Retinal Autoregulation Research Articles

Retinal capillary perfusion heterogeneity in diabetic retinopathy detected by optical coherence tomography angiography

BackgroundDiabetic retinopathy (DR) is a leading cause of blindness and involves retinal capillary damage, microaneurysms, and altered blood flow regulation. Optical coherence tomography angiography (OCTA) is a non-invasive way of visualizing retinal vasculature but has not been used extensively to study blood flow heterogeneity. The purpose of this study is to detect and quantify blood flow heterogeneity utilizing en-face swept source OCTA in patients with DR.MethodsThis is a prospective clinical study which examined patients with either type 1 or 2 diabetes mellitus. Each included eye was graded clinically as no DR, mild DR, or moderate-severe DR. Ten consecutive en face 6 × 6 mm foveal SS-OCTA images were obtained from each eye using a PLEX Elite 9000 (Zeiss Meditec, Dublin, CA). Built-in fixation-tracking, follow-up functions were utilized to reduce motion artifacts and ensure same location imaging in sequential frames. Images of the superficial and deep vascular complexes (SVC and DVC) were arranged in temporal stacks of 10 and registered to a reference frame for segmentation using a deep neural network. The vessel segmentation was then masked onto each stack to calculate the pixel intensity coefficient of variance (PICoV) and map the spatiotemporal perfusion heterogeneity of each stack.ResultsTwenty-nine eyes were included: 7 controls, 7 diabetics with no DR, 8 mild DR, and 7 moderate-severe DR. The PICoV correlated significantly and positively with DR severity. In patients with DR, the perfusion heterogeneity was higher in the temporal half of the macula, particularly in areas of capillary dropout. PICoV also correlates as expected with the established OCTA metrics of perfusion density and vessel density.ConclusionPICoV is a novel way to analyze OCTA imaging and quantify perfusion heterogeneity. Retinal capillary perfusion heterogeneity in both the SVC and DVC increased with DR severity. This may be related to the loss of retinal capillary perfusion autoregulation in diabetic retinopathy.

The characteristics of fundus microvascular alterations in the course of glaucoma: a narrative review.

Background and ObjectiveAs the vascular theory has led many researchers to focus on vascular dysfunction in the pathogenesis of glaucoma, a better understanding of ocular microcirculation would be of great significance. The emergence of optical coherence tomography angiography (OCTA) has shed light on the various fundus microvascular changes that occur in glaucoma, thus providing ample evidence in the role of microvascular dysfunction in glaucoma. The aim of this review is to provide an overview of the retinal and choroidal microvascular alterations that occur in glaucoma and to address the role of microvascular alterations in the pathogenesis, diagnosis, prognosis, and treatment of glaucoma.MethodsThe literature regarding fundus microvascular alterations in glaucoma and after glaucoma treatment, including alterations of vascular perfusion and vascular reactivity, was broadly researched using PubMed and Web of Science databases. The endothelium involvements during the glaucoma course were also searched in the databases broadly.Key Content and FindingsPrevious OCTA studies show vessel density (VD) decreases in the retinal macular and peripapillary regions and choroidal microvascular dropout. Such microvascular alterations are correlated with structural and functional defects and have potential value for the early diagnosis and prognosis of glaucoma. Retinal microvascular autoregulation is also impaired in glaucomatous eyes. Furthermore, various studies have demonstrated the role of the vascular endothelium in glaucoma. Different topical medications and surgical interventions have been shown to have an impact on microvasculature in glaucoma, and animal experiments have indicated the endothelial system may be a new target in glaucoma treatment.ConclusionsAmple evidence proved the involvement of retinal and choroidal microvascular structural and functional changes in the course of glaucoma. This review makes a novel contribution to the literature by summarizing the microvascular alterations in glaucoma eyes and the microvascular changes after topical or surgical treatments.

