Functional Brain Imaging During Extra-Ocular Light Stimulation in Anophthalmic and Sighted Participants: No Evidence for Extra-Ocular Photosensitive Receptors.

Light plays a critical role in regulating physiology and behavior, including both visual and non-visual responses. In mammals, loss of both eyes abolishes all of these responses, demonstrating that the photoreceptors involved are exclusively ocular. By contrast, many non-mammalian species possess extra-ocular photoreceptors located in the pineal complex and deep brain. Whilst there have been suggestions of extra-ocular photoreception in mammals, including man, evidence for these photoreceptors is limited. One approach to objectively determine the presence of such receptors is to measure brain responses to light using functional magnetic resonance imaging (fMRI). Moreover, by using participants who are clinically anophthalmic (congenital and acquired), it is possible to investigate potential light detection in the absence of the retina. Here we scanned participants with anophthalmia and sighted participants in 4 different conditions; the first 3 conditions had a bright light source applied to the following locations: behind the right ear ("ear"), just below the nasal bridge and between the eyes ("head"), and at the right popliteal fossa ("knee"). In the fourth and final scan, the light source was switched off so that there was no light stimulus. All participants were scanned in a completely dark room. No consistent brain activity was detected during any of the light conditions in either sighted controls or anophthalmic participants. Thus, we do not provide any evidence for the presence of extraocular photoreceptors modulating human brain activity, despite recent evidence for gene transcription that may occur as a result of these photoreceptors.

The Effect of Congenital and Acquired Bilateral Anophthalmia on Brain Structure.

The aim of this study was to compare the pattern of changes in brain structure resulting from congenital and acquired bilateral anophthalmia. Brain structure was investigated using 3T magnetic resonance imaging (MRI) in Oxford (congenital) or Manchester (acquired). T1-weighted structural and diffusion-weighted scans were acquired from people with anophthalmia and sighted control participants. Differences in grey matter between the groups were quantified using voxel-based morphometry and differences in white matter microstructure using tract-based spatial statistics. Quantification of optic nerve volume and cortical thickness in visual regions was also performed in all groups. The optic nerve was reduced in volume in both anophthalmic populations, but to a greater extent in the congenital group and anophthalmia acquired at an early age. A similar pattern was found for the white matter microstructure throughout the occipitotemporal regions of the brain, suggesting a greater reduction of integrity with increasing duration of anophthalmia. In contrast, grey matter volume changes differed between the two groups, with the acquired anophthalmia group showing a decrease in the calcarine sulcus, corresponding to the area that would have been peripheral primary visual cortex. In contrast, the acquired anophthalmia group showed a decrease in grey matter volume in the calcarine sulcus corresponding to the area that would have been peripheral primary visual cortex. There are both qualitative and quantitative differences in structural brain changes in congenital and acquired anophthalmia, indicating differential effects of development and degeneration.

Correction to: Iluvien™ (Fluocinolone Acetonide 0.19 mg Intravitreal Implant) in the Treatment of Diabetic Macular Edema: A Review.

This article was originally published with the copyright: the author(s) 2018, CC-BY-NC. However, the license should be the author(s) 2018, CC-BY.

Impact of Diabetic Retinopathy on Sleep, Mood, and Quality of Life.

Purpose: Diabetic retinopathy (DR) is associated with retinal neuronal and vascular damage. DR has previously been shown to affect the photosensitive retinal ganglion cells (pRGCs). PRGCs are essential for the entrainment of circadian rhythms; thus, DR progression could lead to worsening sleep quality and mood. We investigate the relationship between increasing DR severity, and its impact on sleep quality and mood. Methods: A total of 430 participants with DR, and 303 healthy controls with no ocular disease or preexisting sleep disorders were recruited. DR severity was grouped as follows: 1, mild nonproliferative (NPDR); 2, moderate/severe NPDR; and 3, proliferative diabetic retinopathy (PDR). Sleep, mood, and quality of life were assessed using the Pittsburgh Sleep Quality Index (PSQI), quality of life (SF-36), and Hospital Anxiety and Depression Score (HADS) questionnaires. Data were analyzed by severity of DR, and correlated with sleep, QOL, and mood and compared to controls. Results: No significant difference between PSQI scores in the DR group or the control group was identified despite severity of DR. Mean anxiety and depression scores were within the normal range for both groups. Despite a lower general health and physical function, the DR group had lower anxiety scores than controls. Conclusions: These data show that even in severe DR, sleep quality is similar to controls. However, this could be explained by the majority of individuals in this study having good visual acuities in the better eye with a residual population of pRGCs remaining unaffected by DR.

