David B. Henson

The Role of Oxidative Stress in the Pathogenesis of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blind registration in the developed world, and yet its pathogenesis remains poorly understood. Oxidative stress, which refers to cellular damage caused by reactive oxygen intermediates (ROI), has been implicated in many disease processes, especially age-related disorders. ROIs include free radicals, hydrogen peroxide, and singlet oxygen, and they are often the byproducts of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, its high proportion of polyunsaturated fatty acids, and its exposure to visible light. In vitro studies have consistently shown that photochemical retinal injury is attributable to oxidative stress and that the antioxidant vitamins A, C, and E protect against this type of injury. Furthermore, there is strong evidence suggesting that lipofuscin is derived, at least in part, from oxidatively damaged photoreceptor outer segments and that it is itself a photoreactive substance. However, the relationships between dietary and serum levels of the antioxidant vitamins and age-related macular disease are less clear, although a protective effect of high plasma concentrations of alpha-tocopherol has been convincingly demonstrated. Macular pigment is also believed to limit retinal oxidative damage by absorbing incoming blue light and/or quenching ROIs. Many putative risk-factors for AMD have been linked to a lack of macular pigment, including female gender, lens density, tobacco use, light iris color, and reduced visual sensitivity. Moreover, the Eye Disease Case-Control Study found that high plasma levels of lutein and zeaxanthin were associated with reduced risk of neovascular AMD. The concept that AMD can be attributed to cumulative oxidative stress is enticing, but remains unproven. With a view to reducing oxidative damage, the effect of nutritional antioxidant supplements on the onset and natural course of age-related macular disease is currently being evaluated.

Macular pigment and age related macular degeneration

The yellow coloration of the macula lutea is attributable to the presence of macular pigment in the axons of its photoreceptors.1 In the 1980s several investigators demonstrated that macular pigment consists of the xanthophyll isomers, lutein and zeaxanthin.2 3 Although the role of the macular pigment remains uncertain, several functions have been hypothesised and these include reduction of the effects of light scatter and chromatic aberration on visual performance,4 5 limitation of the damaging photo-oxidative effects of blue light through its absorption,6-8 and protection against the adverse effects of photochemical reactions because of the antioxidant properties of the carotenoids.9 10 Age related macular degeneration (AMD) is the leading cause of visual loss in people over the age of 65 years in the Western world.11 Although the aetiopathogenesis of AMD remains a matter of debate, there is a growing body of evidence to indicate that oxidative damage plays a role.12-14 Consequently, the possibility that the absorption characteristics and antioxidant properties of macular pigment confer protection against AMD has been postulated.10 15 A proved protective effect of macular pigment may be of therapeutic value, as it has recently been reported that human macular pigment can be augmented with dietary modification.16 In this article we review the current literature germane to macular pigment and AMD, and examine the evidence that retinal carotenoids are protective against AMD. The absorption of blue light by the macular pigment was first described in 1866 by Max Schultze who concluded: “Therefore, under an otherwise equal organisation, a retina without a yellow spot would see more blue light than one with such a spot”.17 He believed that absorption of the “most refractable violet” reduced chromatic aberration, but also hypothesised that macular pigment might provide some protection against the hazards …

Adaptation to Prism-induced Heterophoria

Abstract Measurements of the way the oculomotor system adapts to prisminduced heterophorias have been made in eight normal subjects. Adaptation to 2&dgr; vertically and, on separate occasions, to 6&dgr; horizontally was found to be substantially completed after only 2‐3 minutes of binocular visual experience. The form of the adaptive process for distant targets was asymmetrical in the horizontal meridian, being faster after the insertion of 6&dgr; base‐out than for 6&dgr; base‐in. This asymmetry largely disappeared for near vision.

Community refinement of glaucoma referrals

AbstractAim To describe a Manchester-based glaucoma referral refinement scheme designed to reduce the number of false-positive referrals to the hospital eye service. To report on the first years results of this scheme and its financial costs to the NHS.Methods Patients with suspected glaucoma, instead of being referred to their GP and then on to the hospital eye service, were referred to a group of specially trained community optometrists working to an agreed set of referral criteria. Those patients who did not meet the referral criteria were returned to the referring optometrist, while those who met the referral criteria were referred directly to Manchester Royal Eye Hospital. The patients GP was informed in all cases.Results The number of suspect glaucoma cases referred to the Manchester Royal Eye Hospital was reduced by 40%. This figure is close to the percentage of false-positive referrals measured at Manchester Royal Eye Hospital prior to the onset of this study. The information accompanying referral has been improved and the scheme produces a small financial cost saving to the NHS of approximately £17 per patient.Conclusion Community refinement of suspect glaucoma offers some important benefits over the current referral pathway.

