OCT and IOP findings in a healthy worker cohort: results from a teleophthalmic study in occupational medicine.

PURPOSE: To avoid significant loss of vision in employees, the working population could be examined with ophthalmic methods as OCT and IOP measurement for detection of serious eye diseases. The value of "virtual eye clinics" in occupational preventive medicine has been previously shown. We used a telemedical approach to gather epidemiological information about prevalence of eye diseases such as glaucoma, ocular hypertension, hypertensive retinopathy, diabetic retinopathy, epiretinal membrane, AMD, adult vitelliform maculopathy, cystoid maculopathy, choroidal nevi, and macular drusen. METHODS: The study included 931 people ranging from age 39 to 65 years. Using a telemedical approach, all medical examinations and the ophthalmic examination were performed by a technician using an optical coherence tomography (SD-OCT) and a pulse air tonometer. The data were saved in the web-based patient chart MedStage® of the Talkingeyes® Collaboration Network. RESULTS: We found a high prevalence of eye diseases in a group representative for the working-age population by telemedical examination. 13.47% of the workers examined showed ocular findings necessitating treatment or control by an ophthalmologist, including ocular hypertension (5.7%), hypertensive retinopathy with loss of temporal retinal nerve fiber thickness (2.3%), epiretinal membrane (1.07%), glaucoma (0.97%), age-related macular degeneration and adult vitelliform maculopathy (0.53%), and diabetic retinopathy (0.2%). Two of the examined persons presented ocular findings requiring urgent treatment to prevent serious vision loss. CONCLUSION: Using a telemedical approach, we collected epidemiological information about prevalence of eye diseases in the working-age population. Virtual eye clinics in occupational preventive medicine are a useful method to improve sight and reduce vision loss of workers by reducing travel time and inconvenience associated with an in-person appointment with an ophthalmologist.

Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function.

AIMS: The aim of this study was to investigate the vascular effects of liraglutide in patients well controlled on metformin monotherapy. METHODS: Forty-four patients with Type 2 diabetes were included in the study. Main inclusion criteria were: pretreatment with metformin on a stable dosage, HbA(1c) < 53 mmol/mol (7.0%), age 30-65 years. Patients were randomized to receive additional liraglutide or to remain on metformin monotherapy. After 6 weeks (1.2 mg) and after 12 weeks (1.8 mg), venous blood was taken for the measurement of several laboratory markers characterizing vascular and endothelial function. In addition, retinal microvascular endothelial function and arterial stiffness were measured. RESULTS: HbA(1c) levels declined from 45 ± 4 mmol/mol (6.3 ± 0.4%; mean ± SD) to 40 ± 3 mmol/mol (5.8 ± 0.3%) during liraglutide treatment. Asymmetric dimethylarginin was reduced by liraglutide treatment from 0.39 ± 0.08 to 0.35 ± 0.06 µmol/l, E-selectin from 43.6 ± 15.4 to 40.8 ± 15.1 ng/ml, plasminogen activator inhibitor 1 from 861.6 ± 584.3 to 666.1 ± 499.4 ng/ml and intact proinsulin from 9.0 ± 7.2 to 7.0 ± 4.8 pmol/l at 12 weeks of treatment. The microvascular response to flicker light increased from 7.0 ± 15.1 to 15.4 ± 11.5% after 6 weeks and to 11.1 ± 9.9% after 12 weeks. No change could be observed for high-sensitivity C-reactive protein, monocyte chemotactic protein 1, vascular cell adhesion molecule or arterial stiffness parameters. CONCLUSIONS: In patients with Type 2 diabetes, well controlled with metformin monotherapy, addition of liraglutide improves several cardiovascular risk markers beyond glycaemic control.

[Integrity/demyelination of the optic radiation, morphology of the papilla, and contrast sensitivity in glaucoma patients]. / Integrität/Demyelinisierung der Radiatio optica, Morphologie der Papille und Kontrastsensitivität bei Glaukompatienten.