PERG adaptation for detection of retinal ganglion cell dysfunction in glaucoma: a pilot diagnostic accuracy study

It has been previously demonstrated that the adaptive phase changes of steady-state pattern electroretinogram (SS-PERG), recorded during 4-min presentation of patterned stimuli, are reduced in glaucoma suspects and patients compared to normal subjects. Our study aims at testing the hypothesis that adaptive changes of SS-PERG, recorded using the novel optimized Next Generation PERG (PERGx) protocol, differ between glaucoma patients and controls. In this pilot cross-sectional study, we included 28 glaucoma patients and 17 age-matched normal subjects. Both patients and controls underwent a full ophthalmologic examination, visual field testing, OCT and PERGx. The PERGx signal was sampled over 2 min (providing 1 noise and 9 signal packets) in response to alternating gratings generated on an OLED display. PERGx amplitude and phase were analyzed to quantify adaptive changes over recording time. Receiver operating characteristic (ROC) curves were used to study the diagnostic accuracy of PERGx parameters in distinguishing glaucoma patients from normal subjects. PERGx amplitude and phase data showed declining trends in both groups. PERGx amplitude slope and grand-average vector amplitude and phase were significantly different in patients compared to controls (p < 0.01), whereas phase angular dispersion was greater in patients but not significantly different between the two groups. The area under the ROC curves were 0.87 and 0.76 for PERGx amplitude slope and grand-average vector amplitude, and 0.62 and 0.87 for PERGx angular dispersion and grand-average vector phase, respectively. The PERGx paradigm resulted highly accurate in detecting the reduction of amplitude adaptive changes in glaucoma patients, presumably due to the loss of functional retinal ganglion cell autoregulation. Thus, PERG adaptation, recorded by this new protocol, might be helpful in the identification and diagnosis of early glaucomatous dysfunction.

Ion channels and myogenic activity in retinal arterioles.

Retinal pressure autoregulation is an important mechanism that protects the retina by stabilizing retinal blood flow during changes in arterial or intraocular pressure. Similar to other vascular beds, retinal pressure autoregulation is thought to be mediated largely through the myogenic response of small arteries and arterioles which constrict when transmural pressure increases or dilate when it decreases. Over recent years, we and others have investigated the signaling pathways underlying the myogenic response in retinal arterioles, with particular emphasis on the involvement of different ion channels expressed in the smooth muscle layer of these vessels. Here, we review and extend previous work on the expression and spatial distribution of the plasma membrane and sarcoplasmic reticulum ion channels present in retinal vascular smooth muscle cells (VSMCs) and discuss their contribution to pressure-induced myogenic tone in retinal arterioles. This includes new data demonstrating that several key players and modulators of the myogenic response show distinctively heterogeneous expression along the length of the retinal arteriolar network, suggesting differences in myogenic signaling between larger and smaller pre-capillary arterioles. Our immunohistochemical investigations have also highlighted the presence of actin-containing microstructures called myobridges that connect the retinal VSMCs to one another. Although further work is still needed, studies to date investigating myogenic mechanisms in the retina have contributed to a better understanding of how blood flow is regulated in this tissue. They also provide a basis to direct future research into retinal diseases where blood flow changes contribute to the pathology.

Dilatation of Retinal Arterioles Induced by Topical Dorzolamide for One Week Is Impaired in Patients with Type 1 Diabetes and Mild Retinopathy

Background: Diabetic retinopathy is characterised by morphological lesions in the retina secondary to disturbances in retinal blood flow. Previous studies have shown that the carbonic anhydrase inhibitor (CAI) dorzolamide can induce immediate dilatation of retinal arterioles and a sustained increase in retinal blood flow in primary open-angle glaucoma. However, the effect of sustained treatment with CAI on retinal arterioles in normal persons and in patients with diabetic retinopathy is unknown. Methods: The Dynamic Vessel Analyzer was used to assess the baseline diameter and the diameter response of retinal arterioles during an increase in arterial blood pressure induced by isometric exercise and during flicker stimulation before and 2 h, 24 h and 1 week after onset of topical treatment with dorzolamide. At each examination the diameter responses were studied before and during breathing in of a hypercapnic gas mixture. Results: Treatment with dorzolamide for 1 week significantly increased the diameter of retinal arterioles in normal persons, and breathing in of a hypercapnic gas mixture reduced this response. The pathological vasodilatation and reduced retinal autoregulation in patients with diabetic retinopathy were unaffected by dorzolamide and hypercapnia. Conclusions: The study suggests a lack of relevance of CAI for the treatment of pathological vasodilatation in early diabetic retinopathy.

Heart rate variability, the dynamic nature of the retinal microvasculature and cardiac stress: providing insight into the brain-retina-heart link: the SABPA study.

