Omar A. Mahroo

Recovery of the human photopic electroretinogram after bleaching exposures: estimation of pigment regeneration kinetics

We used a fibre electrode in the lower conjunctival sac of the human eye to record the a‐wave of the photopic electroretinogram elicited in response to dim red flashes, delivered in the presence of a rod‐saturating blue background, before and after exposure of the eye to bright white illumination that bleached a significant fraction of cone photopigment. Responses were recorded from two normal subjects whose pupils were maximally dilated. A range of intensities of bleaching light were used, from 500 to 3000 photopic cd m−2, and exposures were made sufficiently long in duration to achieve a steady‐state bleach. In addition, responses were also recorded following shorter durations of exposures to the highest intensity (3000 cd m−2); these durations ranged from 5 to 60 s. The amplitude of the a‐wave response to dim flashes was reduced following the exposures, with brighter or longer exposures causing greater reduction. The amplitude then recovered within about 4 min to the prebleach level. The amplitudes measured at ca 15 ms after the flash were used to derive the effective intensity of the flashes, thereby quantifying the fraction of photopigment available at the time of delivery of each flash. Recovery from all exposures in both subjects followed a common time course, which could be described well by a model of pigment kinetics based on rate‐limited regeneration, where the initial rate of recovery following a total bleach was ca 50% of the total pigment per minute, and the residual pigment level for half the maximal rate was ca 20% of the total pigment. The same parameters, together with a fixed photosensitivity, could account for the steady‐state pigment levels seen at each bleaching intensity, and also for the fraction of pigment bleached following exposures of different duration at the highest intensity. The dim‐flash ERG thus provides a novel method for assessing pigment regeneration in vivo. Our finding that pigment regeneration follows rate‐limited kinetics may explain previous reports of pigment regeneration deviating from first order kinetics. We present a model of regeneration in which the rate limit arises from a limitation in the delivery of 11‐cis‐retinoid to the photoreceptor outer segments.

Complications of cataract surgery

Modern cataract surgery is safe in more than 95 per cent of patients. In the small number of cases where a serious complication occurs, the most common is an intra-operative posterior capsular rupture. This can lead to vitreous loss or a dropped nucleus and can increase the risk of post-operative cystoid macular oedema or retinal detachment. Post-operatively, posterior capsular opacification is the most common complication and can be readily treated with a YAG capsulotomy. The most devastating complication is endophthalmitis, the rate of which is now significantly decreased through the use of intracameral antibiotics. As a clinician, the most important step is to assess the patient pre-operatively to predict higher risk individuals and to counsel them appropriately. In these patients, various pre- or intra-operative management steps can be taken in addition to routine phacoemulsification to optimise their visual outcome.Modern cataract surgery is safe in more than 95 per cent of patients. In the small number of cases where a serious complication occurs, the most common is an intra‐operative posterior capsular rupture. This can lead to vitreous loss or a dropped nucleus and can increase the risk of post‐operative cystoid macular oedema or retinal detachment. Post‐operatively, posterior capsular opacification is the most common complication and can be readily treated with a YAG capsulotomy. The most devastating complication is endophthalmitis, the rate of which is now significantly decreased through the use of intracameral antibiotics. As a clinician, the most important step is to assess the patient pre‐operatively to predict higher risk individuals and to counsel them appropriately. In these patients, various pre‐ or intra‐operative management steps can be taken in addition to routine phacoemulsification to optimise their visual outcome.

Human cone photoreceptor responses measured by the electroretinogram a-wave during and after exposure to intense illumination

1 We recorded the a‐wave of the electroretinogram from human subjects with normal vision, using a corneal fibre electrode and ganzfeld stimulation under photopic conditions, so as to extract the parameters of cone phototransduction. The amplitude of bright flash responses provided a measure of the massed circulating current of the cones, while the amplitude of dim flash responses provided a measure of the product of the fraction of cone photopigment present, and the amplification constant of transduction within the cones. 2 In the presence of steady background illumination, the cone circulating current declined to half at 3000 photopic trolands, and to a quarter at 20 000 photopic trolands. 3 At very early times after the delivery of a near‐total bleach, we could not determine the level of circulating current as our bright flashes did not appear to saturate the a‐wave (presumably because so little pigment was present). However, by 20–30 s after a total bleach, the cone circulating current had returned to its dark‐adapted level. 4 Following smaller bleaches (when ca 50 % of the pigment remained present) the bright flashes were able to saturate the a‐wave even at very early times. Within 3 s of extinction of the illumination, the cone circulating current had returned to its dark‐adapted level. 5 This is at least a factor of 300 times faster than the period of ca 15 min required for full recovery of rods exposed to the same level of bleach, and indicates a major difference between rods and cones in the way that they cope with the photoproducts of bleaching. 6 Despite the very rapid recovery of circulating current after bleaches, the recovery of dim‐flash sensitivity was much slower, with a time constant of ca 1.5 min after a near‐total bleach. This time course is very similar to previous measurements of the regeneration of cone photopigment, and it seems highly probable that the reduction in dim‐flash sensitivity results from pigment depletion.

