Publications by authors named "Jean-François Girmens"

23 Publications

  • Page 1 of 1

Intravitreal Gene Therapy vs. Natural History in Patients With Leber Hereditary Optic Neuropathy Carrying the m.11778G>A Mutation: Systematic Review and Indirect Comparison.

Front Neurol 2021 24;12:662838. Epub 2021 May 24.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

This work aimed to compare the evolution of visual outcomes in Leber hereditary optic neuropathy (LHON) patients treated with intravitreal gene therapy to the spontaneous evolution in prior natural history (NH) studies. A combined analysis of two phase three randomized, double-masked, sham-controlled studies (REVERSE and RESCUE) and their joint long-term extension trial (CLIN06) evaluated the efficacy of rAAV2/2- vs. 11 pooled NH studies used as an external control. The LHON subjects carried the m.11778G>A mutation and were aged ≥15 years at onset of vision loss. A total of 76 subjects received a single intravitreal rAAV2/2- injection in one eye and sham injection in the fellow eye within 1 year after vision loss in REVERSE and RESCUE. Both eyes were considered as treated due to the rAAV2/2- treatment efficacy observed in the contralateral eyes. Best corrected visual acuity (BCVA) from REVERSE, RESCUE, and CLIN06 up to 4.3 years after vision loss was compared to the visual acuity of 208 NH subjects matched for age and genotype. The NH subjects were from a LHON registry (REALITY) and from 10 NH studies. A locally estimated scatterplot smoothing (LOESS), non-parametric, local regression model was used to modelize visual acuity curves over time, and linear mixed model was used for statistical inferences. The main outcome measure was evolution of visual acuity from 12 months after vision loss, when REVERSE and RESCUE patients had been treated with rAAV2/2-. The LOESS curves showed that the BCVA of the treated patients progressively improved from month 12 to 52 after vision loss. At month 48, there was a statistically and clinically relevant difference in visual acuity of -0.33 logarithm of the minimal angle of resolution (LogMAR) (16.5 ETDRS letters equivalent) in favor of treated eyes vs. NH eyes ( < 0.01). Most treated eyes (88.7%) were on-chart at month 48 as compared to 48.1% of the NH eyes ( < 0.01). The treatment effect at last observation remained statistically and clinically significant when adjusted for age and duration of follow-up (-0.32 LogMAR, < 0.0001). The m.11778G>A LHON patients treated with rAAV2/2- exhibited an improvement of visual acuity over more than 4 years after vision loss to a degree not demonstrated in NH studies. NCT02652767, NCT02652780, NCT03406104, and NCT03295071.
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May 2021

Safety of Intravitreal Gene Therapy for Treatment of Subjects with Leber Hereditary Optic Neuropathy due to Mutations in the Mitochondrial ND4 Gene: The REVEAL Study.

BioDrugs 2021 Mar 10;35(2):201-214. Epub 2021 Feb 10.

CHNO des Quinze Vingts, Institut Hospitalo Universitaire FOReSIGHT, INSERM-DGOS CIC 1423, Paris, France.

Background: Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease whose primary clinical manifestation is bilateral visual loss. Only a single therapy, idebenone, is approved in Europe for use in exceptional circumstances and no therapy is currently approved in the USA. LHON remains a disease with a high unmet medical need.

Objective: This is a report of an open-label, single-center, dose-escalation study that evaluated the safety and tolerability of lenadogene nolparvovec in 15 subjects with LHON for up to 5 years following a single intravitreal injection at four dose levels.

Methods: Subjects were enrolled sequentially in four cohorts followed by an additional cohort at the dose selected, and safety was assessed by an independent data safety monitoring board (DSMB) prior to any dose escalation.

