Richard M H Lee

Opaque intraocular lens implantation: a case series and lessons learnt

Purpose To report the use of opaque intraocular devices in three patients with complex neuro-ophthalmic symptoms. Methods A case series of three patients with neuro-ophthalmic symptoms requiring occlusion of one eye when alternative methods had failed to control symptoms. Morcher (Stuttgart, Germany) opaque intraocular implants were used in all patients. Results All three patients observed an improvement in symptoms following opaque intraocular device implantation. One patient (Case 2) required multiple devices for symptom relief. Conclusion Opaque intraocular occlusive devices are an increasingly popular choice for clinicians in patients with intractable diplopia but we highlight their use in patients with other complex neuro-ophthalmic symptoms. We learned a number of useful lessons in these patients as summarized in this case series.

Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5u2009μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (Pu2009<u20090.0005) and 33% (Pu2009<u20090.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues.

Macular grid laser photocoagulation for branch retinal vein occlusion

BACKGROUNDnBranch retinal vein occlusion (BRVO) is the second most common cause of retinal vascular abnormality after diabetic retinopathy. Persistent macular oedema develops in 60% of eyes with a BRVO. Untreated, only 14% of eyes with chronic macular oedema will have a visual acuity (VA) of 20/40 or better. Macular grid laser photocoagulation is used for chronic non-ischaemic macular oedema following BRVO and has been the mainstay of treatment for over 20 years. New treatments are available and a systematic review is necessary to ensure that the most up-to-date evidence is considered objectively.nnnOBJECTIVESnTo examine the effects of macular grid laser photocoagulation in the treatment of macular oedema following BRVO.nnnSEARCH METHODSnWe searched CENTRAL, Ovid MEDLINE, EMBASE, Web of Science Conference Proceedings Citation Index, the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 August 2014.nnnSELECTION CRITERIAnWe included randomised controlled trials (RCTs) comparing macular grid laser photocoagulation treatment to another treatment, sham treatment or no treatment.nnnDATA COLLECTION AND ANALYSISnWe used standard methodological procedures expected by Cochrane.nnnMAIN RESULTSnWe included five studies conducted in Europe and North America. Four separate trials compared grid laser to no treatment, sham treatment, intravitreal bevacizumab and intravitreal triamcinolone. One further trial compared subthreshold to threshold laser. Two of these trials were judged to be at high risk of bias in one or more domains.In one trial of grid laser versus observation, people receiving grid laser were more likely to gain visual acuity (VA) (10 or more ETDRS letters) at 36 months (RR 1.75, 95% confidence interval (CI) 1.08 to 2.84, 78 participants, moderate-quality evidence). The effect of grid laser on loss of VA (10 or more letters) was uncertain as the results were imprecise (RR 0.68, 95% CI 0.23 to 2.04, 78 participants, moderate-quality evidence). On average, people receiving grid laser had better improvement in VA (mean difference (MD) 0.11 logMAR, 95% CI 0.05 to 0.17, high-quality evidence). In a trial of early and delayed grid laser treatment versus sham laser (n = 108, data available for 99 participants), no participant gained or lost VA (15 or more ETDRS letters). At 12 months, there was no evidence for a difference in change in VA (from baseline) between early grid laser and sham laser (MD -0.03 logMAR, 95% confidence interval (CI) -0.07 to 0.01, 68 participants, low-quality evidence) or between delayed grid laser and sham laser (MD 0.00, 95% CI -0.04 to 0.04, 66 participants, low-quality evidence).The relative effects of subthreshold and threshold laser were uncertain. In one trial, the RR for gain of VA (15 or more letters) at 12 months was 1.68 (95% CI 0.57 to 4.95, 36 participants, moderate-quality evidence); the RR for loss of VA (15 or more letters) was 0.56 (95% CI 0.06 to 5.63, moderate-quality evidence); and at 24 months the change in VA from baseline was MD 0.07 (95% CI -0.10 to 0.24, moderate-quality evidence).The relative effects of macular grid laser and intravitreal bevacizumab were uncertain. In one trial, the RR for gain of 15 or more letters at 12 months was 0.67 (95% CI 0.39 to 1.14, 30 participants, low-quality evidence). Loss of 15 or more letters was not reported. Change in VA at 12 months was MD 0.11 logMAR (95% CI -0.36 to 0.14, low-quality evidence).The relative effects of grid laser and 1mg triamcinolone were uncertain at 12 months. RR for gain of VA (15 or more letters) was 1.13 (95% CI 0.75 to 1.71, 1 RCT, 242 participants, moderate-quality evidence); RR for loss of VA (15 or more letters) was 1.20 (95% CI 0.63 to 2.27, moderate-quality evidence); MD for change in VA was -0.03 letters (95% CI -0.12 to 0.06, moderate-quality evidence). Similar results were seen for the comparison with 4mg triamcinolone. Beyond 12 months, the visual outcomes were in favour of grid laser at 24 months and 36 months with people in the macular grid group gaining more VA.Four studies reported on adverse effects. Laser photocoagulation appeared to be well tolerated in the studies. One participant (out of 71) suffered a perforation of Bruchs membrane, but this did not affect visual acuity.nnnAUTHORS CONCLUSIONSnModerate-quality evidence from one RCT supports the use of grid laser photocoagulation to treat macular oedema following BRVO. There was insufficient evidence to support the use of early grid laser or subthreshold laser. There was insufficient evidence to show a benefit of intravitreal triamcinolone or anti-vascular endothelial growth factor (VEGF) over macular grid laser photocoagulation in BRVO. With recent interest in the use of intravitreal anti-VEGF or steroid therapy, assessment of treatment efficacy (change in visual acuity and foveal or central macular thickness using optical coherence tomography (OCT)) and the number of treatments needed for maintenance and long-term safety will be important for future studies.

