Retinal capillary blood flow in exudative age-related macular degeneration

PURPOSE: The purpose of this study was to evaluate retinal capillary blood flow in patients with exudative AMD. MATERIAL AND METHODS: Twenty patients with exudative AMD and twenty four patients age-matched control subjects, were included into the study. Retinal capillary blood flow was evaluated with Heidelberg Retinal Flowmeter (HRF), measurements were taken in two macular regions. The total mean flow and mean velocity were calculated usingthe technique of automatic full field perfusion image analysis (AFFPIA). The U Mann-Whitney test was used for statistical analysis. RESULTS: Patients with exudative AMD revealed slightly lower retinal blood flow than control subjects in area I and in area II. In the AMD group total mean flow values were: 295.75 AU/ 303.85 AU, while in the control group were: 302.37 AU/ 304.42 AU. The mean velocity values were: 1.48 AU/ 1.42 AU in AMD patients and: 1.49 AU/ 1.52 AU in control group. The differences did not reach the statistical significance. CONCLUSIONS: The study results showed no changes in retinal capillary blood flow in patients with exudative AMD comparing to normal subjects.     

Retinal sensitivity in hereditary retinal degeneration in Abyssinian cats: electrophysiological similarities between man and cat.

The functional and electrophysiological similarities in the changes in the electroretinogram (ERG) of man and cat affected by hereditary retinal degenerative disease were studied. The results of a series of log intensity-amplitude studies in a group of young affected Abyssinian cats were fitted to the Naka-Rushton relationship by means of a mathematical package on the University of London mainframe. The analysis showed that the amplitude of the maximum dark-adapted b-wave was significantly reduced by the end of the period studied but that the value of k, a variable inversely equivalent to retinal sensitivity, was only slightly reduced by the retinal degenerative process. The electrophysiological findings thus are similar to those found in cases of human diffuse dominantly inherited retinitis pigmentosa.     

视网膜缺血-再灌注损伤中小胶质细胞对微循环的破坏作用

目的　探讨视网膜缺血-再灌注损伤(retinal ischemia-reperfusion injury,RIRI)中小胶质细胞活化与视网膜微循环损伤的关系及作用机制。方法　160只雄性C57BL/6小鼠右眼均采用前房灌注建立RIRI模型为RIRI组，左眼不作处理为正常对照组。在损伤后24 h、48 h、72 h分别进行视网膜冰冻切片、视网膜铺片免疫荧光染色检测小胶质细胞的活化情况，检测相关缺氧因子及炎症因子的表达，与正常对照组比较，研究小胶质细胞的激活状态与微循环损伤的关系，并初步分析其作用机制。结果　视网膜微循环结构损伤观察结果显示，与正常对照组相比，RIRI后24 h组大部分血管仍呈正常形态；RIRI后48 h组，闭塞的血管数量增多；RIRI后72 h组，血管损伤明显加重。浅层毛细血管密度正常对照组，RIRI后24 h、48 h、72 h组间两两比较差异均无统计学意义（均为P>0.05）。而深层血管网毛细血管密度RIRI后72 h组与其余3组相比明显减少，差异均有统计学意义（均为P<0.05），其余3组间差异均无统计学意义（均为P>0.05）。视网膜冰冻切片检测显示，RIRI后24 h组与正常对照组各层视网膜中抗离子钙接头蛋白（ionized calcium bindingadaptor molecule-1，Iba-1）阳性细胞数差异无统计学意义（P>0.05）。RIRI后48 h组各层中Iba-1阳性细胞数与正常对照组及24 h组差异均有统计学意义（均为P<0.05）。RIRI后72 h组各层中Iba-1阳性细胞数与正常对照组、24 h组、48 h组差异均有统计学意义（均为P<0.05）。视网膜铺片结果显示，RIRI后48 h组和72 h组活化的小胶质细胞数明显增加，与正常对照组和RIRI后24 h组在两个层次毛细血管中差异均有统计学意义（均为P<0.05），而72 h组小胶质细胞的活化达到高峰值，与其余组差异均有统计学意义（均为P<0.05）。RT-PCR检测结果显示:血管内皮生长因子和缺氧诱导因子-1α的缺血缺氧因子，肿瘤坏死因子-α和白细胞介素-1β的炎症因子在正常对照组与RIRI后24 h组、48 h组、72 h组，组间比较差异均有统计学意义（均为P<0.05）。结论　激活的小胶质细胞在RIRI中发挥了对微循环的破坏作用，损伤早期抑制小胶质细胞的活化可能成为此类疾病治疗的新思路。     

