Guidance on noncorticosteroid systemic immunomodulatory therapy in noninfectious uveitis: fundamentals of care for uveitis (focus) initiative

Topic: An international, expert-led consensus initiative to develop systematic, evidence-based recommendations for the treatment of noninfectious uveitis in the era of biologics. Clinical Relevance: The availability of biologic agents for the treatment of human eye disease has altered practice patterns for the management of noninfectious uveitis. Current guidelines are insufficient to assure optimal use of noncorticosteroid systemic immunomodulatory agents. Methods: An international expert steering committee comprising 9 uveitis specialists (including both ophthalmologists and rheumatologists) identified clinical questions and, together with 6 bibliographic fellows trained in uveitis, conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol systematic reviewof the literature (English language studies from January 1996 through June 2016; Medline [OVID], the Central Cochrane library, EMBASE,CINAHL,SCOPUS,BIOSIS, andWeb of Science). Publications included randomized controlled trials, prospective and retrospective studies with sufficient follow-up, case series with 15 cases or more, peer-reviewed articles, and hand-searched conference abstracts from key conferences. The proposed statements were circulated among 130 international uveitis experts for review.Atotal of 44 globally representativegroupmembersmet in late 2016 to refine these guidelines using a modified Delphi technique and assigned Oxford levels of evidence. Results: In total, 10 questions were addressed resulting in 21 evidence-based guidance statements covering the following topics: when to start noncorticosteroid immunomodulatory therapy, including both biologic and nonbiologic agents; what data to collect before treatment; when to modify or withdraw treatment; how to select agents based on individual efficacy and safety profiles; and evidence in specific uveitic conditions. Shared decision-making, communication among providers and safety monitoring also were addressed as part of the recommendations. Pharmacoeconomic considerations were not addressed. Conclusions: Consensus guidelines were developed based on published literature, expert opinion, and practical experience to bridge the gap between clinical needs and medical evidence to support the treatment of patients with noninfectious uveitis with noncorticosteroid immunomodulatory agents

Inhibitors of corneal inflammation and angiogenesis : Prospectives and challenges

Pathologic angiogenesis is involved in cancer and several blinding conditions such as wet age-related macular degeneration, proliferative retinopathies and corneal neovascularization. In these dieseases, the angiogenic triggers are hypoxia and inflammation, and both involve the main angiogenic mediator, which is Vascular Endothelial Growth Factor (VEGF). Among available treatments, anti-VEGF often shows limited or temporary efficacy, while steroids are potentially responsible for many side-effects. This thesis presents a series of linked studies aimed at elucidating the early pathologic changes leading to inflammation and corneal neovascularization, and how various treatments affect this process. In this thesis, anti-inflammatory and anti-angiogenic treatments are applied in corneal neovascularization models, to identify VEGF-independent pathways and other novel factors as future therapy targets, as well as to investigate the endogenous modulation of angiogenesis. A model of experimental neovascularization in the rat cornea was used as main model, where the neovascular response is triggered by a surgical suture placed into the cornea. Investigational treatments (anti-Vegf, dexamethasone, IMD0354, Gap27, or control substances) were then given topically, with the exception of IMD0354, which was given systemically. The effects in the cornea were studied in vivo with slit lamp photography to assess and quantify macroscopic vessel growth and using in vivo confocal microscopy (IVCM) to study cell infiltration and limbal vessel dilation and detect microscopic vessel sprouts; these examinations were performed longitudinally. Genomic analysis with RNA microarray, selected gene expression with q-RT-PCR, and selected protein expression in tissue (immunohistochemistry, immunofluorescence, Western blot) were performed at different time-points. Moreover, other experiments on cell cultures (HUVEC and HCEC), organ cultures (human corneas), ex vivo models (aortic rings) and in vivo studies (zebrafish vasculogenesis) were performed. Dexamethasone suppressed limbal vasodilation and corneal neovascularization more than anti-Vegf, despite no difference in inflammatory cell infiltration into the cornea. Five-hundred eleven fewer genes were differentially expressed in dexamethasone-treated corneas relative to naïve corneas, compared to anti-Vegf. Among them, several major pro-angiogenic and pro-inflammatory factors and chemokines were suppressed only by dexamethasone and represent novel candidate factors to target in order to improve anti-VEGF treatment. On the other hand, selective inhibition of a single inflammatory pathway (NF-κB), despite showing similar early effects as dexamethasone in suppressing tissue inflammation, was not effective enough to suppress new vessel growth. The same factors suppressed by dexamethasone are also inhibited in endogenous modulation of angiogenesis. Surprisingly, dexamethasone activated several complement factors, which could possibly be beneficial in the anti-angiogenic response. In a different therapeutic approach, promoting cell migration to accelerate epithelial wound closure similarly was not sufficient to avoid inflammation and angiogenesis in the cornea. In conclusion, new and more effective treatments are needed for corneal inflammation and neovascularization with fewer side-effects. In this thesis, several novel factors and mechanisms related to inflammation are identified, factors that are not addressed by anti-Vegf therapy, and therefore represent interesting objects for further study, as they have the potential to be targets for adjuvant therapy. Specific anti-inflammatory treatment as well as therapeutic activation of endogenous regulatory pathways, and potentially complement modulation, might represent new strategies to improve anti-angiogenic therapy, but when used alone they do not seem to avoid corneal neovascularization

