Recovery Of Retinal Function Research Articles

Lack of netrin-4 modulates pathologic neovascularization in the eye.

Netrins are a family of matrix-binding proteins that function as guidance signals. Netrin-4 displays pathologic roles in tumorigenesis and neovascularization. To answer the question whether netrin-4 acts either pro- or anti-angiogenic, angiogenesis in the retina was assessed in Ntn-4−/− mice with oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV), mimicking hypoxia-mediated neovascularization and inflammatory mediated angiogenesis. The basement membrane protein netrin-4 was found to be localised to mature retinal blood vessels. Netrin-4, but not netrin-1 mRNA expression, increased in response to relative hypoxia and recovered to normal levels at the end of blood vessel formation. No changes in the retina were found in normoxic Ntn-4−/− mice. In OIR, Ntn-4−/− mice initially displayed larger avascular areas which recovered faster to revascularization. Ganzfeld electroretinography showed faster recovery of retinal function in Ntn-4−/− mice. Expression of netrin receptors, Unc5H2 (Unc-5 homolog B, C. elegans) and DCC (deleted in colorectal carcinoma), was found in Müller cells and astrocytes. Laser-induced neovascularization in Nnt-4−/− mice did not differ to that in the controls. Our results indicate a role for netrin-4 as an angiogenesis modulating factor in O2-dependent vascular homeostasis while being less important during normal retinal developmental angiogenesis or during inflammatory neovascularization.

Recovery of photoreceptor inner and outer segment layer thickness after reattachment of rhegmatogenous retinal detachment

AimsTo evaluate the recovery of retinal function and the thicknesses of the photoreceptor inner (IS) and outer segment (OS) layers after a reattachment of a rhegmatogenous retinal detachment (RRD).Methods49 eyes...

Neurologic state transitions in the eye and brain: kinetics of loss and recovery of vision and consciousness.

Visual alterations, peripheral light loss (PLL) and blackout (BO), are components of acceleration (+Gz) induced loss of consciousness (LOC) and recovery of consciousness (ROC). The kinetics of loss of vision (LOV) and recovery of vision (ROV) were determined utilizing ocular pressure induced retinal ischemia and compared to the kinetics of LOC and ROC resulting from +Gz-induced cephalic nervous system (CPNS) ischemia. The time from self-induced retinal ischemia in completely healthy subjects (N = 104) to the onset of PLL and complete BO was measured. The time from release of ocular pressure, with return of normal retinal circulation, to the time for complete recovery of visual fields was also measured. The kinetics of pressure induced LOV and ROV was compared with previously developed kinetics of +Gz-induced LOC and ROC focusing on the rapid onset, vertical arm, of the +Gz-induced LOC and ROC curves. The time from onset of increased ocular pressure, immediately inducing retinal ischemia, to PLL was 5.04 s with the time to BO being 8.73 s. Complete recovery of the visual field from BO following release of ocular pressure, immediately abolishing retinal ischemia, was 2.74 s. These results confirm experimental findings that visual loss is frequently not experienced prior to LOC during exposure to rapid onset, high levels of +Gz-stress above tolerance. Offset of pressure induced retinal ischemia to ROV was 2.74 s, while the time from offset of +Gz-induced CPNS ischemia to ROC was 5.29 s. Recovery of retinal function would be predicted to be complete before consciousness is regained following +Gz-induced LOC. Ischemia onset time normalization in neurologic tissues permits comparison between different stress-induced times to altered function. The +Gz-time tolerance curves for LOV and LOC provide comparison and integration of neurologic state transition kinetics in the retina and CPNS.

Could Crocus sativus (saffron) be combined with conventional therapies for ocular diseases?