Retinal degeneration and local oxygen metabolism

Vision loss due to various forms of outer retinal degeneration remains a major problem in clinical ophthalmology. Most retinal degenerations are precipitated by genetic mutations affecting the retinal pigment epithelium and sensory retina, but it is becoming increasingly evident that resultant metabolic changes within the retina may also contribute to the further progression of photoreceptor cell loss. In particular, a role for the local oxygen environment within the retina has been proposed. The correct balance between retinal oxygen supply and oxygen consumption in the retina is essential for retinal homeostasis, and disruption of this balance is a factor in many retinal diseases. In animal models of photoreceptor degeneration, manipulation of environmental oxygen levels has been reported to be able to modulate the rate of photoreceptor degeneration. Clinically, hyperbaric oxygen therapy has already been used in retinitis pigmentosa patients and other types of oxygen therapy have been proposed. It therefore seems appropriate to review our current understanding of the oxygen environment in the normal and degenerating retina, and to build a clearer picture of how the retinal oxygen environment can be modulated. We focus on techniques that have been, or may be, applied clinically, such as modulation of systemic oxygen levels and modulation of retinal oxygen metabolism by light deprivation. Data from direct measurements of intraretinal oxygen distribution in rat models at different stages of photoreceptor degeneration will be reviewed. These models include the Royal College of Surgeons (RCS) rat, and the P23H rat model of outer retinal degeneration. Microelectrode based techniques have allowed the intraretinal oxygen distribution to be measured as a function of retinal depth under well-controlled systemic conditions at different stages of the degeneration process. Both models showed changes in the intraretinal oxygen distribution during the degenerative period, with the changes reflecting the gradual loss of oxygen metabolism of the degenerating photoreceptors. This results in higher than normal oxygen levels in the remaining outer retina and a significant alteration in the oxygen flux from the choroid to the inner retina. The maintenance of normal oxygen levels in the inner retina implies that inner retinal oxygen uptake is well preserved, and that there is also reduced oxygen input from the deeper capillary layer of the retinal circulation. Choroidal oxygen tension and the oxygen tension in the pre-retinal vitreous were unaffected at any of the time periods studied prior to, and during, the degeneration process. It is well known that both hypoxia and hyperoxia can cause neural cell stress and damage. Logically, any therapeutic intervention based on oxygen therapy should attempt to restore the oxygen environment of the remaining retinal cells to within the physiological range. Before any oxygen based therapies for the treatment of retinal degeneration should be seriously considered, the oxygen environment in the degenerating retina should be determined, along with clinically usable methods to restore the oxygen environment to the critical cell layers.     

Retinal microcirculation in patients with diabetes mellitus: dynamic and morphological analysis of perifoveal capillary network.

The new scanning laser technique allows one to quantify the retinal microcirculation. A digital image analysing system was used to study capillary blood flow velocities and morphological parameters of perifoveal intercapillary areas and foveal avascular zones in normal and diabetic subjects. Diabetic patients showed a significant reduction in capillary blood cell velocities in comparison with normal subjects. Perifoveal intercapillary areas and foveal avascular zones were significantly increased in all stages of diabetic retinopathy, and both parameters increased with progressing diabetic retinopathy. Significant changes in the perifoveal intercapillary areas were observed between normal subjects and patients with no retinopathy.     

Retinal capillary hemangiomas and von Hippel-Lindau disease

von Hippel-Lindau disease is a multisystem familial cancer syndrome that commonly manifests in the eye as retinal capillary hemangiomas. As the earliest manifestation of the disease, these benign hamartomas can lead to secondary visual loss. Their typical clinical characteristics can lead to accurate diagnosis and appropriate treatment with either laser photocoagulation or cryotherapy enhancing one's probability of preserving vision before becoming symptomatic. Accurate diagnosis can also lead to surveillance of the various other organ systems involved in the disease such as the CNS, kidneys, adrenal glands and pancreas. This will also enable the clinician to provide genetic counseling for patients regarding the lifelong manifestations of this disease.     

