Boris Bienvenu

Université de Caen Basse-Normandie, Caen, Lower Normandy, France

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Publications (65)189.7 Total impact

  • La Revue de Médecine Interne 06/2014; 35:A155-A156. · 0.90 Impact Factor
  • B Bienvenu
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    ABSTRACT: Calcinosis cutis constitutes a heterogeneous group of chronic disorder. It can be associated with disturbance of calcium and/or phosphate metabolism (metastatic, tumor calcinosis, calciphylaxis) but may also develop without any metabolic disorder, in particular during the course of connective tissue diseases. Among these, the most common are dermatomyositis and the limited form of systemic sclerosis. The physiopathology of calcinosis cutis is poorly known. It can cause pain, chronic ulcerations, infections, which are sources of sometimes major disability. Treatment of calcinosis is challenging because no drug has been shown to be reliably effective in stopping the progression or decreasing dystrophic calcifications in controlled trials. Calcium blocker and colchicine are generally prescribed as the first line systemic therapy. In the localized forms of small lesions, surgical excision is often effective and sometimes preceded by local treatments (laser therapy, extracorporeal shock wave lithotripsy, topical sodium thiosulfate, etc.) or systemic treatment (minocycline, warfarine). When calcinosis is disseminated, it may require additional treatments (aluminium hydroxyde, bisphosphonates) possibly associated with surgery in case of large lesions. Time to response may be prolonged from weeks to months. The calcinosis cutis can lead to secondary infection, pain and functional disability that have to be prevented.
    La Revue de medecine interne / fondee ... par la Societe nationale francaise de medecine interne. 05/2014;
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    ABSTRACT: To describe characteristics and outcomes of a multicenter cohort of patients diagnosed as having primary angiitis of the central nervous system (PACNS). In 2010, we initiated a cohort study of adults diagnosed as having PACNS ≤15 years ago and with followup of >6 months (unless they died earlier of biopsy-proven PACNS). Its first analysis was planned at 2 years. Multidisciplinary investigators verified that appropriate investigations were done and excluded patients with possible alternative diagnoses. We analyzed patient demographics and symptoms, laboratory, radiographic, and histologic findings, and treatments. Studied outcomes included treatment response(s), relapse, death, and disability. We included 52 patients (30 males; median age at diagnosis 43.5 years [range 18-79 years]) in whom PACNS was diagnosed between 1996 and 2012. Nineteen (61%) of 31 patients who had undergone brain biopsy had histologic vasculitis (biopsy-proven PACNS), while the other 12 patients had normal or noncontributive biopsy samples. An additional 21 patients had signs suggestive of PACNS on conventional cerebral angiography. All but 1 patient received corticosteroids, and 44 patients received cyclophosphamide (CYC). After a median followup of 35 months (range 2-148 months) postdiagnosis (1 patient with biopsy-proven PACNS died 2 months after diagnosis), 32 patients responded to treatment with improved modified Rankin scale scores, 4 patients (8%) did not respond, 14 patients (27%) had relapse of their disease at least once, and 3 patients (6%) died (1 patient after a relapse). Relapse was more common in patients with than in those without meningeal gadolinium enhancements on magnetic resonance imaging (MRI) (8 of 10 [80%] versus 6 of 32 [19%]; P = 0.001) and more common in patients with than in those without seizures at diagnosis (8 of 17 [47%] versus 6 of 35 [17%]; P = 0.04). In this cohort of patients with PACNS, most patients received corticosteroids and CYC, and mortality was low. Patients with seizures at diagnosis or meningeal enhancements on MRI may be prone to relapse and require a different treatment strategy.
    Arthritis & rheumatology (Hoboken, N.J.). 05/2014; 66(5):1315-1326.