Dear Sir, Oxidative stress due the continuous contact of ocular tissues with radiation, atmospheric oxygen, environmental chemicals, and physical abrasion has been proposed to play a vital role in diseases such as glaucoma, cataract, uveitis, retrolental fibroplasias, age-related macular degeneration (AMD), and various forms of retinopathy. This offers a prospect for novel approach to their prevention and treatment. Unfortunately, there are no curative treatment options for AMD, and even palliative treatments are few. The utilized therapeutic modalities are associated with various adverse effects, are costly, and only manage the consequence without tackling the cause of the pathology. Hence, many novel options are being investigated. Conventional and newly promising management measures have not accomplished in reversing the outcome of ocular diseases to any radical extent. This has implied researchers to investigate alternative treatment options. Hence, the widespread collections of traditional medicinal knowledge systems from various parts of the world are re-investigated for their healing properties. Crocus sativus L., commonly known as saffron, is the raw material for one of the most expensive spices in the world, and it has been used in folk medicine for centuries. The major active constituents of saffron are crocin, crocetin, and safranal. There is increasing substantiation that the spice saffron, which contains powerful anti-oxidants, offers protection against neurodegenerative disorders, including AMD and Alzheimer's disease.[1] Ischemic retinopathy and AMD are the foremost ocular diseases that cause blindness. The etiology of these diseases is due in part to the reduction of blood flow in the retina and/or choroid. Crocin analogs isolated from C. sativus L. were found to significantly increase the blood flow in the retina and choroid and to facilitate retinal function recovery.[2] Experimental studies conducted by Ishizuka et al. have demonstrated that crocetin prevents ischemia-induced retinal damage through its inhibition of oxidative stress.[3] Results from the experiment by Yamauchi et al. suggest that crocetin has protective effects against retinal damage in vitro and in vivo, indicating that crocetin could suppress increase in caspase-3 and caspase-9 activities following retinal damage.[4] In a randomized clinical trial, it was demonstrated that short-term saffron supplementation improves retinal flicker sensitivity in early AMD.[5] Saffron extract prevented selenite-induced cataract formation in Wistar rats, probably due to the fortification of antioxidant status, diminution of the concentration of lipid peroxidation, shielding the sulfhydryl groups, and suppression of proteolysis of the lens water-soluble fraction. These findings highlight the anticataractogenic potential of saffron by virtue of its antioxidant property.[6] These attractive effects propose its presence as a therapeutic agent in future. Though saffron and its constituents have shown multiple useful effects, clinical evidence is still scarce in this regard, and more comprehensive studies with special focus on human clinical trials are required. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Chitosan Oligosaccharides Attenuates Oxidative-Stress Related Retinal Degeneration in Rats

This study investigated the therapeutic potential and mechanisms of chitosan oligosaccharides (COS) for oxidative stress-induced retinal diseases. Retinal oxidative damage was induced in Sprague-Dawley rats by intravitreal injection of paraquat (PQ). Low-dose (5 mg/kg) or high-dose (10 mg/kg) COS or PBS was intragastrically given for 14 days after PQ injection. Electroretinograms were performed to determine the functionality of the retinas. The surviving neurons in the retinal ganglion cell layer and retinal apoptosis were determined by counting Neu N-positive cells in whole-mounted retinas and TUNEL staining, respectively. The generation of reactive oxygen species (ROS) was determined by lucigenin- and luminol-enhanced chemiluminescence. Retinal oxidative damages were assessed by staining with nitrotyrosine, acrolein, and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Immunohistochemical studies were used to demonstrate the expression of nuclear factor-kappa B (NF-κB) p65 in retinas. An in vitro study using RGC-5 cells was performed to verify the results. We demonstrated COS significantly enhanced the recovery of retinal function, preserved inner retinal thickness, and decreased retinal neurons loss in a dose-dependent manner. COS administration demonstrated anti-oxidative effects by reducing luminol- and lucigenin-dependent chemiluminenscense levels and activating superoxide dismutase and catalase, leading to decreased retinal apoptosis. COS markedly reduced retinal NF-κB p65. An in vitro study demonstrated COS increased IκB expression, attenuated the increase of p65 and thus decreased NF-κB/DNA binding activity in PQ-stimulated RGC-5 cells. In conclusion, COS attenuates oxidative stress-induced retinal damages, probably by decreasing free radicals, maintaining the activities of anti-oxidative enzymes, and inhibiting the activation of NF-κB.

