Mesenchymal stem cell based therapies for uveitis: a systematic review of preclinical studies.

Cell therapy has shown promising results for treating uveitis in preclinical studies. As the field continues to grow towards clinical translation, it is important to review and critically appraise existing studies. Herein, we analysed and critically appraised all preclinical studies using cell therapy or cell derived extracellular vesicles (EVs) for uveitis, and provided insight into mechanisms regulating ocular inflammation. We used PubMed, Medline, and Embase to search for preclinical studies examining stem cell therapy (e.g., mesenchymal stem cells [MSC]) and secreted EVs. All included studies were assessed for quality using the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) checklist. Sixteen preclinical studies from 2011 to 2022 were analysed and included in this review of which 75% (n = 12) focused only on cell therapy, 18.7% (n = 3) studies focused on EVs, and 6.3% (n = 1) study focused on both cells and EVs. MSCs were the most common type of cells used in preclinical studies (n = 15) and EVs were commonly isolated from MSCs (n = 3). Overall, both MSCs and EVs showed improvements in ocular inflammation (seen on fundoscopy/slit lamp and histology) and electroretinogram outcomes. Overall, MSC and MSC-derived EVs shown great potential as therapeutic agents for treating uveitis. Unfortunately, small sample size, risk of selection/performance bias, and lack of standardized cell harvesting or delivery protocols are some factors which limits clinical translation. Large scaled, randomized preclinical studies are required to understand the full potential of MSCs for treating uveitis.

Efficacy of intravitreal dexamethasone implant used as monotherapy for the treatment of macular edema in non-infectious uveitis: a retrospective analysis.

BACKGROUND: Uveitic macular edema is a complication of acute or chronic uveitis. Current treatment regiments frequently have numerous side effects, often requiring supplemental treatment. This study investigates the efficacy of dexamethasone (DEX) intravitreal implants as monotherapy for treatment of macular edema in non-infectious intermediate, posterior or panuveitis. METHODS AND RESULTS: Retrospective chart review of thirty patients with intermediate, posterior and panuveitis treated with DEX. Outcomes measured were central retinal thickness (CRT) and best corrected visual acuity (BCVA). Baseline measurements of CRT and BCVA were measured within 1 month prior to intravitreal DEX implant and follow up measurements were collected until 1 year post implant. 48 implants on 39 eyes of 30 patients were included in this study; 64.1% of patients had an improvement in BCVA and 65.4% had a reduction in CRT. BCVA improved from 0.285 logMAR (SD: 0.312) at baseline to 0.175 logMAR (SD: 0.194) at 1 month and was sustained thereafter. Preliminary CRT data showed a decrease from 392 [Formula: see text] (SD: [Formula: see text]) at baseline to 303 [Formula: see text] (SD: [Formula: see text] at 1 month and 313 [Formula: see text] (SD: [Formula: see text] at 12 months. CONCLUSIONS: The DEX implant as monotherapy for macular edema in non-infectious uveitis was associated with a reduction in CRT and improvement in BCVA. The DEX implant, used as a monotherapy in eyes with intermediate, posterior and panuveitis, has the potential to treat uveitis without oral corticosteroid or other immunomodulatory therapy.

Acute annular outer retinopathy preceded by invasive ductal breast carcinoma: a case report.

BACKGROUND: Acute annular outer retinopathy (AAOR) is an uncommon disease. To date, there are few documented cases in the literature. Our case report is the first to describe a case of acute annular outer retinopathy in a patient with invasive ductal breast carcinoma. CASE PRESENTATION: The patient presented with photopsias and visual loss approximately 3 weeks prior to a diagnosis of invasive ductal breast carcinoma. We have documented the outer annular white ring seen in the acute phase of this disease and correlate it anatomically with Spectral-domain optical coherence tomography (SD-OCT) imaging. We identified RPE atrophy with nodular hyperreflectivity and loss of ellipsoid layer within the white annular ring with corresponding visual field loss. Fundus autofluorescence correlated with structural alterations seen on SD-OCT and showed both presumed active hyperautofluorescent zones with patchy hypoautofluorescent zones of atrophy and a classic annular hyperautofluorescent border. This case provides additional information about the natural history of this rare entity and its prognosis and varied presentation. CONCLUSIONS: The authors report a single case of acute annular outer retinopathy in a patient with invasive ductal breast carcinoma with the corresponding SD-OCT, fundus autofluorescence and visual field findings, during the acute phase of the disease. These findings provide new insight into the characteristic features, etiology and progression of this rare disease.

Intravenous administration of Penicillin results in therapeutic intravitreal levels in chronic postoperative endophthalmitis.