COMPARING MICROPERIMETRIC AND STRUCTURAL FINDINGS IN PATIENTS WITH BRANCH RETINAL VEIN OCCLUSION AND DIABETIC MACULAR EDEMA.

PURPOSE: To compare retinal sensitivity and central retinal thickness in patients with focal diabetic macular edema (DME) and edema secondary to branch retinal vein occlusion (BRVO). METHODS: In this consecutive, cross-sectional, observational study, patients with either DME or BRVO underwent measurements for best-corrected visual acuity, microperimetry, and spectral domain optical coherence tomography. Retinal thickness and sensitivity were measured using Optos Spectral optical coherence tomography/scanning laser ophthalmoscopy (Optos plc, Dunfermline, Scotland, United Kingdom). Areas defined as abnormal demonstrated edema with clearly defined cystic spaces. Abnormal and control areas were compared in mean retinal sensitivity and mean retinal thickness for both conditions. RESULTS: Twenty eyes with focal DME and nine eyes with BRVO were included. In DME, mean retinal thickness was 413.6 ± 84.5 µm and 291.7 ± 36.7 µm in abnormal and control areas, respectively. Mean retinal sensitivity was 10.22 ± 4.23 dB and 12.25 ± 3.57 dB, respectively. In BRVO, mean retinal thickness was 491.4 ± 102.9 µm and 315.9 ± 29.9 µm in abnormal and control areas, respectively. Mean retinal sensitivity was 6.36 ± 5.47 dB and 13.05 ± 2.28 dB. In DME, a decrease in retinal thickness of 0.341 µm correlated with 1 dB reduction of retinal sensitivity, although this was not statistically significant (P = 0.717). In BRVO, however, an increase in retinal thickness of 9.702 µm correlated with 1 dB reduction of retinal sensitivity (P = 0.001). CONCLUSION: In BRVO, an increase in retinal thickness corresponded with a significant reduction in retinal sensitivity; in DME, however, there was no significant correlation between retinal thickness and retinal sensitivity. Further study is required to assess why this is the case. The Optos Spectral optical coherence tomography/scanning laser ophthalmoscopy allows for a reliable point-to-point correlation, as microperimetry and spectral domain optical coherence tomography can be performed in the same device.

Toxic epidermal necrolysis: the red eye and red herrings in casualty.

A 38-year-old woman presented to casualty with bilateral red eyes associated with a recent upper respiratory tract infection. This was initially diagnosed as conjunctivitis, however systemic review revealed an erythematous facial and skin rash, mildly swollen lips and mild swallowing difficulties. The patient was referred for an urgent medical assessment, by which time she was found to have erythema affecting 54% of her body surface area and diagnosed with suspected toxic epidermal necrolysis (TEN). She rapidly deteriorated over 24 hours with a spreading blistering skin rash and airway compromise requiring urgent intubation and admission to the intensive treatment unit (ITU). Subsequent skin biopsies confirmed the diagnosis of TEN, attributed to recent use of ibuprofen. Treatment included broad-spectrum antibiotics and high-dose corticosteroids. The patient had a prolonged hospital stay and developed severe scarring of the ocular surface. She was discharged home and remains under continuing outpatient follow-up with ophthalmology and dermatology teams.

