Inflammation after Voretigene Neparvovec Administration in Patients with RPE65-Related Retinal Dystrophy.

PURPOSE: To report on the prevalence of intraocular inflammation after subretinal voretigene neparvovec (VN) administration. DESIGN: Retrospective review of medical files. PARTICIPANTS: All patients receiving VN in Denmark. METHODS: Twelve patients received VN gene therapy as standard of care for biallelic RPE65-related retinal disease. Bilateral treatment was performed in 11 patients and unilateral treatment in 1 patient. Patients were followed clinically before and after VN administration using functional measurements (visual acuity, full-field scotopic threshold test, visual fields) and structural evaluations (fundus imaging [color and autofluorescence], OCT, slit-lamp). MAIN OUTCOME MEASURES: Signs of intraocular inflammation, including vitritis and outer retinal infiltrates. RESULTS: Vitritis was observed in 9 of 23 eyes receiving VN. The median time to resolution of vitritis from the time of treatment was 89 days. Four eyes also presented with outer retinal infiltrates at the time of vitritis. Inflammation subsided on immunosuppressant therapy. The presence of inflammation did not adversely affect visual outcome after VN therapy. In 1 eye, outer retinal infiltrates were demonstrated to precede later development of atrophy. CONCLUSIONS: Patients undergoing subretinal gene therapy need to be closely monitored for signs of inflammation. Although we did not observe a detrimental effect on visual function in eyes with inflammation, it seems wise to treat it appropriately because it may lead to atrophy of the retinal pigment epithelium and outer retina. Also, it seems advisable to reduce the inflammatory load, such as using a surgical technique that minimizes residual viral vectors in the vitreous body.

Bruch's membrane allows unhindered passage of up to 2 µm latex beads in an in vivo porcine model.

PURPOSE: It has been proposed that changes in the permeability of Bruch's membrane play a role in the pathogenesis of age-related macular degeneration (AMD). This paper investigates, in an in vivo porcine model, the migration of fluorescent latex beads across the Bruch's membrane after subretinal injection. METHODS: Forty-one healthy eyes of 33 three-month-old domestic pigs received a subretinal injection of 0.5, 1.0, 2.0, or 4.0 µm fluorescent latex beads. Between three hours and five weeks after injection evaluations were performed with fundus photographs and histology. Fluorescent beads were identified in unstained histologic sections using the rhodamine filter with the light microscope. RESULTS: The fluorescent latex beads relocated from the subretinal space. Intact beads up to 2.0 µm were found in the choroid, sclera, and extrascleral space. The smaller beads were also found inside choroidal and extrascleral blood vessels. In contrast, the larger beads of 4.0 µm did not pass the Bruch's membrane. CONCLUSION: Subretinally implanted beads up to 2.0 µm pass the Bruch's membrane intact and cross the blood-ocular barrier. The intact beads are found in the choroid, sclera and inside blood vessels. The results give reason to consider the role of subretinal clearance and passage of Bruch's membrane in the development of AMD.

Repeated subretinal surgery and removal of subretinal decalin is well tolerated - evidence from a porcine model.

PURPOSE: Subretinal perfluorocarbon liquid (PFCL) is a serious complication that can occur after retinal detachment repair. It is possible to remove the PFCL surgically, but retinal damage related to the procedure is unknown. Also, increasing interest in subretinal treatment makes it relevant to examine the functional and morphological consequences of repeated subretinal manipulation. We hypothesized that PFCL in a porcine model can be injected in the subretinal space and removed with minimal effect on retinal structure and function. METHODS: The left eyes of ten healthy three-month-old female domestic pigs were included. Multifocal electroretinograms (mfERG) were recorded before surgery. Following vitrectomy, a PFCL bleb (decalin) was injected subretinally using a 41G cannula. After 14 days the decalin was removed through a 41G cannula in combination with a 2 ml syringe and an intermediate flexible tube. Two weeks after removal, a control mfERG was recorded, the pigs were enucleated and sacrificed and eyes were examined histologically. All statistics were carried out with a paired t-test in SAS Enterprise Guide 7.1® (SAS Institute Inc., Cary, NC, USA). RESULTS: There was no significant difference in mfERG amplitude ratio (left/right eye) between baseline and recordings two weeks after removal of decalin (P1 (M = 0.26, SD = 0.80, p = 0.39), second order kernel (M = -0.18, SD = 0.86, p = 0.57), Direct Response (M = 0.39, SD = 0.61, p = 0.12) or Induced Component (M = -0.03, SD = 0.40, p = 0.80)). Histologically, the photoreceptor outer segments were minimally affected. Otherwise the retina was normal 14 days after removal of decalin. In four pigs the subretinal decalin displaced inferiorly and was no longer accessible for removal. CONCLUSION: Subretinal decalin can be removed within 14 days without lasting retinal damage. Decalin is a heavy liquid where the risk of displacement is high. Future studies using PFCLs to control duration of an experimental retinal separation should focus on PFCLs that are isodense to the vitreus body.