Treatment algorithm with dexamethasone intravitreal implant in patients with diabetic macular edema

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Retinal changes associated with multivitamin deficiency before and after supplementation

Background: Nutritional visual defects are apparently uncommon nowadays in developed nations. Retinal change-related visual defects caused by hypovitaminoses may be underdiagnosed. Aim of the study: To investigate the retinal structural and functional changes in a patient with multivitamin deficiency before and during vitamin supplementation. Methods: A 51-year-old female had been on vegetarian diet as a child, and on restrict vegan diet during the last 2 years, developing severe bilateral deterioration of visual function and polyneuropathy. Blood test revealed low levels of vitamin A, B6 and D. The patient underwent examinations with optical coherence tomography (OCT), computerized visual field examination (VF), electroretinography (ERG), visual evoked potentials (VEP) and neurography before and after vitamin supplementation. Results: Visual acuity (VA) was 20/1000 and VF examination showed central scotoma in both eyes. Color vision was significantly affected. Full-field ERG showed normal rod and cone function, but a clearly reduced central peak was registered in multifocal ERG (mf-ERG), indicating impaired fovea function. VEP showed delayed latency and low amplitude of P100 in both eyes. Neurography showed sensory polyneuropathy. OCT showed significant thinning of macular ganglion cell plus inner plexiform layer (GCIPL) with rapid progression. Retinal nerve fiber layer (RNFL) was preserved and normal, which is in contrast to neuroinflammatory conditions. After 2.5 years of multivitamin supplementation, the visual functions were improved. GCIPL thickness was stable without further deterioration. Conclusions: Multivitamin deficiency results in progressive thinning of GCIPL with severe visual deterioration. In contrast to neuroinflammation, RNFL is preserved and normal. Stabilized GCIPL during vitamin supplementation was associated with improved visual function. OCT provides a sensitive and objective measure for differential diagnosis, monitoring retinal change and response to therapy

Early effects of dexamethasone and anti-VEGF therapy in an inflammatory corneal neovascularization model

Inflammatory angiogenesis is the pathogenic mechanism of various sight-threatening eye diseases, among them corneal neovascularization. Current treatment options include steroids which have undesirable side effects, or anti-VEGF which has only limited efficacy. In an inflammatory environment, however, angiogenesis can be stimulated by numerous factors not directly targeted by anti-VEGF therapy. The aim of this study was to induce corneal inflammation leading to angiogenesis, and investigate the early, differential effects of steroid and anti-VEGF therapy at the cellular, tissue, and gene expression levels. Fifty-two Wistar rats received a single intrastromal corneal suture to induce a controlled inflammatory angiogenic response. Rats were subsequently treated with dexamethasone, rat specific anti-VEGF, or goat IgG (control), topically 4 times daily for 7 days. In vivo confocal microscopy of the cornea was performed longitudinally from 5 h up to 7 d to investigate morphology at the cellular and tissue-level. In vivo photographic vessel analysis and immunohistochemistry were also performed. RT-PCR for VEGF-A, FGF-2, IL-6, TNF-alpha, CXCL2, CCL2, CCL3 and DLL4 was performed at 24 h, and for VEGF-A, IL-6, TNF-alpha, FGF-2, CXCL2, CCL2, and CCL3 at 7 days. Early infiltration of CD11b + myeloid cells into the cornea at 5 h post-suture was delayed by both treatments relative to controls; however neither treatment was able to suppress accumulation of myeloid cells at day 2 or 7. Limbal vessel dilation was inhibited at 5 h by both treatments, but only dexamethasone showed sustained effect until day 2. Early macrophage recruitment was also suppressed by dexamethasone (but not by anti-VEGF) until day 2. Dexamethasone furthermore suppressed corneal neovascularization at day 7 by over 90%, whereas suppression by anti-VEGF was 14%. Despite differential suppression of vessel dilation, macrophage recruitment, and vascular invasion, anti-VEGF and dexamethasone both down-regulated VEGF-A and IL-6 expression at 24 h with sustained effect to 7 d. They also both down regulated FGF-2 and TNF-alpha at 24 h and CCL2 at 7 d. In conclusion, anti-angiogenic treatments influence early, pre-angiogenic tissue activity such as limbal vessel dilation, inflammatory cell infiltration of the stroma, and macrophage recruitment. Importantly, the differential effects of steroids and anti-VEGF treatment in suppressing neovascular growth could not be attributed to differential inhibition of several major angiogenic and inflammatory factors in the early pre-sprouting phase, including IL-6, VEGF-A, FGF-2, TNF-alpha, CCL2, CCL3, CXCL2, or DLL4.Funding Agencies|Crown Princess Margaretas Foundation; County Council of Ostergotland; Swedish Research Council [2012-2472]</p

