependent in 22 patients (41%); 9 of 22 were treated with diet alone, and 13 were treated with sulfonylureas, metformin, or both. Twenty-five patients (46%) required insulin after experiencing secondary failure with a combination of maximally dosed sulfonylureas and metformin 9.9 5.8 years (range, 1 to 28 years) after diabetes was diagnosed. In 7 patients (13%), diabetes was insulin-dependent from its onset. Islet-cell antibodies were present in only 1 patient. A first-degree family history of diabetes was present in 33 of 40 probands (83%), and a maternal family history of diabetes was present in 29 probands (73%). No patient with MIDD was obese (Table), and 19 of 50 patients (38%) had low body weight. No correlation was found between BMI and hemoglobin A1c level, age, or diabetes duration. However, BMI and hemoglobin A1c values differed among patient groups according to treatment (Table). Table. Hemoglobin A1c Level and Body Mass Index in 54 Patients with Maternally Inherited Diabetes and Deafness Deafness Bilateral neurosensory hearing loss was present in 53 of 54 patients (98%). Hearing loss was clinically significant in all patients and was documented by audiography in 28 patients. Fourteen patients (26%) required a prosthetic hearing aid. Age at diagnosis of deafness was 34.6 13.9 years (range, 2 to 61 years). Twenty-five of 40 probands (63%) had a maternal history of deafness. Diabetes was the first clinical manifestation of the disease in 24 patients, and hearing loss was the first manifestation in 23 patients. In 7 patients, both conditions were diagnosed simultaneously. Macular Pattern Dystrophy We previously reported the presence of a characteristic macular pattern dystrophy in patients with MIDD (20). In our current study, macular pattern dystrophy was present in 42 of 49 examined patients (86%). Age at discovery was 46.5 10.8 years (range, 27 to 71 years). In 6 patients, the pigmented lesions were very small and were localized to the macula (grade 1) (Figure 1, top). In 27 patients, the deposits were more extensive and were localized around the macula and the optic disc (grade 2). In the 9 patients with advanced macular pattern dystrophy, the macula had patches of retinal atrophy (grade 3) (Figure 1, bottom). No correlation was found between grade of macular pattern dystrophy and age or diabetes duration. Figure 1. Macular pattern dystrophy. Top. Bottom. Visual acuity was normal in 43 of 49 patients (88%). Among patients with retinal atrophy, 4 had a visual acuity of 20/50 to 20/32 and 2 had a visual acuity below 20/63. Of the latter 2 patients, 1 had severe astigmatism and 1 had diabetic macular edema. Refraction was between +3 and 3 diopters in all patients with MIDD, except in 1 patient with severe astigmatism. No ocular nerve atrophy was observed. Neuromuscular Disorders Muscular disorders were observed in 22 of 51 documented cases of MIDD (43.1%). Patients reported painful muscle weakness that affected lower limbs during prolonged walking or running. In the 6 patients in whom it was performed, muscle biopsy showed ragged-red fibers typical of mitochondrial myopathy (Figure 2). Eight patients had cardiomyopathy; echocardiography showed typical left ventricular hypertrophy in all. Symptoms of congestive heart failure were present in 2 patients. A preexcitation syndrome (WolffParkinsonWhite) was present in 2 patients, and atrial fibrillation was seen in 1 patient. Mitochondrial myopathy was present in 4 of 8 patients with cardiomyopathy. Coronary heart disease was present in 4 of 54 patients (7%), and clinically significant peripheral artery lesions were observed in 2 of 54 patients. Hypertension was present in 15 of 53 patients (28%). Ocular motor palsy was present in 2 patients from the same family, and cerebellar ataxia with cerebellar atrophy on nuclear magnetic resonance imaging was seen in another patient. Atrophic changes in the brain were observed in the 4 other patients who underwent nuclear magnetic resonance imaging. Neuropsychiatric disturbances were present in 9 of 51 patients (18%). The

Automatic detection of microaneurysms in color fundus images

This paper addresses the automatic detection of microaneurysms in color fundus images, which plays a key role in computer assisted diagnosis of diabetic retinopathy, a serious and frequent eye disease. The algorithm can be divided into four steps. The first step consists in image enhancement, shade correction and image normalization of the green channel. The second step aims at detecting candidates, i.e. all patterns possibly corresponding to MA, which is achieved by diameter closing and an automatic threshold scheme. Then, features are extracted, which are used in the last step to automatically classify candidates into real MA and other objects; the classification relies on kernel density estimation with variable bandwidth. A database of 21 annotated images has been used to train the algorithm. The algorithm was compared to manually obtained gradings of 94 images; sensitivity was 88.5% at an average number of 2.13 false positives per image.

Optical coherence tomography of idiopathic macular epiretinal membranes before and after surgery

PURPOSE To examine the preoperative and postoperative anatomical features of the macula using optical coherence tomography in patients who underwent surgery for epiretinal membrane and to correlate these features with functional results. METHODS In a noncomparative interventional series, 62 eyes of 62 consecutive patients operated on for an idiopathic epiretinal membrane were followed up using a standardized protocol. Preoperative and postoperative examination included best-corrected visual acuity using an Early Treatment Diabetic Retinopathy Study chart, biomicroscopy of the fundus with a contact lens, fundus photography with blue and green filters, fluorescein angiography, and optical coherence tomography. RESULTS Median preoperative visual acuity was 20/60 (range, 20/32 to 20/320). Median postoperative visual acuity was 20/40 (range, 20/20 to 20/160). Fifty-one eyes (82%) obtained visual acuity of 20/50 or better. Preoperatively, all eyes had increased macular thickness (mean, 419 +/- 105 microm; range, 265.5 to 689 microm), with disappearance of the foveal pit. An epiretinal membrane was visible on optical coherence tomography scans in 26 cases (42%). Intraretinal cystic spaces were present in the thickened macular tissue in 15 cases but corresponded to cystoid macular edema on fluorescein angiography in only three. Postoperatively, mean macular thickness decreased to 300 +/- 65 microm (range, 185 to 511 microm) but returned to normal in only three eyes. The foveal pit reappeared in 20 eyes. Preoperatively, visual acuity correlated with macular thickness (r = 0.56, P <.0001), but not postoperatively (r = 0.12, P =.37). CONCLUSION Macular thickness decreases after epiretinal membrane surgery, but the macular profile rarely returns to normal. However, this does not preclude satisfactory improvement of visual acuity.