Passive immunization with Pneumovax®23 and pneumolysin in combination with vancomycin for pneumococcal endophthalmitis

BackgroundCapsule and pneumolysin (PLY) are two major virulence factors of Streptococcus pneumoniae. S. pneumoniae is one of the leading causes of bacterial endophthalmitis. The aim of this study is to determine whether passive immunization with the 23-valent pneumococcal polysaccharide vaccine (Pneumovax® 23; PPSV23) or PLY protects against pneumococcal endophthalmitis.MethodsNew Zealand white rabbits were passively immunized with antiserum to PLY, PPSV23, a mixture of PPSV23/PLY, or PBS (mock). Vitreous was infected with a clinical strain of S. pneumoniae. In a separate group of experiments, vancomycin was injected 4 hours post-infection (PI) for each passively immunized group. Severity of infection, bacterial recovery, myeloperoxidase (MPO) activity and percent loss of retinal function were determined.ResultsPassive immunization with each antiserum significantly lowered clinical severity compared to mock immunization (PPSV23 = 9.19, PPSV23/PLY = 10.45, PLY = 8.71, Mock = 16.83; P = 0.0467). A significantly higher bacterial load was recovered from the vitreous of PLY passively immunized rabbits 24 hours PI (7.87 log10 CFU) compared to controls (7.10 log10 CFU; P = 0.0134). Retinas from immunized rabbits were more intact. Vitreous of PLY (2.88 MPO untis/mL) and PPSV23/PLY (2.17) passively immunized rabbits had less MPO activity compared to controls (5.64; P = 0.0480), and both passive immunizations (PLY = 31.34% loss of retinal function, PPSV23/PLY = 27.44%) helped to significantly preserve retinal function compared to controls (64.58%; P = 0.0323). When vancomycin was administered 4 hours PI, all eyes were sterile at 24 hours PI. A significantly lower clinical severity was observed for rabbits administered the combination immunization (5.29) or PPSV23 (5.29) with vancomycin treatment compared to controls (17.68; P = 0.0469).ConclusionsPassive immunization with antisera to these antigens is effective in reducing clinical severity of pneumococcal endophthalmitis in rabbits. Addition of vancomycin to immunization is effective at eliminating the bacteria.

Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

Defects in the β subunit of rod cGMP phosphodiesterase 6 (PDE6β) are associated with autosomal recessive retinitis pigmentosa (RP), a childhood blinding disease with early retinal degeneration and vision loss. To date, there is no treatment for this pathology. The aim of this preclinical study was to test recombinant adeno-associated virus (AAV)-mediated gene addition therapy in the rod-cone dysplasia type 1 (rcd1) dog, a large animal model of naturally occurring PDE6β deficiency that strongly resembles the human pathology. A total of eight rcd1 dogs were injected subretinally with AAV2/5RK.cpde6β (n = 4) or AAV2/8RK.cpde6β (n = 4). In vivo and post-mortem morphological analysis showed a significant preservation of the retinal structure in transduced areas of both AAV2/5RK.cpde6β- and AAV2/8RK.cpde6β-treated retinas. Moreover, substantial rod-derived electroretinography (ERG) signals were recorded as soon as 1 month postinjection (35% of normal eyes) and remained stable for at least 18 months (the duration of the study) in treated eyes. Rod-responses were undetectable in untreated contralateral eyes. Most importantly, dim-light vision was restored in all treated rcd1 dogs. These results demonstrate for the first time that gene therapy effectively restores long-term retinal function and vision in a large animal model of autosomal recessive rod-cone dystrophy, and provide great promise for human treatment.