IMPORTANCE: The role of systemic antibiotics in the treatment of bacterial endophthalmitis remains controversial. While penicillin is a highly effective antibiotic against bacteria that frequently cause endophthalmitis, the ability of systemically administered Penicillin G to penetrate into the vitreous at adequate therapeutic concentrations has not been studied. Its role in the treatment of endophthalmitis, particularly for bacteria for which it is the antibiotic of choice, therefore remains unknown. OBJECTIVE: We sought to determine whether intravenous administration of Penicillin G leads to adequate therapeutic concentrations in the vitreous for the treatment of bacterial endophthalmitis. DESIGN AND SETTING: This study was conducted in an ambulatory setting, at the Ottawa Hospital Eye Institute, a university-affiliated tertiary care center, where a 77-year old gentleman with chronic post-cataract surgery Actinomyces neuii endophathalmitis was treated with intravenous Penicillin G (4 × 106 units every 4 h) and intravitreal ampicillin (5000µg/0.1 m1). MAIN OUTCOMES AND MEASURES: Intravitreal concentration of Penicillin G and ampicillin were obtained at the time of intraocular lens removal, measured by high-performance liquid chromatography. RESULTS: The intravitreal concentration of penicillin and ampicillin was 3.5µg/ml and 0.3µg/ml, respectively. Both the concentration of penicillin and ampicillin were within the level of detection of their respective assays (penicillin 0.06-5µg/ml, ampicillin 0.12-2.5µg/ml). CONCLUSION AND RELEVANCE: This study shows that intravenous Penicillin G administered every four-hours allows for adequate intravitreal concentrations of penicillin. Future studies are required to determine if the results of this study translate into improved clinical outcomes.

The Diagnostic Utility of Multifocal Electroretinography in Detecting Chloroquine and Hydroxychloroquine Retinal Toxicity.

PURPOSE: To evaluate multifocal electroretinography (mfERG) as a screening test for detecting hydroxychloroquine and chloroquine toxicity. DESIGN: Diagnostic accuracy study. METHODS: Patients referred to the University of Ottawa for hydroxychloroquine or chloroquine retinopathy screening during 2011-2014 underwent 10-2 automated visual field, spectral domain optical coherence tomography, and mfERG testing. Patients with amblyopia, high myopia or hyperopia, coexisting retinal disease, or prior surgery were excluded. Abnormalities in parafoveal ring amplitudes or ring ratios were considered a positive mfERG result. We used the definition for hydroxychloroquine and chloroquine toxicity provided by the 2016 American Academy of Ophthalmology recommendations. Area under the curve (AUC) for each mfERG parameter and the sensitivity and specificity of mfERG were calculated. Logistic regression was used to model the effect of covariates in receiver operating characteristic (ROC) analyses. RESULTS: In total, 63 patients (47 female, 16 male) were included. Of 120 eyes, 16 (13.3%) had toxicity according to the American Academy of Ophthalmology guidelines, and 39 (32.5%) had positive mfERG findings. mfERG was found to have a sensitivity of 1.00 (95% CI 0.79-1.00) and a specificity of 0.78 (95% CI 0.69-0.85). Ring 2 amplitude had the best performance among all parameters (AUC 0.97, 95% CI 0.94-1.00). Ring 2 amplitude decreased linearly with increasing cumulative dose and daily dose. CONCLUSIONS: The high sensitivity of parafoveal depression on mfERG and its relationship to cumulative and daily dose illustrates an important role for objective functional testing. The high false-positive rate suggests a potential period where physiologic dysfunction is detected objectively on mfERG before structural change on spectral domain optical coherence tomography.

Methotrexate for the treatment of noninfectious scleritis.

OBJECTIVE: To assess corticosteroid-sparing and inflammation control in patients with noninfectious scleritis treated with methotrexate. DESIGN: Retrospective review. PARTICIPANTS: Patients who received methotrexate treatment for noninfectious scleritis and who had 12 months of follow-up after treatment initiation were included in this review. METHODS: The clinical records of noninfectious scleritis patients presenting at the University of Ottawa Eye Institute between September 1, 2010 and December 31, 2014 treated with methotrexate were retrospectively reviewed. Seventeen patients (21 eyes) were included in the study. Main outcome included inflammation control and corticosteroid-sparing success. Secondary outcomes were reduction of immunosuppression load and best-corrected visual acuity. RESULTS: The proportion of eyes with corticosteroid-sparing success was 69.2% at 3 months and 92.3% at 12 months. The proportion of eyes that achieved inflammation control was 61.9% at 3 months and 90.5% at 12 months. The corticosteroid immunosuppression load at treatment start was 1.9 ± 2.07 and at 12 months was 0.48 ± 1.03 (p < 0.01). There was no statistically significant difference in best-corrected visual acuity. CONCLUSIONS: The treatment of noninfectious scleritis with methotrexate appears to be effective at both achieving steroid-sparing success and controlling inflammation during 12 months of therapy. Immunosuppression load decreased significantly over 12 months of therapy while best corrected visual acuity was stable.