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    ABSTRACT: Background To date, there are no large studies on videocapsule endoscopy in systemic sclerosis (SSc). Consequently, the prevalence and features of gastrointestinal mucosal abnormalities in SSc have not been determined.AimsTo determine both prevalence and characteristics of gastrointestinal mucosal abnormalities in unselected patients with SSc, using videocapsule endoscopy. To predict which SSc patients are at risk of developing potentially bleeding gastrointestinal vascular mucosal abnormalities.Methods Videocapsule endoscopy was performed on 50 patients with SSc.ResultsPrevalence of gastrointestinal mucosal abnormalities was 52%. Potentially bleeding vascular mucosal lesions were predominant, including: watermelon stomach (34.6%), gastric and/or small intestinal telangiectasia (26.9%) and gastric and/or small intestinal angiodysplasia (38.5%). SSc patients with gastrointestinal vascular mucosal lesions more often exhibited: limited cutaneous SSc (P = 0.06), digital ulcers (P = 0.05), higher score of nailfold videocapillaroscopy (P = 0.0009), anaemia (P = 0.02), lower levels of ferritin (P < 0.0001) and anti-centromere antibody.Conclusions Our study identifies a high frequency of gastrointestinal mucosal abnormalities in SSc, with a marked predominance of vascular mucosal damage. Furthermore, our study shows a strong correlation between gastrointestinal vascular mucosal lesions and presence of severe extra-digestive vasculopathy (digital ulcers and higher nailfold videocapillaroscopy scores). This latter supports the theory that SSc-related diffuse vasculopathy is responsible for both cutaneous and digestive vascular lesions. Therefore, we suggest that nailfold videocapillaroscopy may be a helpful test for managing SSc patients. In fact, nailfold videocapillaroscopy score should be calculated routinely, as it may result in identification of SSc patients at higher risk of developing potentially bleeding gastrointestinal vascular mucosal lesions.
    Alimentary Pharmacology & Therapeutics 05/2014; · 4.55 Impact Factor
  • La Revue de Médecine Interne. 01/2014; 35:A34–A35.
  • B. Bienvenu
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    ABSTRACT: Calcinosis cutis constitutes a heterogeneous group of chronic disorder. It can be associated with disturbance of calcium and/or phosphate metabolism (metastatic, tumor calcinosis, calciphylaxis) but may also develop without any metabolic disorder, in particular during the course of connective tissue diseases. Among these, the most common are dermatomyositis and the limited form of systemic sclerosis. The physiopathology of calcinosis cutis is poorly known. It can cause pain, chronic ulcerations, infections, which are sources of sometimes major disability. Treatment of calcinosis is challenging because no drug has been shown to be reliably effective in stopping the progression or decreasing dystrophic calcifications in controlled trials. Calcium blocker and colchicine are generally prescribed as the first line systemic therapy. In the localized forms of small lesions, surgical excision is often effective and sometimes preceded by local treatments (laser therapy, extracorporeal shock wave lithotripsy, topical sodium thiosulfate, etc.) or systemic treatment (minocycline, warfarine). When calcinosis is disseminated, it may require additional treatments (aluminium hydroxyde, bisphosphonates) possibly associated with surgery in case of large lesions. Time to response may be prolonged from weeks to months. The calcinosis cutis can lead to secondary infection, pain and functional disability that have to be prevented.
    La Revue de Médecine Interne. 01/2014; 35(7):444–452.
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    ABSTRACT: The purpose of this study was to assess the long-term outcomes of patients with polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS)-defined poor-prognosis factors (FFS = 0) and enrolled in a prospective clinical trial. Patients were followed (2005–2012) under routine clinical care in an extended study and data were recorded prospectively. Long-term survival, disease-free survival (DFS), relapses, therapeutic responses and sequelae were analyzed. Mean ± SD follow-up was 98.2 ± 41.9 months. After having initially received glucocorticoids (GC) alone, according to the study protocol, 82% (97/118) patients achieved remission but 18% (21/118) required ≥ 1 immunosuppressant(s) (IS) before 19/21 achieved remission. Two patients died before entering remission. After remission, 53% (61/116) patients relapsed 25.6 ± 27.9 months after starting treatment. The 5- and 8-year overall survival rates were 93% and 86%, respectively, with no difference between PAN and MPA, and between relapsers and nonrelapsers. DFS was shorter for MPA than PAN patients (P = 0.02). Throughout follow-up, 47% of patients required ≥ 1 IS. At the last follow-up visit, 44% were still taking GC and 15% IS. The mean vasculitis damage index score was 1.9 ± 1.9; the most frequent sequelae were peripheral neuropathy, hypertension and osteoporosis. For PAN or MPA patients without poor-prognosis factors at diagnosis and treated initially with GC alone, long-term survival was excellent. However, relapses remained frequent, requiring IS introduction for nearly half of the patients. To lower the frequencies of relapses and sequelae remains a challenge for FFS = 0 PAN and MPA patients.
