Long term follow up of patients with MNV3 treated with intra-vitreal Aflibercept.

PURPOSE: MNV3 or Retinal angiomatous proliferation is a subtype of neovascular age-related macular degeneration (nAMD). We present the 5 year long term visual and anatomical outcomes of patients with MNV3 lesions treated with intravitreal Aflibercept. METHODS: This is a prospective study of treatment naïve patients with reading centre graded MNV3 lesions. After the loading phase, the patients received intravitreal Aflibercept as per the View study up to year 3, thereafter it was given on a prn basis. At each visit, best corrected visual acuity (BCVA) and optical coherence tomography (OCT) central macular thickness (CMT) was measured. RESULTS: Thirty one patients reached study completion. Mean BCVA of treated eyes had decreased by 0.6 ETDRS letters at the end of year 5 compared with baseline. At study completion, 81% of eyes had stable vision while 19% of eyes had gained 15 letters or more. At study end, 26% of eyes had BCVA of 6/12 or better, while 19% had lost 15 letters or more (all had central foveal photoreceptor loss). There was a maximal mean reduction in CMT of 164 microns (p = <0.0001) while 68% of maculae were fluid free at study completion. Eighty seven percent of treated eyes developed nascent GA, of which in 74% of eyes was involving the fovea. DISCUSSION: Despite initial improvement in mean BCVA, the improvement in BCVA was not maintained despite good overall control of the MNV3 lesions. The loss of BCVA was most likely due to the majority of eyes developing centre involving macular atrophy.

Multiple Evanescent White Dot Syndrome and Choroidal Neovascularization following SARS-COV-2 Infection in a Patient on Dabrafenib and Trametinib.

PURPOSE: to describe multimodal imaging and electrophysiology of multiple evanescent white dot syndrome (MEWDS) concomitant with COVID-19 infection in a patient on BRAF (B Rapidly Accelerated Fibrosarcoma) and MEK (Mitogen-activated Protein Kinase) inhibitors. METHODS: observational case report and literature review. RESULTS: a 37-year-old woman affected by cutaneous melanoma on BRAF and MEK inhibitors developed visual symptoms in the right eye simultaneously with a SARS-COV-2 infection. The right eye visual acuity was hand movement, and clinical examination disclosed vitreous cells, yellow-white retinal spots, and macular yellowish material. Fundus autofluorescence and angiograms were consistent with MEWDS. Angiograms, optical coherence tomography, and optical coherence tomography angiography revealed a macular choroidal neovascular membrane. The infectious and inflammatory work-up was negative. Electrodiagnostic tests revealed cone dysfunction. MEWDS resolved and anti-VEGF treatment allowed partial vision recovery. CONCLUSION: the case illustrates the association of MEWDS and choroidal neovascularization developing after COVID-19 infection in the setting of immunotherapy.

Surgical repair and follow-up of chronic 4th degree obstetric perineal tear (total perineal defect) in 2 centres in eastern Africa.

INTRODUCTION AND HYPOTHESIS: Fourth-degree perineal tear occurs in up to 0.2% of vaginal deliveries. In limited resource communities, women often deliver in local villages without facilities to repair obstetric anal sphincter injuries. These fourth-degree tears heal by secondary intention and result in total perineal defects. The aim of the study is to present medium-term follow-up of a large number of women following repair of chronic fourth-degree tear. METHODS: Repairs of chronic obstetric fourth-degree tears were undertaken during surgical camps at Kagando Hospital, Uganda and Selian Hospital, Tanzania, from December 2013 to October 2019. Women completed Cleveland Clinic Incontinence Scores (CCIS) on admission (face to face) and during the 7-year follow-up period (via telephone). RESULTS: Two hundred fourteen women had medical history and CCIS completed on admission. The mean age at presentation was 33.9 years and mean duration of the condition was 8.9 years. Over a third of women stated they suffered social abandonment because of the unrepaired fourth-degree tear. Nearly 45% of women suffered the tear during the first vaginal delivery. At 1-year follow-up, 87% of 101 women scored 0 (perfect continence) and 94% of 66 women had perfect continence at 2 years. Forty-one births occurred during the follow-up period (32 vaginal deliveries) with two recurrences of fourth-degree tear. CONCLUSIONS: Follow-up in limited resource communities is challenging. Short- to medium-term results of women who had repair of total perineal defect (unrepaired fourth-degree obstetric tears) are encouraging.

