Exploratory study of non-invasive,high-resolution functional macular imaging in subjects with diabetic retinopathy

AIM:To evaluate a high-resolution functional imaging device that yields quantitative data regarding macular blood flow and capillary network features in eyes with diabetic retinopathy(DR).METHODS:Prospective,cross-sectional comparative case-series in which blood flow velocities(BFVs)and noninvasive capillary perfusion maps(nCPMs)in macular vessels were measured in patients with DR and in healthy controls using the Retinal Functional Imager(RFI)device.RESULTS:A total of 27 eyes of 21 subjects were studied[9 eyes nonproliferative diabetic retinopathy(NPDR),9 eyes proliferative diabetic retinopathy(PDR)and 9 controls].All diabetic patients were type 2.All patients with NPDR and 5 eyes with PDR also had diabetic macular edema(DME).The NPDR group included eyes with severe(n=3)and moderate NPDR(n=6),and were symptomatic.A significant decrease in venular BFVs was observed in the macular region of PDR eyes when compared to controls(2.61±0.6 mm/s and 2.92±0.72 mm/s in PDR and controls,respectively,P=0.019)as well as PDR eyes with DME compared to NPDR eyes(2.36±0.51 mm/s and 2.94±1.09 mm/s in PDR with DME and NPDR,respectively,P=0.01).CONCLUSION:The RFI,a non-invasive imaging tool,provides high-resolution functional imaging of the retinal microvasculature and quantitative measurement of BFVs in visually impaired DR patients.The isolated diminish venular BFVs in PDR eyes compared to healthy eyes and PDR eyes with DME in comparison to NPDR eyes may indicate the possibility of more retinal vein compromise than suspected in advanced DR.

Characterization of retinal microvasculature in acute non-arteritic anterior ischemic optic neuropathy using the retinal functional imager: a prospective case series

Background:Non-arteritic anterior ischemic optic neuropathy(NAION)is the most common cause of acute optic neuropathy in patients over 50 years of age,and many affected individuals are left with permanent visual deficits.Despite the frequency of NAION and its often devastating effects on vision,no effective treatment has been established.Further understanding of the acute vascular effects in NAION,using advanced ophthalmic imaging techniques like the retinal function imager,may shed light on potential treatment targets.Methods:Five patients with acute NAION underwent retinal functional imaging within 2 weeks of the onset of their visual symptoms,and at 1 month and 3 months after onset.Average arteriolar and venular blood flow velocities were calculated for each eye at each time point.The Wilcoxon rank sum test was used to compare blood flow velocity results with a normative database.Results:The average arteriolar blood flow velocity in the normative group was 3.8 mm/s,and the average venular blood flow velocity was 3.0 mm/s,versus 4.1 mm/s and 2.7 mm/s,respectively,in the NAION-affected group at presentation.Average arteriolar blood flow increased slightly to 4.2 mm/s one month after the acute NAION event,then decreased to 3.8 mm/s three months after the event.Average venular blood flow velocity was 2.8 mm/s 1 month after the NAION event and 2.7 mm/s 3 months after the event.Differences in blood flow velocity between the NAION-affected and control groups were not statistically significant at any time point;however,there was a trend toward increasing blood flow velocity initially after an NAION,with a decrease over time.Conclusions:This study demonstrates the feasibility of retinal function imaging to quantify macular blood flow velocity in patients with acute NAION.There were no statistically significant differences in blood flow velocity detected between NAION-affected eyes and healthy controls at any of the time points examined;however,there was a trend toward an increase in both arteriolar and venular BFV subacutely,then a decrease in the chronic phase after NAION,which could be suggestive of a mechanism of attempted compensation in the setting of acute ischemia.

Retinal nerve fiber layer (RNFL) integrity and its relations to retinal microvasculature and microcirculation in myopic eyes

