Pierre-Raphaël Rothschild

Ophthalmologic Manifestations of Systemic Necrotizing Vasculitides at Diagnosis: A Retrospective Study of 1286 Patients and Review of the Literature

OBJECTIVE To determine the frequencies and types of ophthalmologic manifestations in patients with systemic necrotizing vasculitides (SNV), including polyarteritis nodosa (PAN) and ANCA-associated vasculitides (granulomatosis with polyangiitis (Wegeners, GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA); Churg-Strauss syndrome (CSS)) and review the literature on eye involvement in these diseases. METHODS This retrospective analysis was conducted on the ophthalmologic manifestations of SNV patients entered into the French Vasculitis Study Group database between July 1955 and August 2008. RESULTS Among the 1286 identified patients, 214 (16.6%) had ophthalmologic manifestations at diagnosis, significantly more often in GPA (117/343, 34.1%) than in EGPA (30/270, 11.1%; P = 0.0001), PAN (42/393, 10.7%; P = 0.0001) or MPA (25/280, 8.9%; P = 0.0001). The 3 most common recorded ophthalmologic manifestations were conjunctivitis (89, (7%)), episcleritis (56, (4%)), and/or blurred vision (44, (3%)), mainly caused by retinal vasculitis in 5, oculomotor nerve palsy in 4, uveitis in 4 and/or optic neuropathy in 3. Orbital inflammatory tumor, another common feature was rather specific to GPA (23/349, 6.6% (P = 0.0001)) compared to other SNV. The literature on ophthalmologic manifestations of SNV is limited to case reports except for GPA, in which the eye involvement frequency ranged from 29% to 57%. CONCLUSIONS Eye manifestations were more common in GPA than MPA, PAN and EGPA, but can be sight-threatening in any SNV. Given the heterogeneity of ophthalmologic involvement in SNV, close collaboration between the ophthalmologists and internists is critical.

SPIRONOLACTONE FOR NONRESOLVING CENTRAL SEROUS CHORIORETINOPATHY: A RANDOMIZED CONTROLLED CROSSOVER STUDY.

Purpose: To evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, for nonresolving central serous chorioretinopathy. Methods: This is a prospective, randomized, double-blinded, placebo-controlled crossover study. Sixteen eyes of 16 patients with central serous chorioretinopathy and persistent subretinal fluid (SRF) for at least 3 months were enrolled. Patients were randomized to receive either spironolactone 50 mg or placebo once a day for 30 days, followed by a washout period of 1 week and then crossed over to either placebo or spironolactone for another 30 days. The primary outcome measure was the changes from baseline in SRF thickness at the apex of the serous retinal detachment. Secondary outcomes included subfoveal choroidal thickness and the ETDRS best-corrected visual acuity. Results: The mean duration of central serous chorioretinopathy before enrollment in study eyes was 10 ± 16.9 months. Crossover data analysis showed a statistically significant reduction in SRF in spironolactone treated eyes as compared with the same eyes under placebo (P = 0.04). Secondary analysis on the first period (Day 0–Day 30) showed a significant reduction in subfoveal choroidal thickness in treated eyes as compared with placebo (P = 0.02). No significant changes were observed in the best-corrected visual acuity. There were no complications related to treatment observed. Conclusion: In eyes with persistent SRF due to central serous chorioretinopathy, spironolactone significantly reduced both the SRF and the subfoveal choroidal thickness as compared with placebo.

Ocular inflammatory diseases associated with rheumatoid arthritis.

The extra-articular complications of rheumatoid arthritis (RA) include ophthalmological manifestations, which can, in some cases, be the first signs of the disease. These inflammatory ophthalmological conditions include episcleritis, scleritis and peripheral ulcerative keratitis (PUK). RA is the leading cause of necrotizing scleritis and of PUK, which are the two most severe ocular conditions associated with the disease. These conditions can rapidly threaten ocular prognosis and are associated with excess mortality in patients with RA owing to their association with systemic vasculitis. Close collaboration between the ophthalmologist and the rheumatologist or internal medicine expert is required for the diagnosis and therapeutic management of these patients. In this Review, we provide an overview of ocular inflammatory diseases in patients with RA with particular focus on the diagnosis and current available therapies (including biologic agents) for these conditions. Furthermore, we propose a decision tree to assist clinicians in their choice of treatment for patients with RA who also have ocular inflammatory disease.