Prophylactic Autologous Slings at the Time of Obstetric Fistula Repair: A Randomized Clinical Trial.

OBJECTIVE: To compare prophylactic slings for women with obstetric fistulas at high risk of residual incontinence. METHODS: This was a multiple-site randomized controlled trial comparing autologous fascia slings to pubococcygeal (PC) slings at time of fistula repair. Women with a Goh type 3 or 4 vesicovaginal fistula (distal edge of the fistula is ≤2.5 cm from the external urethral orifice) with no prior repair were randomized to receive either a rectus fascia sling or a PC sling while undergoing fistula repair. Interviews were performed before surgery and at follow-up 1 to 6 months later including the Michigan Incontinence Symptom Index and the Incontinence Quality of Life Tool. Pad weights were also collected at this time. Safety analysis was performed after 10 participants were enrolled in each arm. RESULTS: Eleven participants randomized to a PC sling and 10 to a rectus sling. There was 1 repair breakdown in the PC group and 3 in the rectus group. There was no significant difference noted in pad weights or quality of life scores between groups. Quality of life and Michigan Incontinence Symptom Index scores improved significantly for both groups after surgery. The study was terminated at safety analysis due to the number of breakdowns and difficulty of follow-up at 1 site. CONCLUSIONS: There was no superiority between slings. Randomization proved problematic given the vast heterogeneity between fistula injuries. There is a need for an innovative anti-incontinence technique.ClinicalTrials.gov identifier: NCT03236922 https://www.clinicaltrials.gov/ct2/show/NCT03236922?cond=vesico-vaginal+fistula&rank=2.

Intravitreal Aflibercept for Retinal Angiomatous Proliferation: Results of a Prospective Case Series at 96 Weeks.

INTRODUCTION: Retinal angiomatous proliferation (RAP) is a subtype of neovascular age-related macular degeneration (nAMD). Untreated, the lesions are thought to be aggressive and lead to a poor visual outcome. Despite some limitations, studies reporting the treatment of RAP lesions with the intravitreal anti-VEGF drugs ranibizumab and bevacizumab have demonstrated variable but generally favourable responses. More recently, aflibercept has been licensed for the treatment of nAMD and may offer some advantages over other agents. We present the visual and anatomical outcomes at 96 weeks of patients with RAP lesions who were treated with intravitreal aflibercept, according to the pivotal VIEW study nAMD treatment protocol. METHODS: This is a prospective study of treatment-naïve patients with Reading Centre-graded RAP lesions. The patients received aflibercept every 8 weeks, after 3 initial monthly injections, up to and including week 48. During weeks 52-96, patients received injections at least every 12 weeks, with monthly evaluations for interim injections if they fulfilled the retreatment criteria. At each visit, best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) central macular thickness (CMT) were measured. RESULTS: Forty-six patients reached study completion at week 96. Mean BCVA had improved by 6.0 (standard deviation [SD] 7.9) and 4.8 (SD 7.4) ETDRS letters at 52 (p = 0.003) and 96 (p = 0.02) weeks, respectively, from a baseline of 57.3 (SD 12.0) letters. At 52- and 96-week time points, 45/46 (98%) and 41/46 (89%) of patients, respectively, had maintained their vision (<15 letters of BCVA lost). At the 96-week time point, 13/46 (28%) of patients had gained ≥15 letters and also demonstrated a mean reduction in CMT of 162 µm (SD 106) (p = <0.0001), with 72% of maculae being fluid-free. Using univariate analysis, we found no significant difference between any of the visual outcome measures in this study and the pivotal VIEW study; the mean number of injections required and change in CMT were also similar. CONCLUSIONS: In this study, we present the 96-week results, of the largest series to date, of patients treated prospectively with aflibercept for RAP using the VIEW protocol. We show that they benefited from treatment to a degree similar to those with type 1 and 2 nAMD.