Results: Overall, the treatment was well tolerated during the 5-year follow-up. No serious adverse events were considered related to treatment, no unexpected adverse events occurred, and no grade 3 or 4 Common Terminology Criteria for Adverse Events were reported. Anterior chamber inflammation and vitritis were mostly managed with topical steroids, and ocular inflammation was considered to be dose limiting by the DSMB based on the benefits/risks for the subjects. Analysis of the logarithm of the minimal angle of resolution (LogMAR) visual acuity in both treated and untreated eyes showed clinically relevant and durable improvements compared with baseline. Mean improvements of - 0.44 and - 0.49 LogMAR for treated and untreated eyes, respectively, were noted, with a mean (± standard deviation) final value of LogMAR + 1.96 ± 0.60 and + 1.65 ± 0.34, respectively, at 5 years post-treatment administration. For the six subjects treated with the optimal dose level (9 × 10 viral genomes [vg]/eye), the mean visual acuity improvement from baseline reached - 0.68 LogMAR for treated eyes and - 0.64 LogMAR for untreated eyes, with a mean final value of LogMAR + 1.77 ± 0.52 and + 1.78 ± 0.34, respectively. While there was a meaningful improvement in visual acuity for REVEAL subjects, the final visual acuity was less favorable than that seen in the two subsequent pivotal phase III studies in which subjects were treated earlier during the course of their disease.

Conclusion: Lenadogene nolparvovec was well tolerated with a good safety profile during 5 years of follow-up and may offer meaningful lasting improvements in vision for this LHON population.

Clinical Trial Number: EUDRACT N° 2013-001405-90.
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March 2021

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset.

Ophthalmology 2021 May 12;128(5):649-660. Epub 2021 Jan 12.

Centre Hospitalier National d'Ophtalmologie des Quinze Vingts, Paris, France; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France; Fondation Ophtalmologique A. de Rothschild, Paris, France; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; CHNO des Quinze-Vingts, Institut Hospitalo-Universitaire FOReSIGHT, INSERM-DGOS CIC, Paris, France.

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).

Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.

Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included.

Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 10 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye.

Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.

Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively.

Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.
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May 2021

Real-world outcomes after 36 months treatment with ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (BOREAL-DME).

Ophthalmic Res 2020 Sep 15. Epub 2020 Sep 15.

Purpose: To assess the efficacy, safety and follow-up of 36 months treatment with ranibizumab in patients with diabetic macular edema (DME) in real life setting. Methods This is a prospective phase 4 observational study. Between December 2013 and April 2015, 84 ophthalmologists enrolled a total of 290 adult patients initiating ranibizumab for visual impairment due to diabetic macular edema (DME) and treated them according to their routine practice. The primary outcome (mean change in best-corrected visual acuity [BCVA] after 12 months) was previously reported. Here we present outcomes after 36 months of follow-up for BCVA, change in central subfield thickness (CSFT) and report how participating ophthalmologists treated DME over a 3 year period (number of visits and injections, and evolution of treatment strategy). Results Of the 290 patients enrolled, 187 (64.5%) completed the 36 months of the study (entire cohort). In the entire cohort, 97 patients were treated exclusively with ranibizumab throughout the study and 90 patients switched to other intravitreal treatments. Mean BCVA was 64.2 (20.1) letters, representing a gain of +4.1 (19.9) letters from baseline to Month 36 (M36). CSFT improved over the study, and by M36 had decreased by 127 (138) µm compared to baseline. Over the 36 months of follow-up, patients in the entire cohort paid their ophthalmologists a mean of 30.9 (12.2) visits and had a mean of 7.6 (5.2) any injections Results for quality of life questionnaires NEI-VFQ25 and HUI-3 remained stable throughout the study. Multivariate analysis on the 145 patients with evaluable BCVA data at M36 found that male gender and milder baseline DME characteristics (BCVA ≥59 and CSFT <500 µm) were predictive factors for achieving a BCVA of ≥70 letters at M36. This study did not find any new safety signals, compared to the known profile of ranibizumab. Conclusions Gains in BCVA in this real life study were lower than those observed in randomized clinical trials with ranibizumab, mainly due to under treatment. Safety analysis of ranibizumab did not yield any new safety concerns.
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September 2020

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

Immunity 2020 08;53(2):429-441.e8

Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France. Electronic address:

A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
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August 2020

Odysight: A Mobile Medical Application Designed for Remote Monitoring-A Prospective Study Comparison with Standard Clinical Eye Tests.