PKCζ Mediates Breakdown of Outer Blood-Retinal Barriers in Diabetic Retinopathy

Aims/hypothesis Diabetic macular edema represents the main cause of visual loss in diabetic retinopathy. Besides inner blood retinal barrier breakdown, the role of the outer blood retinal barrier breakdown has been poorly analyzed. We characterized the structural and molecular alterations of the outer blood retinal barrier during the time course of diabetes, focusing on PKCζ, a critical protein for tight junction assembly, known to be overactivated by hyperglycemia. Methods Studies were conducted on a type2 diabetes Goto-Kakizaki rat model. PKCζ level and subcellular localization were assessed by immunoblotting and immunohistochemistry. Cell death was detected by TUNEL assays. PKCζ level on specific layers was assessed by laser microdissection followed by Western blotting. The functional role of PKCζ was then evaluated in vivo, using intraocular administration of its specific inhibitor. Results PKCζ was localized in tight junction protein complexes of the retinal pigment epithelium and in photoreceptors inner segments. Strikingly, in outer segment PKCζ staining was restricted to cone photoreceptors. Short-term hyperglycemia induced activation and delocalization of PKCζ from both retinal pigment epithelium junctions and cone outer segment. Outer blood retinal barrier disruption and photoreceptor cone degeneration characterized long-term hyperglycemia. In vivo, reduction of PKCζ overactivation using a specific inhibitor, restored its tight-junction localization and not only improved the outer blood retinal barrier, but also reduced photoreceptor cell-death. Conclusions In the retina, hyperglycemia induced overactivation of PKCζ is associated with outer blood retinal barrier breakdown and photoreceptor degeneration. In vivo, short-term inhibition of PKCζ restores the outer barrier structure and reduces photoreceptor cell death, identifying PKCζ as a potential target for early and underestimated diabetes-induced retinal pathology.

Patients’ subjective assessment of the duration of cataract surgery: a case series

Objectives Surgery duration is a source of preoperative anxiety for patients undergoing cataract surgery. To better inform patients, we evaluated the agreement between objective and patient-perceived surgery durations. Design Case series. Setting Public teaching university hospital (Paris, France). Participants During the study period, 368 cataract surgery cases performed on 285 patients were included, 85 cases were excluded from the final analysis. All patients who had uneventful phacoemulsification were included. Cases with any significant intraoperative adverse event or cases requiring additional anaesthesia other than topical were excluded. Resident performed cases were also excluded. Primary and secondary outcomes Procedures were timed (objective duration) and patients were asked, immediately afterwards, to assess the duration of their surgery (patient-assessed duration). The agreement between objective and patient-assessed durations as well as influencing factors was studied. Results Mean objective duration (13.9±5 min) and patient-assessed duration (15.3±6.9 min) were significantly correlated (Spearmans r=0.452, p<0.0001). Furthermore, Bland-Altman analysis and the intraclass correlation coefficient (0.341, 95% CI 0.23 to 0.44) were quite in agreement. On univariate analysis, senior-performed procedures were significantly shorter than those performed by juniors (13.4 vs 17.8 min, p=0.0001). Pain was recorded as ‘no sensation’ (31.5% of the cases), ‘mild sensation’ (41%), ‘moderate pain’ (23.3%), ‘intense pain’ (3.5%) and ‘unbearable pain’ (0.7%). Groups with high pain score had significantly longer procedures (p<0.001). Multivariate analysis revealed that the only independent factors associated with both the objective and patient-assessed durations of surgery were surgeons experience and pain-score. Conclusions In our study, patients’ estimated and real duration of the surgery showed moderate agreement, suggesting that emotions associated with eye surgery under topical anaesthesia did not dramatically hinder the patients’ perception of time. However, the benefit of preoperative counselling regarding the duration of surgery will need further evaluation.