Iluvien™ (Fluocinolone Acetonide 0.19 mg Intravitreal Implant) in the Treatment of Diabetic Macular Edema: A Review.

Diabetic macular edema (DMO) is a leading cause of blindness in the working age population. Although anti-vascular endothelial growth factor (VEGF) therapy provided a major advance in treatment of DMO for many patients, there is a significant proportion of patients who maintain persistent DMO and have minimal response to anti-VEGF treatment. Iluvien (fluocinolone acetonide 0.19 mg [FAc]) is an important additional treatment option for DMO. In this review we describe the clinical context and the evidence for the use of the FAc implant in treating DMO, from pilot to randomized controlled studies, to later phase real world data. These studies indicate that the FAc implant is effective, well tolerated and a cost-effective option in the treatment of insufficiently responsive DMO.

Treating Diabetic Macular Oedema (DMO): real world UK clinical outcomes for the 0.19mg Fluocinolone Acetonide intravitreal implant (Iluvien™) at 2 years.

BACKGROUND: To compare visual function and structural improvements in pseudophakic eyes with diabetic macular oedema (DMO) treated with the 0.19mg Fluocinolone Acetonide (FAc) intravitreal implant (IluvienTM) in a 'real world' setting. METHODS: A single centre retrospective evaluation of patients with DMO unresponsive to conventional treatment treated with the FAc implant according to UK guidelines. Primary efficacy endpoint was best corrected visual acuity (BCVA); secondary endpoints included optical coherence tomography evaluations of the macula (a) central retinal and (b) peak macular thickness collected at annual time points. Primary safety endpoint was new rise in IOP >27mmHg or glaucoma surgery. Patients with <1 year follow-up were excluded. RESULTS: Twenty-nine eyes were included, with mean(SD) follow up of 792(270) days. Improvement in BCVA and reduction in macular oedema was noted at all timepoints. Mean improvement in BCVA from baseline was 6 ETDRS letters at year 1(n=29), 6.5L at year 2(n=22) and 11L at year 3(n=6). Mean central retinal thickness at baseline was 451 microns, 337 microns at year 1, 342 microns at year 2 and 314 microns at year 3. Two eyes required IOP-lowering drops post implant. Supplementary treatment for persistence or recurrence of DMO was necessary in 18 eyes over the total study period of 3 years with mean time to supplementary treatment being 12 months. CONCLUSIONS: Our evaluation of the 0.19mg FAc implant delivered in a real-world setting, provides additional evidence that it is effective and safe in the treatment of patients with DMO, and can provide sustained benefit for patients with previously refractory disease.

STRUCTURAL-FUNCTIONAL CORRELATION IN PATIENTS WITH DIABETIC MACULAR EDEMA.

BACKGROUND/PURPOSE: Previous studies have shown that patients with diabetic macular edema (DME) with relatively good visual acuity can have slow reading speed. The aim of this study was to evaluate the structural-functional correlation in a cohort of patients with DME and to assess whether the central four retinal points on microperimetry (MP4) could be used as a potentially faster and more reliable method of assessing retinal function in patients with DME than reading speed. METHODS: The study was performed on patients with clinically significant DME. The best-corrected visual acuity (BCVA) was recorded with letter counting on a modified ETDRS chart, the maximal reading speed (MRS) was recorded with MNREAD, the retinal sensitivity (MP28 and MP4) was measured with Optos OCT/ Scanning Laser Ophthalmoscopy and the central subfield thickness was measured by Heidelberg Spectralis Spectral Domain Optical Coherent Topography. RESULTS: Of 100 eyes analyzed, 76 eyes were included in the study. The mean BCVA was 76.5 letters (Snellen equivalent 6/18), the mean MRS was 156.8 words per minute, the mean MP4 was 9.81 dB per point, and the mean central subfield thickness was 309.3 microns. It was found that faster MRS is correlated with younger age (P = 0.001), better BCVA (P < 0.0001), and better retinal sensitivity (P < 0.0001) for both MP28 and MP4, but not with central subfield thickness (P = 0.66). Central subfield thickness is correlated with MP28 (P = 0.05) but not with age (P = 0.812), BCVA (P = 0.113), or MP4 (P = 0.485). After correction for age and BCVA, MRS is still correlated with MP28 (P = 0.001) and MP4 (P = 0.015). CONCLUSION: Patients with DME can have reduced reading speed despite good visual acuity. Maximal reading speed is often reported to be difficult to perform, inconsistent, and affected by language and educational level. However, in this study, the authors found that the central MP4 points are quick and easy to test in most of the patients, and are highly correlated with MRS. Microperimetry might therefore represent a useful additional functional test that could be considered better than BCVA or reading speed in quantifying visual function in patients with DME.