BACKGROUND: In primary open angle glaucoma (POAG) and its non-barotraumatic subgroup, normal tension glaucoma (NTG), the pathophysiological differences are not clear. A participation of the 4th neuron of the visual pathway (optic radiation) appears possible on the basis of related experimental studies. The goal of the present study was the evaluation of the optic radiation by diffusion tensor imaging (DTI), which is based on the magnetic resonance imaging. The diffusion and anisotropy parameters of the optic radiation as a marker of axonal integrity and demyelination/damage of glial cells, respectively, were used to investigate the relation between the morphology of the papilla (BLDF, linear discriminant function of Burk) and the contrast sensitivity (FDT, frequency doubling test). PATIENTS AND METHODS: In this prospective observational study 13 POAG patients, 13 NTG patients, and 7 control patients of the same mean age were included. For segmentation of the optic radiation a semi-automated algorithm was applied and the diffusion and anisotropy parameters were calculated. The importance of the covariates age, BLDF, and FDT for the DTI parameters was determined using partial correlation analysis. RESULTS: Analysis of the covariates partially showed a clear autocorrelation. The correlations between the DTI parameters and BLDF were significant in all groups after correction of the measurement values for the covariates. FDT correlated with DTI parameters in controls and POAG. The NTG group did not show this correlation due to a strong spreading of the FDT values. CONCLUSION: After statistical elimination of the autocorrelation of the covariates age, BLDF, and FDT the morphology of the papilla correlated with the axonal integrity and demyelination/glia cell impairment of the optic radiation in controls and glaucoma. In NTG the impaired contrast sensitivity is highly variable and is not associated with the condition of the 3rd or 4th neuron, respectively, as compared to POAG. The autocorrelation between individual covariates represents an important element for the judgement of the visual pathway.

[Validation of telemedical fundus images from patients with retinopathy]. / Validierung von telemedizinischen Fundusaufnahmen bei Patienten mit Retinopathie.

BACKGROUND: The degree of retinal microangiopathy is important foran estimation of the vascular risk and for the optimisation of therapy in hypertensive and diabetic patients. Retinal microangiopathy may be determined by examination of the retinal fundus. We examined the reliability of the ophthalmoscopic diagnosis and of the telemedical judgement of fundus images in relation to the presence and the degree of retinopathy. PATIENTS AND METHODS: This comparative observational study included 47 inpatient hypertensive and/or diabetic subjects. The fundus was judged ophthalmoscopically and subsequently, a fundus image was generated by use of a KOWA camera. The images were sent to the Interdisciplinary Center of Ophthalmologic Preventive Medicine. The reliability of the two diagnostic methods was calculated for one of the two eyes, which was selected by a random generator. RESULTS: The largest concordance of the two diagnosis methods was achieved, in descending order, for retinal bleeding, stage of diabetic retinopathy and the papilla findings. Additionally, there were no differences for the stage of hypertensive retinopathy und tortuosity. The reliability of arterio-venous nicking related to the right and the left eye was low or absent, respectively. CONCLUSIONS: The teleophthalmologic diagnosis achieves good results as compared to the ophthalmoscopic judgement in relation to retinopathy assessment criteria.

[Comparison of early retinal microvascular changes and microalbuminuria as indicators for increased cardioascular risk]. / Vergleich von frühen Veränderungen der retinalen Mikrostrombahn und Mikroalbuminurie als Zeichen eines erhöhten kardiovaskulären Risikos.

INTRODUCTION: Prevention of cardiovascular disease is an important goal in clinical medicine and public health. In the process, the diagnosis of early end-organ damage is a priority beside the treatment of classic cardiovascular risk factors. To achieve this, the ophthalmoscopic examination of the retinal vessels plays a prominent role. Alternatively, the quantification of low quantities of albumin in the urine (microalbuminuria) allows the detection of early vascular damage in the kidney. The question is addressed as to whether these two methods are interchangeable or are rather complementary. PATIENTS AND METHODS: We examined 226 members of the staff of the University Hospital Erlangen who volunteered to participate in a preventive campaign. A comprehensive history was taken, and height, weight and blood pressure were measured. Analysis of serum lipids and determination of the urinary albumin/creatinine ratio were performed. Fotos of the central fundus were taken with a non-mydriatic camera and analysed by an experienced ophthalmologist in a standardised fashion. The risk for cardiovascular mortality within the next ten years was estimated from age, sex, blood pressure and serum cholesterol using the euroSCORE tables for Germany. RESULTS: There was no signficant correlation between the arteriovenous ratio of the retinal vessels and the urinary albumin/creatinine ratio. Neither parameter correlated with the euroSCORE Germany. Arteriovenous crossings and focal narrowing of the retinal vessels were associated signficantly with an elevated euroSCORE risk. CONCLUSIONS: In large population-based studies, the arteriovenous ratio and the urinary albumin/creatinine ratio have been confirmed as markers of cardiovascular risk. In our study, there was no correlation between these two parameters. Thus, they seem to present independent risk markers. The presence of arteriovenous crossings and focal narrowing seems to be linked more closely to the classic cardiovascular risk factors from which the euroSCORE is calculated. The ophathlmolscopic examination of retinal vessels and the analysis of urinary albumin/creatinine ratio seem to complement rather than replace each other.