    Autoimmunity Reviews. 01/2014; 13(2):197–205.
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    ABSTRACT: Patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA), non-HBV polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) without Five-Factor Score (FFS = 0)-defined poor-prognosis factors were included in two prospective randomized–controlled trials and were initially treated with corticosteroids (CS) alone. Because some patients required subsequent add-on therapies, inclusion characteristics associated with their use were sought. Add-on treatments (cytotoxic agents, biotherapies, intravenous immunoglobulins and plasma exchanges) were subjected to univariate and multivariate analyses. The study included 193 patients (75 EGPA, 61 MPA and 57 PAN). Mean ± SD follow-up was 97.6 ± 39.6 months. Subsequent add-on treatment(s) were required by 86/193 patients (24 PAN, 32 MPA and 30 EGPA) because of CS failure (37%), relapse (52%) or CS dependence (10%). Seven-year overall survival reached 90% and was comparable for patients given 0 vs ≥ 1 add-on therapies (p = 0.564). However, the mean Vasculitis Damage Index was significantly higher for the latter: 2.93 vs 1.96 (p < 0.001), reflecting more frequent sequelae. Initial mononeuritis multiplex was the only factor significantly associated with requiring add-on therapy in univariate (p = 0.008) and multivariate analyses (hazard ratio = 1.81 [95% CI: 1.12–2.93]; p = 0.02). Although FFS = 0 predicts good and comparable overall survival of EGPA, PAN or MPA patients, 45% of them required adjunctive treatments for relapse, CS failure or corticodependence, with most having more frequent initial mononeuritis multiplex and sequelae. These findings support prospective evaluation of initial immunosuppressant use combined with CS to prevent treatment failure, relapses and sequelae in FFS = 0 patients with mononeuritis multiplex at diagnosis.
    Autoimmunity Reviews. 01/2014;
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    ABSTRACT: The association between vasculitis and large granular lymphocyte (LGL) leukemia has rarely been reported or investigated. Thus, we assessed the clinical and biological phenotypes of LGL leukemia associated with vasculitis. We studied a series of 11 patients displaying LGL leukemia associated with vasculitis (LAV). The mean age at diagnosis of LGL leukemia was 60.3 years; there were nine women and two men. The mean follow-up period was 45 months. The main LGL lineage was T-LGL (10 patients), and only one NK-LGL was identified. Clinical and biological features of T-LGL leukemia were compared with those from the 2009 French T-LGL registry. We did not find any relevant differences except that patients with LAV were predominantly female (p < 0.05). The most frequently observed vasculitis was cryoglobulinemia (n = 5). Three patients presented with cutaneous leukocytoclastic angiitis, two patients had ANCA-negative microscopic polyangiitis, and one patient had giant cell arteritis. The main clinical features involved the skin, e.g., purpura (91%), arthralgia (37%), peripheral neuritis (27%), and renal glomerulonephritis (18%). The most frequent histologic finding was leucocytoclastic vasculitis (54%). The rate of complete remission was high; i.e., 80%. A minority of patients had a vasculitis relapse (27%). Three patients (27%) died; one death was related to LGL leukemia (acute infection) and the two other deaths were related to vasculitis (both with heart failure). We conclude that vasculitis is overrepresented in the population of LGL patients, LAV predominantly affects women, vasculitis preferentially affects the small vessels, and LAV has high rate of complete response.
    Seminars in arthritis and rheumatism 12/2013; 43(3):362-6. · 4.72 Impact Factor
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    ABSTRACT: Increasing rituximab prescription for ANCA-associated necrotizing vasculitides justifies the publication of recommendations for clinicians. Rituximab is approved in the United States to induce and maintain remission. In Europe, rituximab was recently approved for remission induction. However, governmental agencies' approvals cannot replace clinical practice guidelines. Herein, the French Vasculitis Study Group Recommendations Committee, comprised of physicians with extensive experience in the treatment of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.