Ophthalmol Ther 2019 Sep 25;8(3):461-476. Epub 2019 Jul 25.

Quinze-Vingts National Eye Hospital, Paris, France.

Introduction: The purpose of this study (Tilak Study No: TIL-001) was to evaluate the medical modules on the mobile medical application OdySight and compare them to the gold standard tests for visual acuity, contrast sensitivity, and Amsler Grid.

Methods: A total of 120 eyes were evaluated in an open-label, single-arm, prospective, single-site study during which participants performed monocular, gold standard tests for measuring visual acuity (Sloan Early Treatment Diabetic Retinopathy Study [ETDRS] letter chart at 40 cm testing distance and ETDRS letter chart at 4 m testing distance [40-cm and 4-m ETDRS, respectively), contrast sensitivity (Pelli-Robson contrast sensitivity chart [Pelli-Robson test]), and metamorphopsia/scotoma (Amsler Grid) followed by the respective modules on OdySight (also monocular). During this study, both the distance between the device and the patient's eye and room illumination were controlled by the examiner.

Results: A Bland-Altman analysis demonstrated that there was no disagreement between the results of the OdySight visual acuity module and both the 40-cm Sloan ETDRS and 4-m ETDRS tests, with a very low level of bias (0.53 and - 1.53 letters, respectively). The same analysis of contrast sensitivity showed a broader disagreement between the results of the OdySight module and those of the Pelli-Robson test. A McNemar test indicated that there was no significant difference between results obtained by the OdySight Amsler Grid module and those obtained by the paper version for the detection of metamorphopsia and scotoma (p = 1.0 for both).

Conclusion: The results from the TIL-001 study demonstrate good agreement, overall, between the measurements taken by the near visual acuity module and the Amsler grid module of OdySight as compared to currently used gold standards. The contrast sensitivity module of OdySight will require additional investigation. OdySight could be used for remote monitoring of vision between clinic visits and potentially assist in follow-up planning.

Funding: Tilak Healthcare funded the study and the Rapid Service Fees.

Trial Registration: identifier: NCT03457441.
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September 2019

Real-World Outcomes with Ranibizumab 0.5 mg in Patients with Visual Impairment due to Diabetic Macular Edema: 12-Month Results from the 36-Month BOREAL-DME Study.

Ophthalmic Res 2019 29;62(2):101-110. Epub 2019 Mar 29.

Bordeaux PharmacoEpi, INSERM CIC1401, Université de Bordeaux, Bordeaux, France.

Purpose: To report the real-world effectiveness and safety of ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (DME).

Methods: This is a French, 36-month, multicenter, observational cohort study. Between December 2013 and April 2015, ophthalmologists enrolled diabetic patients aged ≥18 years with DME-related visual impairment and for whom ranibizumab 0.5 mg was initiated. Here, we present the 12-month results from this cohort. The primary endpoint was the mean change in best-corrected visual acuity (BCVA); sample size calculations were based on RESTORE trial data (BCVA mean change = 6.8 letters, preci sion = 0.7 letters). Secondary endpoints included the change in central subfield thickness (CSFT), number of visits, number of injections received, and frequency of ocular and nonocular adverse events and serious adverse events.

Results: Between December 2013 and April 2015, a total of 290 patients with DME were enrolled by 84 ophthalmologists; 12-month data are available for 242 patients (due to low recruitment rates, precision was recalculated for 242 evaluable patients: the precision was then of 1.0 letters). Mean age (± standard deviation) was 66.1 ± 11.0 years and 56.6% were male. The mean baseline BCVA and CSFT were 59.2 letters (95% confidence interval [CI] 57.3, 61.0) and 457 μm (95% CI: 438, 476), respectively. At month 12, the mean gain in BCVA from baseline was 7.4 letters (95% CI: 5.4, 9.4), with 36.8% of patients with BCVA > 70 letters versus 13.2% at baseline. Mean change in CSFT was -125 μm (95% CI: -146, -103). The mean number of ranibizumab injections was 5.1 ± 2.3 over an average of 10.4 ± 3.0 visits. No new safety findings were identified.