Decreased heart-rate-variability (HRV) indicates increased sympathetic nervous system (SNS) activity and modulation with a shift in the sympatho-vagal balance towards SNS predominance. Increased SNS activity may precede volume-loading hypertension, contribute to increases in cardiac troponin T (cTnT), endothelial dysfunction and small vessel disease. Therefore, we investigated the retinal vasculature, HRV during flicker-light-induced-provocation (FLIP) and systemic cTnT, a marker of cardiac stress, to provide further evidence in support of the brain-retina-heart link. Cross-sectional observations were obtained from a bi-ethnic cohort (N = 264), aged 23-68 years. Fasting serum samples for cTnT were obtained. Retinal vascular calibres were quantified from mydriatic eye fundus images and dynamic retinal vessel calibre responses were determined during FLIP. Time-and frequency domain parameters of HRV were calculated during FLIP for each participant. Africans had wider venules and attenuated time domain parameters during FLIP. In Africans, inverse associations emerged between arteriolar dilation and both cTnT and root-mean squared of the standard deviations of successive RR-intervals (rMSSD) (p = 0.030), and between arteriolar constriction and both low-frequency expressed in normalised units (LFnu) (p = 0.003) and high-frequency expressed in normalised units (p = 0.021). Wider venules inversely associated with standard deviation of the NN intervals (SDNN) as well as LFnu (p = 0.009) in Africans. An opposite profile was observed in Caucasians with both time-and frequency domain parameters of HRV in relation to retinal vessel structure and function. FLIP elicited increased SNS activity and modulation in this bi-ethnic cohort. In Africans, decreased HRV during FLIP accompanied arteriolar and venular responses and elevated systemic levels of cTnT, implying that the SNS exerted a significant effect on the smooth muscle tone of the retinal vasculature. Disrupted retinal autoregulation may imply general autonomic nervous system dysfunction; exemplifying central control by the brain on all systemic regulatory functions, across different vascular beds.

Systemic hypertension is not protective against chronic intraocular pressure elevation in a rodent model

High intraocular pressure is the most well documented glaucoma risk factor; however many patients develop and/or show progression of glaucoma in its absence. It is now thought that in some instances, ocular perfusion pressure (blood pressure – intraocular pressure) may be as important as intraocular pressure alone. Thus, systemic hypertension would be protective against glaucoma. Epidemiological studies, however, are inconclusive. One theory of why hypertension may not protect against elevated intraocular pressure in spite of increasing ocular perfusion pressure is that with time, morphological changes to the vasculature and autoregulatory failure outweigh the benefits of improved perfusion pressure, ultimately leading to poor retinal and optic nerve head blood supply. In this study we showed the presence of increased wall:lumen ratio and wall area of the ophthalmic artery in rats with chronic hypertension in addition to failure of retinal autoregulation in response to acute modification of ocular perfusion pressure. Subsequently we found that in spite of dramatically increasing ocular perfusion pressure, chronic systemic hypertension failed to protect retinal structure and function from a rodent model of glaucoma.

The effect of different adaptation conditions on the dynamic vessel analysis

Purpose : Retinal arterioles and venules dilate when stimulated with flickering light. This phenomenon is described as functional hyperemia. Flicker light stimulation is an established noninvasive means of assessing the endothelial function and the retinal autoregulation by continuous measurement of vessel diameters. Investigation of the flicker-induced retinal vasodilation, known as dynamic vessel analysis (DVA), is often conducted under reduced ambient lighting conditions but the influence of various adaptation levels is still unclear. This work aims to clarify whether light or dark adaptation affects the DVA. Methods : We studied 15 volunteers (8m, 7f, 24.7±2.4 years, one eye) using the Retinal Vessel Analyzer (Imedos Systems UG). Exclusion criteria were VA 2.0D, myopia 5 D and systemic diseases. We investigated four primary vessel segments (superior as well as inferior temporal artery (STa/ITa) and vein (STv/ITv)) located in a range from 0.5–2 disc diameters from the optic disc. For each volunteer DVA was performed three times in random order. DVA after light adaptation (129cd/m2) and after dark adaptation (0.02cd/m2) were performed according to the standard protocol timing (350s total time, 3 flicker cycles; Garhofer et al. 2010). Both the vaso-dilatation values and baseline diameters were analyzed. The effect on regulatory vessel diameter changes during the transition between dark and light adaptation was examined measuring only baseline diameters. For statistical analysis t-test and Wilcoxon test for paired samples were used. Results : Vaso-dilatation values and baseline diameters between light and dark adaptation showed no significant differences (STa: p=0.099/0.977, ITa: p=0.670/0.999, STv: p=0.156/0.820, ITv: p=0.065/0.955). The obtained baseline values during the transitional measure showed increased diameters after dark adaptation (STa: +7%, ITa: +6%, STv: +5%, ITv: +8% = group-means, referred to the baseline values under light adaption) which returned slowly (tau=100 s) to the baseline values under light adaption. Conclusions : The presented work revealed, that adaptation conditions have no effect on DVA following the standard timing. This means, in clinical practice DVA results would not be influenced by different ambient light conditions. However, dark adaptation leads to increased vessel diameters. The large time constant should be considered using short time DVA protocols.