Extremely rapid recovery of human cone circulating current at the extinction of bleaching exposures

We used a conductive fibre electrode placed in the lower conjunctival sac to record the a‐wave of the human photopic electroretinogram elicited by bright white flashes, delivered during, or at different times after, exposure of the eye to bright white illumination that bleached a large fraction (∼90%) of the cone photopigment. During steady‐state exposures of this intensity, the amplitude of the bright‐flash response declined to ∼50% of its dark‐adapted level. After the intense background was turned off, the amplitude of the bright‐flash response recovered substantially, for flashes presented within 20 ms of background extinction, and fully, for flashes presented 100 ms after extinction. In addition, a prominent ‘background‐off a‐wave’ was observed, beginning within 5–10 ms of background extinction. We interpret these results to show, firstly, that human cones are able to preserve around half of their circulating current during steady‐state illumination that bleaches 90% of their pigment and, secondly, that following extinction of such illumination, the cone circulating current is restored within a few tens of milliseconds. This behaviour is in stark contrast to that in human rods, where the circulating current is obliterated by a background that bleaches only a few percent of the pigment, and where full recovery following a large bleach takes at least 20 min, some 50 000 times more slowly than shown here for human cones.

Dark adaptation of human rod bipolar cells measured from the b-wave of the scotopic electroretinogram

To examine the dark adaptation of human rod bipolar cells in vivo, we recorded ganzfeld ERGs to (a) a family of flashes of increasing intensity, (b) dim test flashes presented on a range of background intensities, and (c) dim test flashes presented before, and up to 40 min after, exposure to intense illumination eliciting bleaches from a few per cent to near total. The dim flash ERG was characterized by a prominent b‐wave response generated principally by rod bipolar cells. In the presence of background illumination the response reached peak earlier and desensitized according to Webers Law. Following bleaching exposures, the response was initially greatly desensitized, but thereafter recovered slowly with time. For small bleaches, the desensitization was accompanied by acceleration, in much the same way as for real light. Following a near‐total bleach, the response was unrecordable for >10 min, but after ∼23 min half‐maximal sensitivity was reached, and full sensitivity was restored between ∼35 and 40 min. With smaller bleaches, recovery commenced earlier. We converted the post‐bleach measurements of desensitization into ‘equivalent background intensities’ using a Crawford transformation. Across the range of bleaching levels, the results were described by a prominent ‘S2’ component (0.24 decades min−1) together with a smaller and slower ‘S3’ component (0.06 decades min−1), as is found for dark adaptation of the scotopic visual system. We attribute the S2 component to the presence of unregenerated opsin, and we speculate that the S3 component results from ion channel closure by all‐trans retinal.

Common mechanisms underlying refractive error identified in functional analysis of gene lists from genome-wide association study results in 2 European British cohorts

IMPORTANCE To date, relatively few genes responsible for a fraction of heritability have been identified by means of large genetic association studies of refractive error. OBJECTIVE To explore the genetic mechanisms that lead to refractive error in the general population. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association studies were carried out in 2 British population-based independent cohorts (N = 5928 participants) to identify genes moderately associated with refractive error. MAIN OUTCOMES AND MEASURES Enrichment analyses were used to identify sets of genes overrepresented in both cohorts. Enriched groups of genes were compared between both participating cohorts as a further measure against random noise. RESULTS Groups of genes enriched at highly significant statistical levels were remarkably consistent in both cohorts. In particular, these results indicated that plasma membrane (P = 7.64 × 10⁻³⁰), cell-cell adhesion (P = 2.42 × 10⁻¹⁸), synaptic transmission (P = 2.70 × 10⁻¹⁴), calcium ion binding (P = 3.55 × 10⁻¹⁵), and cation channel activity (P = 2.77 × 10⁻¹⁴) were significantly overrepresented in relation to refractive error. CONCLUSIONS AND RELEVANCE These findings provide evidence that development of refractive error in the general population is related to the intensity of photosignal transduced from the retina, which may have implications for future interventions to minimize this disorder. Pathways connected to the procession of the nerve impulse are major mechanisms involved in the development of refractive error in populations of European origin.

Patient-reported benefit from oculoplastic surgery.