Conclusions: The BOREAL study confirms the effectiveness and safety of ranibizumab for the treatment of DME-related visual impairment in routine clinical practice with fewer injections than reported in clinical trials.
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August 2019

Safety of rAAV2/2-ND4 Gene Therapy for Leber Hereditary Optic Neuropathy.

Ophthalmology 2018 06 14;125(6):945-947. Epub 2018 Feb 14.

Centre d'Investigation Clinique 1423, Inserm-DGOS, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France; Rothschild Ophthalmology Foundation Hospital, Paris, France; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France; Department of Ophthalmology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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June 2018

[Exudative age-related macular degeneration: self-monitoring by patients allows for rapid response].

Rev Prat 2017 01;67(1):101

Centre hospitalier national d'ophtalmologie des Quinze-Vingts, Paris, France.

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January 2017

Indocyanine-green-guided targeted laser photocoagulation of capillary macroaneurysms in macular oedema: a pilot study.

Br J Ophthalmol 2017 Feb 6;101(2):170-174. Epub 2016 Jun 6.

Ophthalmology Department, Hôpital Lariboisière, Université Paris 7, Paris, France.

Aims: In longstanding diabetic macular oedema (DME) or retinal vein occlusion (RVO), capillary macroaneurysms may develop. Indocyanine green angiography (ICGA) has been shown to optimise their detection. Here, we report the anatomical and functional outcome of the elective photocoagulation of capillary macroaneurysms.

Methods: A retrospective, interventional, two-centre study. In eyes with chronic macular oedema and severe hard exsudates due to diabetic retinopathy or RVO, the presence of capillary macroaneurysms (defined by a diameter larger than 150 µm) was assessed by ICGA and optical coherence tomography (OCT). Capillary macroaneurysms were selectively photocoagulated, the presence of photothrombosis within the lumen being assessed by immediate OCT.

Results: Four eyes from three patients with DME and five eyes from five patients with RVO were included. The median duration of visual loss was 4 years. Median initial visual acuity (VA) was 20/200. The median number of capillary macroaneurysms per eye was 2 (range, 1-8) and their median size was 410 µm (range, 154-603). Six months after photocoagulation, there was a significant reduction in macular thickness (mean±SD, 528 µm±200 vs 271 µm±152, p<0.05) and improvement of VA (mean log MAR, 0.82 vs 0.58, p<0.05).

Conclusions: During macular oedema with severe hard exsudates due to DME or RVO, systematic detection of capillary macroaneurysms by ICGA followed by their OCT-controlled photocoagulation may be of interest. These results may contribute to re-evaluate the role of photocoagulation in the management of longstanding macular oedema.
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February 2017

Venous Nicking Without Arteriovenous Contact: The Role of the Arteriolar Microenvironment in Arteriovenous Nickings.

JAMA Ophthalmol 2015 Aug;133(8):947-50

Quinze-Vingts Hospital, DHU SightMaintain, INSERM-DHOS CIC 1423, Paris, F-75012 and Université Pierre et Marie Curie-Paris 6, Paris, France.

Importance: Arteriovenous nickings (AVNs) in the retina are the cause of retinal vein occlusions and are also surrogates of cerebrovascular aging. The prevalent mechanistic model of AVNs stating that arteries crush veins remains somewhat unchallenged despite the lack of evidence other than fundus photographs. Here, we observed that venous nicking may be observed in the absence of physical contact with an arteriole.

Observations: This observational study, conducted from January 2013 to September 2014, included 7 patients showing remodeling of a venous segment close to a retinal arteriole without arteriovenous overlap were imaged by adaptive optics imaging. Affected venous segments showed a variable association of nicking, narrowing, deviation, and opacification. Venous segments were deviated toward the arterioles in 6 of the 7 cases. The degree of venous narrowing ranged from 40% to 77%, while at these sites, the width of the intervascular space ranged from 16 µm to 42 µm. Similar features were identified in typical AVNs.