Intravitreal Dexamethasone Implant for the Treatment of Macular Edema in Chronic Non-infectious Uveitis.

PURPOSE: To report observations on the single and repeat use of the dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc, Irvine, CA) for the treatment of macular edema in patients with non-infectious posterior segment uveitis. METHODS: A chart review of 15 consecutive patients (25 eyes) was conducted. The primary outcome measure of the first and subsequent implants was central retinal thickness (CRT) on spectral-domain optical coherence tomography (sdOCT). Secondary outcomes were best-corrected visual acuity (BCVA), time to repeat implant, and adverse events. Multilevel mixed-effects linear regression was used to determine the effect of the DEX implant compared with baseline. The Kaplan-Meier estimator was used to examine survival from relapse. RESULTS: A total of 35 implants on 25 eyes of 15 patients were included in the analysis. Of these, 91.4% (32 of 35 eyes) had a reduction in CRT and 80% (20 of 25 eyes) had improved BCVA. After the first DEX implant, CRT decreased from 590 µm (SE: 28 µm) at baseline to 370 µm (SE: 31 µm) at 3 months (p < 0.001). The logMAR VA was 0.614 (SE: 0.089) at baseline and improved to 0.35 (SE: 0.10, p = 0.002), reaching a statistically significant difference at 3 months. A repeat implant led to VA improvement of -0.184 logMAR (SE: 0.171 logMAR) and CRT reduction of -291 µm (SE: 74 µm). There was no significant difference in effect between the first repeat implant and the initial implant. Kaplan-Meier estimates of treatment success were 72% between 3 and 6 months. CONCLUSIONS: The DEX implant is an effective adjunct treatment to systemic corticosteroid or immunomodulatory therapy. Additional research is required to determine the efficacy of DEX implant as monotherapy for controlling chronic uveitic macular edema.

A national survey of Canadian ophthalmologists to determine awareness of published guidelines for the management of uveitis.

BACKGROUND: The objectives of this study are to assess Canadian ophthalmologists' awareness of established uveitis treatment guidelines and clinical management of uveitis and to assess the frequency of government applications for immunomodulatory therapy (IMT) and identify primary prescribers. A 25-item questionnaire was sent to 759 practicing Canadian ophthalmologists. Six questions assessed demographics including the year of residency completion, training by uveitis specialists during residency, and fellowship training. Five questions assessed application of guidelines to clinical scenarios, and 12 questions assessed referral patterns and success of obtaining coverage for IMT. RESULTS: Of 144 respondents, 12 (8.3 %) were uveitis specialists; 45.1 % of respondents had uveitis training during residency by a uveitis specialist. Sixty-one percent reported awareness of management guidelines. Recent graduates (2001-2012) referred patients to uveitis specialists (55.3 %) less frequently than earlier graduates. Recent graduates also managed uveitis patients more frequently with corticosteroid injections (15.6 %) than those who graduated before 1980 (9.75 %). The majority (93.6 %) of respondents submitted less than six IMT funding applications for provincial drug coverage yearly, and 5.5 % reported prescribing IMT themselves, rather than referring to other specialists. CONCLUSIONS: Although greater than half of respondents reported awareness of uveitis treatment guidelines, Canadian ophthalmologists' awareness of uveitis treatment guidelines and application of the guidelines to patient care could be improved. Few applications are made for IMT, and the majority of applications are sent by non-ophthalmologists. This suggests the need for further education of ophthalmologist about uveitis treatment guidelines and for more ophthalmologists trained to manage uveitis with IMT.

Is Acute Zonal Occult Outer Retinopathy an Autoimmune Condition? A Case Report and Literature Review.

A 42-year-old woman with multiple sclerosis presented with focal decreased vision and photopsia in the left eye. Funduscopy and fluorescein angiography revealed focal chorioretinal atrophy, vascular attenuation, and bone spicules. Electroretinography revealed interocular reduction in b-wave amplitude, and Goldmann visual field perimetry studies revealed an inferior scotoma. The authors performed a literature review and conclude that the prevalence of acute zonal occult outer retinopathy in patients with autoimmune conditions may suggest that the condition is autoimmune in nature. Clinical history as well as funduscopic and retinal investigations are important in diagnosing acute zonal occult outer retinopathy.