    La Presse Médicale 10/2013; · 0.87 Impact Factor
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    ABSTRACT: Melanoma-associated retinopathy (MAR) is a rare autoimmune syndrome in patients with melanoma characterized by visual disorders. MAR is induced by the degeneration of bipolar cells of the retina and the presence of serum autoantibodies against retina proteins. Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 antibody, improves survival in previously treated patients with metastatic melanoma, but is responsible for a spectrum of immune-related adverse events. Administration of ipilimumab to patients with autoimmune diseases (such as MAR or vitiligo) is actually not recommended. We report a patient presenting with MAR occurring during a melanoma relapse. Surgery and chemotherapy had no effect on visual acuity and melanoma increased. In the absence of alternative antitumoral treatment, we focused on the vital prognosis and treated the patient with ipilimumab. Two years after the treatment the patient is free from new metastasis but has presented with exacerbation of vitiligo and MAR. In the very rare case of melanoma with autoimmune disease without a therapy option, ipilimumab could be discussed, taking into account the fact that it can be effective on tumor burden but can also increase autoimmunity. © 2013 S. Karger AG, Basel.
    Dermatology 09/2013; · 2.02 Impact Factor
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    ABSTRACT: Giant cell arteritis (GCA) is the most common form of vasculitis in western countries. (18)F-FDG PET has been shown to be a valuable tool for the diagnosis of extracranial GCA, but results of studies are inconsistent due to a lack of standardized (18)F-FDG PET criteria. In this study, we compared different semiquantitative approaches using a controlled design to define the most efficient method. All patients with biopsy-proven GCA who had undergone an (18)F-FDG PET/CT scan in our PET unit were reviewed and matched with a control group based on age and sex. Different semiquantitative arterial (ascending and descending thoracic aorta and aortic arch) to background (liver, lung and venous blood pool) SUV ratios were blindly compared between GCA patients and matched controls. We included 11 patients with biopsy-proven GCA cases and 11 matched controls. There were no differences between the groups with regard to body weight, injected radioactivity, blood glucose level or CRP. The arterial to venous blood pool ratios discriminated the two groups better than other methods when applied to the aortic arch and the descending thoracic aorta (p < 0.015). In particular, the highest aortic to highest blood pool SUVmax ratio, when applied to the aortic arch, provided optimal diagnostic performance (sensitivity 81.8 %, specificity 91 %, AUC 0.87; p < 0.0001) using a cut-off value of 1.53. Among all tested (18)F-FDG PET/CT methods, the aortic to blood pool SUVmax ratio outperformed the liver and lung ratios. We suggest the use of this ratio for the assessment of aortic inflammation in GCA patients.
    European Journal of Nuclear Medicine 09/2013; · 4.53 Impact Factor
  • Arthritis & Rheumatology 08/2013; · 7.48 Impact Factor
  • L. Sailler, G. Pugnet, B. Bienvenu
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    ABSTRACT: Corticosteroids (CS) remain the main treatment for giant cell arteritis (GCA). The choice of initial prednisone dosage (from 0.5 to 1 mg/kg/d) takes into account the disease severity and comorbidities in order to reduce the drug side effects. Low-dose aspirin may benefit to patients suffering ischemic complications or with multiple cardiovascular risk factors. Randomised controlled trials are necessary to precise its benefit-to-risk ratio. Methotrexate has a moderate corticosteroid sparing effect but it does not prevent cephalic complications and there is no evidence of a reduced frequency of CS adverse effects with this drug. Hydroxychloroquine and infliximab or adalimumab did not prevent relapses in double blind controlled trials. High doses of intravenous methylprednisolone are often prescribed for severe ischemic complications though there is no evidence that such doses are superior to classical doses. In corticosteroid dependent patients, the benefit-to-risk ratio of immunosuppressive drugs is unknown. Dapsone is no longer prescribed due to severe adverse effects. Efficacy of tocilizumab is very promising but its benefit-to-risk ratio in old people is largely unknown. Finding a well tolerated corticosteroid sparing drug remains a challenge and further studies are necessary to reduce the long term rate of cardiovascular events and the burden of CS adverse effects.
    La Revue de Médecine Interne. 07/2013; 34(7):431–437.