Conclusions And Relevance: Arteriovenous nickings do not necessarily involve an arteriovenous compression. Instead, the topology of venous changes suggests a retractile process originating in the intervascular space. These findings have important implications for the understanding of retinal vein occlusions and of cerebrovascular aging.
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August 2015

Bevacizumab and ranibizumab for neovascular age-related macular degeneration: an updated meta-analysis of randomised clinical trials.

Graefes Arch Clin Exp Ophthalmol 2014 Oct 22;252(10):1529-37. Epub 2014 Aug 22.

Service d'ophtalmologie, Hospices Civils de Lyon, Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, 103 Grande Rue de la Croix-Rousse, F-69317, Lyon Cedex 04, France,

Purpose: Neovascular age-related macular degeneration (AMD) is the main cause of central vision loss among individuals aged 50 years or older in developed countries. The aim of this study was to review systematically the effect of bevacizumab compared to ranibizumab in patients with AMD at 1 year.

Methods: A systematic review was performed on Medline, Embase, and the Cochrane Library and Trial registers to October 2013. Eligibility criteria for selecting studies were randomised controlled trials (RCT) comparing bevacizumab with ranibizumab in patients with neovascular AMD. Odds ratio (OR) and mean difference (MD) estimates were synthesized under fixed- and random-effects models. Heterogeneity was assessed using the Q statistic and I(2).

Results: Five RCTs were included, representing 2,686 randomised patients. The meta-analysis confirmed the non-inferiority of bevacizumab compared to ranibizumab for change in visual acuity at 1 year (MD 0.57 letters, -1.80 to 0.66, p = 0.37, I(2) = 0 %). Better anatomical results were found for ranibizumab. Bevacizumab was associated with a 34 % increase in the number of patients with at least one serious systemic adverse event (OR 1.34, 1.08 to 1.66, p = 0.01, I(2) = 0 %).

Conclusions: The pooled evidence confirmed that, compared with ranibizumab, bevacizumab was associated with equivalent effects on visual acuity at 1 year and with a higher risk of systemic serious adverse events. The current available data do not show which types of adverse events occur more frequently. In practice, bevacizumab should be used under a risk-management plan until further studies have been carried out to assess accurately the increased risk of systemic adverse events.
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October 2014

[Therapeutic innovation in AMD and other retinal diseases].

Rev Prat 2013 Jan;63(1):68-73

Université Pierre-et-Marie-Curie, Paris-6, France.

Age-related macular degeneration (AMD) is a leading cause of severe visual impairment in individuals over 50 years in developed countries. Latest advances in imaging techniques have led to improved and accurate diagnosis of AMD. We witness a major breakthrough in the treatment of the neovascular form of AMD with the antiangiogenic (anti-VEGF) drugs. However, no therapy is yet available for the atrophic dry form of AMD. Innovative strategies gene therapy, cell therapy, nanotechnology neuroprotection- and multidisciplinary approaches are emerging to prevent the decline in vision in aging populations and its health implications.
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January 2013

Dry age-related macular degeneration: A currently unmet clinical need.

Intractable Rare Dis Res 2012 Aug;1(3):103-14

French National Institute of Health and Medical Research, Paris, France; ; National Center for Scientific Research, Paris, France;

Age-related macular degeneration (AMD) is a leading cause of severe visual impairment and disability in older people worldwide. Although considerable advances in the management of the neovascular form of AMD have been made in the last decade, no therapy is yet available for the advanced dry form of AMD (geographic atrophy). This review focuses on current trends in the development of new therapies targeting specific pathophysiological pathways of dry AMD. Increased understanding of the complex mechanisms that underlie dry AMD will help to address this largely unmet clinical need.
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August 2012

Evaluation of retinal function and flicker light-induced retinal vascular response in normotensive patients with diabetes without retinopathy.

Invest Ophthalmol Vis Sci 2011 May 2;52(6):2861-7. Epub 2011 May 2.