Suturing techniques and postoperative management in penetrating keratoplasty in the United Kingdom

Aims To report on the suturing techniques and aspects of postoperative management in penetrating keratoplasty in the United Kingdom. Methods A postal questionnaire was sent to 137 ophthalmic consultants identified from a Royal College of Ophthalmology database as having a special interest in anterior segment surgery. The questionnaire surveyed surgeon preferences for surgical and suturing technique for penetrating keratoplasty surgery, and the postoperative care of corneal grafts. Results In all, 68% of questionnaires were completed and returned: 73% of respondents used a Flieringa ring or equivalent, 94% routinely used cardinal sutures, with 50.5% removing them at the end of the procedure. The most common suturing technique for routine penetrating keratoplasty was a single continuous suture (35%). In these cases, a 10/0 nylon suture was used by 89%. Sixty-six percent changed their technique in high-risk cases, 52% used a 3-1-1 knot, and 75% made a distinction between a reef and granny knot, with 76% using a reef. Thirty percent buried the knots within the donor material, and 29% within the host tissue. Twenty-five percent had no routine time for graft suture removal, but 41% removed them between 1 and 2 years post-surgery. After suture removal, 98% used steroids and 88% used topical antibiotics. Thirty-four percent stopped topical steroids before suture removal, with 38% stopping topical steroids more than 3 months prior to suture removal. Conclusion This survey demonstrates that there is considerable variation in suturing techniques and postoperative care for penetrating keratoplasty. These significant variations in practice need to be considered when interpreting outcomes and research.

Black-on-clear piggyback technique for a black occlusive intraocular device in intractable diplopia

Black occlusive intraocular devices have been used successfully for intractable binocular diplopia. We describe a novel technique of implanting both a black occlusive device and a clear poly(methyl methacrylate) intraocular lens (IOL) in the capsular bag during phacoemulsification surgery. If the need should arise at a later date, this approach will allow safer and easier explantation of the black occlusive device, avoiding the need for IOL exchange.

Optical functional performance of the osteo-odonto-keratoprosthesis

Purpose: The aim of this study was to evaluate optical and visual functional performance of the osteo-odonto-keratoprosthesis (OOKP). Methods: Optical design and analysis was performed with customized optical design software. Nine patients with implanted OOKP devices and 9 age-matched control patients were assessed. Contrast sensitivity was assessed and glare effect was measured with a brightness acuity test. All OOKP patients underwent kinetic Goldmann perimetry and wavefront aberrometry and completed the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). Results: Optical analysis showed that the optical cylinder is near diffraction-limited. A reduction in median visual acuity (VA) with increasing glare settings was observed from 0.04 logMAR (without glare) to 0.20 logMAR (with glare at “high” setting) and significantly reduced statistically when compared with the control group at all levels of glare (P < 0.05). Contrast sensitivity was significantly reduced when compared with age-matched controls at medium and high spatial frequencies (P < 0.05). Median Goldmann perimetry was 65 degrees (interquartile range, 64–74 degrees; V-4e isopters) and 69 degrees excluding 2 glaucomatous subjects. Several vision-related NEI VFQ-25 subscales correlated significantly with VA at various brightness acuity test levels and contrast sensitivity at medium spatial frequencies, including dependency, general vision, near activities and distance activities. Conclusions: The OOKP optical cylinder provides patients with a good level of VA that is significantly reduced by glare. We have shown in vivo that updates to the optical cylinder design have improved the patients field of view. Reduction of glare and refinement of cylinder alignment methods may further improve visual function and patient satisfaction.