Hydroxychloroquine and chloroquine retinopathy: a systematic review evaluating the multifocal electroretinogram as a screening test.

PURPOSE: To determine the validity of multifocal electroretinography (mfERG) as a screening tool for detecting chloroquine (Aralen, Sanofi Aventis, Bridgewater, NJ) (CQ) and hydroxychloroquine (Plaquenil, Covis Pharmaceuticals, Inc, Zug, Switzerland) (HCQ) retinal toxicity in patients using these medications. To evaluate the sensitivity and specificity of mfERG when compared with automated visual fields (AVFs), fundus autofluorescence (FAF), and optical coherence tomography (OCT). CLINICAL RELEVANCE: The 2011 American Academy of Ophthalmology recommendations on screening for CQ/HCQ retinopathy recommended a shift toward more objective testing modalities. Multifocal electroretinography may be effective in detecting functional change before irreversible structural damage from CQ/HCQ toxicity. METHODS: We performed a search for records reporting the use of mfERG for screening CQ/HCQ retinopathy in MEDLINE (PubMed and OVID), EMBASE, and Web of Science, and assessed these using the QUADAS-2 risk of bias tool. We conducted an analysis of 23 individual studies and their reported individual patient data (449 eyes of 243 patients) published from January 2000 to December 2014. RESULTS: Multifocal electroretinography had the greatest proportion of positive test results, followed by AVF. The pooled sensitivity and specificity of mfERG were 90% (95% confidence interval [CI], 0.62-0.98) and 52% (CI, 0.29-0.74), respectively, with AVF as reference standard (13 studies). Sensitivity was high, but specificity was variable when OCT, FAF, and the positivity of 2 of 3 tests was used as the reference standard. When verified against AVF as the reference test, patients with a false-positive mfERG result received higher HCQ cumulative doses (1068 g) than patients with true-negative (658 g, P < 0.01) and false-negative (482 g, P < 0.01) results. CONCLUSIONS: Multifocal electroretinography was shown to have a high sensitivity but variable specificity when verified against AVF, OCT, FAF, and a combination of tests. The greater average cumulative dose in the false-positive group compared with the true-negative group when mfERG was verified against AVF suggests that mfERG may have the ability to detect cases of toxicity earlier than other modalities. There is an unclear risk of bias in the available evidence, and future studies should adhere to Standards for Reporting of Diagnostic Accuracy reporting guidelines.

Bilateral multifocal choroidal melanosis: a report of two cases.

Flat choroidal pigmented lesions have few differential diagnoses but encompass a wide range of clinical presentations. The authors report two cases of bilateral multifocal choroidal hyper-pigmented patches discovered in asymptomatic patients. Fluorescein angiography showed a normal pattern without blockage in the hyperpigmented areas with an otherwise normal choroidal vascular architecture. Optical coherence tomography with enhanced depth imaging demonstrated normal choroidal thickness and structure in the hyperpigmented areas. These cases may represent an atypical presentation of previously described bilateral isolated choroidal melanocytosis or a different clinical entity. Histopathological evidence and longer follow-up of these patients and patients with isolated choroidal melanocytosis may elucidate the best descriptive term for this unusual condition.

Specific combination of compound heterozygous mutations in 17ß-hydroxysteroid dehydrogenase type 4 (HSD17B4) defines a new subtype of D-bifunctional protein deficiency.

BACKGROUND: D-bifunctional protein (DBP) deficiency is typically apparent within the first month of life with most infants demonstrating hypotonia, psychomotor delay and seizures. Few children survive beyond two years of age. Among patients with prolonged survival all demonstrate severe gross motor delay, absent language development, and severe hearing and visual impairment. DBP contains three catalytically active domains; an N-terminal dehydrogenase, a central hydratase and a C-terminal sterol carrier protein-2-like domain. Three subtypes of the disease are identified based upon the domain affected; DBP type I results from a combined deficiency of dehydrogenase and hydratase activity; DBP type II from isolated hydratase deficiency and DBP type III from isolated dehydrogenase deficiency. Here we report two brothers (16½ and 14 years old) with DBP deficiency characterized by normal early childhood followed by sensorineural hearing loss, progressive cerebellar and sensory ataxia and subclinical retinitis pigmentosa. METHODS AND RESULTS: Biochemical analysis revealed normal levels of plasma VLCFA, phytanic acid and pristanic acid, and normal bile acids in urine; based on these results no diagnosis was made. Exome analysis was performed using the Agilent SureSelect 50Mb All Exon Kit and the Illumina HiSeq 2000 next-generation-sequencing (NGS) platform. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of the 17ß-hydroxysteroid dehydrogenase type 4 gene (HSD17B4). These mutations have been previously reported in patients with severe-forms of DBP deficiency, however each mutation was reported in combination with another mutation affecting the same domain. Subsequent studies in fibroblasts revealed normal VLCFA levels, normal C26:0 but reduced pristanic acid beta-oxidation activity. Both DBP hydratase and dehydrogenase activity were markedly decreased but detectable. CONCLUSIONS: We propose that the DBP phenotype seen in this family represents a distinct and novel subtype of DBP deficiency, which we have termed type IV based on the presence of a missense mutation in each of the domains of DBP resulting in markedly reduced but detectable hydratase and dehydrogenase activity of DBP. Given that the biochemical testing in plasma was normal in these patients, this is likely an underdiagnosed form of DBP deficiency.