Departments of Ophthalmology, Hôpital Fernand Widal, Assistance Publique-Hôpitaux de Paris, Paris 7 University, Paris, France.

Purpose: To correlate retinal function with vascular response to flicker light in normotensive patients with diabetes without diabetic retinopathy (DR).

Methods: Twenty-eight normotensive patients with diabetes (11 with type 1, 17 with type 2) without DR and 28 sex- and age-matched healthy control subjects underwent color vision and contrast sensitivity testing, pattern, full-field, and multifocal electroretinography, and evaluation of the vascular response to flicker light with the dynamic vessel analyzer.

Results: In the patients with diabetes, electroretinogram (ERG) pattern responses, b-wave in the scotopic bright flash ERG, a-wave and b-wave in the photopic single-flash ERG, and oscillatory potential responses were significantly impaired compared with those in control subjects. Vascular response to flicker light was also impaired in patients with diabetes compared with controls. In the whole population, correlations were found between flicker light-induced arterial retinal vasodilation and the amplitude and implicit time of the N95 wave of pattern ERG (r = -0.27, P = 0.047 and r = -0.35, P = 0.008, respectively), the b-wave implicit time of rod ERG (r = -0.36; P = 0.01) and the oscillatory potentials (r = 0.4; P = 0.003), suggesting that impairment of the vascular response to flicker light may reflect inner retinal neural impairment. However, no correlation between these factors was found when only patients with diabetes were considered.

Conclusions: In patients with diabetes, neural and neurovascular dysfunctions both precede the onset of clinically detectable DR. To which extent these abnormalities are related to each other remains to be determined. ( number, NCT00839150.)
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May 2011

Imaging of macroaneurysms occurring during retinal vein occlusion and diabetic retinopathy by indocyanine green angiography and high resolution optical coherence tomography.

Graefes Arch Clin Exp Ophthalmol 2010 Feb 25;248(2):161-6. Epub 2009 Aug 25.

Department of Ophthalmology of the Fondation Ophtalmologique Rothschild, Université Pierre et Marie Curie Paris6, 75019 Paris, France.

Background: Macular edema occurring after retinal vein occlusion (RVO) or diabetic retinopathy (DR) may be due to the development of capillary and/or venous macroaneurysms (MAs). Here, we investigated the respective contribution of fluorescein angiography (FA), of indocyanine green angiography (ICGA) and of high-resolution optical coherence tomography (HR-OCT) to their detection.

Methods: Review of the charts of six consecutive patients with MAs secondary to RVO (n = 4) or DR (n = 2). For each patient, FA, ICGA and HR-OCT data were analyzed and compared.

Results: All detectable MAs were detected by ICGA, while in three eyes FA failed to show them. Overall, ICGA provided a better delineation of MAs than FA. In all cases, HR-OCT identified MAs under the form of a vascular structure with a reflective wall surrounding a lumen containing variably reflective material.

Conclusions: MAs can develop during the course of RVO and DR. ICGA and HR-OCT improves the identification of capillary and venous MAs, and may thus be of interest to better identify sites of blood-retinal barrier rupture during chronic macular edema due to RVO or DR.
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February 2010

Malformation of junctional microdomains in cataract lens membranes from a type II diabetes patient.

Pflugers Arch 2009 Apr 26;457(6):1265-74. Epub 2008 Nov 26.

Institut Curie, Equipe INSERM Avenir, UMR168-CNRS, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.

In eye core lens membranes, aquaporin-0 (AQP0) and connexins (Cx) form together well-structured supramolecular assemblies, the junctional microdomains, in which they assure water, ion, metabolite, and waste transport. Additionally, they mediate cell-cell adhesion-forming thin junctions (AQP0) and gap junctions (Cx). We have used atomic force microscopy and biochemical methods to analyze and compare the structure of junctional microdomains in human cataract lens membranes from a type II diabetes patient and healthy lens membranes from calf. A healthy intercellular junctional microdomain consists in average of approximately 150 tetragonally arranged (a = b = 65.5 A, gamma = 90 degrees) AQP0 tetramers surrounded by densely packed non-ordered connexon channels. Gap-junction connexons act as lineactants inside the membrane and confine AQP0 in the junctional microdomains. In the diabetic cataract lens, connexons were degraded, and AQP0 arrays are malformed. We conceptualize that absence of connexons lead to breakdown of cell nutrition.
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April 2009

Endogenous erythroid colony formation in patients with retinal vein occlusion.