[Prevalence of glaucomatous optic nerve atrophy among a working population in Germany diagnosed by a telemedical approach]. / Telemedizinische Erfassung der Prävalenz der glaukomatösen Optikusatrophie in einer arbeitenden Bevölkerungsgruppe.

PURPOSE: The aim of this study was to determine the prevalence of glaucomatous optic nerve atrophy among a working population in Germany by secondary evaluation of a study conducted to estimate the prevalence of retinal microangiopathic abnormalities by telemedical examination of the retina. PATIENTS AND METHODS: From August 2002 until January 2004 the retina and optic nerve head were examined in 19,294 Caucasians using a non-mydriatic fundus camera (Kowa, nonmyd-alpha 45), which produces colour images with 45 degrees. The images of the retina and optic nerve head were evaluated telemedically by glaucoma specialists in respect to optic nerve pathologies and microangiopathic abnormalities by a standardised procedure. Glaucomatous optic nerve atrophy was diagnosed when specific glaucomatous morphological alterations of the optic nerve head were present. A complete medical history including reported elevated intraocular pressure (IOP) and blood pressure was obtained. RESULTS: The intra-observer and inter-observer reliability were 0.884 and 0.740, respectively. Cronbach's alpha for two evaluation cycles each of two observers was 0.870. The prevalences of glaucomatous optic nerve atrophy in the different age groups were 0.07 % (45 - 49 years), 0.40 % (50 - 54 years), 0.45 % (55 - 59 years) and 0.82 % (60 - 64 years). Age could be established as an important risk factor for glaucomatous optic nerve atrophy, while no influence of gender or family history was found. CONCLUSION: Telemedical evaluation of colour images of the retina and optic nerve acquired by a non-mydriatic fundus camera allows a fast and efficient screening of many subjects with medium reliability.

[Web-based electronic patient record as an instrument for quality assurance within an integrated care concept]. / Webbasierte elektronische Krankenakte im Rahmen eines integrierten Versorgungskonzepts als Instrument der Qualitätssicherung.

OBJECTIVE: A prerequisite for integrated care programmes is the implementation of a communication network meeting quality assurance standards. Against this background the main objective of the integrated care project between the University Eye Hospital Erlangen and the health insurance company AOK Bayern was to evaluate the potential and the acceptance of a web-based electronic patient record in the context of cataract and retinal surgery. METHODS: Standardised modules for capturing pre-, intra- and post-operative data on the basis of clinical pathway guidelines for cataract- and retinal surgery have been developed. There are 6 data sets recorded per patient (1 pre-operative, 1 operative, 4-6 post-operative). For data collection, a web-based communication system (Soarian Integrated Care) has been chosen which meets the high requirements in data security, as well as being easy to handle. This teleconsultation system and the embedded electronic patient record are independent of the software used by respective offices and hospitals. Data transmission and storage were carried out in real-time. RESULTS: At present, 101 private ophthalmologists are taking part in the IGV contract with the University Eye Hospital Erlangen. This corresponds to 52% of all private ophthalmologists in the region. During the period from January 1st 2006 to December 31st 2006, 1844 patients were entered. Complete documentation was achieved in 1390 (75%) of all surgical procedures. For evaluation of this data, a multidimensional report and analysis tool (Cognos) was used. The deviation from target refraction as one quality indicator was in the mean 0.09 diopter. CONCLUSIONS: The web-based patient record used in this project was highly accepted by the private ophthalmologists. However there are still general concerns against the exchange of medical data via the internet. Nevertheless, the web-based patient record is an essential tool for a functional integration between the ambulatory and stationary health-care units. In addition to the telemedicine functions of the system, we achieved the export of the data to a data warehouse system in order to provide a flexible and powerful tool for quality assurance analysis and reporting.

Visual field defect during therapy with valproic-acid.

