Retinal neurovascular coupling in patients with glaucoma and ocular hypertension and its association with the level of glaucomatous damage

Purpose: To analyze neurovascular coupling in the retina of untreated primary open-angle glaucoma (POAG) and ocular hypertension (OHT) patients. Patients and methods: Maximal vessel dilation in response to flicker light was analyzed with Retinal Vessel Analyzer (RVA) in temporal superior/inferior arterioles and veins in 51 POAG patients, 46 OHT and 59 control subjects. RVA parameters were compared between groups, between contralateral POAG eyes, and correlated to intraocular pressure, visual field mean defect and retinal nerve fiber layer thickness. Results: POAG eyes demonstrated generally smaller response of all vessels to flicker light than the other two groups (ANOVA p = 0.026; mean arterial flicker response in percent of baseline, averaged superior and inferior was 3.48 ± 2.22% for controls , 2.35 ± 2.06 % for POAG patients , and 2.97 ± 2.35 % for OHT patients; corresponding values for venules were 3.88 ± 1.98%, 2.89 ± 1.72%, 3.45 ± 2.77%). There was no difference in flicker response between the eye with more and less advanced damage in each patient of the POAG group (ANOVA p = 0.79). Correlation of flicker response to intraocular pressure (IOP) was borderline at best, correlations to the level of glaucomatous damage were not significant. Correlation of flicker response of superior and inferior vessels of the same eye was significant for the arteries (Pearson r = 0.23, p = 0.004), as well as venules (r = 0.52, p < 0.001). Conclusion: General vessel response to flicker light was decreased in POAG patients, compared to normal controls and OHT patients. In contrast to significant correlation between the two contralateral eyes of the flicker response itself, only its borderline correlation to IOP was seen. There was no correlation to the level of damage, altogether indicating a systemic dysregulation phenomenon. Grants: Swiss National Foundation Grant 3200B0-113685, Velux Stiftung Grant, Freie Akademische Gesellschaft (FAG) Grant, Pfizer Inc. Grant Clinical trial registration reference number: ClinicalTrials.gov NCT0043020

Dynamics of retinal vessel response to flicker light in glaucoma patients and ocular hypertensives

Purpose: To analyze dynamics of retinal vessel dilation response to flicker light in patients with glaucoma and ocular hypertension. Patients and methods: Response to flicker light was measured in retinal vessels by means of Retinal Vessel Analyzer. After the baseline 50seconds long diameter recording of inferior and superior temporal artery and vein, three flicker stimulations of 20seconds duration was applied, with a 80seconds break in between. Area under the curve of the vessel diameter (AUC) was compared during 3 flicker periods in the open angle glaucoma patients group (POAG, n = 47) and ocular hypertensives (OHT, n = 46) and age-matched healthy controls (n = 56) Results: POAG eyes demonstrated smaller response of all vessels to flicker light in general than the other two groups (p = 0.0008), but the response dynamics was significantly different between the groups (p = 0.038), showing in three flicker periods a delayed increasing response in the POAG and OHT groups, and remaining stable in healthy subjects. Conclusion: General vessel response to flicker light was decreased in POAG patients despite the slow improvement in repeated flicker stimulation, indicating an altered response patter

Ischemic Tolerance Protects the Rat Retina from Glaucomatous Damage

Glaucoma is a leading cause of acquired blindness which may involve an ischemic-like insult to retinal ganglion cells and optic nerve head. We investigated the effect of a weekly application of brief ischemia pulses (ischemic conditioning) on the rat retinal damage induced by experimental glaucoma. Glaucoma was induced by weekly injections of chondroitin sulfate (CS) in the rat eye anterior chamber. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started after 6 weekly injections of vehicle or CS and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. Glaucoma was evaluated in terms of: i) intraocular pressure (IOP), ii) retinal function (electroretinogram (ERG)), iii) visual pathway function (visual evoked potentials, (VEPs)) iv) histology of the retina and optic nerve head. Retinal thiobarbituric acid substances levels were assessed as an index of lipid peroxidation. Ischemic conditioning significantly preserved ERG, VEPs, as well as retinal and optic nerve head structure from glaucomatous damage, without changes in IOP. Moreover, ischemia pulses abrogated the increase in lipid peroxidation induced by experimental glaucoma. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies in glaucoma treatment