Retinal arteriolar and capillary vascular reactivity in response to isoxic hypercapnia

The aim of the study was to compare the magnitude of vascular reactivity of the retinal arterioles in terms of percentage change to that of the retinal capillaries using a novel, standardized methodology to provoke isoxic hypercapnia. Ten healthy subjects (mean age 25 years, range 21–31) were recruited. Subjects attended a single visit comprising two study sessions separated by 30 min. Subjects were fitted with a sequential re-breathing circuit connected to a computer-controlled gas blender. Each session consisted of breathing at rest for 10 min (baseline), increase of P_ETCO₂ (maximum partial pressure of CO₂ during expiration) by 15% above baseline whilst maintaining isoxia for 20 min, and returning to baseline conditions for 10 min. Retinal hemodynamic measurements were performed using the Canon Laser Blood Flowmeter and the Heidelberg Retina Flowmeter in random order across sessions. Retinal arteriolar diameter, blood velocity and flow increased by 3.3%, 16.9% and 24.9% (p < 0.001), respectively, during isoxic hypercapnia. There was also an increase of capillary blood flow of 34.8%, 21.6%, 24.9% (p ≤ 0.006) at the optic nerve head neuroretinal rim, nasal macula and fovea, respectively. The coefficient of repeatability (COR) was 5% of the average P_ETCO₂ both at baseline and during isoxic hypercapnia and was 10% and 7% of the average P_ETO₂ (minimum partial pressure of oxygen at end exhalation), respectively. The overall magnitude of retinal capillary vascular reactivity was equivalent to the arteriolar vascular reactivity with respect to percentage change of flow. The magnitude of isoxic hypercapnia was repeatable.     

Retinal arteriolar and capillary vascular reactivity in response to isoxic hypercapnia

The aim of the study was to compare the magnitude of vascular reactivity of the retinal arterioles in terms of percentage change to that of the retinal capillaries using a novel, standardized methodology to provoke isoxic hypercapnia. Ten healthy subjects (mean age 25 years, range 21-31) were recruited. Subjects attended a single visit comprising two study sessions separated by 30 min. Subjects were fitted with a sequential re-breathing circuit connected to a computer-controlled gas blender. Each session consisted of breathing at rest for 10 min (baseline), increase of P_ETCO₂ (maximum partial pressure of CO₂ during expiration) by 15% above baseline whilst maintaining isoxia for 20 min, and returning to baseline conditions for 10 min. Retinal hemodynamic measurements were performed using the Canon Laser Blood Flowmeter and the Heidelberg Retina Flowmeter in random order across sessions. Retinal arteriolar diameter, blood velocity and flow increased by 3.3%, 16.9% and 24.9% (p < 0.001), respectively, during isoxic hypercapnia. There was also an increase of capillary blood flow of 34.8%, 21.6%, 24.9% (p ≤ 0.006) at the optic nerve head neuroretinal rim, nasal macula and fovea, respectively. The coefficient of repeatability (COR) was 5% of the average P_ETCO₂ both at baseline and during isoxic hypercapnia and was 10% and 7% of the average P_ETO₂ (minimum partial pressure of oxygen at end exhalation), respectively. The overall magnitude of retinal capillary vascular reactivity was equivalent to the arteriolar vascular reactivity with respect to percentage change of flow. The magnitude of isoxic hypercapnia was repeatable.     

Retinal ischemia: mechanisms of damage and potential therapeutic strategies

Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx and oxidative stress initiated by energy failure and increased glutamatergic stimulation. There is a cell-specific sensitivity to ischemic injury which may reflect variability in the balance of excitatory and inhibitory neurotransmitter receptors on a given cell. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the "ischemic cascade" and attenuate the detrimental effects of retinal ischemia. Thus far, however, success in the laboratory has not been translated to the clinic. Difficulties with the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies for stroke have so far been disappointing. However, compared to the brain, the retina exhibits a remarkable natural resistance to ischemic injury, which may reflect its peculiar metabolism and unique environment. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available.     

Retinal degeneration,apoptosis and the c-fos gene

In the past few years, the interest in the research field of apoptosis in the retina has been growing rapidly. We will give a short overview of apoptosis in the context of retinal degeneration and summarize recent data obtained in our laboratory. Based on our findings, we will also discuss possible future strategies to influence apoptotic cell death in the retina and to modulate the time course of retinal dystrophies. Apoptosis is the final common pathway of photoreceptor cell death in several retinal dystrophies as well as in light-induced photoreceptor degeneration. We investigated potential signal transducers for apoptosis in our laboratory and found an essential role of the immediate-early gene product c-Fos in light-induced photoreceptor degeneration. This is of particular interest in light of the finding that c-fos is continuously upregulated concomitant with apoptotic photoreceptor death in animal models of the retinal dystrophy retinitis pigmentosa. Interference with c-fos expression or function might therefore represent a novel means to influence the time course of retinal dystrophies, which are at present incurable diseases.     