Visual field defect because of antiepileptic drug (AED) treatment has been widely reported during the clinical application of vigabatrin. But other gamma-aminobutyric acid (GABA)-ergic and non-GABA-ergic AEDs could also affect the visual field with different mechanisms of action. Here we report a case of a 22-year-old female patient, who suffered from bilateral concentric visual field defect during the long-term therapy with valproic-acid (VPA). A VPA-related metabolic dysfunction was found through blood and urine examination. Reduced B-waves were shown by electroretinography and a bilateral concentric visual field defect was confirmed by both manual and automated perimetry. In conclusion, the concentric visual field defect related to VPA treatment is rare but possible.

[Diffusion tensor imaging of the visual pathway in glaucomatous optic nerve atrophy]. / Diffusionsbildgebung der Sehbahn bei glaukomatöser Optikusatrophie.

In Germany more than one million inhabitants suffer from glaucoma, more than 100,000 are threatened with blindness because glaucoma is often diagnosed too late or not at all. Diagnosis and monitoring is usually carried out "only" by examination of the retina and not the whole visual pathway. However, the eye is just "the tip of the iceberg" of the actual visual pathway, which extends through the brain to the visual cortex. The interdisciplinary holistic assessment of the whole visual pathway in glaucoma is of crucial importance because glaucoma is a complex neurodegenerative disease. Subtypes, such as normal tension glaucoma (NTG), seem to originate from primary damage to the intracranial visual pathway with secondary retrograde retinal degeneration. Recent studies including glaucoma patients and healthy controls could show that diffusion tensor imaging with calculation of diffusion coefficients, i.e. fractional anisotropy (FA), mean and radial diffusivity (MD and RD) as markers of axonal integrity, provide the potential to assess the intracranial visual pathway with a high correlation to established ophthalmological examinations. In particular, calculation of FA maps of the visual pathway and accompanying voxel-based approaches, can be integrated into clinical routine. Thus, detection of glaucoma-related intracranial alterations, even in early stages of the disease, as well as differentiation of different glaucoma subtypes, is made possible. Furthermore, the diagnosis of normal tension glaucoma seems to be possible much earlier with these new imaging techniques compared to established ophthalmological work-up. Moreover, holistic imaging provides new insights into the pathophysiology of this form of glaucoma. This review article gives an overview of these novel magnetic resonance imaging techniques for assessment of the visual pathway in glaucomatous optic nerve atrophy and reveals the potential of an interdisciplinary approach.

Automated segmentation of the optic nerve head for diagnosis of glaucoma.

Glaucoma is the second most common cause of blindness worldwide. Low awareness and high costs connected to glaucoma are reasons to improve methods of screening and therapy. A well-established method for diagnosis of glaucoma is the examination of the optic nerve head using scanning-laser-tomography. This system acquires and analyzes the surface topography of the optic nerve head. The analysis that leads to a diagnosis of the disease depends on prior manual outlining of the optic nerve head by an experienced ophthalmologist. Our contribution presents a method for optic nerve head segmentation and its validation. The method is based on morphological operations, Hough transform, and an anchored active contour model. The results were validated by comparing the performance of different classifiers on data from a case-control study with contours of the optic nerve head manually outlined by an experienced ophthalmologist. We achieved the following results with respect to glaucoma diagnosis: linear discriminant analysis with 27.7% estimated error rate for automated segmentation (aut) and 26.8% estimated error rate for manual segmentation (man), classification trees with 25.2% (aut) and 22.0% (man) and bootstrap aggregation with 22.2% (aut) and 13.4% (man). It could thus be shown that our approach is suitable for automated diagnosis and screening of glaucoma.

[TalkingEyes-and-more]. / [In Process Citation]

To avoid the clinical manifestation of a vascular disease like stroke it is necessary to detect early vascular signs, to begin a therapy before the outbreak of the vascular disease happens. "TalkingEyes-and-more" is an interdisciplinary and quality-assessed program for prevention of vascular diseases. In several "screening-centers" in Germany interested citized were examined by non-invasive and fast methods to estimate the vascular risk. The examinations were performed on site, the medical evaluation of the data and images were performed centrally in the reading center of the Private Center of Preventive Medicine and Eye Diagnostics" in Erlangen by medical doctors. Alterations of the microvessels become often at first visible in retinal vessels. "TalkingEyes-and-more" examined telemedically the retinal vessels by a patented approach regarding microangiopathic abnormalities. In addition other risk factors like arterial blood pressure, intima media thickness of the carotid artery, cholesterol, fasting glucose, extended bodymass index, and others were documented. By these data a risk index is calculated and a proposal for improving the risk factors is generated.