Background:The aim was to determine retinal nerve fiber layer function and its relations to retinal microvasculature and microcirculation in patients with myopia.Method:Polarization-sensitive optical coherence tomography(PS-OCT)was used to measure phase retardation per unit depth(PR/UD,proportional to the birefringence)of the retinal nerve fiber layer(RNFL).Optical coherence tomography angiography(OCTA)was used to measure macular vessel density analyzed using fractal analysis.In addition,a retinal function imager(RFI)was used to measure macular blood flow velocities in arterioles and venules.Twenty-two patients with moderate myopia(MM,refraction>3 and<6 diopters),seventeen patients with high myopia(HM,≥6 D)and 29 healthy control subjects(HC,≤3.00 D)were recruited.One eye of each patient was imaged.Results:Although the average PR/UD of the RNFL in the HM group did not reach a significant level,the birefringence of the inferior quadrant was significantly lower(P<0.05)in the HM group compared to the HC group.Significant thinning of the average RNFL and focal thinning of RFNL in temporal,superior and inferior quadrants in the HM group were found,compared to the HC group(P<0.05).There were no significant differences of retinal blood flow velocities in arterioles and venules among groups(P>0.05).The macular vessel density in both superficial and deep vascular plexuses was significantly lower in the HM group than in the other two groups(P<0.05)as well as in the MM group than in the HC group(P<0.05).The average PR/UD and PR/UD in the inferior quadrant were not related to refraction,axial length,blood flow velocities and macular vessel densities(r ranged from−0.09 to 0.19,P>0.05).Conclusions:The impairment of the retinal nerve fiber birefringence in the HM group may be one of the independent features in high myopic eyes,which appeared not to relate to macular microvascular density and blood flow velocity.

Retinal tissue hypoperfusion in patients with clinical Alzheimer’s disease

Background:It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease.The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease(CAD).Methods:Twenty-four CAD patients and 19 cognitively normal(CN)age-matched controls were recruited.A retinal function imager(RFI,Optical Imaging Ltd.,Rehovot,Israel)was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea.Blood flow volumes of arterioles(entering the macular region)and venules(exiting the macular region)of the supplied area were calculated.Macular blood flow was calculated as the average of arteriolar and venular flow volumes.Custom ultra-high-resolution optical coherence tomography(UHR–OCT)was used to calculate macular tissue volume.Automated segmentation software(Orion,Voxeleron LLC,Pleasanton,CA)was used to segment six intra-retinal layers in the 2.5 mm(diameter)area centered on the fovea.The inner retina(containing vessel network),including retinal nerve fiber layer(RNFL),ganglion cell-inner plexiform layer(GCIPL),inner nuclear layer(INL)and outer plexiform layer(OPL),was segmented and tissue volume was calculated.Perfusion was calculated as the flow divided by the tissue volume.Results:The tissue perfusion in CAD patients was 2.58±0.79 nl/s/mm^(3)(mean±standard deviation)and was significantly lower than in CN subjects(3.62±0.44 nl/s/mm^(3),P<0.01),reflecting a decrease of 29%.The flow volume was 2.82±0.92 nl/s in CAD patients,which was 31%lower than in CN subjects(4.09±0.46 nl/s,P<0.01).GCIPL tissue volume was 0.47±0.04 mm^(3) in CAD patients and 6%lower than CN subjects(0.50±0.05 mm^(3),P<0.05).No other significant alterations were found in the intra-retinal layers between CAD and CN participants.Conclusions:This study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer’s disease.

The retinal function imager and clinical applications

Background:The Retinal Function Imager(RFI)provides in vivo and noninvasive imaging of both the retinal structure and function.Review:The RFI can create capillary perfusion maps,measure blood flow velocity,and determine metabolic function including blood oximetry.It can aid clinical diagnosis as well as assess treatment response in several retinal vascular diseases including diabetic retinopathy.Blood flow velocity abnormalities have also been implicated in disease such as age-related macular degeneration and require further investigation.Compared with optical coherence tomography angiography,the RFI produces capillary maps of comparable image quality and wider field of view but it is unable to provide depth-resolved information and has longer image acquisition time.Currently,functional imaging using blood oximetry has limited applications and additional research is required.Conclusion:The RFI offers noninvasive,high-resolution imaging of retinal microvasculature by creating capillary perfusion maps.In addition,it is capable of measuring retinal blood velocity directly and performs functional imaging with retinal blood oximetry.Its clinical applications are broad and additional research with functional imaging may potentially lead to diagnosis of diseases and their progression before anatomic abnormalities become evident,but longer image acquisition times may limit its clinical adoption.

Microvascular blood flow velocities measured with a retinal function imager: inter-eye correlations in healthy controls and an exploration in multiple sclerosis