In vivo oximetry of human bulbar conjunctival and episcleral microvasculature using snapshot multispectral imaging

Multispectral imaging (MSI) is a well-established technique for non-invasive oximetry of retinal blood vessels, which has contributed to the understanding of a variety of retinal conditions, including glaucoma, diabetes, vessel occlusion, and retinal auto-regulation. We report the first study to use snapshot multi-spectral imaging (SMSI) for oximetry of the bulbar conjunctival and episcleral microvasculature in the anterior segment of the eye. We report the oxygen dynamics of the bulbar conjunctival and episcleral microvasculature at normoxia and at acute mild hypoxia conditions.A retinal-fundus camera fitted with a custom Image-Replicating Imaging Spectrometer was used to image the bulbar conjunctival and episcleral microvasculature in ten healthy human subjects at normoxia (21% Fraction of Inspired Oxygen [FiO2]) and acute mild hypoxia (15% FiO2) conditions. Eyelid closure was used to control oxygen diffusion between ambient air and the sclera surface. Four subjects were imaged for 30 seconds immediately following eyelid opening. Vessel diameter and Optical Density Ratio (ODR: a direct proxy for oxygen saturation) of vessels was computed automatically. Oximetry capability was validated using a simple phantom that mimicked the scleral vasculature.Acute mild hypoxia resulted in a decrease in blood oxygen saturation (SO2) (i.e. an increase in ODR) when compared with normoxia in both bulbar conjunctival (p < 0.001) and episcleral vessels (p = 0.03). Average episcleral diameter increased from 78.9 ± 8.7 μm (mean ± standard deviation) at normoxia to 97.6 ± 14.3 μm at hypoxia (p = 0.02). Diameters of bulbar conjunctival vessels showed no significant change from 80.1 ± 7.6 μm at normoxia to 80.6 ± 7.0 μm at hypoxia (p = 0.89). When exposed to ambient air, hypoxic bulbar conjunctival vessels rapidly reoxygenated due to oxygen diffusion from ambient air. Reoxygenation occured in an exponential manner, and SO2 reached normoxia baseline levels. The average ½ time to full reoxygenation was 3.4 ± 1.4 s. As a consequence of oxygen diffusion, bulbar conjunctival vessels will be highly oxygenated (i.e. close to 100% SO2) when exposed to ambient air. Episcleral vessels were not observed to undergo any significant oxygen diffusion, instead behaving similarly to pulse oximetry measurements.This is the first study to the image oxygen dynamics of bulbar conjunctival and episcleral microvasculature, and consequently, the first study to directly observe the rapid reoxygenation of hypoxic bulbar conjunctival vessels when exposed to ambient air. Oximetry of bulbar conjunctival vessels could potentially provide insight into conditions where oxygen dynamics of the microvasculature are not fully understood, such as diabetes, sickle-cell diseases, and dry-eye syndrome. Oximetry in the bulbar conjunctival and episcleral microvasculature could be complimentary or alternative to retinal oximetry.