Enhanced retinal pigment epithelium regeneration after injury in MRL/MpJ mice

Regenerative medicine holds the promise of restoring cells and tissues that are destroyed in human disease, including degenerative eye disorders. However, development of this approach in the eye has been limited by a lack of animal models that show robust regeneration of ocular tissue. Here, we test whether MRL/MpJ mice, which exhibit enhanced wound healing, can efficiently regenerate the retinal pigment epithelium (RPE) after an injury that mimics the loss of this tissue in age-related macular degeneration. The RPE of MRL/MpJ and control AKR/J mice was injured by retro-orbital injection of sodium iodate at 20 mg/kg body weight, which titration studies indicated was optimal for highlighting strain differences in the response to injury. Five days after sodium iodate injection at this dose, electroretinography of both strains revealed equivalent retinal responses that were significantly reduced compared to untreated mice. At one and two months post-injection, retinal responses were restored in MRL/MpJ but not AKR/J mice. Bright field and fluorescence microscopy of eyecup cryosections indicated an initial central loss of RPE cells and RPE65 immunostaining in MRL/MpJ and AKR/J mice, with preservation of peripheral RPE. Phalloidin staining of posterior eye whole mounts confirmed this pattern of RPE loss, and revealed a transition region characterized by RPE cell shedding and restructuring in both strains, suggesting a similar initial response to injury. At one month post-injection, central RPE cells, RPE65 immunostaining and phalloidin staining were restored in MRL/MpJ but not AKR/J mice. BrdU incorporation was observed throughout the RPE of MRL/MpJ but not AKR/J mice after one month of administration following sodium iodate treatment, consistent with RPE proliferation. These findings provide evidence for a dramatic regeneration of the RPE after injury in MRL/MpJ mice that supports full recovery of retinal function, which has not been observed previously in mammalian eyes. This model should prove useful for understanding molecular mechanisms that underlie regeneration, and for identifying factors that promote RPE regeneration in age-related macular degeneration and related diseases.

Follow-up study on multifocal electroretinogram of acute and convalescence stage of Vogt-Koyanagi-Harada syndrome

Background Researches showed that multifocal electroretinogram （mfERG） is able to assess the retinal function in the eyes with acute Vogt-Koyanagi-Harada （VKH） syndrome. But the mfERG characteristics of convalescence stage of VKH are still below clear. Objective Present study was to compare and follow up the variation process of visual acuity and mfERG in acute and recovery stages of VKH syndrome. Methods This was a clinic-based retrospective study. Visual acuity, mfERG and fundus fluorescence angiography （FFA） were recorded from 35 eyes of 18 acute VKH cases. The period of follow-up in recovery stage lasted about 18 months with the repetitive recording results for 4 times. Results In this study,the visual acuity range in acute stage VKH was 0.01 to 1.0, and 91.4% （32/35 eyes） was below 0.6. Compared with normal control group, the visual acuity wassignificantly decreased （ P〈0. O1 ）. The response densities （amplitudes） of N,, PI waves of the first-order kernel were significantly lowed in all the 6 rings,and the implicit times of 1-4 rings of both waves were significantly prolonged in acute VKH eyes（P〈0.05 ）. The abnormalities of retinal function showed a regional difference at the posterior pole retina with the dominant change in the first ring,showing a cutting off 78% in the PI amplitude. The abnormal degree of mfERG was more serious as the the increase of retinal eccentricity. In 2 months of convalescence after glucocorticosteroids therapy, the range of visual acuity were 0. 1-1.2, and the amplitudes of N1 ,Pl of 1-2 rings were greatly elevated in comparison with acute on-set （P〈0.05）. However, there was still a remarkable difference in the amplitudes of from 1 through 6 rings,comparing with normal. The response density of Pl wave from whole recording region was only 44% of normal. Though the visual acuity was stable during the follow-up duration, a decreasing tendency in NI and PI amplitudes were seen. The implicit times of both wave shortened only in 1-3 rings in recovery stages of VKH （ P 〈 0. 05 ）. Conclusion VKH syndrome cause serious damage of posterior retinal function. Macular region is the site with greater retinal functional lesion and restore before and after medication. This hardly recovery of retinal function can last over one and half year, even satisfied visual acuity is stable after proper treatment. Key words: Vogt-Koyanagi-Harada syndrome; Visual acuity; Multifocal electroretinogram

The human visual cortex responds to gene therapy–mediated recovery of retinal function

The human visual cortex responds to gene therapy–mediated recovery of retinal function

The human visual cortex responds to gene therapy–mediated recovery of retinal function

Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity.

