Search

Background Eyes sustaining open globe trauma are at high risk of severe visual impairment. Proliferative vitreoretinopathy is the most common cause of retinal detachment and visual loss in eyes with open globe trauma. There is evidence from experimental studies and pilot clinical trials that the use of adjunctive steroid medication triamcinolone acetonide can reduce the incidence of proliferative vitreoretinopathy and improve outcomes of surgery for open globe trauma. Objective The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study aimed to investigate the clinical effectiveness of adjunctive triamcinolone acetonide given at the time of vitreoretinal surgery for open globe trauma. Design A phase 3 multicentre double-masked randomised controlled trial randomising patients undergoing vitrectomy following open globe trauma to either adjunctive triamcinolone acetonide or standard care. Setting Hospital vitreoretinal surgical services dealing with open globe trauma. Participants Patients undergoing vitrectomy surgery who had sustained open globe trauma. Interventions Triamcinolone acetonide 4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s or standard vitreoretinal surgery and postoperative care. Main outcome measures The primary outcome was the proportion of patients with at least 10 letters of improvement in corrected visual acuity at six months. Secondary outcomes included retinal detachment secondary to proliferative vitreoretinopathy, retinal reattachment, macula reattachment, tractional retinal detachment, number of operations, hypotony, elevated intraocular pressure and quality of life. Health-related quality of life was assessed using the EuroQol Five Domain and Visual Function Questionnaire 25 questionnaires. Results A total of 280 patients were randomised; 129 were analysed from the control group and 130 from the treatment group. The treatment group appeared, by chance, to have more severe pathology on presentation. The primary outcome (improvement in visual acuity) and principal secondary outcome (change in visual acuity) did not demonstrate any treatment benefit for triamcinolone acetonide. The proportion of patients with improvement in visual acuity was 47% for triamcinolone acetonide and 43% for standard care (odds ratio 1.03, 95% confidence interval 0.61 to 1.75, p = 0.908); the baseline adjusted mean difference in the six-month change in visual acuity was –2.65 (95% confidence interval –9.22 to 3.92, p = 0.430) for triamcinolone acetonide relative to control. Similarly, the secondary outcome measures failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal reattachment and stable macular retinal reattachment, outcomes for the treatment group were significantly worse for triamcinolone acetonide at the 5% level (respectively, odds ratio 0.59, 95% confidence interval 0.36 to 0.99, p = 0.044 and odds ratio 0.59, 95% confidence interval 0.35 to 0.98, p = 0.041) compared with control in favour of control. The cost of the intervention was £132 per patient. Health economics outcome measures (Early Treatment Diabetic Retinopathy Study, Visual Function Questionnaire 25 and EuroQol Five Dimensions) did not demonstrate any significant difference in quality-adjusted life-years. Conclusions The use of combined intraocular and sub-Tenon’s capsule triamcinolone acetonide is not recommended as an adjunct to vitrectomy surgery for intraocular trauma. Secondary outcome measures are suggestive of a negative effect of the adjunct, although the treatment group appeared to have more severe pathology on presentation. Future work The use of alternative adjunctive medications in cases undergoing surgery for open globe trauma should be investigated. Refinement of clinical grading and case selection will enable better trail design for future studies. Trial registration This trial is registered as ISRCTN 30012492, EudraCT number 2014-002193-37, REC 14/LNO/1428, IRAS 156358, Local R&D registration CHAD 1031. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (12/35/64) and will be published in full in Health Technology Assessment; Vol. 27, No. 12. See the NIHR Journals Library website for further project information. Plain language summary Despite advances in surgical techniques, eye trauma remains a leading cause of blindness and visual impairment. The main cause of trauma is a scarring process within the eye – proliferative vitreoretinopathy. There is good evidence from laboratory work and small-scale clinical studies that the addition of a steroid medication, triamcinolone acetonide, given in and around the eye at the time of surgery for eye trauma, can reduce the incidence of proliferative vitreoretinopathy scarring and improve the outcomes of surgery. The Adjunctive Steroid Combination in Ocular Trauma or ASCOT study was a multicentre clinical trial designed to test the use of triamcinolone acetonide as an addition to surgery to improve outcomes in eyes with ‘open globe’ penetrating injuries. A total of 280 patients were recruited and randomised to receive standard surgery or surgery with the additional steroid (triamcinolone acetonide). No benefit was found from the addition of the steroid medication. The addition of steroid medication was not good value for money. Secondary outcome measures suggested that triamcinolone acetonide may have had a negative effect on outcomes, although this may have been due to the presence of more severe cases amongst the patients allocated to receive the additional steroid (triamcinolone acetonide). The use of adjunctive triamcinolone acetonide in eye trauma cases undergoing surgery is therefore not recommended. Future studies with different additional medications and/or more targeted case selection are indicated to improve outcomes for eyes experiencing penetrating trauma. Scientific summary Background Eyes sustaining penetrating or open globe trauma (OGT) are a group at high risk of severe visual impairment. Retinal detachment (RD) is common in these eyes and multiple surgical interventions are often necessary. Proliferative vitreoretinopathy (PVR) is the most common cause of recurrent RD and visual loss in eyes, with OGT occurring in 10–45% of cases. There is good evidence from experimental, preclinical studies and pilot clinical trials that the use of adjunctive steroid medication, in particular triamcinolone acetonide (TA), can reduce the incidence of PVR and improve outcomes of surgery for OGT. Objective The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) study aimed to investigate the clinical effectiveness of adjunctive TA given at the time of vitreoretinal surgery for OGT. This included analysis of the economic and quality of life benefits of the adjunctive treatment. From an NHS perspective, to explore the incremental cost-effectiveness of TA and to explore the cost per quality-adjusted life-year (QALY) of adjunctive TA in vitreoretinal surgery for OGT to determine whether this falls below the National Institute of Health and Care Excellence threshold of £20,000–30,000 per QALY. Methods A phase 3 multicentre double-masked randomised controlled clinical trial randomising patients undergoing vitrectomy following OGT to either adjunctive TA (4 mg/0.1 ml into the vitreous cavity and 40 mg/1 ml sub-Tenon’s) or standard care. Inclusion criteria were as follows: 1.adult subjects (aged 18 years or over at the time of enrolment) 2.full thickness, open globe ocular trauma undergoing vitrectomy 3.ability to give written informed consent 4.willingness to accept randomisation and attend follow-up for six months. Patients were recruited prior to vitrectomy surgery and randomised at the completion of surgery. The primary outcome was to determine whether adjunctive intraocular and periocular steroid (TA) improves visual acuity (VA) at six months compared with standard treatment in eyes undergoing vitreoretinal surgery for OGT. This was defined as the proportion of patients with at least 10 letters of improvement in corrected VA on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at six months. Secondary outcomes were to determine whether adjunctive intraocular and periocular steroid (TA) influences the development of scarring (PVR), RD (stable complete retinal and macular reattachment), intraocular pressure abnormalities and other complications in eyes undergoing surgery for OGT. In addition, to assess the effects of treatment on quality of life measured using the EuroQol Five Dimensions (EQ-5D) questionnaire and the Visual Function Questionnaire-25 (VFQ-25) tools. The study sample size was calculated from previously published work and two non-randomised trials carried out by the investigators. Based on previous studies, to detect a 19% increase in the proportion of patients with clinically meaningful improvement in VA [from 55% to 74%, corresponding to an odds ratio (OR) of 2.33], with an allowance for an estimated 7% dropout rate, the target sample size was 300 patients (150 per study arm). The main analysis followed the intention-to-treat principle and was conducted subgroup blind (i.e. as group A vs. group B) in accordance with the prespecified ASCOT statistical analysis plan. The primary analysis model consisted of a mixed logistic model with change in VA (