THE ASSOCIATION BETWEEN CUTICULAR DRUSEN AND KIDNEY FUNCTION: A Population-Based Case-Control Study.

PURPOSE: To determine the association between cuticular drusen (CD) and kidney function. DESIGN: observational case-control study. SETTING: Population-based. Patients or Study Population: 53 participants with (CD) and 53 age- and sex-matched controls, selected from the Danish Rural Eye Study. Cuticular drusen participants were diagnosed using fluorescein angiography and controls were excluded if the patients were suspected of having CD on fundus photography or did not have an available estimated glomerular filtration rate. MAIN OUTCOME MEASURES: creatinine and estimated glomerular filtration rate. RESULTS: The mean estimated glomerular filtration rate of those with CD was 73.3 mL·min·1.73 m (95% confidence interval [CI]: 70.0-76.6) and 73.4 mL·minute·1.73 m (95% CI: 69.5-77.3) in controls. The difference was not significant (P: 0.970). The mean creatinine among those with CD was 72.8 µmol/L (69.3-76.4) and 73.5 µmol/L (95% CI: 69.3-77.6) among controls. The difference was not significant (P = 0.820). CONCLUSION: The authors did not find an association between a (CD) diagnosis and decreased kidney function at a population level.

[Gene therapy for hereditary eye diseases].

Inherited retinal disorders (IRD) are a common cause of severe visual impairment among children and young adults in Denmark. Gene therapy with voretigene neparvovec for a specific, and in Denmark common, cause of IRD (RPE65-related retinal dystrophy) was implemented as standard clinical practice in 2020 as the first of its kind. Twelve Danish patients have been treated with very positive outcomes. Genetically based therapies for other genetic causes of IRD are underway in clinical trials and are expected to change the outlooks for patients who would otherwise become blind early in life.

Retinal layer segmentation in rodent OCT images: Local intensity profiles & fully convolutional neural networks.

BACKGROUND AND OBJECTIVE: Optical coherence tomography (OCT) is a useful technique to monitor retinal layer state both in humans and animal models. Automated OCT analysis in rats is of great relevance to study possible toxic effect of drugs and other treatments before human trials. In this paper, two different approaches to detect the most significant retinal layers in a rat OCT image are presented. METHODS: One approach is based on a combination of local horizontal intensity profiles along with a new proposed variant of watershed transformation and the other is built upon an encoder-decoder convolutional network architecture. RESULTS: After a wide validation, an averaged absolute distance error of 3.77 ± 2.59 and 1.90 ± 0.91 µm is achieved by both approaches, respectively, on a batch of the rat OCT database. After a second test of the deep-learning-based method using an unseen batch of the database, an averaged absolute distance error of 2.67 ± 1.25 µm is obtained. The rat OCT database used in this paper is made publicly available to facilitate further comparisons. CONCLUSIONS: Based on the obtained results, it was demonstrated the competitiveness of the first approach since outperforms the commercial Insight image segmentation software (Phoenix Research Labs) as well as its utility to generate labelled images for validation purposes speeding significantly up the ground truth generation process. Regarding the second approach, the deep-learning-based method improves the results achieved by the more conventional method and also by other state-of-the-art techniques. In addition, it was verified that the results of the proposed network can be generalized to new rat OCT images.

3D image-guided treatment planning for Ruthenium-106 brachytherapy of choroidal melanomas.