A Case of Monocular Retinal Blot Hemorrhage in a Patient with Raynaud's Phenomenon

Purpose: To report a case of retinal blot hemorrhage localized to 1 eye accompanied by Raynaud’s phenomenon. Case summary: A 65-year-old female was referred for vision disorder in the right eye. She had been taking an antihypertensive drug since diagnosed with systemic hypertension 2 years previously. On initial examination, her best corrected visual acuity was 20/25 in the right eye and 20/20 in the left eye and intraocular pressure was 15 mm Hg in the right eye and 21 mm Hg in the left eye. Fundus examination showed retinal blot hemorrhage across the entire retina and increased retinal vascular tortuosity. No specific finding was found on visual field examination, transthoracic ultrasonography and carotid Doppler ultrasound. The blood test was positive for antinuclear and anticentromere antibodies, thus she was referred to the rheumatologic department. The patient was diagnosed with primary Raynaud’s phenomenon because no correlation with other rheumatologic diseases was found. Subsequently, she was scheduled for regular follow-ups with a prescription of circulatory stimulant. Five months later, her best corrected visual acuity was 20/20 in the both eyes and retinal blot hemorrhage in the right eye was significantly decreased based on fundus examination. Conclusions: In the case of atypical retinal blot hemorrhage without other ophthalmic causes except Raynaud’s phenomenon, the change in retinal circulatory autoregulation associated with the mechanism of retinal blot hemorrhage can be presumed. Therefore, a close examination and history taking should be conducted so that Raynaud’s phenomenon as a pathological factor is not overlooked. J Korean Ophthalmol Soc 2015;56(4):620-626

Influence of Latanoprost on Retinal Microcirculation in Glaucoma

Purpose : To test whether latanoprost has an influence on ocular haemodynamics, considering the general reputation of prostaglandins which is frequently associated with vasoconstriction. The effect of latanoprost on the retinal blood supply of treatment-naïve glaucoma patients was tested.Materials and Methodology : 13 patients (7 male, 6 female) who had just recently been diagnosed with primary open-angle glaucoma (POAG) were treated with latanoprost (0.005%). The average age of our study group was 63.8 years (+/- 2.9 years).The drug’s effect on retinal autoregulation was assessed by flicker test using the Dynamic Vessel Analyzer (DVA). Examinations took place before initializing treatment, after 4 weeks and once again after 4 to 6 months.Results : In our group of POAG patients, the IOP under treatment was significantly reduced about 25%. No intraindividual differences in systemic blood pressure and heart rate were observed. In DVA measurements of glaucoma patients, the maximum flicker dilation of the arteries was significantly lower than reported for healthy volunteers. Beyond that, POAG patients did not show significant differences in vessel diameters, peak amplitudes as well as maximum dilations of retinal arteries and veins before and under treatment with latanoprost (0.005%).Conclusion : Latanoprost markedly lowered the IOP but it did not exert a significant effect on retinal haemodynamics. There was neither a tendency towards vasoconstriction nor towards vasodilation. Sustaining reperfusion damage after topical latanoprost therapy thus seems to be highly unlikely. Further studies must show if sole IOP lowering or a dual positive effect – IOP lowering and improvement of retinal vessel autoregulation – have a more positive impact on the long term follow-up of glaucoma patients.

Improvement of mild retinopathy in type 2 diabetic patients correlates with narrowing of retinal arterioles. A prospective observational study

Diabetic retinopathy is one of the leading causes of blindness in the Western world. The disease is characterized by morphological lesions secondary to disturbances in retinal blood flow assumed to be related to disturbances in retinal autoregulation. However, there is a need for elucidating the relation between disturbances in diameter regulation of retinal vessels and the development of diabetic retinopathy in longitudinal studies. Sixty-four patients with type 2 diabetes mellitus were subjected to measurement of pressure autoregulation of retinal arterioles using the Dynamic Vessel Analyzer (DVA) and measurement of retinal thickness using OCT scanning, and after a mean of 6.8 years, 42 of the patients were re-examined. The vascular response was compared in patients in whom retinopathy had disappeared, was unchanged, or had worsened. At baseline, hemoglobin A1c (HbA1c) was significantly higher in the patients who would later experience worsening of diabetic retinopathy than in the other groups, but had been reduced at the follow-up examination. During the follow-up period, the resting diameter of retinal arterioles decreased significantly in the patients who experienced improvement in diabetic retinopathy but was unchanged in the other groups, whereas both the diameter response of retinal arterioles to isometric exercise and retinal thickness increased non-significantly with worsening of retinopathy. The development of diabetic retinopathy is related to the diameter of retinal arterioles. Future clinical intervention studies should aim at investigating the effects of normalizing arteriolar diameters in diabetic retinopathy.