Ophthalmology 2007 Dec;114(12):2155-61

Department of Internal Medicine, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France.

Purpose: The pathophysiology and causes of retinal vein occlusion (RVO) remain largely unknown. Latent forms of myeloproliferative disorders, which are diagnosed by the presence of in vitro endogenous erythroid colony (EEC) formation, are a well-known cause of intraabdominal vein thrombosis. The suspected diagnosis of a latent myeloproliferative disorder in a patient with RVO, based on the presence of EEC formation, led us to evaluate the association between latent myeloproliferative disorders and RVO.

Design: Observational case series in a national eye center.

Participants: Forty-four patients, with a mean age of 46 years (range, 21-62) and central (n = 38) or peripheral (n = 6) RVO responsible for visual acuity decreased to 6/12 or less.

Methods: In vitro bone marrow culture.

Main Outcome Measure: Endogenous erythroid colony formation in cytokine-free culture medium. Conventional diagnostic criteria for myeloproliferative disorders and the JAK2 V617F mutation (which is strongly associated with myeloproliferative disorders) were assessed in RVO patients showing EECs.

Results: Endogenous erythroid colony formation was observed in 12 of 44 (27%) patients with RVO, 13 of 35 (37%) patients with Budd-Chiari syndrome, and 52 of 53 (98%) patients with primary polycythemia (positive control groups) but not in 22 healthy bone marrow donors (negative controls) evaluated at the same time and by the same hematology laboratory. Neither conventional nor genetic diagnostic criteria for myeloproliferative disorders were observed in any patient with both RVO and an EEC at the time of diagnosis or during follow-up.

Conclusions: Endogenous erythroid colony formation is frequently observed in patients with RVO independently of any detectable myeloproliferative disorder. This opens a new aspect of research on the pathophysiology of this sight-threatening disease.
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December 2007

Human cataract lens membrane at subnanometer resolution.

J Mol Biol 2007 Nov 14;374(1):162-9. Epub 2007 Sep 14.

Institut Curie, UMR168-CNRS, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.

Human pathologies often originate from molecular disorders. Therefore, imaging technology as one of the bases for the identification and understanding of pathologies must provide views of single molecules at subnanometer resolution. Membrane proteins mediate many of life's most important processes, and their malfunction is often lethal or leads to severe disease. The membrane proteins aquaporin-0 (AQP0) and connexons form junctional microdomains between healthy lens core cells in which AQP0 form square arrays surrounded by connexons. Malfunction of both proteins results in the formation of cataract. We have used high-resolution atomic force microscopy (AFM) to image junctional microdomains in membranes from an individual human eye lens with senile cataract. Images at subnanometer resolution report individual helix-connecting loops of four amino acid residues on the AQP0 surface. We describe the supramolecular assembly and the conformational state of AQP0 in junctional microdomains, where a mixture of truncated junctional and full-length water channel AQP0 form square arrays. Imaging of microdomain borders revealed individual AQP0 tetramers and no associated connexon, indicating a lack of metabolite transport, waste accumulation, and enlarged regions of non-adhering membranes, causing cataract in this individual. This first high-resolution view of the membrane of this pathological human tissue provides insights into cataract pathology at the single membrane protein level, and indicates the power of the AFM as a future tool in medical imaging at subnanometer resolution.
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November 2007

Dilation of the minor arterial circle of the iris preceding rubeosis iridis during retinal vein occlusion.

Am J Ophthalmol 2004 Dec;138(6):1083-6

Department of Ophthalmology of the Fondation Ophtalmologique Rothschild, Paris, France.