A possible strategy for implanting blue-blocking intraocular lenses

Editor, A ge-related macular degeneration (AMD) is said to be associated with sunlight exposure. This is supported by some epidemiological studies but not others. Epidemiological studies have also shown AMD progression following cataract surgery (Cuthbertson et al. 2009). Lipofuscin is considered a biomarker for cellular ageing and oxidative damage with one fluorophore A2E found in the retinal pigment epithelium (RPE) with peak sensitivity of short wavelength. It is thought to be an important mediator of AMD progression generating reactive oxygen species on photoexcitation and being phototoxic to RPE cells in culture (Algvere et al. 2006). Short wavelength light is absorbed by the ageing crystalline lens and this protective effect is lost following cataract surgery, likely resulting in cellular damage as a result (Algvere et al. 2006). Experimental studies showing the protective nature of a yellow intraocular lens (IOL) against radiation damage between 400 and 500 nm and the peak blue-light hazard of wavelengths at 435–440 nm (ICNIRP 1997) support this hypothesis (Cuthbertson et al. 2009). However the data is experimental and with conflicting evidence from epidemiological studies, the role of sunlight exposure in AMD remains inconclusive. In the 1980s, patients undergoing phacoemulsification surgery were given protection against radiation of wavelengths below 400 nm with clear UVR-blocking IOLs but not the bluelight hazard. Considering the experimental (Ham et al. 1976) and the epidemiological evidence that blue light induces damage in the retina, it is rational to implant a yellow IOL following phacoemulsification surgery, in patients at risk of AMD. However, early theoretical reports suggest yellow IOLs may have an effect on scotopic vision, reducing visual performance and contrast sensitivity when compared to a clear IOL due to blue light absorption. On the other hand, filtering out blue light improves the contrast on the retina in the sense that Rayleigh scattering in the vitreous is inversely proportional to the forth power of the wavelength. With foveal scotopic vision decreasing with age, the loss of blue light in the image caused by yellow IOLs may have an impact on night activities such as walking down stairs. Theoretical comparison between yellow IOLs and a middle aged crystalline lens indicated that the loss of blue light in the image may cause reduced scotopic sensitivity but this may not be clinically significant for scotopic vision and clinical trials with blue blocking IOLs have demonstrated no impact on contrast sensitivity (Cuthbertson et al. 2009). Blue light is said to have a role in the regulation of circadian rhythms which could affect sleep and lead to depression, although it is unclear how clinically relevant this is. Therefore, using clear IOLs with UV filters is also recommended over yellow IOLs further complicating the choice in IOL selection. Ideally, an IOL should have no effect on scotopic sensitivity and circadian rhythm with maximal protective effective against short wavelength phototoxicity. However, each of these scenarios has different peak wavelengths and therefore IOL selection will be a balance of these functions. Thus, clinical trials were not able to demonstrate a negative impact of blue blocking IOLs (Cuthbertson et al. 2009). However, if concern exists one option is to implant a clear IOL in one eye and a yellow IOL in the fellow eye. In a patient with bilateral asymmetrical AMD, we recommend that consideration should be given to implanting the yellow IOL in the eye with less severe disease to minimize AMD progression. The literature reports that most patients do not notice a problem with colour vision having a clear IOL in one eye and a yellow one in the other (Marshall et al. 2005; Algvere et al. 2006). There is only one case report of a patient who required explantation of the yellow IOL due to colour perception problems (Shah & Miller 2005). We anticipate this strategy will help minimize AMD progression and while preserving scotopic vision for patients undergoing cataract surgery if scotopic vision is an issue.

Dimensional and Flow Properties of the EX-PRESS Glaucoma Drainage Device

We read with interest the article by Sheybani et al. demonstrating the assessment of fluid dynamics and flow control between the XEN 45 microfistula implant (AqueSys, Aliso Viejo, CA, USA), EX-PRESS implant (Alcon Laboratories, Inc., Fort Worth, TX, USA), and silicone tubing from a Baerveldt implant (Abbott Medical Optics, Abbott Park, IL, USA). The authors demonstrated that the Hagen-Poiseuille equation can be used to calculate the required dimensions of a tube that would prevent hypotony at average aqueous humour production and that the EX-PRESS device, when placed without a sclera flap, results in hypotony. The article describes the EX-PRESS device to have an opening of 200 lm in inner diameter that tapers to a 50-lm inner lumen. Our group has previously reported our evaluation of the EX-PRESS device. Two device models are available, the P50 and P200, with advertised 50and 200-lm luminal internal diameters (ID), respectively. Esterman et al. previously reported that the resistance to the flow with the EX-PRESS device would decrease by 256 times if the luminal diameter were increased by 4 times, as expected from the HagenPoiseuille equation. However, they only observed a resistance value obtained with the P200 device in the order of 6 to 7 times lower than the P50 device, a finding we previously corroborated in our own study. The reduction in resistance with increased lumen ID cannot be explained with the Hagen-Poiseuille equation on the basis of the lumen ID criteria alone. On scanning electron microscopy, we observed that the internal diameters of the lumen of the P50 and P200 were in the region of 200 lm at the subconjunctival space and anterior chamber end. We confirmed with Alcon, Inc. that the P50 differs from the P200 only in having a 150-lm diameter bar lying across its lumen in the middle of the device. The P50 and P200 devices also have a side orifice at the anterior chamber end of their bodies, which means they do not have a constant circular cross section. This, together with the presence of the bar lying across the lumen of the P50 device, means that Poiseuille’s Law is not applicable. Sheybani et al. also state that the EX-PRESS does not provide significant outflow resistance. We too observed that there were minimal differences in pressures between the EXPRESS device and a typical trabeculectomy. However, we observed that device implantation resulted in less variability in pressure readings. This may be due to more consistent lumen sizes with small tolerances, compared to making a sclerostomy with a punching device or knife. We also observed that more manipulation was required subjectively with a smaller 27-gauge (G) versus 25-G needle stab on device insertion. This may result in a poorer fit around the body of the device, resulting in leakage. We agree with Sheybani et al. that use of the EX-PRESS device without a scleral flap carries significant risk of hypotony and has similar equilibrium pressures as the trabeculectomy procedure. We would highlight that the effective luminal diameter of the P50 is much larger than 50 lm and that intraoperative surgical technique may reduce tissue manipulation and, therefore, reduce postoperative pressure fluctuations.