Foveal pseudocyst as the first step in macular hole formation: A prospective study by optical coherence tomography

OBJECTIVE To establish the natural history of a series of impending macular holes presenting as foveal pseudocysts using optical coherence tomography (OCT). DESIGN In a prospective observational case series, patients exhibiting a foveal pseudocyst on biomicroscopy were examined with OCT and were followed up for 3 to 26 months (mean, 9.4 months) PARTICIPANTS Twenty-two eyes of 20 consecutive patients examined for a macular hole in the fellow eye or reporting visual symptoms in only one eye, in whom a foveal pseudocyst was diagnosed on OCT. METHODS In all cases, fundus biomicroscopy and OCT findings were compared. MAIN OUTCOME MEASURES Biomicroscopic fundoscopy, OCT scans, and visual acuity. RESULTS Eight foveal pseudocysts occurred in the fellow eye of an eye with a macular hole, and 14 were diagnosed in patients with unilateral visual symptoms. In four of the 22 eyes, the macula was considered normal on biomicroscopy. In the 18 others, biomicroscopy detected a foveal pseudocyst, radial striae, a yellow spot or ring, or a combination of these findings. No posterior vitreous detachment was seen on biomicroscopy in any of the eyes. On OCT, the cystoid space occupied the inner part of the foveal tissue in the stage 1A impending hole; a stage 1B impending hole corresponded to a cystoid space that extended posteriorly, disrupting the outer retinal layer. During the follow-up period, three pseudocysts evolved into full-thickness macular holes, four turned into lamellar holes, seven resolved completely after detachment of the posterior hyaloid, and eight remained unchanged for a long time. CONCLUSIONS Foveal pseudocysts are a specific entity occurring either as a primary ocular involvement or in the fellow eye of an eye with a macular hole. Foveal pseudocysts are the first step of full thickness macular hole formation, but they also may evolve into a lamellar hole, may persist unchanged for months, or may resolve completely. Foveal pseudocyst formation may be the result of the incomplete separation of the vitreous cortex at the foveal center and the particular structure of the foveal Müller cells.

Macular retinoschisis in highly myopic eyes

PURPOSE To describe the characteristics and evolution of macular retinoschisis in high myopia observed by optical coherence tomography (OCT). DESIGN A consecutive, retrospective, observational case series. METHODS Twenty-one highly myopic eyes (mean refractive error, -15.2, range -6 to -25) of 17 patients presenting with the unusual feature of macular thickening without a macular hole and associated with a posterior staphyloma were examined by biomicroscopy and OCT. Ten patients (13 eyes) were followed up for 12 months or more. RESULTS On biomicroscopy, the macula of all 21 eyes had a microcystic appearance without macular hole. In all eyes, OCT showed that retinal thickening was mainly due to an extensive hyporeflective space splitting the neuroretina into a thick inner layer and a thin outer layer. We called this condition outer retinoschisis. In six cases, inner splitting, termed inner retinoschisis, was also present. The macular profile exhibited a foveal cyst in 10 eyes, a lamellar hole in six, and a foveal detachment in six. In four of the 21 eyes, a hyperreflective preretinal structure resembling the posterior hyaloid was stretched over the retinoschisis, causing foveal traction. Two of these four eyes subsequently evolved into a full-thickness macular hole. CONCLUSION Macular retinoschisis is not uncommon in highly myopic eyes with staphyloma and is better characterized by OCT than by biomicroscopy. Intraretinal splitting occurs in both the outer and inner layers of the retina, leading to the formation of cystoid spaces. In most cases, the condition is fairly stable in terms of visual acuity and retinal thickness and change occurs slowly over time. However, a macular hole may occur when the retinoschisis is associated with tangential traction of the posterior hyaloid.

Retinal thickness in healthy and diabetic subjects measured using optical coherence tomography mapping software

Purpose To define the normal retinal thickness in healthy subjects using optical coherence tomography (OCT) mapping software and to assess the ability of OCT to detect early macular thickening in diabetic patients. Methods Six radial scans centered on the fixation point were done on 60 healthy eyes and 70 eyes of 35 diabetic patients without macular edema on biomicroscopy. Retinal thickness was measured automatically with OCT mapping software. Mean retinal thickness was compared in subgroups of healthy patients based on age, sex, and eye, and in the eyes of diabetic patients and healthy subjects. Thickening was diagnosed if mean retinal thickness of an area was greater than the mean thickness + 2SD in the corresponding area in healthy subjects; or if the difference between right and left eye exceeded the mean difference + 2 SD in a given area in healthy subjects. Results In healthy subjects, mean retinal thickness in the central macular area 1000 μm in diameter was 170±18 μm. There was no significant difference according to age, or left or right eye, but central macular thickness was significantly greater in men than women (p=0.0139). No difference was observed between the eyes of healthy subjects and diabetic patients without macular edema on biomicroscopy, but OCT detected early macular thickening in 12 diabetic eyes. Conclusions In this study average retinal thickness and mean local variations in a normal population were defined using a commercially available mapping software. OCT seems a sensitive tool for detecting early retinal thickening.