Retinal detachment and degeneration in response to subretinal perfluorodecalin in rabbit eyes

Perfluorocarbon liquids, including perfluorodecalin (PFD), are useful intraoperative tools in complicated vitreoretinal surgery, such as for giant retinal tears, PVR and intraocular foreign bodies. Due to its high specific gravity (1.91 g/cm³) subretinal complications of PFD may occur. The consequences of subretinal PFD were studied in 23 albino rabbits (28 eyes). Using glass micropipettes (outer diameter of tip 100–120 qm), we injected 50–100 l PFD subretinally via the vitreous space. The same volume of BSS was injected into 18 control eyes. Eyes were monitored by indirect ophthalmoscopy and examined by light and electron microscopy at 1, 2 and 3 days, and 1, 2, 4 and 12 weeks. Progressive retinal detachments with newly formed retinal breaks in the inferior quadrants developed in 26 of 28 eyes. As early as 1 day postoperatively, subretinal PFD induced loss of outer and inner segments. Local retinal necrosis occurred in 4 eyes 5–7 days after surgery. A marked vacuole formation in retinal layers and PFD emulsification were regularly seen. The control eyes healed spontaneously. Toxic, mechanical and barrier effects may have caused the retinal damage. We advocate that all PFD be removed from the eye at surgery.Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Sarasota, Florida, May 8, 1992     

Retinal neurodegeneration: early pathology in diabetes

Normal vision depends on the normal function of retinal neurons, so vision loss in diabetes must ultimately be explained in terms of altered neuronal function. However to date relatively little attention has been paid to the impact of diabetes on the neural retina. Instead, the focus of most research has been primarily on retinal vascular changes, with the assumption that they cause altered neuronal function and consequently vision loss. An increasing body of evidence suggests that alterations in neuronal function and viability may contribute to the pathogenic mechanisms of diabetic retinopathy beginning shortly after the onset of diabetes. This view arises from neurophysiological, psychometric, histopathological and biochemical observations in humans and experimental animals. The collective evidence from past and recent studies supports the hypothesis that neurodegeneration, together with functional changes in the vasculature, is an important component of diabetic retinopathy. The authors invite other investigators to include the neural retina as a component of their studies so that the pathogenesis of diabetic retinopathy can be understood more clearly.     

Retinal capillary hemangioma and von Hippel-Lindau disease: diagnostic and therapeutic implications

CLINICAL CASE: Man carrier of the von Hippel-Lindau (VHL) gene, with long-onset loss of vision in left eye. He had a retinal capillary hemangioma (HCR) and diffuse cystic edema in posterior pole. The systemic study revealed bilateral kidney tumors. Laser photocoagulation was performed which produced a subretinal and vitreous hemorrhage that required vitrectomy. DISCUSSION: Retinal capillary hemangioma (HCR) is the earliest and most frequent manifestation of the von Hippel-Lindau disease. Its detection requires it to be treated early and to rule out other visceral lesions. Laser photocoagulation is the most recommended treatment of small-size HCR. The most frequent complications are vitreous and subretinal haemorrhages.     

Retinal degeneration in children: dark adapted visual threshold and arteriolar diameter

To assess the condition of the retina in children with retinal degeneration due to Bardet-Biedl syndrome (BBS, n=41), Leber congenital amaurosis (LCA, n=31), or Usher syndrome (USH, n=13), the dark adapted visual threshold (DAT) and arteriolar diameters were measured. Compared to controls, the initial DATs of nearly all (83/85) were significantly elevated, and in 26/62 with serial DATs, significant progressive elevation occurred. Arteriolar diameters were significantly attenuated and narrowed with age in BBS and USH, but not LCA. Higher DATs were associated with narrower arterioles. Such non-invasive procedures can document the natural history of these retinal diseases and have the potential to assess response to future treatment.     

Retinal pigment epitheliopathy and neuroretinal degeneration in ascarid-infected eyes

The generalized choroidal and retinal response to a focal nonreplicating infection of the eye with ascarid larvae was examined in an animal model. Intravitreal injection of Ascaris suum larvae in guinea pigs induced a diffuse eosinophilic choroiditis, retinal pigment epitheliopathy and neuroretinal degeneration, distant from focal reactions about larvae. As the choroiditis progressed, inflammatory cells separated the choriocapillaris from Bruch's membrane, and the endothelial cells lost their fenestrations. Focal disruption of the elastic and outer collagenous layers of Bruch's membrane occurred, but inflammatory cells rarely invaded the retina. Progressive generalized degenerative and proliferative RPE changes produced a multilayered RPE with loss of cell polarity, RPE basal infoldings and apical microvilli, formation of multiple giant cystic spaces, and proliferation of subretinal fibroblasts. Early loss of photoreceptor outer segments progressed to a generalized disruption of the outer neural retina and cystoid retinal degeneration. Eosinophil mediators and alterations of the choriocapillaris may contribute to the generalized progressive retinal degeneration distant from a parasite larva in ascarid-infected eyes.