  • Joint, bone, spine: revue du rhumatisme 05/2013; · 2.25 Impact Factor
  • L Sailler, G Pugnet, B Bienvenu
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    ABSTRACT: Corticosteroids (CS) remain the main treatment for giant cell arteritis (GCA). The choice of initial prednisone dosage (from 0.5 to 1 mg/kg/d) takes into account the disease severity and comorbidities in order to reduce the drug side effects. Low-dose aspirin may benefit to patients suffering ischemic complications or with multiple cardiovascular risk factors. Randomised controlled trials are necessary to precise its benefit-to-risk ratio. Methotrexate has a moderate corticosteroid sparing effect but it does not prevent cephalic complications and there is no evidence of a reduced frequency of CS adverse effects with this drug. Hydroxychloroquine and infliximab or adalimumab did not prevent relapses in double blind controlled trials. High doses of intravenous methylprednisolone are often prescribed for severe ischemic complications though there is no evidence that such doses are superior to classical doses. In corticosteroid dependent patients, the benefit-to-risk ratio of immunosuppressive drugs is unknown. Dapsone is no longer prescribed due to severe adverse effects. Efficacy of tocilizumab is very promising but its benefit-to-risk ratio in old people is largely unknown. Finding a well tolerated corticosteroid sparing drug remains a challenge and further studies are necessary to reduce the long term rate of cardiovascular events and the burden of CS adverse effects.
    La Revue de Médecine Interne 04/2013; · 0.90 Impact Factor
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    ABSTRACT: Biotherapies used in clinical practice for the treatment of ophthalmologic manifestations of systemic diseases include interferons (IFN), intravenous immunoglobulins (IVIG) and monoclonal antibodies (anti-TNF, anakinra, tocilizumab and rituximab). Several open prospective studies have shown the effectiveness of IFN-α (78 to 98% complete remission) for the treatment of severe uveitis in Behçet's disease. IFN is capable of inducing prolonged remission and continued after his arrest, in 20-40% of patients. Side effects (flu-like, psychological effects) limit its use in practice. Anti-TNFα (infliximab and adalimumab) represent an attractive alternative therapeutic in severe uveitis refractory to immunosuppressants, especially in Behcet's disease. They are almost always (> 90% of cases) and rapidly effective but their action is often suspensive. Anti-TNFα requires an extended prescription or takes over from another immunosuppressant once ocular inflammation has been controlled. IVIG are used for the treatment of Kawasaki disease and Birdshot's disease. Several open or retrospective studies showed their effectiveness for the treatment of severe and refractory cicatricial pemphigoid. Tolerance of IVIG is good but their efficacy is transient. Rituximab showed an efficacy in few observations of various inflammatory eye diseases (uveitis, scleritis and idiopathic inflammatory pseudo-tumors or associated with granulomatosis with polyangiitis) and cicatricial pemphigoid. The risk of infection associated with this biotherapy limit its use in refractory diseases to conventional therapy. Anakinra (a soluble antagonist of IL-1R) showed interesting results in terms of efficiency in one small open study in Behçet's disease. Its safety profile is good and with a quick action that could be interesting for the treatment of severe uveitis.
    Autoimmunity reviews 03/2013; · 6.37 Impact Factor
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    ABSTRACT: OBJECTIVE: To report on the effectiveness of cyclophosphamide (CYC) to treat glucocorticoid (GC)-dependent giant-cell arteritis (GCA) and/or severe GC-related side effects. METHODS: Fifteen patients with GCA and treated with CYC were retrieved from the computerized patient-record system. Glucocorticoid dependence was defined as a prednisone dose of >20mg/day for 6 months or >10mg/day for 1 year in order not to relapse. Response to CYC was defined as improved clinical and biological findings. Remission was defined as a sustained absence (>12 months) of active signs of vasculitis at a daily GC dose of <7.5mg. A literature review searched PubMed for all patients diagnosed with GCA and who received CYC. RESULTS: Our 15 patients responded to monthly pulses of CYC, and all experienced a GC-sparing effect, including five patients who discontinued GC long term. At a median follow-up of 43 (range: 14-75) months after CYC, nine (53%) patients were still in remission and six (40%) had relapsed at 6 (3-36) months after the last CYC infusion. Twelve (80%) patients experienced side effects, leading to discontinuation of CYC in two (13%). A literature review retrieved 88 patients who received CYC: 66 for GC-dependent disease, 53 for GC toxicity, and 14 for severe organ involvement. Their median follow-up time was 24 (4-60) months. Among the 88 patients, 74 (84%) were responsive to CYC and 17 (19%) relapsed, although all were receiving a maintenance therapy with immunosuppressive agents (such as methotrexate). Twenty-nine (33%) patients experienced side effects and 11 (12.5%) discontinued treatment. CONCLUSION: Cyclophosphamide is an interesting option for GCA patients with GC-dependent disease or with severe GC-related side effects, especially when conventional immunosuppressive agents have failed.
