Advantages of robotic assistance over a manual approach in simulated subretinal injections and its relevance for gene therapy.

Subretinal injection is a method for gene delivery to treat genetic diseases of the photoreceptors and retinal pigment epithelium. A reflux-free subretinal injection is important to allow effective, safe, and cost-effective gene therapy to the retina. We report on a comparison between manual and robotic assistance in simulated subretinal injections using an artificial retina model. Nine surgeons carried out the procedure with and without the Preceyes Surgical System, using an OPMI Lumera 700 Zeiss surgical microscope equipped with intra-operative optical coherence tomography. Success in creating a bleb without reflux, injection duration, drift, tremor, and increase in the diameter of the puncture hole were analyzed. Robotic assistance improved drift (median 16 vs 212 µm), tremor (median 1 vs 18 µm), enlargement of the retinal hole, and allowed for prolonged injection times (median 52 vs 29 sec). Robotic assistance allowed higher rate of bleb formation (8/9 vs 4/9 attempts) with a moderate reduction in reflux (7/9 vs 8/9 attempts) in this artificial model. Robotic assistance can significantly contribute to subretinal injections and provide quantifiable parameters in assessing surgical and clinical success of novel retinal gene therapies.

Refractory post-surgical cystoid macular edema managed following suprachoroidal microcatheterization and delivery of triamcinolone.

BACKGROUND: Post-surgical macular edema (ME) is a common cause of prolonged visual impairment. Here we report on the feasibility and clinical outcomes from the use of a novel suprachoroidal microcatheter to treat post-surgical chronic ME by the posterior suprachoroidal placement of a triamcinolone acetonide (TA) suspension. METHODS: Two patients were catheterized with the Oxulumis suprachoroidal delivery system on two separate occasions starting 5 and 10 mm posterior to the limbus. The catheter only remains in the suprachoroidal space for the time of the drug administration. Visual acuity and spectral domain optical coherence tomography (SD-OCT) changes were followed over several weeks to months to determine the duration of ME resolution. RESULTS: Suprachoroidal microcatheterization for posterior delivery of triamcinolone was possible in all attempts using the illuminated Oxulumis catheter. No reflux, scleral or choroidal trauma was observed. There was no intraocular pressure rise during the follow-up period. The triamcinolone deposit was visible on infrared imaging and on SD-OCT a choroidal elevation was visible. Both progressively disappeared over time. A rapid resolution of ME associated with improved vision was observed following each injection for 3 to 7 months with a TA dose of 2.4 mg or 4 mg. CONCLUSIONS: In these patients with poorly responsive ME, posterior suprachoroidal TA led to a visible suprachoroidal drug deposit and prolonged visual improvement. The Oxulumis microcatheterization device performed as expected and was not associated with any complications.

Robotic Assistance for Intraocular Microsurgery: Challenges and Perspectives.

Intraocular surgery, one of the most challenging discipline of microsurgery, requires sensory and motor skills at the limits of human physiological capabilities combined with tremendously difficult requirements for accuracy and steadiness. Nowadays, robotics combined with advanced imaging has opened conspicuous and significant directions in advancing the field of intraocular microsurgery. Having patient treatment with greater safety and efficiency as the final goal, similar to other medical applications, robotics has a real potential to fundamentally change microsurgery by combining human strengths with computer and sensor-based technology in an information-driven environment. Still in its early stages, robotic assistance for intraocular microsurgery has been accepted with precaution in the operating room and successfully tested in a limited number of clinical trials. However, owing to its demonstrated capabilities including hand tremor reduction, haptic feedback, steadiness, enhanced dexterity, micrometer-scale accuracy, and others, microsurgery robotics has evolved as a very promising trend in advancing retinal surgery. This paper will analyze the advances in retinal robotic microsurgery, its current drawbacks and limitations, as well as the possible new directions to expand retinal microsurgery to techniques currently beyond human boundaries or infeasible without robotics.

Manifestations of intraocular inflammation over time in patients on brolucizumab for neovascular AMD.

PURPOSE: To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO). METHODS: This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on IOI following anti-VEGF therapy was also conducted. RESULTS: Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received ≥ 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event. CONCLUSIONS: IOI may precede RV or RO in some patients treated with brolucizumab.

Randomised controlled trial on robot-assisted versus manual surgery for pucker peeling.