BACKGROUND: Current standard treatment procedures for Ruthenium-106 (Ru-106) brachytherapy for choroidal melanomas do not use 3D image-guided treatment planning. We evaluated the potential impact of introducing 3D treatment planning and quantified the theoretical clinical benefits in terms of tumour control probability (TCP) and normal tissue complication probability (NTCP). MATERIALS AND METHODS: Treatment plans for thirty-two patients were optimized using 3D image-guided treatment planning and compared to the original 2D clinical plans. Optimization of plans was done in an image-based treatment planning system by optimizing the plaque position and treatment time such that the entire tumour received the prescribed dose of 100 Gy. TCP and NTCP for 2D clinical plans and optimized 3D image-guided plans were estimated from published outcome prediction models and compared within patients using Wilcoxon signed-rank test. RESULTS: The median minimum tumour dose (D99% ) for 2D clinical plans was 93 Gy (range: 23-158 Gy), corresponding to 5-year TCP of 75% (IQR 61-86%), while median tumour D99% for optimized 3D image-guided plans was 115 Gy (range 103-141 Gy), corresponding to TCP of 82% (IQR 80-84%). This was a statistically significant increase in estimated TCP (median increase in TCP 8% (IQR: -5-23, p = 0.006). While the dose to normal tissue increased somewhat, there was no significant change in NTCP. CONCLUSION: 3D treatment planning theoretically allows for improved tumour dose delivery for Ru-106 brachytherapy of choroidal melanomas, resulting in a significant increase in expected tumour control compared to traditional approaches using 2D calculations. The deliverability of optimized plans, and potential increased risk of late complications, will have to be confirmed in future clinical studies.

Loss of retinal tension and permanent decrease in retinal function: a new porcine model of rhegmatogenous retinal detachment.

PURPOSE: Permanent loss of visual function after rhegmatogenous retinal detachment can occur despite successful surgical reattachment in humans. New treatment modalities could be explored in a detachment model with loss of retinal function. In previous porcine models, retinal function has returned after reattachment, regardless of height and duration of detachment. Difference in retinal tension between the models and the disease might explain these different outcomes. This study investigates, for the first time in an in vivo porcine model, another characteristic of rhegmatogenous retinal detachment - the loss of retinal tension. METHODS: Left eyes (n = 12) of 3-month-old domestic pigs were included. Baseline multifocal electroretinogram (mfERG) and a fundus photograph were obtained following anaesthesia (isoflurane). The pigs were vitrectomized, saline was injected subretinally, and the RPE was removed. The eyes were evaluated at 2, 4 and 6 weeks after surgery. Four eyes were enucleated at each evaluation for histologic examinations. RESULTS: A retinal detachment structurally resembling rhegmatogenous retinal detachment was induced in 11 out of 12 pigs. MfERG amplitudes were significantly decreased despite partial reattachment four and 6 weeks after detachment. The retinal thickness decreased with 27%, the inner nuclear layer degenerated, Müller cells hypertrophied, and outer segments were lost. In the ganglion cell layer, cellularity increased and there was cytoplasmic staining with Cyclin D1. Vimentin and GFAP staining for glial cells increased. After 2 weeks of detachment, the ganglion cells had lost their nucleus and nucleolus. CONCLUSIONS: Loss of retinal tension in the detached retina seems to induce permanent damage with loss of retinal function. Death of ganglion cells, observed as soon as 2 weeks after detachment, explains the permanent loss of retinal function. The new model enables investigations of time-relationship between retinal detachment and lasting damage in addition to exploration of novel treatment modalities.

[Gene therapy for central nervous system disorders].

In recent years, gene therapy has resurged as a potential treatment for an increasing number of medical diseases including those affecting the central nervous system (CNS), which is discussed in this review. Clinical trials have revealed promising results particularly in gene therapy for Parkinson's disease with upregulation of dopamine synthesis or downregulation of huntingtin synthesis in Huntington's disease. Gene therapy for spinal motor atrophy has received FDA approval this year. The biggest success is seen in ophthalmology, where gene therapy has been FDA/EU-approved for retinitis pigmentosa, sparking further hope of use for other CNS diseases in a near future.