Possible mechanisms of retinal function recovery with the use of cell therapy with bone marrow-derived stem cells

Bone marrow has been proposed as a potential source of stem cells for regenerative medicine. In the eye, degeneration of neural cells in the retina is a hallmark of such widespread ocular diseases as age-related macular degeneration (AMD) and retinitis pigmentosa. Bone marrow is an ideal tissue for studying stem cells mainly because of its accessibility. Furthermore, there are a number of well-defined mouse models and cell surface markers that allow effective study of hematopoiesis in healthy and injured mice. Because of these characteristics and the experience of bone marrow transplantation in the treatment of hematological disease such as leukemia, bone marrow-derived stem cells have also become a major tool in regenerative medicine. Those cells may be able to restore the retina function through different mechanisms: A) cellular differentiation, B) paracrine effect, and C) retinal pigment epithelium repair. In this review, we described these possible mechanisms of recovery of retinal function with the use of cell therapy with bone marrow-derived stem cells.

Comparative study of patients with central serous chorioretinopathy undergoing focal laser photocoagulation or photodynamic therapy

AimsTo compare clinical outcomes for patients with central serous chorioretinopathy (CSC) undergoing either focal laser photocoagulation or photodynamic therapy (PDT).Methods26 eyes of 26 patients with symptomatic CSC underwent focal laser...

Granulocyte colony-stimulating factor facilitates recovery of retinal function following retinal ischemic injury

The purpose of the present study was to investigate whether systemically administered granulocyte colony-stimulating factor (G-CSF) can protect against acute ischemic reperfusion injury. Two groups of anesthetized adult male Lewis rats ( n = 8 per group) were subjected to an acute (45 min) episode of retinal ischemic injury followed by subcutaneous administration of vehicle (5% dextrose) or G-CSF (0.1 mg/kg/day) once per day × 5 days. Prior to and one week following ischemic insult, retinal function was measured by scotopic electroretinography (ERG). Retinas were harvested and morphologically analyzed one week after ischemic insult. ERG a- and b-wave amplitudes were significantly reduced following ischemic reperfusion injury. G-CSF treatment attenuated ischemic-induced loss of retinal function. In control vehicle-treated rats, ischemic reperfusion injury elicited marked and selective thinning of inner retinal layers while only minimally affecting outer retinal layers. Therapeutically administered G-CSF minimized ischemic-mediated thinning of whole retina and inner retinal layers. G-CSF may be of therapeutic interest for the management of retinal ischemic disorders.

CHANGES IN RETINAL SENSITIVITY FROM RETAINED SUBRETINAL PERFLUOROCARBON LIQUID

To study the effect of retained subretinal perfluorocarbon liquid (PFCL) on retinal function. Scanning laser ophthalmoscope microperimetry was performed on four eyes with retained subretinal PFCL after vitreoretinal surgery for complicated retinal detachments with and without proliferative vitreoretinopathy. Scotomas to the highest intensity stimulus were noted in the area of the subretinal PFCL in all four eyes. All scotomas encompassed approximately the same area as the retained PFCL droplets. In the area vacated by a migrating PFCL droplet in one eye, the highest intensity stimulus could be perceived, but a relative scotoma (to a lower intensity stimulus) was present. There is a local reduction in retinal function in the area of retained subretinal PFCL. There may be partial recovery of retinal function in an area vacated by the subretinal PFCL. Subretinal PFCL beneath the fovea or at risk for migration beneath the fovea should be considered for removal.