BACKGROUND: The aim was to explore the feasibility and safety of performing common surgical steps in epiretinal membrane (ERM) peeling using the Preceyes Surgical System (PSS). METHODS: In a tertiary centre, 15 pseudophakic patients with an idiopathic ERM were randomised to robot-assistance or manual surgery in a 2:1 ratio. In the robot-assisted group, the following steps were performed using PSS: (1) staining the internal limiting membrane (ILM), (2) removal of the dye, (3) creating an ILM flap, (4) completing the peeling, (5) holding a light pipe and (6) fluid-air exchange. Primary outcome measures were feasibility and safety. Secondary outcome measures were duration, best-corrected visual acuity (BCVA) and central retinal thickness (CRT). Moreover, the distance travelled by the instrument during peeling was assessed using motion tracking software. RESULTS: All steps performed with PSS were feasible with no clinical adverse events or complications. The surgical time was longer in the robot-assisted group (mean 56 min, SD = 12 vs. 24 min, SD = 5). During the study, the duration of robot-assisted surgeries decreased from 72 to 46 min. The distance travelled by the forceps was shorter in the robot-assisted group (mean 403 mm, SD = 186 vs. 550 mm, SD = 134). BCVA and CRT improved equally in both groups. CONCLUSIONS: This is the world's first randomised controlled trial on robotic surgery for ERM. Although more time-consuming, we found that several surgical steps were feasible with assistance of the PSS.

The Role of Intravitreal Corticosteroids in the Treatment of DME: Predictive OCT Biomarkers.

This work aims to summarize predictive biomarkers to guide treatment choice in DME. Intravitreal anti-VEGF is considered the gold standard treatment for centers involving DME, while intravitreal steroid treatment has been established as a second-line treatment in DME. However, more than 1/3 of the patients do not adequately respond to anti-VEGF treatment despite up to 4-weekly injections. Not surprisingly, insufficient response to anti-VEGF therapy has been linked to low-normal VEGF levels in the serum and aqueous humor. These patients may well benefit from an early switch to intravitreal steroid treatment. In these patients, morphological biomarkers visible in OCT may predict treatment response and guide treatment decisions. Namely, the presence of a large amount of retinal and choroidal hyperreflective foci, disruption of the outer retinal layers and other signs of chronicity such as intraretinal cysts extending into the outer retina and a lower choroidal vascular index are all signs suggestive of a favorable treatment response of steroids compared to anti-VEGF. This paper summarizes predictive biomarkers in DME in order to assist individual treatment decisions in DME. These markers will help to identify DME patients who may benefit from primary dexamethasone treatment or an early switch.

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis.

TOPIC: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU). CLINICAL RELEVANCE: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition. METHODS: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process. RESULTS: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive. DISCUSSION: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.

A comparison of robotic and manual surgery for internal limiting membrane peeling.

PURPOSE: To compare the Preceyes Surgical Robotic System (Eindhoven, Netherlands) to manual internal limiting membrane (ILM) peeling using the Eyesi surgical simulator (VRmagic, Mannheim, Germany) as the operative platform. METHODS: A comparative study was carried out with surgeons initially performing ILM peeling manually and then with the robot. Twenty-three vitreoretinal surgeons agreed to participate and all consented to the use of their surgical data from the Eyesi surgical simulator. Surgeons were given a 5-min demonstration of the devices and were allowed to practice for 10 min before attempting the membrane peel. Initially, the peel was performed manually and afterwards, this was repeated using the robot-controlled forceps. Surgical simulator outcome measures were compared between approaches. RESULTS: The average time required for the procedure was 5 min for the manual approach and 9 min with the robot (paired t test, p = 0.002). Intraocular instrument movement was reduced by half with the robot. On average 344 mm was required to complete the ILM peeling with the robot compared with 600 mm using the manual approach (paired t test, p = 0.002). There were fewer macular retinal hemorrhages with the robot: 53 with manual surgery, 32 with the robot (Mann-Whitney U test, p = 0.035). Retinal injuries were eliminated with the robot. CONCLUSIONS: Intraocular robotic surgery is still in its infancy and validation work is needed to understand the potential benefits and limitations of emerging technologies. Safety enhancements over current techniques may be possible and could lead to the broader adoption of robotic intraocular surgery in the future.

Efficacy and Safety of Sarilumab for the Treatment of Posterior Segment Noninfectious Uveitis (SARIL-NIU):: The Phase 2 SATURN Study.