Ocular involvement in acute febrile neutrophilic dermatosis (Sweet syndrome): new cases and review of the literature.

Sweet syndrome (acute febrile neutrophilic dermatosis) is a dermatologic disorder with accompanying features of systemic inflammation. It is commonly associated with conjunctivitis, but a variety of types of ocular inflammation have been reported. The ocular manifestations of Sweet syndrome include periorbital and orbital inflammation, dacryoadenitis, conjunctivitis, episcleritis, scleritis, limbal nodules, peripheral ulcerative keratitis, iritis, glaucoma, and choroiditis. The ocular inflammation appears concurrently with skin lesions. An overview of Sweet syndrome is presented with a review of cases in the literature describing ocular involvement. We report two additional cases of ocular involvement, one with conjunctivitis and a second with iritis, peripheral ulcerative keratitis, and episcleritis. Of the 20 cases, half were bilateral. Thirteen cases occurred in the setting of classical or idiopathic Sweet syndrome and seven in association with malignancy. Biopsies of ocular tissue were infrequent, but, in the seven cases where ocular tissue was analyzed, the histopathology was similar to that of the cutaneous lesions. The ocular complications of Sweet syndrome resolved with systemic administration of corticosteroid or cyclosporine. Topical ocular steroid treatment was frequently used in conjunction with oral steroid but may not have been valuable.

Intraocular ophthalmic ointment following clear corneal phacoemulsification: Clinical implications.

We report 4 cases of apparent ophthalmic ointment in the anterior chamber after sutureless clear corneal phacoemulsification and posterior chamber intraocular lens implantation. The cases, as well as previous literature, indicate that ointment for topical use can be well tolerated in the eye, although glaucoma and uveitis can be potential negative outcomes. Possible risk factors, some of which may be related to current rates of endophthalmitis after clear corneal cataract surgery, and methods to prevent intraocular ophthalmic ointment after cataract surgery are discussed.

Phacovitrectomy with internal limiting membrane peeling for idiopathic macular hole.

BACKGROUND: Progressive nuclear sclerosis is a known complication of macular hole surgery that hinders patients' recovery to their best visual acuity postoperatively. We report the visual outcome, complications and efficacy of combined phacoemulsification, intraocular lens (IOL) insertion and vitrectomy with internal limiting membrane (ILM) peeling for patients with cataract undergoing macular hole surgery. METHODS: We reviewed the records of 32 consecutive patients (36 eyes) who underwent phacoemulsification with insertion of a polymethylmethacrylate lens into the capsular bag and pars plana vitrectomy with ILM peeling in one session for repair of idiopathic macular hole. Patients were assessed between February 1998 and August 2001. RESULTS: The mean age of the patients was 70 (range 52 to 83) years, and 25 (78%) were women. The median duration of the holes before surgery was 8.3 months; in 19 eyes (53%) the duration was 6 months or less. Twenty eyes (56%) had stage 3 holes. The preoperative vision was 20/200 or worse in 29 eyes (80%). The mean grade of nuclear sclerosis was 2.4. The average length of follow-up after surgery was 11 (range 1.5 to 37) months. Primary hole closure was achieved in 28 eyes (78%). In five of the remaining eight cases the patient consented to a second procedure, which was successful in four cases, for a final closure rate of 89%. Postoperatively, the visual acuity improved by 2 lines or more in 22 eyes (61%). Of the 32 eyes with final closure, 11 (34%) attained a visual acuity of 20/40 or better, and 25 (78%) had an acuity of 20/100 or better. The most common complication was posterior capsular opacification (27 eyes [75%]), an expected complication when perfluoropropane or other gases are used for tamponade. INTERPRETATION: The results are comparable to those with standard macular hole surgery. Combined surgery is reliable and safe; the benefits support its use as a routine procedure for patients with cataract undergoing macular hole repair.