Background:The retinal microcirculation has been studied in various diseases including multiple sclerosis(MS).However,inter-eye correlations and potential differences of the retinal blood flow velocity(BFV)remain largely unstudied but may be important in guiding eye selection as well as the design and interpretation of studies assessing or utilizing retinal BFV.The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls(HCs).Since prior studies raise the possibility of reduced BFV in MS eyes,a secondary aim was to compare retinal BFVs between MS eyes,grouped based on optic neuritis(ON)history and HC eyes.Methods:Macular arteriole and venule BFVs were determined using a retinal function imager(RFI)in both eyes of 20 HCs.One eye from a total of 38 MS patients comprising 13 eyes with ON(MSON)and 25 eyes without ON(MSNON)history were similarly imaged with RFI.Results:OD(right)and OS(left)BFVs were not significantly different in arterioles(OD:3.95±0.59 mm/s;OS:4.08±0.60 mm/s,P=0.10)or venules(OD:3.11±0.46 mm/s;OS:3.23±0.52 mm/s,P=0.06)in HCs.Very strong inter-eye correlations were also found between arteriolar(r=0.84,P<0.001)and venular(r=0.87,P<0.001)BFVs in HCs.Arteriolar(3.48±0.88 mm/s)and venular(2.75±0.53 mm/s)BFVs in MSNON eyes were significantly lower than in HC eyes(P=0.009 and P=0.005,respectively).Similarly,arteriolar(3.59±0.69 mm/s)and venular(2.80±0.45 mm/s)BFVs in MSON eyes were also significantly lower than in HC eyes(P=0.046 and P=0.048,respectively).Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other(P=0.42 and P=0.48,respectively).Conclusions:Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated.Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes.Moreover,this seems to be the case in both MS eyes with and without a history of ON,raising the possibility of global blood flow alterations in MS.Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes.

The inter-visit variability of retinal blood flow velocity measurements using retinal function imager (RFI)

Background:To determine the inter-visit variability of retinal blood flow velocities(BFVs)using a retinal function imager(RFI)in healthy young subjects.Methods:Twenty eyes of 20 healthy young subjects were enrolled.RFI imaging was performed to obtain the BFVs in retinal arterioles and venules in a field measuring 7.3×7.3 mm^(2)(setting:35 degrees)centered on the fovea,and repeated measurements were obtained on two separate days.The inter-visit variability of BFVs was assessed by the concordance correlation coefficient(CCC)and coefficient of variance(CV).Results:At the first visit,the mean BFV was 3.6±0.8 mm/s and 3.0±0.7 mm/s in arterioles and venules,respectively,which were not significantly different from those at the second visit(the BFV of arterioles was 3.5±0.8 mm/s,and the BFV of venules was 3.0±0.7 mm/s,P>0.05,respectively).The CCC was 0.72 in the BFVs of arterioles and 0.67 in venules,and the CV was 10.8%in the BFVs of arterioles and 11.0%in venules.Conclusion:The inter-visit variability using the retinal function imager(RFI)with a large field of view appeared to be good and comparable to previously reported intra-visit and inter-eye variability.

The effect of sildenafil on retinal blood velocity in healthy subjects

Purpose:It has been suggested that Sildenafil may have beneficial therapeutic effects in the treatment of neurodegenerative disorders.The retinal circulation is of significant interest as a marker of cerebral vascular disease since the retinal and cerebral vasculatures share many morphological and physiological properties,yet only the retinal circulation can be directly visualized.Therefore,our aim was to assess the change induced by Sildenafil on retinal blood velocity.Methods:Retinal flow velocity was measured 0.5,3 and 6 h following administration of 100 mg of Sildenafil using the Retinal Function Imager.Results:No clinical change in either systemic blood pressure or retinal flow velocities were observed.However,when controlling for heart rate and blood pressure,a significant drop in venous flow velocity 6 h following treatment(mean drop 0.3±0.07;95%CI:0.44–0.56,P=0.023)was revealed.Conclusions:In healthy volunteers,retinal venous flow velocity was significantly reduced at the 6-h time point following Sildenafil treatment.No effect was observed on arterial retinal flow velocity.

Microcirculation in the conjunctiva and retina in healthy subjects

Background:The aim was to determine the relationship between bulbar conjunctival microcirculation and retinal microcirculation in a healthy population.Method:A functional slit-lamp biomicroscope(FSLB)was used to measure blood flow velocity(BFV)and blood flow rate(BFR)in the conjunctiva while a retinal function imager(RFI)was used to measure macular BFV and BFR in the retina.One eye of each subject of 58 self-reported healthy subjects was imaged in the same session on the same day.Results:The mean BFV in the venules of the conjunctiva was 0.49±0.13 mm/s,which was significantly slower than that in the retinal arterioles(3.71±0.78 mm/s,P<0.001)and retinal venules(2.98±0.58 mm/s,P<0.001).The BFR in the conjunctiva(0.09 nl/s)was also significantly lower than that in the retina(arterioles=0.81 nl/s,venules=0.68 nl/s,all P<0.001).The BFVs and BFRs were not related between the conjunctiva and retina(r ranged from−0.17 to−0.05,all P>0.05).Conclusion:The microcirculation in the retina appeared to be different from that in the conjunctiva.