PurposeIt is vital that surgeons undertaking oculoplastic procedures are able to show that the surgery they perform is of benefit to their patients. Not only is this fundamental to patient-centred medicine but it is also important in demonstrating cost effectiveness. There are several ways in which benefit can be measured, including clinical scales, functional ability scales, and global quality-of-life scales. The Glasgow benefit inventory (GBI) is an example of a patient-reported, questionnaire-based, post-interventional quality-of-life scale that can be used to compare a range of different treatments for a variety of conditions.MethodsA cross-sectional study was undertaken using the GBI to score patient benefit from four commonly performed oculoplastic procedures. It was completed for 66 entropion repairs, 50 ptosis repairs, 41 ectropion repairs, and 41 external dacryocystorhinostomies (DCR). The GBI generates a scale from −100 (maximal detriment) through zero (no change) to +100 (maximal benefit).ResultsThe total GBI scores of patients undergoing surgery for entropion, ptosis, ectropion, and external DCR were: +25.25 (95% CI 20.00–30.50, P<0.001), +24.89 (95% CI 20.04–29.73, P<0.001), +17.68 (95% CI 9.46–25.91, P<0.001), and +32.25 (95% CI 21.47–43.03, P<0.001), respectively, demonstrating a statistically significant benefit from all procedures.ConclusionPatients derived significant quality-of-life benefits from the four most commonly performed oculoplastic procedures.

Transient Smartphone "Blindness".

Two patients presented with loss of vision after viewing a smartphone screen in bed in the dark. The cause appeared to be differential bleaching of photopigment, with one eye becoming light-adapted while the other eye (blocked by a pillow) became dark-adapted.

Spectral domain optical coherence tomography findings in long-term silicone oil-related visual loss.

Purpose: To investigate spectral domain optical coherence tomography findings in long-term silicone oil–related visual loss. Methods: Four symptomatic patients were reviewed 4 years to 9 years after vitrectomy with silicone oil tamponade for macula-on retinal detachment. Three lost vision with oil in situ, with one at the time of oil removal. Eleven control eyes with good vision were included. Patients underwent assessment of best-corrected visual acuity, contrast sensitivity, Farnsworth-Munsell 100 Hue testing, static perimetry, and spectral domain optical coherence tomography imaging of the macula and disk. Results: Long-term best-corrected visual acuity was significantly reduced in affected eyes (range, 0.44–1.02), as was contrast sensitivity (0.75–1.35) and color discrimination (Farnsworth-Munsell-100 Hue score, 151–390). Static perimetry showed a central scotoma in all affected eyes. Optical coherence tomography revealed microcystic macular changes in the inner nuclear layer of all affected eyes associated with severe loss of the papillofoveal retinal nerve fiber layer. In one patient, serial optical coherence tomography images showed development of microcystic macular changes 18 months after oil removal. Control eyes lacked these features, except two asymptomatic eyes that showed microcystic changes on optical coherence tomography with a corresponding paracentral scotoma. Conclusion: We have demonstrated microcystic macular changes in the inner nuclear layer of affected eyes, as well as focal severe loss of the papillofoveal projection. These changes share significant morphologic features reported in multiple sclerosis–associated optic neuritis and Leber hereditary optic neuropathy.

Macular spectral domain optical coherence tomography findings in Tanzanian endemic optic neuropathy.

Bilateral optic neuropathy in Dar es Salaam is now considered endemic and is estimated to affect 0.3-2.4% of young adults. The condition is characterized by a subacute bilateral loss of central vision of unknown aetiology. Findings of spectral domain optical coherence tomography have not previously been reported for these patients. All patients diagnosed with endemic optic neuropathy over a 2-year period at the Muhimbili National Hospital underwent spectral domain optical coherence tomography macular imaging. Scans were graded qualitatively for severity of retinal nerve fibre layer loss as well as the presence of microcystic macular changes, which have not previously been described in this condition. Of the 128 patients included (54.7% male; median age 20 years), severe retinal nerve fibre layer loss was found in 185 eyes (74.0%). There was full concordance in retinal nerve fibre layer thickness between the two eyes in 113 (91.1%) patients. Microcystic macular spaces were found in 16 (12.5%) patients and were bilateral in nine (7.0%) individuals. These changes were typically more prominent in the nasal than the temporal macula, predominantly involving the inner nuclear layer, and often occurred in an annular configuration that was evident on en face infra-red imaging, though not discernible on colour fundus photography or clinically. All patients with microcystic macular changes had severe thinning of the retinal nerve fibre layer (P = 0.02). Four patients in whom cystic spaces were demonstrated had sequential scans, and there was no detectable alteration in the configuration of these changes over a period of up to 16 months. This is the first study to document optical coherence tomography findings in endemic optic neuropathy. We have observed symmetrical severe loss of the caeco-central projection (papillomacular bundle) with otherwise well-preserved macular architecture. Also, we have observed microcystic retinal changes in a significant proportion of patients, which were associated with severe retinal nerve fibre layer loss. Similar changes have recently been reported from optical coherence tomography images of patients with multiple sclerosis, relapsing isolated optic neuritis, dominant optic atrophy, Lebers hereditary optic neuropathy and a patient with a chronic compressive optic neuropathy, supporting the hypothesis that this may be a non-specific phenomenon secondary to ganglion cell death. The correspondence of the changes to an annulus discernible on infra-red en face imaging, but not using other conventional retinal imaging techniques highlights the potential usefulness of this modality.