Die Bedeutung der arteriellen Hypertonie für das primäre Offenwinkelglaukom

Primary open-angle glaucoma is a multifactorial disease with a lot of different risk factors. Beside the fact that intraocular pressure (IOP) is the most important risk factor, the reduction of IOP alone is in most cases not sufficient to stop the progression of glaucoma. Therefore, other risk factors play also an important role. One of them is arterial hypertension, the most common systemic disease in glaucoma patients. Arterial hypertension increases IOP slightly, but has an important negative effect on ocular perfusion. Especially the endothelial dysfunction with a disturbed retinal autoregulation plays an important role. Therefore, ischaemic and reperfusion effects alter the optic nerve head and have negative input to the glaucomatous optic neuropathy. In future glaucoma patients should be monitored by ophthalmologists as well as by general physicians/cardiologists to optimise their treatment and to stabilise their glaucoma as well as possible.

Theoretical Analysis of Vascular Regulatory Mechanisms Contributing to Retinal Blood Flow Autoregulation

To study whether impaired retinal autoregulation is a risk factor for glaucoma, the relationship between vascular regulatory mechanisms and glaucoma progression needs to be investigated. In this study, a vascular wall mechanics model is used to predict the relative importance of regulatory mechanisms in achieving retinal autoregulation. Resistance vessels are assumed to respond to changes in pressure, shear stress, carbon dioxide (CO2), and the downstream metabolic state communicated via conducted responses. Model parameters governing wall tension are fit to pressure and diameter data from porcine retinal arterioles. The autoregulation pressure range for control and elevated levels of IOP is predicted. The factor by which flow changes as the blood pressure exiting the central retinal artery is varied between 28 and 40 mm Hg is used to indicate the degree of autoregulation (1 indicates perfect autoregulation). In the presence of only the myogenic response mechanism, the factor is 2.06. In the presence of the myogenic and CO2 responses, the factor is 1.22. The combination of myogenic, shear, CO2, and metabolic responses yields the best autoregulation (factor of 1.10). Model results are compared with flow and pressure data from multiple patient studies, and the combined effects of the metabolic and CO2 responses are predicted to be critical for achieving retinal autoregulation. When IOP is elevated, the model predicts a decrease in the autoregulation range toward low perfusion pressure, which is consistent with observations that glaucoma is associated with decreased perfusion pressure.

Purtscher’s retinopathy in pre-eclampsia: a blinding combination

Blindness in pregnancy can occur due to cortical infarcts, retinal vascular occlusions and retinal detachment. Purtscher's retinopathy is a rare entity causing visual loss during pregnancy and has so far been reported in association with complicated labor. We report here on a case of Purtscher's retinopathy leading to bilateral blindness in a pre-eclamptic multigravida after an uncomplicated spontaneous delivery. The patient had no visual recovery after 3months postpartum. Poorly controlled pregnancy-induced hypertension coupled with the hypercoagulable state of pregnancy probably led to a compromised optic nerve microvasculature and loss of retinal autoregulation. Subsequently the acute event of parturition triggered a complement-mediated leucocyte embolization to this already compromised microvasculature resulting in Purtscher's retinopathy.

Effect of NO synthase inhibition on retinal vessel reaction to isometric exercise in healthy humans

It has been shown that retinal blood flow is autoregulated, meaning that flow is independent of perfusion pressure within a certain range. We tested the hypothesis that nitric oxide (NO) synthase inhibition alters the response of retinal arterial and venous vessels during isometric exercise. In this study, nine healthy subjects were included. Each subject received the NO synthase inhibitor Ng-monomethyl-l-Arginine (l-NMMA, the α-receptor agonist phenylephrine or placebo intravenously on three study days. Retinal vessel diameter was assessed with the retinal vessel analyser (RVA), at baseline and during a squatting period of 6-7 min in absence or presence of l-NMMA, phenylephrine or placebo. Mean arterial pressure (MAP) and pulse rate (PR) increased significantly during all pretreatment squatting periods (p < 0.001) Retinal venous and arterial diameters showed a continuous decrease during squatting (p < 0.001). Phenylephrine increased MAP and PR but did not alter the retinal vessel diameter response to squatting. Administration of l-NMMA lead to a significant decrease in venous diameter before isometric exercise (p = 0.004). In addition, the retinal venous diameter response during administration of the NO synthase inhibitor was less pronounced than during phenylephrine or placebo (p < 0.001). Our study confirms that NO plays an important role in the control of retinal vascular tone at rest. In addition, the present data indicate a role of NO in retinal autoregulation, because the response of retinal venous diameters was altered after NO synthase inhibition. The nature of involvement, however, appears to be complex and requires further studies.