Blood velocity in the ophthalmic artery in normal subjects and patients with endophthalmitis.

Some ocular diseases lead to temporary changes in the ocular blood circulation. This study was undertaken to evaluate changes in the blood-flow velocity of the ophthalmic artery in patients with endophthalmitis. With pulsed Doppler sonography the blood velocity of the ophthalmic artery was measured in 50 normal subjects and in ten patients with bacterial endophthalmitis. In normal subjects blood velocity decreased with increasing age, and the average systolic/diastolic blood velocity in cm/sec were 38.8 +/- 6.3/11.6 +/- 4.7 in the 18-50-year-old age group and 28.3 +/- 4.6/6.7 +/- 3.3 in the 51-88-year-old age group. Endophthalmitis produced increased systolic/diastolic blood velocity in the ophthalmic artery in the affected eyes in cm/sec (99.7 +/- 15.5/26.6 +/- 10.5 in the 16-50-year-old age group; 60.4 +/- 8.8/16.6 +/- 4.8 in the 51-83-year-old age group). Some patients showed similar changes in the unaffected fellow eyes. The noted elevation of the blood velocity in unaffected eyes may be due to the bilaterally projected parasympathetic fibers of the oculomotor nerve.

Two dimensional mapping of the perfusion of the retina and optic nerve head.

AIM: To present a new non-invasive method of performing a high definition topography of perfused vessels of the retina and the optic nerve head with simultaneous evaluation of blood flow. METHOD: By a combination of a laser Doppler flowmeter with a scanning laser system the perfusion of the retina and the optic nerve head is visualised. The principles of measuring blood flow by laser Doppler flowmetry are based on the optical Doppler effect: laser light scattered by a moving particle is shifted in frequency by an amount delta f. Our data acquisition and evaluation system is a modified laser scanning tomograph. The technical data are retinal area of measurement 2.7 mm x 0.7 mm, 10 degrees field with 256 points x 64 lines, measurement accuracy 10 microns, wavelength 670 nm and 790 nm, light power 100 microW and 200 microW, data acquisition time 2.048 s. Every line is scanned 128 times by a line sampling rate of 4000 Hz. By performing a discrete fast Fourier transformation over 128 intensities of each retinal point the laser Doppler shift is calculated for each retinal point. With these data a two dimensional map with 256 x 64 points of the retinal perfusion is created. The brightness of the pixel is coded by the value of the Doppler shift. Offline capillary blood flow is estimated in arbitrary units according to the theory of laser Doppler flowmetry in every region of interest of the perfusion picture. We estimated the reliability and the validity of the method. Retinal blood flow was measured by scanning laser Doppler flowmetry (SLDF) while varying intraocular pressure by a suction cup of three healthy volunteers. Measurements of retinal blood flow performed in 47 eyes by the presented method (SLDF) were correlated with data gained by a commercially available laser Doppler flowmeter. Perfusion pictures of the superficial retinal layer and of deep prelaminar layers in the optic nerve head are presented. RESULTS: The reliability coefficients r1 of 'flow', 'volume', and 'velocity' were 0.84, 0.85, and 0.84 respectively. We found a significant linear relation between SLDF flow and the ocular perfusion pressure (r = 0.84, p < 0.001). Comparative measurements of the retinal blood flow by SLDF and a commercially available laser Doppler flowmeter showed a linear and significant relation (flow r = 0.6, p < 0.0001, volume r = 0.4, p < 0.01). Capillaries of the retinal superficial vasculature or deep ciliary sourced capillaries of the optic nerve head became visible with a high resolution by the confocal technique dependent on the focus. Offline, the blood flow variables of areas of 100 microns x 100 microns were calculated. CONCLUSION: SLDF enables the visualisation of perfused capillaries and vessels of the retina and the optic nerve head in high resolution by two dimensional mapping of perfusion variables which are encoded by the Doppler signal. This method achieves simultaneously qualitative and quantitative evaluation of capillary blood flow of distinct areas of the capillary meshwork.

Regulation of ocular blood flow during increases of arterial blood pressure.