A case of ocular cystinosis associated with two potentially severe CTNS mutations.

BACKGROUND: Ocular cystinosis is a rare autosomal recessive disorder caused by one severe and one mild mutation in the CTNS gene. It is characterised by cystine deposition within the cornea and conjunctiva however, the kidneys are not affected. We report a case of ocular cystinosis caused by two potentially severe CTNS mutations and discuss the possible mechanism of renal sparing. METHODS: This is an observational case report of the proband and her unaffected relatives. All subjects underwent ophthalmic examination, whilst in the proband, In vivo laser scanning confocal microscopy was used to demonstrate cystine crystals within her corneas and conjunctiva. Genetic diagnosis was confirmed by DNA sequencing of the proband and the segregation of the mutations was established in her relatives. RT-PCR of leukocyte RNA was undertaken to determine if aberrant splicing of the CTNS gene was taking place Results: The proband was found to have cystine crystals limited to the anterior corneal stroma and the conjunctiva. Sequencing of the proband's CTNS gene found her to be a compound heterozygote for a 27bp deletion in exon8/intron 8 (c.559_561 + 24del) and a novel c.635C>T variant in exon 9 that is predicted be pathogenic and to result in the substitution of alanine with valine at amino acid position 212 (p.Ala212Val), which is within the 3rd transmembrane spanning domain of the CTNS protein. Examination of the proband's leukocyte RNA failed to demonstrate any aberrant CTNS gene splicing. CONCLUSION: We present a case of ocular cystinosis caused by two potentially severe CTNS gene mutations. The lack of renal involvement may be due to localised (ocular) aberrant CTNS RNA splicing.

Out of the shadows and 6000 reasons to celebrate: An update from FIGO's fistula surgery training initiative.

Obstetric fistula is a devastating childbirth injury caused by unrelieved obstructed labor. Obstetric fistula leads to chronic incontinence and, in most cases, significant physical and emotional suffering. The condition continues to blight the lives of 1-2 million women in low-resource settings, with 50 000-100 000 new cases each year adding to the backlog. A trained, skilled fistula surgeon is essential to repair an obstetric fistula; however, owing to a global shortage of these surgeons, few women are able to receive life-restoring treatment. In 2011, to address the treatment gap, FIGO and partners released the Global Competency-Based Fistula Surgery Training Manual, the first standardized curriculum to train fistula surgeons. To increase the number of fistula surgeons, the FIGO Fistula Surgery Training Initiative was launched in 2012, and FIGO Fellows started to enter the program to train as fistula surgeons. Following a funding boost in 2014, the initiative has grown considerably. With 52 fellows involved and a new Expert Advisory Group in place, the program is achieving major milestones, with a record-breaking number of fistula repairs performed by FIGO Fellows in 2017, bringing the total number of repairs since the start of the project to more than 6000.

Cataract surgery in patients with late-onset retinal degeneration.

PURPOSE: To review the outcomes in a series of patients with long anterior lens zonular fibers associated with late-onset retinal degeneration who had phacoemulsification cataract surgery. SETTING: Newcastle Eye Centre, Newcastle upon Tyne, United Kingdom. DESIGN: Retrospective case series. METHODS: Inclusion criteria were patients with genetically confirmed late-onset retinal degeneration requiring cataract surgery. Perioperative data relating to surgery were collected. In addition, the corrected distance visual acuity (CDVA) and retinal imaging data were recorded. Selected lens capsules were examined using immunohistochemistry or scanning electron microscopy (SEM). RESULTS: Eleven eyes of 7 patients were included. The long anterior lens zonular fibers made capsulorhexis challenging; however, it was completed safely in all cases. There were no intraoperative or postoperative issues with lens stability. The CDVA improved postoperatively in those cases with intact foveal photoreceptors and retinal pigment epithelium. Over the longer term, the CDVA slowly declined because of progressive atrophy of the macula. Most patients noticed a subjective improvement in vision, even those with advanced disease at baseline. Immunohistochemistry showed that the C1QTNF5 protein was expressed within the lens capsule epithelial cells, although SEM of the long anterior lens zonular fibers showed them to be smaller in diameter than normal anterior lens zonular fibers and to be composed of a helix of fibers. CONCLUSIONS: In this small series of patients with late-onset retinal degeneration, cataract surgery was successfully performed without long-term complications involving intraocular lens stability. The objective improvement in CDVA seemed to be limited to patients with good foveal photoreceptor architecture.