PURPOSE: To assess efficacy and safety of sarilumab, a human anti-interleukin-6 receptor antibody, for treatment of posterior segment noninfectious uveitis (NIU). DESIGN: Randomized, double-masked, placebo-controlled, phase 2 study. PARTICIPANTS: Fifty-eight patients (eyes) with noninfectious intermediate, posterior, or panuveitis. METHODS: Eyes received treatment every 2 weeks for 16 weeks with subcutaneous sarilumab 200 mg or placebo. MAIN OUTCOME MEASURES: The primary end point was the proportion of patients with ≥2-step reduction in vitreous haze (VH) on the Miami scale or with a reduction of systemic corticosteroids (prednisolone or equivalent) to a dose of <10 mg/day at week 16. Primary end point was based on VH evaluation by a central reading center. Investigator evaluation of VH was a prespecified, planned secondary analysis. RESULTS: At week 16, proportion of patients taking sarilumab or placebo with ≥2-step reduction in VH or corticosteroid dose <10 mg/day was 46.1% vs. 30.0% (P = 0.2354) based on central reading center assessment of VH and 64.0% vs. 35.0% (P = 0.0372) based on investigator assessment of VH, respectively. In the subgroup of eyes with VH grade ≥2 at baseline, the mean VH reduction from baseline to week 16 was significantly greater with sarilumab vs. placebo regardless of assessment by the central reading center (-2.1 [n = 11] vs. -1.7 [n = 3], respectively; P = 0.0255) or investigator (-2.5 [n = 19] vs. -1.2 [n = 11], respectively; P = 0.0170). The mean best-corrected visual acuity gain from baseline to week 16 was greater with sarilumab vs. placebo in the overall population (8.9 vs. 3.6 letters, respectively; P = 0.0333) and in the subgroup of eyes with central subfield thickness (CST) ≥300 µm at baseline (12.2 [n = 13] vs. 2.1 [n = 7] letters, respectively; P = 0.0517). Corresponding changes in CST were -46.8 vs. +2.6 µm (P = 0.0683) in the overall population and -112.5 [n = 13] vs. -1.8 [n = 6] µm (P = 0.1317) in the subgroup of eyes with CST ≥300 µm at baseline, respectively. The most common ocular adverse events were worsening of uveitis (0 [placebo] and 3 [sarilumab] patients) and retinal infiltrates (1 [placebo] and 2 [sarilumab] patients). CONCLUSIONS: Subcutaneous sarilumab may provide clinical benefits in the management of NIU of the posterior segment, especially in eyes with uveitic macular edema.

Robotic-assisted surgery in ophthalmology.

PURPOSE OF REVIEW: Provide an overview of the current landscape of robotics in ophthalmology, including the pros and cons of system designs, the clinical development path, and the likely future direction of the field. RECENT FINDINGS: Robots designed for eye surgery should meet certain basic requirements. Three designs are currently being developed: smart surgical tools such as the steady hand, comanipulation devices and telemanipulators using either a fixed or virtual remote center of motion. Successful human intraocular surgery is being performed using the Preceyes surgical system. Another telemanipulation robot, the da Vinci Surgical System, has been used to perform a pterygium repair in humans and was successful in ex-vivo corneal surgery despite its nonophthalmic design. Apart from Preceyes' BV research platform, none of the currently eye-specific systems has reached a commercial stage. Systems are likely to evolve from robotic assistance during specific procedural steps to semiautonomous surgery, as smart sensors are introduced to enhance the basic functionalities of robotic systems. SUMMARY: Robotics is still in its infancy in ophthalmology but is rapidly reaching a stage wherein it will be introduced into everyday ophthalmic practice. It will most likely be introduced first for demanding vitreo-retinal procedures, followed by anterior segment applications.

Effect of vitreous opacities on straylight measurements.

PURPOSE: To evaluate the effect of vitreous floaters on intraocular straylight. METHODS: Records of bilaterally phakic patients with unilateral complaint of floaters as the main symptom were identified from an electronic database. Patients who underwent straylight measurements on both affected and unaffected eyes using a C-Quant straylight meter were selected. Data were collected on age, sex, visual acuity, straylight measurements, and optical coherence tomography. The unaffected eye served as a control. RESULTS: Fifteen cases were included (7 women and 8 men; mean age, 54.3 years; age range, 24-71 years). Visual acuity was not correlated with the complaint of floaters. Average straylight value in eyes with floaters was 1.426 log(s) (±0.23 SD) with a median value of 1.52 log(s). The mean value for fellow eyes was 1.275 (±0.23 SD) with a median of 1.25 log(s). The differences between both groups using a Wilcoxon matched-pair signed-rank test was statistically significant at P = 0.0009. On optical coherence tomography, most patients had a confirmed or probable posterior vitreous detachment. However, in four patients, a posterior vitreous detachment was absent in the affected eyes. Vitreous floaters were inconsistently imaged by optical coherence tomography, with only a few patients presenting appreciable condensations close to the retinal surface. These were present in both affected and unaffected eyes. CONCLUSION: Intraocular straylight is significantly increased in eyes affected by floaters. No correlation was seen with vision or optical coherence tomography appearance. Straylight is an independent objective measure of visual perception that seems to be closely correlated to complaints expressed by patients experiencing floaters.