The blood flow in the uvea in cats and monkeys during acute increases of arterial blood pressure is well controlled by a sympathetic mechanism protecting the eye from overperfusion. Ocular macrocirculation (ophthalmic artery) and ocular microcirculation (iris) were examined in 22 healthy subjects during acute increases of arterial blood pressure induced by physical exercise (125 W). With a data acquisition and storage software in real time mode several parameters of ocular perfusion and systemic functions were measured simultaneously. Blood flow parameters were measured in the ophthalmic artery by pulsed Doppler sonography and in the iris by laser Doppler flowmetry. Systolic, diastolic, and mean velocities of the ophthalmic artery peak velocity pulse curve, the ophthalmic artery mean velocity pulse curve, and the iris velocity pulse curve were estimated off line. The ophthalmic artery mean velocity pulse curve resembles the integrated velocity of all erythrocytes in the vessel including the slowly running cells near the vessel wall. The iris velocity pulse curve was calculated by a special statistic procedure (ALDF). After exercise there was a significant increase in systolic and diastolic blood pressure and heart rate. The pulse curve of the ophthalmic artery showed significantly increased systolic and decreased diastolic velocities. The vascular resistance of the branches of the ophthalmic artery increased significantly. The iridal vasculature showed no significant change in blood cell velocity but an increased vascular resistance. It was observed that the elevated perfusion pressure was associated with an increased vascular resistance and a constant mean blood velocity in the ophthalmic artery and iridal vessels. The parallel elevation of vascular resistance and blood pressure during exercise may be the reason for a constant blood flow in the ophthalmic artery and the iris. This may be accounted for by a sympathetic mechanism for protecting the eye from overperfusion.

Effect of breathing 100% oxygen on retinal and optic nerve head capillary blood flow in smokers and non-smokers.

AIM: The effect of breathing 100% oxygen on retinal and optic nerve head capillary blood flow in smokers and non-smokers was investigated using scanning laser Doppler flowmetry (SLDF) as a new non-invasive method to visualise and quantify ocular blood flow. METHOD: 10 eyes of 10 young healthy non-smoking volunteers (mean age 26 (SD 3) years) and nine eyes of nine young healthy smoking volunteers (mean age 26 (4) years) were investigated. All participants were asked not to smoke or consume caffeine containing drinks for at least 4 hours before the measurements. Blood flow measurements were performed before and after 100% oxygen was applied to the subjects through a mask over a period of 5 minutes (6 litres per minute). Juxtapapillary retinal and optic nerve head blood flow were determined in arbitrary units using SLDF representing a combination of laser Doppler flowmetry and a scanning laser system allowing visualisation and quantification of the retinal and optic nerve head blood flow. Blood flow was determined in an area of 100 microns x 100 microns. The level of carboxyhaemoglobin was determined in all subjects. A Wilcoxon matched pairs signed ranks test (non-parametric) was used for statistical evaluation. RESULTS: In the non-smoking group, retinal 'flow' was reduced by 33% (p = 0.005), optic nerve head 'flow' by 37% (p = 0.005). In the smoking group retinal flow was reduced by 10% (p = 0.01), optic nerve head flow by 13% (p < 0.008). The difference in reactivity to oxygen breathing between smokers and non-smokers was highly significant (p < 0.00001). Increased carboxyhaemoglobin levels were not found in either of the groups. A significant reduction of the mean arterial blood pressure of 6% (5%) (p < 0.02) was observed in the non-smoking group after administration of oxygen. CONCLUSION: These results indicate that hyperoxia leads to a decrease in capillary blood flow of the retina and optic nerve head secondary to vasoconstriction, and that smokers do not respond to oxygen breathing as non-smokers do. The findings might be based on factors such as long term effects of nicotine on the sympathetic and parasympathetic nervous system.

Automatic full field analysis of perfusion images gained by scanning laser Doppler flowmetry.