Comparing Macular Thickness Measurements in Patients with Diabetic Macular Edema with the Optos Spectral OCT/SLO and Heidelberg Spectralis HRA + OCT.

The aim of this study was to compare measurements of macular thickness, obtained from patients with diabetic macular edema, using two spectral-domain optical coherence tomography (SD-OCT) devices. These were the Spectralis Heidelberg Retina Angiograph + Optical Coherence Tomography (HRA + OCT) (Heidelberg Engineering), which is often considered the gold-standard for OCT measurement, and the Spectral Optical Coherence Tomography/Scanning Laser Ophthalmoscopy (OCT/SLO) (Optos plc), which can additionally perform microperimetry, a useful measure of visual function. In this prospective observational study, each eye had SD-OCT performed with both devices on the same day by the same investigator. Mean retinal thickness was calculated, and compared between the devices, for central and parafoveal zones within 3 mm of the fovea. 62 eyes were included. In the central, superior, temporal, inferior and nasal zones respectively, mean retinal thickness with Spectralis HRA+OCT was (in microns) 310, 343, 344, 332 and 340; measurements with Spectral OCT/SLO were 237, 298, 297, 289 and 290. Pearson correlations between the devices were 0.752, 0.85, 0.928, 0.839, and 0.823 (p < 0.0001). Although absolute measurements between the devices were significantly different and therefore not interchangeable, the correlation between the devices was over 75% and statistically significant in all zones. Thus, the Spectral OCT/SLO could reliably be used for SD-OCT in patients who may also require microperimetry assessment.

Intravitreal pegaptanib for the treatment of ischemic diabetic macular edema.

PURPOSE: Pegaptanib has been shown to be effective in treating diabetic macular edema (DME). In the original Phase II/III trial, however, patients with macular ischemia were excluded. In this study, we treated patients with ischemic DME. METHODS: Macular ischemia was defined as a 30% increase in the area of the foveal avascular zone (FAZ) at 45 seconds on fundus fluorescein angiography. In addition, the participants had diffuse foveal-involving DME with a central subfield thickness (CST) of >300 µm on spectral-domain optical coherence tomography. Five intravitreal pegaptanib injections were given 6 weeks apart. The final study visit was 6 weeks after the fifth injection. The primary outcome was change in the size of FAZ. Secondary outcomes were change in best-corrected visual acuity (BCVA) and the change in CST. RESULTS: Thirty participants were enrolled. Three were unable to complete the full course of treatment. Their outcomes were carried forward for the first part of this analysis. There was no statistically significant change in the mean size of the FAZ from baseline to the final visit. Subclassifying participants as those with minimal/moderate ischemia (16 participants, FAZ area <1,000 pixels) and those with more severe ischemia (14 participants, FAZ area >1,000 pixels) also showed no statistically significant change in the mean area of the FAZ. On average, BCVA increased and CST decreased from baseline to the final visit, but these changes were not statistically significant. Using per protocol analysis on those participants who completed the full course of treatment, the mean BCVA increased from 49.2 to 53.9 letters (P=0.046). CONCLUSION: In this study, intravitreal injection of pegaptanib did not significantly alter the size of the FAZ in participants with varying degrees of ischemic DME. There was, however, a significant improvement in mean BCVA in those who completed the treatment course.