Surgical management of severe complications arising from uveitis in juvenile idiopathic arthritis.

PURPOSE: Evaluate outcomes from severe ocular complications of juvenile idiopathic arthritis following surgery. METHODS: Eleven eyes of 7 patients underwent complete vitrectomy and peeling of the inner limiting membrane. Inclusion criteria were: anteroposterior segment involvement, hypotony, inflammation control of less than 3 months, compliance issues, rapidly progressive disease. Phacoemulsification was allowed if the patient was >6 years old and inflammation free >3 months. The alternative was a complete lensectomy. RESULTS: Visual acuity improved from a logMAR of 1.48 to 0.37 (p < 0.0001), and 0.20 at 6 and 12 months (p < 0.0001). No flare-up was observed within the first 6 months. Five eyes developed inflammation between 7 and 19 months. Glaucoma developed in 5 eyes at a median of 16 months. No patient developed cystoid macular edema. CONCLUSION: Extensive pars plana vitrectomy and cataract extraction can lead to significant improvement in visual acuity. Patients continue to require long-term immunosuppression and adequate follow-up.

Viscoelastics Enable Dissection of Anterior Closed Funnels in Proliferative Vitreoretinopathy: A Retrospective Case Series.

Introduction: The present study aimed to describe a case series of patients in which a cohesive ophthalmic viscous device (OVD) was used to viscodissect and posteriorly displace the retina in cases of total retinal detachment complicated by proliferative vitreoretinopathy, operated with minimally invasive pars plana vitrectomy. Case Presentations: Three patients with a mean age of 67 years were included in the present study. One eye was aphakic, while the others were pseudophakic. OVD injection was performed through the limbus in the aphakic eye and via pars plana in the pseudophakic eyes. In all cases, the OVD injection led to a posterior displacement of the detached retina with a smooth dissection. No complications related to the surgery were observed. At the last follow-up visit, the retina was attached in all cases, with an improvement in visual acuity. Conclusion: To conclude, the injection of a cohesive OVD anterior to the detached retina allowed to posteriorize and viscodissect to some extent the retina, facilitating the implant of trocars.

Systemic lupus erythematosus purtscher like retinopathy: Optical coherence tomography angiography assessment implications.

PURPOSE: to underline the importance of optical coherence tomography angiography (OCT-A) in the diagnosis, assessment of final visual outcome and better understanding of the Purtscher like retinopathy, as well as to emphasize on performing an ophthalmologic evaluation in all patients with systemic lupus erythematosus, as eye involvement is closely related with disease activity. METHODS: case report. Ophthalmologic multimodal imaging assessment of a patient short after experiencing a systemic lupus erythematosus severe outset. RESULTS: fundus examination revealed multiple cotton-wool exudates and sharp defined intraretinal white flecken lesions, concentrated in the posterior pole, which along macular edema and the context of lupus disease led to the diagnosis of Purtscher like retinopathy, raising concern about underlying disease activity. OCT-A evidenced ischemic affront in the superficial and deep vascular plexuses but also at choroidal level, preconizing a poor visual outcome. Precapillary retinal vascular stops and choroid lobular ischemic images, with a honey comb configuration in the latter, were of note. Six months after initial consultation, previously displayed ischemic images gave rise to retinal and choroidal atrophy translated into counting fingers best corrected visual acuity with the posterior ensue of retina neovascularization. CONCLUSIONS: This case proves ophthalmologic evaluation mandatory for all patients suffering from lupus and reveals OCT-A as an imaging tool of great value in the assessment of Purtscher retinopathy. To our knowledge, this would be the first report of a SLE Purtscher-like retinopathy characterized by OCT-A, matching graphically and unprecedently vascular micro-embolism stops and ischemic areas, seen as void signals, with the pathognomonic Purtscher flecken, and Paracentral Acute Middle Maculopathy (PAMM) lesions.

Epiretinal implant of human amniotic membrane to treat highly myopic macular hole retinal detachments: A novel surgical technique.