Natural history and effect of therapeutic interventions on subretinal fluid causing foveal detachment in macular telangiectasia type 2.

AIM: To report the natural history of subretinal fluid (SRF) causing foveal detachment in macular telangiectasia type 2 (MacTel) and our experience of therapeutic intervention with intravitreal steroids or antivascular endothelial growth factor inhibitor (anti-VEGF) agents in some cases. METHODS: Retrospective case series. Three of the MacTel study's largest registries were searched to identify eyes with foveal detachment. RESULTS: We identified 7 eyes from 6 exclusively female patients. The prevalence of foveal detachment was low, present in 1.4% of the assessed MacTel population. Age at presentation ranged from 50 to 66 years. Follow-up ranged from 2 to 8 years. There was late-phase leakage on fluorescein angiography from what was presumed to be ectatic capillaries. The SRF fluctuated without a rapid decline in visual acuity in cases that were not treated. When they were, intravitreal anti-VEGF and steroid therapy in general reduced SRF, at least temporarily, but did not halt the gradual long-term decrease in visual acuity. In one case, optical coherence tomography angiography showed significant reduction in the extent of the predominantly deep intraretinal vascular complex 1 month after anti-VEGF therapy. DISCUSSION AND CONCLUSIONS: As the natural history of this unusual MacTel phenotype is not characterised by rapid visual decline, intervention with intravitreal anti-VEGF or steroid therapy may not be necessary.

Parity as a predictor of obstetric fistula classification.

INTRODUCTION AND HYPOTHESIS: Obstetric fistulas are injuries to the genital tract in women without emergency obstetric services. Parity may predict the characteristics of fistulas that affect closure success and residual incontinence. Circumferential fistulas may predispose patients to postoperative incontinence. We hypothesized that primiparous women have more distal fistulas than multiparous women, leading to more scarring and circumferential fistulas. METHODS: A retrospective observational study was conducted on 1,856 women with obstetric fistula evaluated at three sites by three providers. Fistulas were classified using the Goh classification system. Women aged 10 to 55 years were classified as primiparas or multiparas. Analysis by parity of fistula type and size, degree of scarring, and presence of circumferential defect used the Chi squared or Fisher's exact test, and binary logistic regression. RESULTS: Of the 1,841 (99.2 %) women included, 878 (47.7 %) were primiparas and 963 (52.3 %) were multiparas. Primiparas were more likely to have distal fistulas, type 4 being most common (31.5 %), whereas multiparas were more likely to have proximal fistulas, most commonly type 1 (48.1 %). Primiparas were more likely to have moderate to severe scarring (11.7 % vs 5.6 %; p < 0.001), and category III (57.1 % vs 39.2 %; p < 0.001), but not to develop circumferential fistulas (5.6 % vs 4.0 %; p = 0.127), be present for repeat surgery (7.1 % vs 7.6 %; p = 0.721), or have ureteric involvement (1.5 % vs 2.2 %; p = 0.301). Multivariate analyses confirmed increased risk with primiparity for distal fistula and scarring. CONCLUSIONS: As hypothesized, primiparas were more likely to have distal fistulas and more scarring, but were not more likely to have circumferential fistulas. Surgeons should plan accordingly.

Characteristics, management, and outcomes of repair of rectovaginal fistula among 1100 consecutive cases of female genital tract fistula in Ethiopia.