BACKGROUND: Scanning laser Doppler flowmetry (SLDF) enables the measurement of the laser Doppler frequency shift in retinal tissue. This process allows the quantification of retinal and optic nerve head perfusion in an area of 2.7 mm x 0.7 mm within 2 seconds and with a spatial resolution of 10 microns x 10 microns. Owing to the local heterogeneity of the retinal microcirculation itself and to heart associated pulsation the capillary retinal blood flow depends on location and time. Because of technical limitations measurements of flow are only valid in retinal points with adequate brightness and focus, and away from big vessels. To include the heart beat associated pulsation and the spatial heterogeneity of retinal blood flow into the evaluation of blood flow an algorithm was developed examining automatically the whole SLDF perfusion image. AIM: To report intraobserver reliability and interobserver reliability of a new method for analysing automatically full field perfusion images. METHOD: The base of blood flow calculation by the automatic full field perfusion image analyser (AFFPIA) was 16,384 intensity time curves of all pixels of the whole perfusion image gained by the SLDF. AFFPIA calculates the Doppler frequency shift and the haemodynamic variables flow, volume, and velocity of each pixel. The resulting perfusion image was processed with respect to (1) underexposed and overexposed pixels, (2) saccades, and (3) the retinal vessel tree. The rim area and the saccades were marked interactively by the operator. The capillaries and vessels of the retinal vessel tree were identified automatically by pattern analysis. Retinal vessels with a diameter greater than 30 microns, underexposed or overexposed areas, and saccades were excluded automatically. Based on the whole perfusion image total mean flow, total mean volume, total mean velocity, standard deviation, cumulative distribution curve of flow, and the capillary pulsation index were calculated automatically. Heart beat associated pulsation of capillary blood flow was estimated by plotting the mean capillary flow of each horizontal line against time. Intraobserver reliability was estimated by measuring 10 eyes of 10 subjects on five different days by one observer. Interobserver reliability of AFFPIA was evaluated by analysing 10 perfusion maps by five different operators. To find a baseline of retinal blood flow, perfusion maps of 67 eyes of normal subjects with a mean age of 40.4 (SD 15) years were evaluated by AFFPIA. RESULTS: The coefficient of reliability of the intraobserver reproducibility of flow was 0.74. The coefficient of reliability of the interobserver reproducibility was 0.95. The juxtapapillary retinal capillary flow was temporally 484 (SD 125), nasally 450 (117); the rim area capillary flow was 443 (110). The mean capillary pulsation index of retinal flow was 0.56 (0.14). CONCLUSION: Retinal blood flow evaluation by the AFFPIA increases significantly the interobserver reliability compared with conventional evaluation of 100 microns x 100 microns areas in SLDF images with the original Heidelberg retina flowmeter software. The intraobserver reliability of AFFPIA was in the same range as conventional evaluation.

Phase I study of paclitaxel and day 1/day 8 gemcitabine in patients with solid malignancies.

A phase I study was designed to evaluate the toxicity of escalating doses of gemcitabine along with fixed-dose paclitaxel in patients heavily pretreated with chemotherapy or radiotherapy. All patients had no prior therapy with the study drugs and possessed both adequate performance and end organ function. Eighteen patients were entered in the study. Characteristics included a median age of 66 years (range, 41 to 77) and stage IV disease in all patients; there were six patients with colon cancer, two with bladder cancer, three with non-small-cell lung cancer, two with esophageal cancer, three with pancreatic cancer, and two with cancer of unknown primary. Paclitaxel (150 mg/m2 over 3 hours) was given on day 1 and gemcitabine (800, 900, and 1,000 mg/m2 over 15 minutes) was given in three separate dose-escalating cohorts (1-3) on days 1 and 8. The treatment cycled every 21 days. The dose-limiting toxicity (DLT) proved to be neutropenia. All nonhematologic toxicities were mild and included gastrointestinal (nausea, vomiting, and diarrhea), dermatologic (rash), and neurologic (paresthesias) disturbances along with transient elevations of liver function tests. The combination of gemcitabine and paclitaxel seems to be well tolerated, and the recommended starting dose for a phase II study, in pretreated patients using a day 1/day 8 treatment schedule, should be 900 mg/m2 for gemcitabine (days 1 and 8) along with 150 mg/m2 for paclitaxel (day 1).

Retinal microcirculation correlates with ocular wall thickness, axial eye length, and refraction in glaucoma patients.

PURPOSE: To examine the correlations of refraction, axial eye length, and posterior eye wall thickness with retinal microcirculation. PATIENTS AND METHODS: In a prospective study, 25 patients with primary open-angle glaucoma, 12 patients with ocular hypertension, and 12 healthy subjects were examined; only one eye of each participant was considered in the analysis. Posterior eye wall thickness and axial eye length were measured with standardized A-scan ultrasonography. Retinal microcirculation temporal to the optic disc was determined by a scanning laser Doppler flowmeter using automatic full-field perfusion image analyzer software. RESULTS: In glaucoma patients, temporal retinal mean flow exhibited significant correlation to the eye wall thickness (r = 0.470, P = 0.042), axial eye length (r = -0.570, P = 0.011), and refraction of the eye (r = 0.520, P = 0.022). In glaucomatous eyes, the temporal retinal mean flow was significantly lower than in healthy subjects or in ocular hypertensive patients (P = 0.01). CONCLUSIONS: Myopic eyes have longer axial eye length and thinner ocular wall than emmetropic eyes. In glaucoma patients, the longer the axial eye length and the thinner the ocular wall, the more reduced the retinal microcirculation. The reduced microcirculation found in myopic glaucomatous eyes might contribute to the development of glaucomatous damage in these eyes.