PURPOSE: To describe a new surgical technique involving the use of a human amniotic membrane (hAM) epiretinal patch to treat a primary macular hole retinal detachment (MHRD) in a highly myopic patient. METHODS: A 60 years old highly myopic man was referred to our clinic with a diagnosis of MHRD in his right eye. The patient was pseudophakic, with a visual acuity of counting fingers at the baseline evaluation. Pars plana vitrectomy was performed, a small retinotomy was created at the inner margin of the staphyloma, and membrane blue dual was used to obtain an adequate peeling of the inner limiting membrane. Then, a 1.5 mm diameter circular hAM patch was obtained and positioned over the macular hole with the chorion layer settled over the retina. After a complete fluid-air exchange, 20% sulfur hexafluoride gas was used as endotamponade, and the patient was asked to remain face down for three days. RESULTS: Four weeks after surgery, optical coherence tomography (OCT) scan showed the hAM patch, visualized as a distinct hyperreflective layer well integrated with the retina. Nine months after surgery, the macular hole was closed, the retina reattached, the hAM patch was adherent to the retina, and the patient presented a best-corrected visual acuity improved to 0.7 logMar. No postoperative adverse events were registered during the follow-up. CONCLUSIONS: Epiretinal hAM implant could represent a novel surgical technique, feasible and easier compared to other current techniques used to treat MHRD in highly myopic patients.

Knowledge and Current Practices in Monogenic Uveitis: An International Survey by IUSG and AIDA Network.

INTRODUCTION: This study aims to explore awareness, knowledge, and diagnostic/therapeutic practices in monogenic uveitis (mU) among uveitis experts. METHODS: This is an explorative, cross-sectional survey study. An anonymous, semi-structured, electronic survey was delivered to uveitis experts from the Autoinflammatory Diseases Alliance (AIDA) Network and International Uveitis Study Group (IUSG). We included respondents answering ≥ 50% of the survey. RESULTS: Seventy-seven participants rated their knowledge of mU as proficient (3.9%), adequate (15.6%), sufficient (16.9%), or poor (63.6%). When asked about the first mU gene they thought of, 60.4% mentioned NOD2, 3.9% mentioned NLRP3 or MEFV, and 49.4% provided incorrect or no answers. Success rates in clinical scenarios varied from 15.6% to 55.8% and were higher for ophthalmologists working in multidisciplinary teams (p < 0.01). Genetic testing was ordered for suspected mU by 41.6% of physicians. The availability of molecular techniques did not significantly differ based on geography (p > 0.05). The public healthcare system ensured a higher percentage of tests prescribed were obtained by patients compared to private insurances (p < 0.00). In terms of disease-modifying anti-rheumatic drugs (DMARDs), tumor necrosis factor-α inhibitors were the most familiar to uveitis experts. The difficulties with off-label therapy procedures were the primary barrier to DMARDs prescription for patients with mU and correlated inversely with the obtained/prescribed drug ratio for interleukin-1 (p < 0.01) and interleukin-6 (p < 0.01) inhibitors. CONCLUSIONS: This survey identifies proficiency areas, gaps, and opportunities for targeted improvements in patients care. The comprehensive outputs may inform evidence-based guidelines, empowering clinicians with standardized approaches, and drive an AIDA Network-IUSG unified effort to advance scientific knowledge and clinical practice.

The Infectious Uveitis Treatment Algorithm Network (TITAN) Report 1-global current practice patterns for the management of Herpes Simplex Virus and Varicella Zoster Virus anterior uveitis.

AIMS: To present current expert practice patterns and to formulate a consensus for the management of HSV and VZV AU by uveitis specialists worldwide. METHODS: A two-round online modified Delphi survey with masking of the study team was conducted. Responses were collected from 76 international uveitis experts from 21 countries. Current practices in the diagnosis and treatment of HSV and VZV AU were identified. A working group (The Infectious Uveitis Treatment Algorithm Network [TITAN]) developed data into consensus guidelines. Consensus is defined as a particular response towards a specific question meeting ≥75% of agreement or IQR ≤ 1 when a Likert scale is used. RESULTS: Unilaterality, increased intraocular pressure (IOP), decreased corneal sensation and diffuse or sectoral iris atrophy are quite specific for HSV or VZV AU from consensus opinion. Sectoral iris atrophy is characteristic of HSV AU. Treatment initiation is highly variable, but most experts preferred valacyclovir owing to simpler dosing. Topical corticosteroids and beta-blockers should be used if necessary. Resolution of inflammation and normalisation of IOP are clinical endpoints. CONCLUSIONS: Consensus was reached on several aspects of diagnosis, choice of initial treatment, and treatment endpoints for HSV and VZV AU. Treatment duration and management of recurrences varied between experts.