Deletions Overlapping VCAN Exon 8 Are New Molecular Defects for Wagner Disease

Wagner disease is a rare nonsyndromic autosomal‐dominant vitreoretinopathy, associated with splice mutations specifically targeting VCAN exon 8. We report the extensive genetic analysis of two Wagner probands, previously found negative for disease‐associated splice mutations. Next‐generation sequencing (NGS), quantitative real‐time PCR, and long‐range PCR identified two deletions (3.4 and 10.5 kb) removing at least one exon–intron boundary of exon 8, and both correlating with an imbalance of VCAN mRNA isoforms. We showed that the 10.5‐kb deletion occurred de novo, causing somatic mosaicism in the probands mother who had an unusually mild asymmetrical phenotype. Therefore, exon 8 deletions are novel VCAN genetic defects responsible for Wagner disease, and VCAN mosaic mutations may be involved in the pathogenesis of Wagner disease with attenuated phenotype. NGS is then an effective screening tool for genetic diagnosis of Wagner disease, improving the chance of identifying all disease‐causative variants as well as mosaic mutations in VCAN.

Molecular basis for a novel systemic form of human hereditary apoA-I amyloidosis with vision loss

Hereditary apolipoprotein A-I (apoA-I) amyloidosis (AApoAI) is a life-threatening incurable genetic disorder whose molecular underpinnings and the full spectrum of afflicted organs are unclear. We report a new form of AApoAI with amyloid deposition in multiple organs, including an unprecedented retinal amyloidosis. Genetic and proteomic analyses identified Glu34Lys apoA-I as the fibrillar protein causing the clinical manifestations. A life-saving combined hepatorenal transplantation was performed for one Glu34Lys carrier. To elucidate structural underpinnings for amyloidogenic properties of Glu34Lys, we generated its recombinant globular domain and compared the conformation and dynamics of its lipid-free form with those of two other naturally occurring apoA-I variants, Phe71Tyr (amyloidogenic) and Leu159Arg (non-amyloidogenic). All variants showed reduced stability and altered aromatic residue packing. Molecular dynamics simulations revealed local helical unfolding and suggested that transient opening of Trp72 induced mutation-dependent structural perturbations in a sensitive region, including the major amyloid hotspot residues 14-22. We posit that a shift from the “closed” to an “open” orientation of Trp72 modulates structural protection of amyloid hotspots, suggesting a previously unknown early step in protein misfolding.

Impact of Video Technology for Improving Success of Medial Canthus Episcleral Anesthesia in Ophthalmology

Background and Objectives Efficient learning of regional anesthesia in ophthalmology remains challenging because trainees are afforded limited opportunity to practice ocular anesthesia. The aim of this prospective, randomized, blinded study was to determine whether teaching with video improves regional anesthesia skills of residents in ophthalmology. Methods From January to October 2016, 32 novice anesthesiology residents were evaluated while performing medial canthus episcleral procedures during a 5-day rotation. Residents were randomly assigned to either receive or not receive a video review of their performance at day 3. The primary outcome was a comparison of akinesia using a 12-point scale before incision assessed by the blinded surgeon. Results A total of 288 blocks were performed by 32 residents and were assessed by 3 surgeons before the intervention (144 blocks) and after the intervention (144 blocks). Residents in the review group improved to a greater degree compared with residents in the no-review group. The median overall akinesia scores for the review and no-review groups were similarly low (6; interquartile range [IQR], 2–11; and 6 [IQR, 2–9], respectively) on day 1 of the rotation, whereas anesthesia performed by residents in the video group provided a better akinesia score (12 [IQR, 10–12] vs 8 [IQR, 6–10]; P < 0.001) on day 5 of the rotation. Conclusions Video-assisted teaching significantly improves performance of medial canthus episcleral anesthesia performed by novice trainees.

Retinal and choroidal vascular abnormalities in TTR-FAP

Methods This monocentric observational study was conducted at the French National Reference Center for TTR-FAP. Genetically confirmed TTR-FAP patients with suspected retinal and/or choroidal vascular abnormalities underwent fluorescein and indocyanine green angiography. Sensorimotor polyneuropathy (SPN) was staged with the Polyneuropathy Disability (PND) score, vegetative neuropathy was staged with the Compound Autonomic Dysfunction Test (CADT). Medical and surgical treatments were analyzed for all patients.