Intravitreal Bevacizumab for Choroidal Neovascularization Attributable to Pathological Myopia: One-Year Results

To assess the potential effect of intravitreal bevacizumab (IVB) (Avastin) on retinal function and anatomic recovery in eyes with choroidal neovascularization attributable to pathological myopia (mCNV). Retrospective case series. setting: Institutional. patient population: Sixty-three eyes of 63 patients were treated with IVB for mCNV. intervention procedure: 1 mg of bevacizumab was injected into the vitreous via the pars plana. IVB was repeated after two to three months if there was fluorescein leakage in fluorescein angiogram (FA), apparent subretinal fluid in optical coherence tomography (OCT) persisted, or both. main outcome measurement: Best-corrected visual acuity (BCVA) and CNV size measured on FA. IVB was performed one to six times during the first 12 months (mean, 2.4 +/- 1.4 times). The size of the mCNV decreased and the BCVA improved significantly (P < .01 for both comparisons). The BCVA improved more than three lines in 25 eyes (40%), worsened more than three lines in three eyes (5%), and was unchanged in 35 (56%) eyes 12 months after. Fluorescein leakage from the mCNV ceased in 30 eyes (48%), diminished in 28 (44%), and was unchanged in five (8%) eyes. Stepwise analysis showed that the number of IVB (P < .01), macular atrophy associated with mCNV (P < .05), and myopic atrophy (P < .05) were significant predictive factors for BCVA at 12 months. Although the current study lacked a control group, IVB seems to be an effective treatment for mCNV after a long-term. The absence of chorioretinal atrophy and that of recurrence and persistency of mCNV are positive predictive factors.

Hyperbaric oxygen treatment for experimental intraocular hypertension in rats: An lectroretinogram detection

Background Hyperbaric oxygen (HBO) is used for treating glaucoma, and affirmative curative effect has been obtained. HBO can sensitively reflect the obviously heightened b wave of electroretinogram (ERG) of injured tissue. Objective To observe the effect of HBO treatment on retinal function of rats with acute experimental intraocular hypertension with ERG. Design Randomized controlled experiment. Setting Department of Ophthalmology, Third Xiangya Hospital, Central South University; Department of Hyperbaric Oxygen, Xiangya Hospital, Central South University; Department of Anatomy, Xiangya Hospital, Central South University. Materials Eighteen adult healthy Wistar rats, of either gender, weighing from 150 to 250 g, were provided by the Animal Room of Central South University. Type YLCO. 5/?A baby hyperbaric oxygen chamber, type LMS-2A two-channel physiological recorder, type BG-1 retina exposure system, Jiangwan type ?stereotaxis instrument. Methods This experiment was carried out in the Central South University between March and September 2006. Eighteen healthy Wistar rats were made into models of acute experimental intraocular hypertension. Then, they were divided into two groups: model group and HBO treatment group, with 9 in each group. Following 7 days of HBO treatment, the rats in HBO treatment group were placed in Type YLCO. 5/?A baby hyperbaric oxygen chamber, which was pressurized with pure oxygen (volume fraction 0.825±0.025). The treatment pressure was 0.2 MPa. The rats in HBO treatment group daily inhaled HBO for 80 minutes within 7 days; Rats in the model group were untouched. The performance of eyes was observed under the status of intraocular hypertension. ERG was recorded before, during and 7 days after modeling, meanwhile, the recovery rate of b wave from ERG was calculated. Recovery rate of b wave from ERG=(amplitude of b wave 7 days after modeling/amplitude of b wave before modeling)×100%. Main outcome measures ▪ Performance of eyes under the status of intraocular hypertension. ▪ Recovery rate of b wave of ERG. Results All the 18 rats were involved in the final analysis. ▪ Performance of eyes under the status of intraocular hypertension.: When intraocular pressure increased until b wave of ERG disappeared, two eyes of rats with corneal opacity, dilated pupils, pale iris and stiffened eyeballs were found. ▪ Recovery rate of b wave of ERG in the HBO treatment group was significantly higher than that in the model group [(60.04±19.33)% vs. (41.85±13.20)%, t =3.298, P < 0.01]. Conclusion HBO treatment can obviously promote the recovery of retinal function following acute intraocular hypertension.