Localization, distribution, and connectivity of neuropeptide Y in the human and porcine retinas-A comparative study.

Neuropeptide Y (NPY) is a peptide neurotransmitter abundantly expressed in the mammalian retina. Since its discovery, NPY has been studied in retinas of several species, but detailed characterization of morphology, cell-type, and connectivity has never been conducted in larger mammals including humans and pigs. As the pig due to size and cellular composition is a well-suited animal for retinal research, we chose to compare the endogenous NPY system of the human retina to that of pigs to support future research in this field. In the present study, using immunohistochemistry, confocal microscopy and 3D reconstructions, we found NPY to be expressed in GABAergic and calretinin-immunoreactive (-ir) amacrine cells of both species as well as parvalbumin-ir amacrine cells of humans. Furthermore, we identified at least two different types of medium- to wide-field NPY-ir amacrine cells. Finally, we detected likely synaptic appositions between the NPY-ir amacrine cells and melanopsin- and nonmelanopsin-ir ganglion cells, GABAergic and dopaminergic amacrine cells, rod bipolar cells, and horizontal cells, suggesting that NPY-ir cells play diverse roles in modulation of both image and non-image forming retinal signaling. These findings extend existing knowledge on NPY and NPY-expressing cells in the human and porcine retina showing a high degree of comparability. The extensive distribution and connectivity of NPY-ir cells described in the present study further highlights the potential importance of NPY signaling in retinal function.

Neuropeptide Y treatment induces retinal vasoconstriction and causes functional and histological retinal damage in a porcine ischaemia model.

PURPOSE: To investigate the effects of intravitreal neuropeptide Y (NPY) treatment following acute retinal ischaemia in an in vivo porcine model. In addition, we evaluated the vasoconstrictive potential of NPY on porcine retinal arteries ex vivo. METHODS: Twelve pigs underwent induced retinal ischaemia by elevated intraocular pressure clamping the ocular perfusion pressure at 5 mmHg for 2 hr followed by intravitreal injection of NPY or vehicle. After 4 weeks, retinas were evaluated functionally by standard and global-flash multifocal electroretinogram (mfERG) and histologically by thickness of retinal layers and number of ganglion cells. Additionally, the vasoconstrictive effects of NPY and its involved receptors were tested using wire myographs and NPY receptor antagonists on porcine retinal arteries. RESULTS: Intravitreal injection of NPY after induced ischaemia caused a significant reduction in the mean induced component (IC) amplitude ratio (treated/normal eye) compared to vehicle-treated eyes. This reduction was accompanied by histological damage, where NPY treatment reduced the mean thickness of inner retinal layers and number of ganglion cells. In retinal arteries, NPY-induced vasoconstriction to a plateau of approximately 65% of potassium-induced constriction. This effect appeared to be mediated via Y1 and Y2, but not Y5. CONCLUSION: In seeming contrast to previous in vitro studies, intravitreal NPY treatment caused functional and histological damage compared to vehicle after a retinal ischaemic insult. Furthermore, we showed for the first time that NPY induces Y1- and Y2- but not Y5-mediated vasoconstriction in retinal arteries. This constriction could explain the worsening in vivo effect induced by NPY treatment following an ischaemic insult and suggests that future studies on exploring the neuroprotective effects of NPY might focus on other receptors than Y1 and Y2.

The effect of acute hypoxia and hyperoxia on the slow multifocal electroretinogram in healthy subjects.