This issue of Acta, printed and electronic

This issue of Acta, printed and electronic

This issue of Acta, printed and electronic

The cover illustration shows a painting of Allvar Gullstrand painted in 1915, 4 years after he received the Nobel Prize for medicine. This issue is dedicated to the centennial of Allvar Gullstrand’s Nobel Prize. He is the only ophthalmologist ever to receive this prestigious price. Stefan Seregard writes an editorial commemorating this event. This is followed by an historical article by Ehinger and Grzybowski on the life and times of Allvar Gullstrand. Yilmaz et al. in USA, Spain and Ireland review the use of intravitreal bevacizumab for diabetic macular oedema. This is an extensive review of the literature for this new and important treatment modality. Lundström et al. in Sweden and Australia found the Catquest questionnaire useful for measuring self-assessed visual function before and after cataract surgery. Mönestam and Behndig found that light scattering and glistening in intraocular lenses does not affect visual acuity. Gazieva et al. in Denmark performed LASIK with two types of laser systems, both which effectively reduce high degrees of myopia with reasonable but slightly different predictability. Rijneveld et al. in the Netherlands found that emergency corneal grafts fail mostly due to host factors, not the quality of the donor tissue. Reinshagen et al. in Switzerland and Germany used mesenchymal stem cell in rabbits to treat total limbal stem cell deficiency. Heijl et al. in Sweden and USA report that intraocular pressure reduction with drug treatment depends on the baseline IOP level and suggest that the baseline IOP level should be documented when reporting treatment effect on intraocular pressure. Larsson et al. in Sweden used the Heidelberg retina tomography system to evaluate optic nerve heads in children. Lin et al. in Taiwan describe lacrimal canaliculitis in a series of patients. Mehlsen et al. in Denmark found that a calcium channel blocker and an angiotensin converting enzyme inhibitor did not influence retinal autoregulation in diabetic patients. Kook et al. in Germany found that intravitreal bevacizumab and/or triamcinolone do not provide long-term improvement for diabetic macular oedema. Kofoed et al. in Copenhagen found that hyperbaric oxygen exposure influenced electrophysiological components related to bipolar in Müller cells. It did not influence retinal thickness. Holton et al. in Denmark examined the influence of light source on contrast sensitivity in patients with AMD. They found that full spectral radiance incandescent light sources seem optimal. Available on http://www.actaophthalmologica.com Stalmans and a large international group review extensively the use of colour Doppler imaging in ocular blood flow research. Founti et al. in Greece and USA found good reproducibility between technicians in imaging retrobulbar blood flow in healthy volunteers. Frøen et al. in Norway and Hungary found that cells from the iris pigment epithelium have limited capabilities as retinal stem cells. Andjelić et al. in Slovenia found that lens capsule contraction with changing in calcium levels or mechanical stimulus. Sieving in USA explains Medline indexing and keywords. Bull in Bergen proposes that fireworks should be banned to reduce eye injuries. Basit et al. in Trondheim describe a case of Wernicke’s encephalopathy in a young boy. Russo et al. in Liverpool found scleral calcification in a case of recurrent melanoma after brachytherapy. Rama et al. in Italy report severe keratitis following corneal cross-linking for keratoconus. Jonas and Jonas in Germany compare peripapillary scleral thickness in glaucoma patients and normal subjects. Lim and An in Korea report good results after epiretinal membrane removal. Kernt et al. in Germany had good experiences with focal and panretinal photocoagulation with a navigated laser. Fielden et al. in Canada describe a cluster of cases with intraocular inflammation following bevacizumab injection. Bloch et al. in Denmark and Egypt describe neovascular membrane contraction and retinal pigment epithelial rupture following verteporfin and bevacizumab treatment. Caramoy et al. in Germany found recurrent choroidal neovascular membrane after autologous RPE transplantation. I wish all readers a Merry Christmas and a Happy New Year and hope that they enjoy reading ACTA during the holidays.