New therapeutic avenues in glaucoma surgery

Glaucoma filtration surgery (GFS) can be divided into penetrating and non-penetrating glaucoma surgery. Non-penetrating glaucoma surgeries (comprising deep sclerostomy and viscocanuloplasty) may have a more favorable risk profile in terms of hypotony-related complications [1] and infections [2]. However, due to its long learning curve and lower efficacy at reducing intraocular pressure (IOP), trabeculectomy remains the gold standard and the most commonly performed GFS [1]. Aqueous shunts have traditionally been used in cases of refractory glaucoma following unsuccessful GFS surgery or in patients at high risk of GFS failure. Over the past decade, there has been marked increase in the development of new glaucoma drainage devices (GDDs). Emerging stents in the context of minimally invasive glaucoma surgery (MIGS) aim to improve the safety of glaucoma surgery without compromising efficacy and promote earlier surgical intervention. MIGS can have ab interno or ab externo approaches, some of which do not require a filtering bleb. Regardless of the type of filtration surgery or placement of devices draining into the subconjunctival or suprachoroidal space, scarring is the predominant cause of surgical failure. MIGS encompass a wide range of procedures utilizing endolasers, electrocautery devices, microcatheters, and stent implants with minimum or no scleral dissection. This editorial will focus on approved GDDs, stents, and anti-scarring therapies in glaucoma surgery.

A phase II trial protocol of Tocilizumab in anti-TNF refractory patients with JIA-associated uveitis (the APTITUDE trial)

BackgroundJuvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of intraocular inflammation (uveitis). In the initial stages of mild-moderate inflammation uveitis is asymptomatic. Most children with mild-moderate uveitis are managed on topical steroid drops with or without systemic methotrexate (MTX). When children with moderate-severe uveitis are refractory to MTX, monoclonal anti-tumour necrosis factor agents have been trialled, interim analysis data showed positive results. However, several children with severe recalcitrant disease or non-responsive to anti-tumour necrosis factor agents remain and are at greater risk of significant ocular complications and visual loss. Further evidence of alternative therapies is needed with evidence of a potential role of anti-interleukin-6 agents in the management of severe refractory uveitis.MethodsThe trial will be conducted following a two-stage Simon design. The trial will register at least 22 patients aged 2 to 18xa0years with active JIA-associated uveitis, who have taken MTX for at least 12xa0weeks and have failed an anti-TNF agent. It will take place in 7 centres across the UK. All participants will be treated for 6xa0months, with follow up of 9xa0months from registration. Participants will receive a stable dose of MTX and those weighing ≥30xa0kg will be dosed with 162xa0mg of Tocilizumab every 2 weeks and participants weighing <u200930xa0kg dosed with 162xa0mg of Tocilizumab every 3 weeks. Primary outcome is treatment response at 12xa0weeks. Adverse events will be collected up to 30 calendar days following treatment cessation.DiscussionThis is a novel adaptive design study of subcutaneous IL-6 inhibition in anti-TNF refractory JIA associated uveitis which will be able to determine if further research should be conducted. This is the first trial to look at ophthalmology outcomes in the efficacy of Tocilizumab in uveitis.This is the first paediatric clinical trial to assess the clinical effectiveness and safety of tocilizumab with MTX in JIA associated uveitis.Trials registrationThe Trial is registered on the ISRCTN registry (ISRCTN95363507) on the 10/06/2015 and EU Clinical Trials Register on the 03/07/2015 (EudraCT Number: 2015–001323-23).