PURPOSE: To characterize the topographic response of the healthy human retina to acute oxygenation changes in vivo, using multifocal electroretinography (mfERG). METHODS: Ten eyes in 10 subjects were examined while they breathed 21% oxygen (normoxia), 10% oxygen (hypoxia, with 90% nitrogen), or 100% oxygen (hyperoxia). Capillary oxygenation was monitored by percutaneous infrared oximetry. RESULTS: Compared with normoxia (mean Pao(2), 124 mm Hg), hypoxia (mean Pao(2), 36 mm Hg) was associated with an overall mfERG amplitude reduction, including a reduction in the multifocal oscillatory potentials (mfOPs). The hypoxic amplitude reduction of the first-order P1 response decreased monotonically (P < 0.0001) from 38.5% at 0 degrees to 2 degrees eccentricity to 17.8% at the highest eccentricity (25 degrees ). Likewise, the amplitude reduction of first-order N2 decreased from 33.0% centrally to 18.3% at the highest eccentricity (P = 0.0019). In contrast, hypoxia only reduced the average first-order N1 amplitude by 9.5% (P = 0.016). Hypoxia also reduced mfOP amplitudes, by 16.6% to 34.8%, but no effect of eccentricity was detectable. Hyperoxia had no significant effect on amplitude. Neither hypoxia nor hyperoxia had any effect on the latency of the P1 implicit times. CONCLUSIONS: The present study demonstrated regional differences in response to hypoxia. The origin of this difference is not known but may be explained by a combination of differences in cone structure, circulation of different regions, or differences in the microenvironment around different cones. The function of the central retina is expected to be more susceptible to the hypoxia that may occur in disease. The relative effect of hypoxia on the photopic N1 and P1 is similar to that on the scotopic a- and b-wave in other mammals, and the present work extends the current knowledge by showing regional effects that were previously undetected.

Time-Dependent Decline in Multifocal Electroretinogram Requires Faster Recording Procedures in Anesthetized Pigs.

PURPOSE: The time-dependent effect of anesthetics on the retinal function is debated. We hypothesize that in anesthetized animals there is a time-dependent decline that requires optimized multifocal electroretinogram (mfERG) recording procedures. METHODS: Conventional and four-frame global-flash mfERG recordings were obtained approximately 15, 60, and 150 minutes after the induction of propofol anesthesia (20 pigs) and isoflurane anesthesia (nine pigs). In six of the propofol-anesthetized pigs, the mfERG recordings were split in 3-minute segments. Two to 4 weeks after initial recordings, an intraocular injection of tetrodotoxin (TTX) was given and the mfERG was rerecorded as described above. Data were analyzed using mixed models in SAS statistical software. RESULTS: Propofol significantly decreases the conventional and global-flash amplitudes over time. The only significant effect of isoflurane is a decrease in the global-flash amplitudes. At 15 minutes after TTX injection several of the mfERG amplitudes are significantly decreased. There is a linear correlation between the conventional P1 and the global-flash DR mfERG-amplitude (R2 = 0.82, slope = 0.72, P < 0.0001). There is no significant difference between the 3-minute and the prolonged mfERG recordings for conventional amplitudes and the global-flash direct response. The global flash-induced component significantly decreases with prolonged mfERG recordings. CONCLUSIONS: A 3-minute mfERG recording and a single stimulation protocol is sufficient in anesthetized pigs. Recordings should be obtained immediately after the induction of anesthesia. The effect of TTX is significant 15 minutes after injection, but is contaminated by the effect of anesthesia 90 minutes after injection. Therefore, the quality of mfERG recordings can be further improved by determining the necessary time-of-delay from intraocular injection of a drug to full effect. TRANSLATIONAL RELEVANCE: General anesthesia is a possible source of error in mfERG recordings. Therefore, it is important to investigate the translational relevance of the results to mfERG recordings in children in general anesthesia.

Bilateral diffuse uveal melanocytic proliferation: Case report and literature review.

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular disease that causes progressive visual loss in patients driven by an IgG factor associated with an underlying malignancy. Characteristic ocular findings include exudative retinal detachment, rapid cataract formation and uveal melanocytic tumours. The awareness and documentation of BDUMP has increased during the past decade, and the increasing amount of data collected demonstrates the effect of treatment with plasmapheresis and the value of diagnostic tools in BDUMP such as genetic and immunologic investigations. The literature of BDUMP has not been reviewed since 2003, and there is a growing need for an updated review on diagnosis and management of BDUMP. We review the literature and report a case of BDUMP with a white ciliary body tumour, iris rubeosis, increased iris pigmentation and cataract.

Ultrasonic mirror image from ruthenium plaque facilitates calculation of uveal melanoma treatment dose.