Perfusion of the juxtapapillary retina and the neuroretinal rim area in primary open angle glaucoma.

PURPOSE: The objective of this study is to evaluate capillary blood flow of the juxtapapillary retina and neuroretinal rim area in primary open angle glaucoma (POAG) by a new noninvasive method performing a high-definition topography of perfused vessels of the retina and the optic nerve head with simultaneous evaluation of blood flow. METHODS: Juxtapapillary retinal and neuroretinal rim area blood flow were measured by scanning laser Doppler flowmetry (SLDF). This new technique is a combination of a laser Doppler flowmeter with a scanning laser system by which the retinal perfusion is simultaneously quantified in 16,000 sites of a retinal area of 2.7 x 0.7 mm. In study I, retinal and optic nerve head blood flow were evaluated by SLDF in 43 patients with POAG and 43 healthy individuals. The mean age of the POAG group was 56 +/- 12 years and of the control group 42 +/- 15 years. In study II, age-matched normals (n = 21) were compared with glaucoma eyes with topical therapy (n = 30) and with glaucoma eyes without topical therapy (n = 16). RESULTS: In study I, the eyes with POAG had an average cup/disc ratio (C/D) of 0.75 +/- 0.20, with an average mean defect of the visual field of 5.3 +/- 5.4 dB. The actual intraocular pressure was 17.8 +/- 4.18 mm Hg in the POAG group and 15.45 +/- 1.82 mm Hg in the control group. For statistical analysis, two age-matched groups of 28 normal eyes of 28 persons with 27 glaucomatous eyes of 27 patients were compared. In normals the blood flow of the neuroretinal rim area was significantly higher than that of the juxtapapillary retinal area (+7.73%, p < 0.01). In POAG both juxtapapillary retinal blood flow and neuroretinal rim area blood flow were significantly decreased compared to an age-matched control group: neuroretinal rim area flow -71% and juxtapapillary retina flow -49%. The decrease of neuroretinal rim area blood flow did significantly correlate with C/D. We found no correlation between reduction of juxtapapillary retinal blood flow and C/D or mean defect. Both glaucoma eyes with and glaucoma eyes without topical therapy showed significant decreased juxtapapillary blood flow compared to normals. We found no significant difference in the juxtapapillary blood flow between glaucoma eyes with and without topical therapy. CONCLUSIONS: In POAG, optic nerve head blood flow and juxtapapillary blood flow were significantly decreased.

Principle, validity, and reliability of scanning laser Doppler flowmetry.

PURPOSE: The objective of this study is to present the reliability and validity of scanning laser Doppler flowmetry (SLDF) performing a high-definition topography of perfused vessels of the retina and the optic nerve head with simultaneous evaluation of blood flow. METHODS: The examination of blood flow by SLDF is based on the optical Doppler effect. The data acquisition and evaluation system is a modified laser scanning device; the wavelength of the laser source is 670 mm, with a power of 100 microW (Heidelberg Engineering, HRF). The reliability of SLDF was estimated by performing five separate measurements in 10 eyes on 5 days. The validity of the method was tested by two experiments. First, in an experimental set-up, the capability of SLDF to measure the velocity of a moving plane in absolute units was estimated. Second, comparative measurements were performed of retinal blood flow in normal eyes and in 33 glaucomatous eyes with SLDF and a commercially available single-point laser Doppler flowmeter (Oculix). RESULTS: We found SLDF to produce a high reliability. The reliability coefficients r1 of flow, volume, and velocity were 0.82, 0.81, and 0.83, respectively. Comparative measurements of the retinal blood flow by SLDF and a single-point laser Doppler flowmeter of corresponding retinal points showed a linear and significant relationship between flow (r = 0.83, p < 0.0001), volume (r = 0.51, p < 0.0001), and velocity (r = 0.59, p < 0.0001). In the experimental set-up, SLDF was able to quantitatively measure velocity in absolute units. CONCLUSIONS: SLDF enables the visualization of perfused vessels of the juxtapapillary retina and the optic nerve head in high resolution by two-dimensional mapping of the optical Doppler shift and a reproducible evaluation of capillary blood flow.