OBJECTIVE: To characterize the incidence, presentation, management, and outcomes of rectovaginal fistula (RVF) in Ethiopia. METHODS: In a retrospective study, demographic and clinical data were obtained for all women with genital tract fistulas admitted to the Barhirdar Hamlin Fistula Hospital, Ethiopia, for fistula repair surgery between January 2005 and October 2008. RESULTS: Of 1100 cases, 1057 were suitable for analysis. Vesicovaginal fistula (VVF) without RVF was present in 933 (88.3%) cases, combined VVF and RVF in 79 (7.5%), and isolated RVF in 45 (4.3%). Only 4 (0.4%) women had isolated RVFs that could be attributed to prolonged obstructed labor; the remaining 41 RVFs were due to trauma (including sexual trauma), iatrogenic causes, infection, perineal tears, or previous failed repairs. All RVFs were managed with a flap-splitting operative technique, without grafts or diverting colostomies. Overall, 120 (98.4%) of 122 RVFs repaired at the study hospital remained closed at discharge. Combined VVF and RVF was associated with a longer labor (P<0.001), more stillbirths (P=0.028), a larger and lower VVF (P<0.001 for both), and more vaginal scarring than was isolated VVF (P<0.001). CONCLUSION: An obstetric RVF represents a more severe injury process than does a VVF. RVFs rarely occur without a VVF if due to obstructed labor. However, they can be managed successfully without diverting colostomies or grafts.

Comparison of choroidal and retinal endothelial cells: characteristics and response to VEGF isoforms and anti-VEGF treatments.

Neovascular eye diseases such as wet age-related macular degeneration and proliferative diabetic retinopathy are two of the most common causes of irreversible visual loss. Although mediated by vascular endothelial growth factor (VEGF), the mechanisms of these diseases are not fully understood. Molecular inhibitors of VEGF including pegaptanib, ranibizumab and bevacizumab are used as treatments for these diseases. However, there have been very few direct comparisons between these agents, and as dose and treatment regimes differ their relative efficacies are hard to determine. In vitro comparisons tend to use cells from different sites or species, which show heterogeneity in their responses. The aim of this study was to compare the characteristics of primary cultures of isolated human choroidal endothelial cells (hCEC) and retinal endothelial cells (hREC), and their proliferation responses to stimulation with VEGF 121 and 165, and to compare the anti-proliferative effects of these three drugs. hCEC and hREC were positive for the cell markers VEGFR1, VEGFR2, CD31, CD34 and von Willebrand's factor (vWF), with greater expression of CD34 on the hREC compared to hCEC. Contrary to previous assumptions VEGF isoforms 121 and 165 were found to be equally potent in stimulating endothelial cell proliferation. However, hREC exhibited higher proliferation with either VEGF isoform compared to hCEC. The anti-VEGF treatments ranibizumab and bevacizumab were effective in decreasing proliferation of hCEC induced by the two VEGF isoforms, individually and in combination, with ranibizumab being moderately more effective, particularly in hREC. Pegaptanib was effective in controlling the proliferation of hCEC stimulated by VEGF 165, but was ineffective against the stimulatory effect of VEGF 121. There were found to be significant differences in microvascular endothelial cells from the retina and choroid, both in the expression of cell markers and their behaviour in response to growth factors and currently available anti-VEGF agents, highlighting the importance of targeting treatments to specific intraocular vascular beds and/or diseases.

The relationship between female genital cutting and obstetric fistulae.

OBJECTIVE: To evaluate any association between female genital cutting and vesicovaginal fistula formation during obstructed labor. METHODS: A comparison was made between 255 fistula patients who had undergone type I or type II female genital cutting and 237 patients who had not undergone such cutting. Women were operated on at the Barhirdar Hamlin Fistula Centre in Ethiopia. Data points used in the analysis included age; parity; length of labor; labor outcome (stillbirth or not); type of fistula; site, size, and scarring of fistula; outcomes of surgery (fistula closed; persistent incontinence with closed fistula; urinary retention with overflow; site, size, and scarring of any rectovaginal fistula; and operation outcomes), and specific methods used during the operation (use of a graft or not, application of a pubococcygeal or similar autologous sling, vaginoplasty, catheterization of ureters, and flap reconstruction of vagina). Primary outcomes were site of genitourinary fistula and persistent incontinence despite successful fistula closure. RESULTS: The only statistically significant differences between the two groups (P=.05) were a slightly greater need to place ureteral catheters at the time of surgery in women who had not undergone a genital cutting operation, a slightly higher use of a pubococcygeal sling at the time of fistula repair, and a slightly longer length of labor (by 0.3 day) in women who had undergone genital cutting. CONCLUSION: Type I and type II female genital cutting are not independent causative factors in the development of obstetric fistulae from obstructed labor.