Ocular angiogenesis and macular oedema are major causes of sight loss across the world. Aberrant neovascularisation, which may arise secondary to numerous disease processes, can result in reduced vision as a result of oedema, haemorrhage, and scarring. The development of antivascular endothelial growth factor (anti-VEGF) agents has revolutionised the treatment of retinal vasogenic conditions. These drugs are now commonly employed for the treatment of a plethora of ocular pathologies including choroidal neovascularisation, diabetic macular oedema, and retinal vein occlusion to name a few. In this paper, we will explore the current use of anti-VEGF in a variety of retinal diseases and the impact that these medications have had on visual outcome for patients.

Ocriplasmin is a protease which has been approved for the treatment of symptomatic vitreomacular adhesion (VMA). A 63-year-old presented with blurred vision in the left eye and a best corrected visual acuity of 6/18. Optical coherence tomography revealed VMA with an underlying macular hole and she subsequently underwent a left intravitreal ocriplasmin injection. One week after the injection, VMA had been released but with enlargement of the macular hole and a drop in her BCVA to 6/60. This persisted at 1 month after the injection. It is important to warn patients that ocriplasmin may lead to an enlargement of their macular hole with resultant loss in visual acuity.

A 74-year-old man developed sudden onset of painless persistent partial loss of vision in the right eye 3 days after right total knee replacement. The initial investigation was for amaurosis fugax with a normal CT scan of the brain but the carotid Doppler confirmed >90% stenosis of the right internal carotid artery. Urgent ophthalmological review confirmed anterior ischaemic optic neuropathy. Subsequently, he lost his vision completely in the right eye. He had a previous high risk hemispheric transient ischaemic attack with carotid Doppler reported as normal.

The protein IF1 limits mitochondrial ATP consumption when mitochondrial respiration is impaired by inhibiting the 'reverse' activity of the F(1)F(o)-ATPsynthase. We have found that IF1 also increases F(1)F(o)-ATPsynthase activity in respiring mitochondria, promoting its dimerization and increasing the density of mitochondrial cristae. We also noted that IF1 overexpression was associated with an increase in mitochondrial volume fraction that was conversely reduced when IF1 was knocked down using small interfering RNA (siRNA). The volume change did not correlate with the level of transcription factors involved in mitochondrial biogenesis. However, autophagy was dramatically increased in the IF1siRNA treated cells (-IF1), assessed by quantifying LC3-GFP translocation to autophagosomes, whilst levels of autophagy were low in IF1 overexpressing cells (+IF1). The increase in LC3-GFP labelled autophagosomes in -IF1 cells was prevented by the superoxide dismutase mimetic, manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP). An increase in the basal rate of generation of reactive oxygen species (ROS) in -IF1 cells was demonstrated using the fluorescent probe dihydroethidium (DHE). Thus, IF1 appears to limit mitochondrial ROS generation, limiting autophagy which is increased by IF1 knockdown. Variations in IF1 expression level may therefore play a significant role in defining both resting rates of ROS generation and cellular mitochondrial content.

When mitochondrial respiration is compromised, the F(1)F(o)-ATP synthase reverses and consumes ATP, serving to maintain the mitochondrial membrane potential (Delta psi(m)). This process is mitigated by IF(1). As little is known of the cell biology of IF(1), we have investigated the functional consequences of varying IF(1) expression. We report that, (1) during inhibition of respiration, IF(1) conserves ATP at the expense of Delta psi(m); (2) overexpression of IF(1) is protective against ischemic injury; (3) relative IF(1) expression level varies between tissues and cell types and dictates the response to inhibition of mitochondrial respiration; (4) the density of mitochondrial cristae is increased by IF(1) overexpression and decreased by IF(1) suppression; and (5) IF(1) overexpression increases the formation of dimeric ATP synthase complexes and increases F(1)F(o)-ATP synthase activity. Thus, IF(1) regulates mitochondrial function and structure under both physiological and pathological conditions.