Retinal vessel diameters and reactivity in diabetes mellitus and/or cardiovascular disease

Background: Retinal vessel calibre and vascular dilation/constriction in response to flicker light provocation may provide a measure distinguishing patients suffering from diabetes mellitus and/or cardiovascular disease. Methods: One hundred and sixteen age and sex matched patients with diabetes mellitus (DM), cardiovascular disease (CVD) and both DM and CVD (DM+CVD) underwent systemic and intraocular pressure measurements. Retinal vessel calibres were assessed using a validated computer-based program to compute central retinal artery and vein equivalents (CRVE) from monochromatic retinal images. Vessel dilation and constriction responses to flicker light provocation were assessed by continuous retinal vessel diameter recordings. Plasma endothelial markers von Willebrand factor (vWf) and soluble E selectin (sEsel) were measured by ELISA. Results: Retinal vessel calibres were comparable across groups but CRVE correlated significantly with disease duration in DM patients (r=0.57, p<0.001). Patients suffering DM only exhibited reduced arterial vasomotion at rest and reduced arterial constriction following flicker light induced vessel dilation compared to patients with CVD and those suffering both CVD+DM (p=0.030). Patients suffering from CVD+DM exhibited significant differences between each flicker cycle in regards to arterial maximum constriction (p=0.006) and time needed to reach arterial maximum dilation (p=0.004), whereas the other two groups did not show such inconsistencies between individual flicker cycles. vWf was raised in CVD+DM compared to the other two groups (p≤0.02), whilst sEsel was raised in CVD+DM compared to DM alone (p=0.044). Conclusions: Dynamic retinal vascular calibres as obtained by continuous diameter measurements using flicker light provocation can reveal subtle differences between groups suffering from CVD with and without DM. This difference in reaction pattern and lack of arterial constriction in DM may provide a suitable marker to monitor progression

The relationship of systemic markers of renal function and vascular function with retinal blood vessel responses

Purpose: To test the hypothesis of a significant relationship between systemic markers of renal and vascular function (processes linked to cardiovascular disease and its development) and retinal microvascular function in diabetes and/or cardiovascular disease.Methods: Ocular microcirculatory function was measured in 116 patients with diabetes and/or cardiovascular disease using static and continuous retinal vessel responses to three cycles of flickering light. Endothelial function was evaluated by von Willebrand factor (vWf), endothelial microparticles and soluble E selectin, renal function by serum creatinine, creatinine clearance and estimated glomerular filtration rate (eGFR). HbA1c was used as a control index.Results: Central retinal vein equivalence and venous maximum dilation to flicker were linked to HbA1c (both p<0.05). Arterial reaction time was linked to serum creatinine (p=0.036) and eGFR (p=0.039), venous reaction time was linked to creatinine clearance (p=0.018). Creatinine clearance and eGFR were linked to arterial maximum dilatation (p<0.001 and p=0.003 respectively) and the dilatation amplitude (p=0.038 and p=0.048 respectively) responses in the third flicker cycle. Of venous responses to the first flicker cycle, HbA1c was linked to the maximum dilation response (p=0.004) and dilatation amplitude (p=0.017), vWf was linked to the maximum constriction response (p=0.016), and creatinine clearance to the baseline diameter fluctuation (p=0.029). In the second flicker cycle, dilatation amplitude was linked to serum creatinine (p=0.022). Conclusions: Several retinal blood vessel responses to flickering light are linked to glycaemia and renal function, but only one index is linked to endothelial function. Renal function must be considered when interpreting retinal vessel responses

[Vascular risk factors in glaucoma - diagnostics]

The major risk factor for glaucoma is the increased intraocular pressure, and its pharmacological and/or surgical reduction slows down the progression of the glaucomatous damage. However, this protective effect is only a partial one, the complete arrest of damage progression does not take place, indicating risk factors other than intraocular pressure. Among vascular factors, reduced ocular perfusion pressure, in particular the nocturnal episodes of arterial hypotony, and the vascular dysregulation play important roles in glaucoma. Combined with variable intraocular pressure, these factors lead to oxidative stress, reperfusion damage and ultimately to the hallmark of glaucoma - loss of axons and tissue remodelling (cupping). Examination of vascular risk profile is necessary in order to tailor the therapy to the patients individual need