Interobserver agreement for the detection of optical coherence tomography features of neovascular age-related macular degeneration.

PURPOSE: To investigate the interobserver agreement for the detection of optical coherence tomography (OCT) features of disease activity in patients with neovascular age-related macular degeneration (nAMD). METHODS: This was a cross-sectional agreement study in which grading of OCT line scans from patients with nAMD was conducted by two retinal specialists before the patients received treatment. Scans were graded for the presence of features of nAMD disease activity (intraretinal cysts [IRC], subretinal fluid [SRF], diffuse retinal edema [DRE], retinal pigment epithelial detachment [PED], and subretinal tissue [SRT]). RESULTS: Although scans from 78 patients were available for analysis, five patients were excluded because of a mean signal strength of <7. Two hundred seventy-eight line scans were analyzed from 73 patients (40 with cross-hair scan sets and 33 with radial line scan sets). Agreement for per line scan analysis was 77% for IRC (kappa = 0.41), 81% for SRF (kappa = 0.62), 91% for macular fluid (kappa = 0.28), 79% for DRE (kappa = 0.10), 90% for PED (kappa = 0.78), and 79% for SRT (kappa = 0.53). Both observers disagreed regarding the presence of macular fluid in one patient (with a cross-hair scan). CONCLUSIONS: Interpretation of OCT line scans from patients with nAMD is subject to interobserver variability. However, when all line scans acquired are examined for the presence of fluid (IRC or SRF), there is a high level of agreement for the detection of macular fluid on a per patient basis.

Predicting the risk of failure of closure of obstetric fistula and residual urinary incontinence using a classification system.

The aim of this study is to assess the possibility of predicting the risk of failure of closure and post-fistula urinary incontinence. Women attending the fistula clinics were assessed pre-operatively, and fistulae were staged prospectively, using a previously published classification system. Assessment for fistula closure and residual urinary incontinence was performed, prior to discharge. Of the 987 women who were assessed, 960 had successful closure of their fistulae. Of those with successful closure, 229 complained of urinary incontinence following surgery. Women with fistulae located closest to the external urinary meatus had the highest rate of urinary incontinence following fistula closure. Women with significant vaginal scarring and circumferential fistulae also had significantly higher rates of urinary incontinence and higher risk of failure of closure. The classification used is able to predict women at risk of post-fistula urinary incontinence and failure of closure.

Duration of bladder catheterization after surgery for obstetric fistula.

OBJECTIVE: To compare the surgical outcome at discharge and at 6-months follow up in patients who underwent repair of obstetric fistulae with postoperative bladder catheterization for 10, 12, or 14 days. METHODS: A retrospective study of 212 obstetric fistula patients who underwent repair with postoperative bladder catheterization for 10 days (group 1), 12 days (group 2), and 14 days (group 3) at the Bahir Dar Hamlin Fistula Center in Ethiopia. Fistulas were classified according to Goh's system. RESULTS: There were 68 women (32%) in group 1, 62 women (29%) in group 2, and 82 women (39%) in group 3. There was a significant difference in the extent of urethral involvement, fistula size, and degree of vaginal scarring among the 3 groups, with the more extensively damaged patients catheterized for longer. Breakdown of repair was seen in 1.5% of patients in group 1, none in group 2, and 2% in group 3 (P=0.47). CONCLUSION: Postoperative catheterization for 10 days may be sufficient for management of less complicated obstetric vesicovaginal fistulae.