Optical Coherence Tomography to Monitor Rebound Intracranial Hypertension with Increased Papilledema after Lumbar Puncture

Objective: We report that lumbar puncture (LP) with removal of cerebrospinal fluid (CSF) induced rebound intracranial hypertension with increased papilledema as monitored by optical coherence tomography (OCT). Background: Severe papilledema causes visual field loss and central vision damage if untreated. Fundoscopy is a key to diagnose papilledema, but is not sensitive enough to monitor therapeutic effects. Methods: OCT was applied to follow a 24-year-old woman with headache, visual dysfunction, severe bilateral papilledema, and elevated CSF opening pressure. She was first treated with serial LP, which led to symptom deterioration, increased CSF pressure, and increased the retinal nerve fiber layer (RNFL) thickness. She was then successfully treated with acetazolamide and furosemide. Results: OCT showed reduction of RNFL thickness directly after LP with CSF removal, accompanied with reduced CSF pressure. Increased RNFL thickness accompanied with worsened headache, visual dysfunction, and increased CSF pressure was observed on the next day after LP. Less than 24 h after start of medication, the symptoms had reversed and RNFL thickness was reduced. The patient was symptom-free 2 weeks after starting on medical treatment. Papilledema had vanished on fundoscopy 6 weeks after the therapy, and RNFL thickness was normalized at 3 months of follow-up. Conclusion: This case provides evidence that OCT is an objective and sensitive tool to monitor papilledema and its response to therapy, and thereby important to help in correct clinical decision-making

Real-Life Efficacy of Bevacizumab Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion according to Pro Re Nata or Treat-and-Extend Regimen in Eyes with or without Epiretinal Membrane

Purpose. To present real-life data of patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO) treated with bevacizumab (BVZ); determine the possible influence of epiretinal membrane (ERM) on treatment efficacy; and compare treatment outcomes in a treat-and-extend regimen (TER) versus pro re nata (PRN). Methods. We carried out a retrospective analysis of 58 eyes (56 patients) with new-onset CRVO treated only with intravitreal bevacizumab according to TER or PRN. Outcome measures were best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline and 12 months after the first treatment, number of visits and injections, and presence of ERM confirmed by optical coherence tomography in the first 6 months. Results. At 12 months, the mean number of injections was 6.3 across all eyes, with significantly more injections given in TER (p &amp;lt; 0.001). Mean CRT improved from 627 mu m to 359 mu m (p &amp;lt; 0.001) in all eyes, with improvement noted in TER (p &amp;lt; 0.001), PRN (p &amp;lt; 0.001), ERM (p=0.003), and non-ERM (p &amp;lt; 0.001) subgroups. The mean BCVA gain was +13.6 letters, and the mean BCVA improved from 0.81 to 0.54 LogMAR (p &amp;lt; 0.001) in all eyes. BCVA improvement from baseline was significant in TER (p &amp;lt; 0.001) and non-ERM (p &amp;lt; 0.001) but not in PRN (p=0.08) or ERM (p=0.2) subgroups. Seven eyes, all receiving PRN treatment, developed neovascularization. Conclusions. Intravitreal bevacizumab according to either PRN or TER resolved edema and stabilized vision in the first 12 months, with TER yielding significant visual improvement and avoiding neovascular complications. ERM had no influence on bevacizumab efficacy in reducing ME in CRVO during 12 months of treatment

Coats\u2019 disease: Very long-term outcome after early stage conventional treatment

PURPOSE: To report on the outcome of conventional therapy in patients with Coats’ disease. METHODS: Retrospective analysis of the charts of thirteen patients with Coats’ disease. RESULTS: Mean age of 9 male (70%) and 4 female (30%) patients was 17.7 (range, 5-33) years; one female had bilateral disease. Eleven eyes with retinal telangiectasia and exudation were treated with argon laser photocoagulation alone or photocoagulation associated with cryotherapy; the mean follow up was 32.5 (range,17-41) years. In four eyes without foveal involvement (stage 2a) the mean presenting visual acuity (VA) remained at 0.8 or improved, whereas poor VA in seven stage 2b eyes deteriorated minimally over time. In one and two of the three eyes with total retinal detachment, phthisis or neovascular glaucoma ensued. CONCLUSION: About three decades after conventional treatment of Coats’ disease stage 2a, treated eyes maintained good VA, and stage 2b eyes did not progress to advanced stages