The Rate of Functional Recovery from Acute IOP Elevation

To evaluate the recovery of retinal function after acute IOP elevation. The electroretinogram (ERG) was measured before, during, and after IOP increased to 50 and 70 mm Hg at different durations in anesthetized, dark-adapted rats (n = 5-7). Signals were collected for dim and bright flashes (-4.95 and 1.0 log cd . s/m(2)) and analyzed in terms of the photoreceptoral (P3), postreceptoral (P2), and inner retinal (negative scotopic threshold response [nSTR]) responses. Parameters (treatment/baseline, %) were compared across time by using repeated-measures ANOVA and t-tests. The rate of recovery was quantified with a logistic function and compared by bootstrap. IOP spikes induce greater loss (P < 0.01) and slower recovery (P < 0.001) in the nSTR compared with the P2 and P3 responses. IOP spikes having common integral (pressure x duration, 2100 mm Hg x minutes) for insult gave significantly greater P2 and nSTR dysfunction at the higher pressure (70 vs. 50 mm Hg, nSTR reduced to -2.5% +/- 0.5% vs. 20.3% +/- 6.5%, P < 0.05). The higher pressure also produced significantly slower nSTR recovery (50% recovery time [t(0.5)] 70 vs. 50 mm Hg: 33.1 vs. 21.7 minutes; P < 0.05). At a given IOP (70 mm Hg), t(0.5) showed a linear relationship with duration (15 vs. 30 vs. 60 minutes' exposure: t(0.5) 16.7 vs. 33.1 vs. 63.2 minutes; P < 0.05) and integral. Ganglion cell function recovers slower than the outer retina after IOP insult, with peak IOP being the principle determinant of functional loss and recovery. For a fixed pressure, functional recovery is linearly related to exposure.

Adeno-associated virus-vectored gene therapy for retinal disease

Recombinant adeno-associated viral (AAV) vectors have become powerful gene delivery tools for the treatment of retinal degeneration in a variety of animal models that mimic corresponding human diseases. AAV vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. AAV vectors are able to maintain high levels of transgene expression in the retinal pigment epithelium, photoreceptors, or ganglion cells for long periods of time after a single treatment. Each cell type can be specifically targeted by choosing the appropriate combination of AAV serotype, promoter, and intraocular injection site. This provides examples of AAV-mediated gene therapy in those animal models of inherited retinal degeneration caused by mutations directly affecting the interacting unit formed by photoreceptors and the RPE. In each case discussed, expression of the therapeutic gene resulted in significant recovery of retinal structure and/or visual function. Because of the key role of the vasculature in maintaining a healthy retina, a summary of AAV gene therapy applications in animal models of retinal neovascular diseases is also included.—Hans E. Grossniklaus

Evaluation of retinal function using the Dynamic Focal Cone ERG

The development of effective means of assessing visual function in retinal disease holds the key to improved understanding of pathogenesis, and better monitoring of treatment outcomes. In diseases such as age-related macular degeneration, in which the primary locus of dysfunction is the outer retina, tests which provide a direct measure of the functional integrity of the photoreceptor/retinal pigment epithelium (RPE) complex are of great importance. Recovery of retinal function following adaptation to a bright light requires the healthy function of photoreceptors, RPE, Bruch's membrane and choroidal circulation, making an assessment of this recovery a potentially useful clinical tool. However, current techniques are either subjective in nature, or are influenced by post-retinal processing of visual information. This report describes a novel technique, the 'Dynamic Focal Cone Electro-retinogram (ERG)', which allows direct, objective assessment of the recovery of macular function following photopigment bleach. A series of 41 Hz ERGs was recorded, and ERG amplitude was plotted as a function of time following cessation of the bleach. Normative data was collected from 10 healthy subjects. For all subjects, there was no measurable ERG immediately after the bleach, but the amplitude had returned to a pre-bleach level within 4 min. The amplitude recovery data were adequately described both by an exponential recovery function and by a model based on a rate-limited recovery process. We conclude that this technique provides a clinically applicable, objective measure of outer retinal recovery.