    Seminars in arthritis and rheumatism 02/2013; · 4.72 Impact Factor
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    ABSTRACT: Giant cell arteritis, temporal arteritis is a systemic vasculitis, which involves large and medium-sized arteries, especially the extracranial branches of the carotid arteries, in patients above the age of 50. Ischemic complications may involve the eye, orbit, or visual pathway, with blindness being the most feared complication. Visual ischemic complications are observed at least in 25% of patients with giant cell arteritis. Irreversible visual loss is mainly due to acute anterior ischemic optic neuropathy. Thus, in any patient above the age of 50 with any manifestation of ocular ischemia, transient or permanent, giant cell arteritis must be considered and ruled out by an emergent targeted investigation and inflammatory work-up. Steroids remain the treatment of choice for giant cell arteritis and must be instituted immediately upon suspicion of the diagnosis, even in the physician's office. The goal is to protect the eye and visual pathways from irreversible blindness or to prevent contralateral disease. Thus, steroid treatment does not constitute a cure for already-incurred visual loss, which will still carry an unfavourable prognosis.
    Journal francais d'ophtalmologie 02/2013; 36(2):178–183. · 0.51 Impact Factor
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    ABSTRACT: Giant cell arteritis, temporal arteritis is a systemic vasculitis, which involves large and medium-sized arteries, especially the extracranial branches of the carotid arteries, in patients above the age of 50. Ischemic complications may involve the eye, orbit, or visual pathway, with blindness being the most feared complication. Visual ischemic complications are observed at least in 25% of patients with giant cell arteritis. Irreversible visual loss is mainly due to acute anterior ischemic optic neuropathy. Thus, in any patient above the age of 50 with any manifestation of ocular ischemia, transient or permanent, giant cell arteritis must be considered and ruled out by an emergent targeted investigation and inflammatory work-up. Steroids remain the treatment of choice for giant cell arteritis and must be instituted immediately upon suspicion of the diagnosis, even in the physician's office. The goal is to protect the eye and visual pathways from irreversible blindness or to prevent contralateral disease. Thus, steroid treatment does not constitute a cure for already-incurred visual loss, which will still carry an unfavourable prognosis.
    Journal francais d'ophtalmologie 01/2013; · 0.51 Impact Factor

Publication Stats

503 Citations
189.70 Total Impact Points

Institutions

  • 2012–2014
    • Université de Caen Basse-Normandie
      Caen, Lower Normandy, France
    • Hospices Civils de Lyon
      Lyons, Rhône-Alpes, France
  • 2013
    • Centre Hospitalier Universitaire de Nancy
      Nancy, Lorraine, France
    • Centre Hospitalier Universitaire de Toulouse
      • Service de Médecine Interne
      Toulouse, Midi-Pyrenees, France
    • Institute Mutualiste Montsouris
      Lutetia Parisorum, Île-de-France, France
  • 2012–2013
    • Centre Hospitalier Universitaire de Caen
      Caen, Lower Normandy, France
  • 2006–2013
    • Université René Descartes - Paris 5
      • • Faculté de Médecine
      • • Faculté de Médecine
      Paris, Ile-de-France, France
  • 2010–2011
    • Hôpital Cochin (Hôpitaux Universitaires Paris Centre)
      Lutetia Parisorum, Île-de-France, France
  • 2009
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
  • 2007–2009
    • Université Paris Descartes
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 2004–2008
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France