An unusual presentation of patent foramen ovale.

We report a case of retinal artery occlusion in a young adult in early pregnancy found to have a patent foramen ovale as the source of the embolism. This report suggests the importance of early cardiac investigation in such individuals.

Peripheral ulcerative keratitis as a complication of acute myeloid leukaemia.

We report a rare presentation of acute bilateral peripheral ulcerative keratitis (PUK) in a patient with a new diagnosis of untreated acute myeloid leukaemia (AML). To the best of our knowledge, this is the first report of PUK associated with untreated AML and we stress the importance of a rapid and thorough testing to exclude other diagnoses. The patient lost his vision within 10 days to counting fingers. Rapid diagnosis allowed a good visual recovery following prompt treatment with oral steroids and systemic chemotherapy treatment for the AML.

Lowering the limit: reducing the CD4 T-cell threshold for ophthalmic screening in patients with HIV in an ethnically diverse UK population.

BACKGROUND: Before highly active antiretroviral therapy, cytomegalovirus (CMV) retinitis was a major threat to vision in individuals with HIV. We investigate whether ophthalmic screening of asymptomatic HIV patients still has value in the highly active antiretroviral therapy era and consider CD4 thresholds in line with the world literature and UK experience. METHODS: A retrospective chart review was conducted of all patients seen by the HIV Ophthalmic Service of a UK university hospital both before (2007-2008) and after (2011-2012) introduction of a threshold of CD4 lower than 100 cells/mm(3). Data collected included CMV and HIV RNA load, CD4 cell counts and CD4 percentage, CMV-immunoglobulin G status, ocular symptoms, and evidence of HIV-related ocular disease. RESULTS: In total, 54 patients were referred to the HIV ophthalmic service. Three patients failed to attend, resulting in complete data for 51 patients (n=24 for 2007-2008; n=27 for 2011-2012). Seven patients had ophthalmic manifestations of their HIV; these cases had lower CD4 counts than those with normal examinations (median [interquartile range], 9 [7-80] versus 175 [44-394]; P=0.0039; Mann-Whitney test). Six cases had HIV retinopathy without sight loss; one case had sight-threatening CMV retinitis associated with a CD4 count of 6 cells/mm(3). CONCLUSION: Before 2008, our practice was to screen all asymptomatic patients with CD4 counts lower than 200 cells/mm(3). Screening asymptomatic patients with CD4 counts below 100 cells/mm(3) was not associated with any missed or late-presenting cases of CMV retinitis in our HIV population.

Pharmacokinetic evaluation of pegaptanib octasodium for the treatment of diabetic edema.

INTRODUCTION: Diabetic macular edema (DME) is a leading cause of visual impairment in patients with diabetic retinopathy. Pegaptanib octasodium (Macugen) was the first anti-VEGF agent approved for the treatment of neovascular age-related macular degeneration. It is a selective anti-VEGF agent, which only blocks VEGF. It has been shown to be safe and effective in treatment of DME in randomized controlled trials and it may be a safer first-line treatment in patients with diabetes with a predisposition to cardiovascular risk factors. AREAS COVERED: This review covers the pharmacokinetics of pegaptanib octasodium. The authors also evaluate pegaptanib octasodium's clinical efficacy, safety and tolerability in DME. EXPERT OPINION: DME is the most common cause of visual loss in patients with diabetes. Pegaptanib has been found to be more effective than laser therapy alone for center-involving DME, its efficacy might be slightly worse than other pan-VEGF blockers, but the number of patients that have significant improvement of vision after treatment are similar to those treated with pan-VEGF blockers. As a selective VEGF blocker, it may have a better ocular and systemic safety profile than pan-VEGF blocking agents. It is reasonable to consider pegaptanib as the first-line treatment for center-involving DME with pan-VEGF blockers reserved for non-responders.