Purpose: To report in four patients with retinal vein occlusion the presence of biomicroscopically visible circulation in the minor arterial circle of the iris, preceding rubeosis iridis in two cases.

Design: Retrospective observational case series.

Methods: Four patients with ischemic type of central or hemi-central retinal vein occlusion seen at a single center.

Results: Dilation of the minor arterial circle remnants with biomicroscopically visible circulation was observed in four eyes of four adult patients with severe retinal ischemia secondary to retinal vein occlusion and preceded the occurrence of anterior segment neovascularization in two cases.

Conclusion: In patients with ischemic retinal vein occlusion, the clinical finding of a dilation of the minor arterial circle may indicate the necessity of a closer follow-up to make a timely decision on panretinal photocoagulation.
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December 2004

Treatment of von Hippel-Lindau retinal hemangioblastoma by the vascular endothelial growth factor receptor inhibitor SU5416 is more effective for associated macular edema than for hemangioblastomas.

Am J Ophthalmol 2003 Jul;136(1):194-6

Service d'Ophtalmologie, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris and Université Paris VII, Paris, France.

Purpose: To test the efficacy of the novel vascular endothelial growth factor (VEGF) receptor inhibitor SU5416, in a case of refractory von Hippel-Lindau (VHL) retinal hemangioblastoma (RHB).

Design: Interventional case report.

Methods: Patient included in a multicenter phase II trial. A 30-year-old woman presenting with VHL disease and multiple RHB on her only eye, refractory to conventional treatments, had decreased visual acuity due to cystoid macular edema (CME). SU5416 was administered intravenously for 7 months. Best-corrected visual acuity (BCVA) and macular thickness were measured by optical coherence tomography.

Results: Under treatment, the size of the RHB did not change, but CME improved significantly. Best-corrected visual acuity rose from 20/40 to 20/25. However, CME recurred after the end of the treatment.

Conclusion: The VEGF receptor inhibitor SU5416 failed to reduce the size of RHB but was very effective for the associated CME.
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July 2003

Persistence of fundus fluorescence after use of indocyanine green for macular surgery.

Ophthalmology 2003 Mar;110(3):604-8

Department of Ophthalmology, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Université Paris 7, 2 rue Ambroise Paré, 75010 Paris, France.

Purpose: To investigate the possible persistence and characteristics of infrared fluorescence of the fundus for several months after surgery with intraocular injection of indocyanine green (ICG).

Design: Interventional, noncomparative, prospective case series.

Participants: Seventeen patients operated on in our department with ICG injection into the vitreous cavity, who gave prior informed consent.

Methods: After standard three-port pars plana vitrectomy and posterior vitreous detachment, 0.1 to 0.2 ml of an ICG solution at a concentration of 2.5 mg/ml was injected through a 5- micro m sterile filter over the posterior pole and left in place for 3 minutes. The stained internal limiting membrane was then peeled off. Patients had postoperative infrared fundus photographs at each consultation in our department. Follow-up ranged from 1 to 7 months. Visual acuity and any unexpected event were also recorded.

Main Outcome Measures: Postoperative infrared fluorescence of the fundus.

Results: The day after surgery, no green ICG staining of the fundus was visible on biomicroscopy. However, infrared photography showed diffuse fluorescence of the fundus. At 1 and 3 postoperative months, infrared fundus photography showed an intensely fluorescent optic nerve disc. In patients with macular hole, the center of the macula also exhibited faint granular fluorescence. At 6 months postoperative or later, only the optic disc remained fluorescent, but the fluorescence was far less intense than at 3 months. Infrared photographs of the fellow eyes exhibited no fluorescence. Visual acuity improved or was unchanged compared with preoperative vision in 16 eyes and decreased by 1 line in 1 eye.

Conclusions: After intraoperative use of ICG for macular surgery, fluorescence of the optic disc and of the macular center after macular hole surgery persisted for months in all cases. ICG may accumulate in the macular pigment epithelium and optic nerve, raising the problem of the as yet unknown pharmacokinetics of ICG after intravitreous administration and of its long-term safety.
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March 2003