Differential diameter responses in macular and peripheral retinal arterioles may contribute to the regional distribution of diabetic retinopathy lesions

Diabetic retinopathy is assumed to be due to impaired retinal autoregulation, involving both pressure autoregulation and metabolic autoregulation. The disease displays regional differences, with signs of hyperperfusion in the macular area and capillary occlusion with retinal ischemia in the peripheral retinal areas. It can be hypothesized that these regional differences in the occurrence of retinopathy lesions may reflect differences in the capacity of retinal arterioles to autoregulate the diameter of retinal arterioles. Seventeen normal persons and two matched groups of patients with respectively diabetic maculopathy and proliferative diabetic retinopathy were examined. The diameter change of a macular and a peripheral retinal arteriole during an increase in the arterial blood pressure induced by isometric exercise, during an increase in retinal metabolism induced by flicker stimulation, and during both stimulus paradigms simultaneously were studied using the dynamic vessel analyzer (DVA). During isometric exercise, the diameter response was reduced in both macular and peripheral retinal arterioles in the two groups of patients with diabetes mellitus. During flicker stimulation, the diameter response was significantly reduced in patients with proliferative diabetic retinopathy, but there was no significant difference between the responses of macular and peripheral arterioles. During simultaneous isometric exercise and flicker stimulation, there was no difference between the diameter response of macular arterioles in the three groups, whereas the diameter response of macular arterioles was significantly lower in normal persons and significantly higher in persons with proliferative diabetic retinopathy as compared to peripheral arterioles. Regional differences in the disturbances of the diameter response to increased blood pressure may contribute to the regional differences in the distribution of diabetic retinopathy lesions. In the central retinal areas, the diameter response to increased blood pressure and retinal metabolism interacted in a way that may potentially protect this area from ischaemia, whereas this protective mechanism was absent in the peripheral retinal arterioles. An elucidation of the mechanisms underlying diameter regulation to increased blood pressure and retinal metabolism, and the interaction between these two mechanisms, may help in understanding the pathophysiology of diabetic retinopathy.

Lack of effect of short-term treatment with Amlodipine and Lisinopril on retinal autoregulation in normotensive patients with type 1 diabetes and mild diabetic retinopathy

Diabetic retinopathy is characterized by morphological changes in the retina secondary to disturbances in retinal blood flow. It has been shown that antihypertensive treatment has a protective effect on the development of diabetic retinopathy, and evidence suggests that inhibitors of the renin-angiotensin system have a protective effect beyond the antihypertensive effect. The background for this additional effect is unknown but might be related to an effect on retinal autoregulation. In a double-blinded, two-way cross-over study, 25 normotensive patients with type 1 diabetes (T1D) aged 20.6-33.9 (mean 27.9) with mild retinopathy were randomized to receive either 5 mg of the calcium channel blocker (CCB) amlodipine for 14 days followed by a washout period and treatment with 10 mg of the angiotensin converting enzyme (ACE) inhibitor lisinopril for another 14 days or the two treatments in the reverse order. Using a Dynamic Vessel Analyzer (DVA), the diameter response of retinal arterioles during an acute increase in the blood pressure induced by isometric exercise, during flicker stimulation and during both stimulus conditions simultaneously was studied before and during the two treatments periods. Amlodipine and lisinopril induced a similar non-significant decrease in the arterial blood pressure. At baseline, the arterial diameter decreased by 2.4 ± 0.9% (p = 0.004) during isometric exercise, increased by 2.2 ± 0.9% (p = 0.019) during flicker stimulation and increased by 1.8 ± 0.9% (p = 0.03) during the combined stimulus conditions. Neither of the antihypertensive drugs amlodipine (p = 0.76) or lisinopril (p = 0.11) changed the diameter response of retinal vessels significantly; however, the two treatments induced a different response in the veins during combined exercise and flicker (p = 0.021). Short-term treatment with amlodipine and lisinopril had no significant effect on retinal autoregulation in young normotensive patients with T1D and mild retinopathy, and this lack of effect was similar for the two drugs. A possible normalizing effect of antihypertensive treatment on retinal autoregulation was not observed; however, it might take longer time to improve autoregulation than to reduce the arterial blood pressure.