Ocular blood flow alteration in glaucoma is related to systemic vascular dysregulation

Aims: To investigate the source of ocular blood flow alterations in glaucoma. Methods: In 56 patients with open angle glaucoma, blood flow parameters were obtained from both eyes in the ophthalmic and central retinal artery by means of colour Doppler imaging, as well as in the choroidal circulation and the neuroretinal rim of the optic nerve by means of laser Doppler flowmetry. Based on these haemodynamic parameters, a cluster analysis (two groups) was performed and differences with regard to risk factors were assessed between clusters. Results: Ocular blood flow data in the two clusters indicated that the two groups (cluster 1 = 26 patient with higher blood flow values; cluster 2 = 30 patients with lower blood flow values) differed mainly in choroidal and optic nerve blood flow. No differences in sex distribution, propensity to have normal tension glaucoma, age, endothelin-1 plasma levels, visual field damage, intraocular pressure, or systemic blood pressure parameters were observed between the two clusters. However, 12 patients (46%) from the cluster with high ocular blood flow values showed a vasospastic response in nailfold capillaroscopy, while such a response was observed in 24 patients (80%) of the cluster with low ocular blood flow values. This difference in vasospastic propensity was statistically significant (p = 0.0121). Conclusions: Ocular blood flow alterations in glaucoma patients seem, at least partly, to be related to a systemic vascular dysregulation

Volumetric blood flow measurement in the ophthalmic artery using colour Doppler

BACKGROUND: Herewith we present a new method for measurement of the volumetric blood flow in absolute units in the ophthalmic artery. PATIENTS AND METHODS: A Philips EnVisor HD ultrasound unit with a 12 - 3 MHz linear transducer was used to measure flow in the ophthalmic artery in 8 healthy young subjects. The transducer was mounted on a custom-made holder which enabled precise and reproducible positioning in 3 axes as well as in rotation angle. Blood flow velocity and vessel diameter were measured during 10 consecutive heartbeats. The measurements were ECG-gated. Blood vessel diameter and blood flow velocity were calculated in an average heartbeat cycle. Hence blood volume over time within a heartbeat cycle as well as blood flow in mL/min were determined. Simultaneously, cardiovascular parameters have been recorded by Finapres. Short time reproducibility (5 measurements on day 1) and long time reproducibility (5 days once daily) as well as interindividual coefficient of variation were evaluated. RESULTS: Average blood flow in the ophthalmic artery in all measurements was 39.7 mL/min. The short-term intraindividual coefficient of variation was 24.1 +/- 9.2 %, the long-term coefficient 32.0 +/- 13.8 %. Interindividual coefficient of variation was 32.8 %. CONCLUSIONS: Our method allows volumetric blood flow measurements in the ophthalmic artery in absolute units, reproducible to a limited extent

Sequential bilateral non-arteritic anterior ischaemic optic neuropathy in superficial intracranial siderosis

Superficial intracranial siderosis (SIS) is a rare and often unrecognized disorder of the central nervous system (CNS) characterized by progressive neuronal degeneration resulting from chronic subarachnoid bleeding. Hemoglobin accumulates in the subarachnoid space where it is metabolized to hemosiderin and deposited in the subpial layer of those parts of the CNS adjacent to the cerebrospinal fluid with predilection for inter alia the cerebellum and cranial nerves I, II and VIII. Hemosiderin deposits lead to neuronal damage, reactive gliosis, and demyelination. Often the hemorrhage is occult and no bleeding source can be detected. Classic symptoms are sensorineural deafness, cerebellar ataxia and pyramidal signs [1]. Ophthalmic symptoms such as nystagmus have also been reported. Visual dysfunction however is not a recognized feature of SIS. Indeed, patients in an advanced stage have been shown to have normal optic nerve function [2]. Polidori et al documented a case of optic nerve dysfunction in a patient with SIS and concomitant glaucoma [3]. In 2008 Koeppen et al postulated that visual failure solely due to SIS does not occur [4]. But Painter et al reported two cases of SIS with strong evidence of optic nerve dysfunction and one postmortem case of histological findings of iron deposition and associated demyelination in the optic nerve [5]. Magnetic resonance imaging (MRI) is the diagnostic method of choice showing features of hemosiderin accumulation on CNS surfaces [4]