BACKGROUND/AIMS: To present a new method to determine dose depth and the distance from the concave side of the plaque to the tumour base in patients with uveal melanoma treated with ruthenium-106 based on ultrasonic mirror image. METHODS: We used the mirror image associated with ultrasound during plaque brachytherapy to determine intraobserver reproducibility and interobserver agreement between two surgeons. 230 eyes with primary uveal melanoma were included in a retrospective analysis to determine the distance from the plaque to the tumour base using ultrasound. A phantom study was used to illustrate the effects on radiation dose to apex of the tumour when the dose depth was incorrectly determined. Doses to apex of the tumour were determined using Plaque Simulator. RESULTS: The intraobserver variation in dose depth measurement with plaque was significantly lower than for measures without plaque (p<0.001). Agreement between the surgeons was better with a plaque in place. Distances from the plaque to the tumour base were distributed with mean=0.99 (median: 1, range: 0.1-2.9 mm). From the phantom study, it was clear that the tumour did not receive the prescribed 100 Gy if the dose depth was incorrectly determined. CONCLUSIONS: The dose depth in patients with uveal melanoma must be measured accurately for correct calculation of the radiation dose to the apex of the tumour. Repeated in vivo and in vitro ultrasound measurements of dose depth showed higher variance than measurements using the mirror image produced from a ruthenium plaque. Using the mirror image thus help to improve the dose calculation.

An evaluation of fundus photography and fundus autofluorescence in the diagnosis of cuticular drusen.

PURPOSE: To examine non-mydriatic fundus photography (FP) and fundus autofluorescence (FAF) as alternative non-invasive imaging modalities to fluorescein angiography (FA) in the detection of cuticular drusen (CD). METHODS: Among 2953 adults from the Danish Rural Eye Study (DRES) with gradable FP, three study groups were selected: (1) All those with suspected CD without age-related macular degeneration (AMD) on FP, (2) all those with suspected CD with AMD on FP and (3) a randomly selected group with early AMD. Groups 1, 2 and 3 underwent FA and FAF and group 4 underwent FAF only as part of DRES CD substudy. Main outcome measures included percentage of correct positive and correct negative diagnoses, Cohen's κ and prevalence-adjusted and bias-adjusted κ (PABAK) coefficients of test and grader reliability. RESULTS: CD was correctly identified on FP 88.9% of the time and correctly identified as not being present 83.3% of the time. CD was correctly identified on FAF 62.0% of the time and correctly identified as not being present 100.0% of the time. Compared with FA, FP has a PABAK of 0.75 (0.60 to 1.5) and FAF a PABAK of 0.44 (0.23 to 0.95). CONCLUSIONS: FP is a promising, non-invasive substitute for FA in the diagnosis of CD. FAF was less reliable than FP to detect CD.

Danish Rural Eye Study: Epidemiology of Adult Visual Impairment.

PURPOSE: To examine the frequency and causes of visual impairment (VI) in a select population of Danish adults. METHODS: A total of 3843 adults aged 20-94 years from the Danish General Suburban Population Study (GESUS) were included in the population-based, cross-sectional ophthalmological study, Danish Rural Eye Study (DRES). All DRES participants received a comprehensive general health examination preceding their eye examination, including measurement of best-corrected visual acuity (BCVA) for each eye, bilateral 45° retinal fundus photographs and further ophthalmological examination where indicated. RESULTS: Overall, 3826 of 3843 participants (99.6%) had bilateral visual acuity measurements. The overall frequency of VI (BCVA <20/40 in the better-seeing eye) was 0.4% (95% confidence interval, CI, 0.2-0.7%; n = 15) among all DRES participants, 0.6% (95% CI 0.3-1.0%; n = 15) among participants >50 years and 3.7% (95% CI 2.1-6.5%; n = 11) in participants >80 years. The primary causes of VI in the better-seeing eye were age-related macular degeneration (AMD) in 46.7% (7/15) and cataract in 26.7% (4/15). A total of 43.3% (n = 115) of participants >80 years were pseudophakic in one or both eyes. The frequency of diabetes (HbA1c ≥ 48 mmol/mol or self-reported diagnosis) was 5.9% (n = 227), including 1.3% (n = 51) newly diagnosed in the GESUS. Of participants determined to have VI due to exudative AMD, 50% had received anti-vascular endothelial growth factor (VEGF) treatment. CONCLUSION: We report a relatively low frequency of VI among Danish adults over 59 years of age compared with that observed 10-15 years ago, which is both consistent with other recent Scandinavian studies and reflective of our relatively healthy and mobile population sample.