Assessment of the Diurnal Variation in Central Corneal Thickness and Intraocular Pressure for Patients with Suspected Glaucoma

OBJECTIVE To assess whether a single daily measurement using ultrasonic pachymetry gives a representative assessment of mean central corneal thickness (CCT) in patients with suspected glaucoma and whether diurnal changes in CCT are related to diurnal variations in intraocular pressure (IOP). DESIGN Cross-sectional study. METHOD Central CCT and IOP were measured by a single observer in 56 eyes of 28 patients with suspected glaucoma using an ultrasonic pachymeter and a Goldmann tonometer. Four measurements were made over a 24-hour period: at 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM. MAIN OUTCOME MEASURES Intraocular pressure and pachymetry. RESULTS Mean IOP was 19.80 mmHg at 8:00 AM (95% confidence interval [CI], 18.95-20.66 mmHg), 20.38 mmHg at 12:00 PM (95% CI, 19.49-21.26 mmHg), 19.91 mmHg at 4:00 PM (95% CI, 19.99-21.83 mmHg), and 19.23 mmHg at 8:00 PM (95% CI, 18.35-20.11 mmHg). Mean CCT was 569.4 microm (95% CI, 560.2-578.7 microm), 567.6 microm (95% CI, 558.4-576.7 microm), 569.1 microm (95% CI, 559.5-578.6 microm), and 567.2 microm (95% CI, 557.9-576.4 microm) at the four respective time points. There was no significant correlation between IOP and CCT in any patient (Pearson rank correlation coefficient); nor was there any significant correlation between the mean diurnal variations of IOP and CCT. CONCLUSIONS In this group of patients with suspected glaucoma, there was no significant variation in CCT. Therefore, a single measurement of CCT is sufficient when assessing patients with suspected glaucoma. There was no correlation between change of IOP and change of CCT.

Pain responses of Pascal 20 ms multi-spot and 100 ms single-spot panretinal photocoagulation: Manchester Pascal Study, MAPASS report 2.

Aims To evaluate pain responses following Pascal 20 ms multi-spot and 100 ms single-spot panretinal photocoagulation (PRP). Methods Single-centre randomised clinical trial. 40 eyes of 24 patients with treatment-naive proliferative diabetic retinopathy randomised to 20 and 100 ms PRP under topical 0.4% oxybuprocaine. A masked grader used a pain questionnaire within 1 h (numerical pain score (NPS)) and 1 month after treatment (numerical headache score (NHS)). Primary outcome measure was NPS immediately post-PRP. Secondary outcome measures were mean NHS scores and levels of photophobia reported within 4 weeks of primary PRP. Results Mean laser fluence was significantly lower using 20 ms PRP (4.8 J/cm2) compared to 100 ms PRP (11.8 J/cm2; p<0.001). Mean NPS scores for treatment were 2.4 (2.3) (mild) for 20 ms PRP group compared to 4.9 (3.3) (moderate) in 100 ms PRP group—a significant difference (95% CI 4.3 to 0.68; p=0.006). Mean NHS score within 1 month was 1.5 (2.7) in 20 ms PRP group compared to 3.2 (3.5) in the 100 ms PRP group (p<0.05). The median duration of photophobia after 20 ms PRP was 3 h, and significantly less compared to 100 ms PRP after which 72 h of photophobia was reported (p<0.001). Conclusions Multi-spot 20 ms PRP was associated with significantly lower levels of anxiety, headache, pain and photophobia compared to 100 ms single-spot PRP treatment. Possible reasons include lower fluence, shorter-pulse duration, and spatial summation of laser nociception with multi-spot Pascal technique.

The correlation between optic nerve head topographic measurements, peripapillary nerve fibre layer thickness, and visual field indices in glaucoma

Aims: To establish whether the structural parameters provided by the Heidelberg retina tomograph (HRT) and the laser diagnostics glaucoma scanning system (GDx) can be used to reflect functional damage in the visual field. Methods: 62 patients with primary open angle glaucoma underwent examination with the HRT, GDx, and Humphrey field analyser. The relations between the topographic parameters, retinal nerve fibre parameters, and visual field indices were analysed by scatter plot and linear regression. Results: Among the topographic parameters generated by the HRT, rim area had the best correlation with visual field indices. The “number,” maximum modulation, and ellipse modulation generated by the GDx also had correlations with visual field indices. The correlations were better for the sectoral parameters than the global parameters. However, great interindividual variation was found in the association. Conclusion: Although relations were found between some topographic parameters, RNFL parameters, and visual field indices, great interindividual variation limits the prediction of one parameter from the other. Therefore, both structural and functional aspects should be evaluated in order to obtain full characterisation of the glaucomatous damage for clinical judgment and treatment.

Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy

Purpose:  To investigate the clinical effects and safety of targeted pattern scan laser (Pascal) retinal photocoagulation (TRP) in proliferative diabetic retinopathy (PDR).

In Vivo Laser-Tissue Interactions and Healing Responses From 20- vs 100-Millisecond Pulse Pascal Photocoagulation Burns

OBJECTIVES To compare in vivo burn morphologic features and healing responses of Pascal 20- and 100-millisecond panretinal photocoagulation (PRP) burns in proliferative diabetic retinopathy. DESIGN Prospective randomized controlled trial with 24 eyes assigned to either 20- or 100-millisecond Pascal PRP. Fundus autofluorescence and Fourier domain optical coherence tomography (FD-OCT) were performed 1 hour and 2 and 4 weeks after treatment. Main outcome measures included burn morphologic features on FD-OCT and greatest linear diameter (GLD) of laser burns as evaluated in 6 standard Early Treatment of Diabetic Retinopathy Study photographic fields using autofluorescence. RESULTS The contemporaneous increase in autofluorescence is observed with increasing pulse duration. Differences in mean GLD between 100- and 20-millisecond burns were 63 mum at 1 hour and 198 mum at 4 weeks (P < .001 for both). At 4 weeks, all burns corresponded to defects at the junction of inner and outer segments of photoreceptors (JI/OSP) and apical retinal pigment epithelium. After 4 weeks, the GLD of 20-millisecond burns reduced significantly by 35% (P < .001), with no change in 100-millisecond burns. CONCLUSIONS All burns initially appear as equivalent square-edged, columnar foci of hyperreflectivity in the outer retina. Pascal 20-millisecond burns progressively reduce in size, and this suggests a novel healing response localized to the JI/OSP and apical retinal pigment epithelium. The higher-fluence 100-millisecond burns develop larger defects due to thermal blooming and collateral damage.

Single-session vs multiple-session pattern scanning laser panretinal photocoagulation in proliferative diabetic retinopathy: The Manchester Pascal Study.

OBJECTIVE To investigate the effects of pattern scanning laser (Pascal; OptiMedica, Santa Clara, California) multispot panretinal photocoagulation given in a single-session (SS-PRP) vs single-spot multiple-session PRP (MS-PRP) on proliferative diabetic retinopathy (PDR). METHODS Single-center, randomized clinical trial of 40 eyes. Proliferative diabetic retinopathy was treated with a 400-mum spot size in 1500 burns given either as Pascal in 20-millisecond SS-PRP or in 3 sessions (100-millisecond MS-PRP) during a 4-week period. Visual acuity, central subfield retinal thickness (CRT), and 24-2 Swedish interactive thresholding algorithm visual fields were recorded at baseline and 4 and 12 weeks. MAIN OUTCOME MEASURES Central subfield retinal thickness, mean deviation, and PDR grade at 12 weeks. RESULTS There was a significant increase in mean CRT with MS-PRP (22 mum at 4 weeks, 95% CI, -32.25 to -10.75; 20 mum at 12 weeks, 95% CI, -28.75 to -10.82; P < .001) and no significant increase in the SS-PRP group. The mean deviation increased significantly in the SS-PRP group after 4 weeks (0.73 dB, P = .048), with no significant changes in either group at other points. A positive effect on PDR was observed in 74% of eyes in the SS-PRP group vs 53% in the MS-PRP group (P = .31). Mean treatment time for SS-PRP was 5.04 minutes (SD, 1.5 minutes) compared with 59.3 (SD, 12.7 minutes) in the MS-PRP group (P < .001). CONCLUSIONS There were no adverse outcomes (CRT, visual acuity, or visual field) from using multispot SS-PRP vs single-spot MS-PRP at 12 weeks postlaser, and treatment times were significantly shorter for multispot SS-PRP. Pascal SS-PRP was as effective as MS-PRP in the treatment of PDR. APPLICATION TO CLINICAL PRACTICE Twenty-millisecond Pascal SS-PRP may be safely and rapidly performed in 1500 burns with a similar efficacy to conventional MS-PRP. TRIAL IDENTIFIER: Research and Development Office PIN R00037, Central Manchester University Hospitals Foundation Trust.