The multifocal ERG in diabetic patients without retinopathy during euglycemic clamping.

PURPOSE: Prolonged multifocal electroretinogram (mfERG) implicit times have been observed in diabetes, although the acute response to hyperglycemia is an acceleration of the ERG. The hypothesis for the current investigation was that this discrepancy is caused by a protracted adaptational response of the retina to hyperglycemia. METHODS: Fourteen patients with type 1 diabetes without retinopathy were blood glucose clamped at 5 mM for 75 minutes before the recording of the mfERG. The results were compared with those found in 14 age-matched healthy subjects. RESULTS: During acute normoglycemia, patients with type 1 diabetes without retinopathy demonstrated an overall 1.36-ms delay of the P1 first-order implicit times (P = 0.0013) and a 0.72-ms delay of the second-order P1 (P = 0.0049) compared with healthy subjects at 4.9 +/- 0.28 mM blood glucose. During acute hyperglycemia, the P1 first-order delay was only 0.81 ms (P = 0.02), and the P1 second-order implicit time was comparable to that of healthy subjects (P > 0.05). The magnitude of the diabetes-associated implicit time delay, at both levels of glycemia, was proportional to the level of chronic hyperglycemia at study entry, as expressed by the patients' HbA1c. CONCLUSIONS: During acute normoglycemia, patients with type 1 diabetes without retinopathy demonstrated a delayed mfERG response compared with the healthy subjects. The delay was more pronounced during euglycemia than during hyperglycemia, and at both levels of glycemia, the delay was proportional to the patients' habitual hyperglycemia. The results show that chronic hyperglycemia induces an adaptational response that tends to normalize retinal implicit times at a higher level of habitual glycemia.

Effect of ruboxistaurin on blood-retinal barrier permeability in relation to severity of leakage in diabetic macular edema.

PURPOSE: The purpose of the study was to investigate the effect of orally administered ruboxistaurin (RBX, LY333531), a selective protein kinase C beta inhibitor, on the permeability of the blood-retinal barrier in patients with diabetic macular edema. METHODS: Forty-one patients with diabetic macular edema were randomly assigned to an 18-month randomized, placebo-controlled, double-masked trial including four study arms (4, 16, or 32 mg/d RBX, or placebo). The RBX group comprised 30 patients (42 eyes) and the placebo group 11 patients (13 eyes). Retinal vascular leakage was assessed using vitreous fluorometry at baseline and after 3, 12, and 18 months. Statistical analysis of the effect of treatment accounted for repeated measurements and tested potential interaction with baseline permeability, HbA(1c), and arterial blood pressure. RESULTS: Statistical analysis and modeling demonstrated a significant interaction between RBX treatment at any dosage and baseline permeability (P = 0.032, mixed models). A threefold or higher increase in retinal vascular leakage at baseline was associated with a significant reduction (30%) in retinal vascular leakage after RBX treatment compared with placebo. Visual acuity was normal at baseline and remained unchanged throughout the study. CONCLUSIONS: RBX treatment was associated with a reduction of retinal vascular leakage in eyes that had diabetic macular edema and markedly elevated leakage at baseline. These data suggest that clinical benefit from RBX treatment may be most prominent in patients with severe macular edema at baseline, and trials investigating this therapy may benefit from stratification according to baseline leakage.

Transorbital impalement by a wooden stick in a 3-year-old child.

We present a case of a 3-year-old girl with a transorbital impalement injury due to a wooden stick penetrating the lower inferior palpebra and progressing through the orbita, after the child jumped from a table and hit a wooden basket containing pieces of exposed stick. CT revealed the stick progressing transorbitally through the medial wall and terminating just below the sella turcica. The stick was successfully removed by neurosurgical and ophthalmological specialists. The eye was subsequently inspected, and showed no pathological findings. The girl was treated with topical chloramphenicol and discharged 2 days later. Follow-up examination 2 months after the trauma demonstrated normal visual acuity and ocular motility, with no diplopia, tearing or pain.